We found 36 diseases and 143 genes matching your search

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Filters: mental retardation, moderate x

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Mental retardation, autosomal recessive 31

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2

Clinical features

Kuss et al. (2011) reported a consanguineous Iranian family (8700017) in which 4 individuals had moderate to severe nonsyndromic mental retardation.

Mapping

By homozygosity mapping in a consanguineous Iranian family (8700017) in which 4 individuals had moderate to severe nonsyndromic mental retardation, Kuss et al. (2011) found linkage to a 10.5-Mb region on proximal chromosome 4q between SNPs dbSNP rs11944876 and dbSNP rs6551838 (lod score of 4.8).

Symptoms

INHERITANCE: Autosomal recessive

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe

MISCELLANEOUS: One family reported (last curated November 2011)
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Ketoadipicaciduria

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Bremer et al. (1976) described a female infant (the offspring of a probably incestuous mating of a mentally retarded mother) who was a typical 'collodion baby.' The skin cleared, but retarded development and floppiness with edema of the dorsum of the hands and feet later became evident. The mother was said to have shown similar features as a baby. The urine showed alpha-ketoadipicacid (COOH-CH(O)-(CH2)3-COOH). The infant's fibroblasts showed a defect in degradation of alpha-ketoadipicacid. The mother also secreted this substance in the urine. This may be an instance of pseudodominance. See aminoadipicaciduria (204750).

Symptoms

INHERITANCE: Autosomal recessive

RESPIRATORY: [Lung]; Bronchiectasis due to chronic upper respiratory tract infections

CHEST: [External features]; Barrel chest

SKELETAL: [Hands]; Clubbed fingers

SKIN, NAILS, HAIR: [Skin]; Neonatal collodion skin

MUSCLE, SOFT TISSUE: Edema of dorsum of hands and feet; Hypotonia

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Delayed motor development; Seizures; [Behavioral/psychiatric manifestations]

LABORATORY ABNORMALITIES: Alpha-ketoadipic aciduria; Alpha-hydroxyadipic aciduria Alpha-aminoadipic aciduria
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Pachygyria, frontotemporal

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Ramirez et al. (2004) described 3 sibs, born to nonconsanguineous Mexican parents, who had bilateral frontotemporal pachygyria without polymicrogyria. The 2 sisters and their brother shared the additional features of moderate mental retardation, esotropia, telecanthus or hypertelorism, and normal or slightly decreased neuromuscular tone and deep tendon reflexes. There were 2 unaffected brothers in the family.

Inheritance

Ramirez et al. (2004) suggested that this syndrome is most likely inherited as an autosomal recessive trait.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Eyes]; Esotropia; Telecanthus; Hypertelorism

NEUROLOGIC: [Central nervous system]; Pachygyria, bilateral frontotemporal; Mental retardation, moderate; Seizure, febrile (2/3 children); [Peripheral nervous system]; Neuromuscular tone slightly decreased; Deep tendon reflexes slightly decreased
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MORM syndrome

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Associated genes: inpp5e, pmpca
MORM syndrome is an autosomal recessive congenital disorder characterized by mental retardation, truncal obesity, retinal dystrophy, and micropenis". It is associated with INPP5E.

External links

MORM syndrome - WrongDiagnosis.org
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MORM syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: inpp5e, pmpca

This syndrome is characterised by the association of intellectual deficit, truncal obesity, retinal dystrophy and micropenis. It has been described in 14 individuals from a consanguineous family. It is transmitted in an autosomal recessive manner. The causative locus has been mapped to chromosome region 9q34. Last update: May 2006
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Mental retardation, truncal obesity, retinal dystrophy, and micropenis syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: inpp5e, pmpca

Clinical features

A number sign (#) is used with this entry because of evidence that a syndrome of mental retardation, truncal obesity, retinal dystrophy, and micropenis syndrome (MORMS) is caused by homozygous mutation in the INPP5E gene (613037) on chromosome 9q34. One such family has been reported.Hampshire et al. (2006) reported a consanguineous Pakistani kindred in which 14 individuals were affected with an autosomal recessive disorder characterized by moderate mental retardation, truncal obesity, congenital nonprogressive retinal dystrophy, and micropenis in males. The authors suggested the acronym 'MORM' syndrome. The phenotype was similar to Bardet-Biedl syndrome (BBS; 209900) and Cohen syndrome (COH1; 216550) but could be distinguished by the age of onset and nonprogressive nature of the visual impairment, and the lack of several characteristics, including dysmorphic facies, skin or gingival infection, microcephaly, 'mottled retina,' polydactyly, and testicular anomalies. The family originated from a valley in the Salt Range of Punjab, Pakistan. Family lore maintained that 16 Arabs settled in the valley 1,000 years ago and that descendants had always married within the family since that time. The village currently numbers about 5,000 with 5 different clans; the affected pedigree is a subgroup of 1 of these 5 clans, and affected individuals could be traced back to 1 founding couple.

Mapping

By genomewide linkage analysis, Hampshire et al. (2006) identified a candidate MORM syndrome locus within an approximately 1-cM subtelomeric region on chromosome 9q34.3 (maximum lod score of 5.64) between markers D9S158 and D9S905.

Molecular genetics

In affected members of a family with MORM syndrome, Jacoby et al. (2009) identified a homozygous mutation (Q627X; 613037.0001) in the INPP5E gene. In vitro functional expression studies showed that the mutant protein had impaired localization in cilia and was unable to stabilize ciliary structures. However, phosphatase activity was retained.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Weight]; Truncal obesity apparent in childhood

HEAD AND NECK: [Eyes]; Retinal dystrophy, congenital, nonprogressive; Reduced visual acuity by age 3 years; Cataracts develop in second or third decade

GENITOURINARY: [External genitalia, male]; Micropenis

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate (apparent by age 4 years); Delayed language acquisition

MOLECULAR BASIS: Caused by mutation in the inositol polyphosphate-5-phosphatase, 72-kd gene (INPP5E, 613037.0001).
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Acro-pectoral syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2, acrps

Acro-pectoral syndrome is characterized by a combination of distal limb abnormalities (syndactyly of all fingers and toes, preaxial polydactyly in the feet and/or hands) and upper sternum malformations. It has been described in 22 patients from a six-generation Turkish family. It is transmitted as an autosomal dominant trait and the causative gene is located at 7q36. Last update: January 2007
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Acropectoral syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, acrps

Clinical features

Dundar et al. (2001) reported a 6-generation Turkish family with a combination of distal limb and sternal abnormalities, inherited in an autosomal dominant fashion. All 22 affected subjects manifested soft tissue syndactyly of all fingers and toes, and preaxial polydactyly was present in 14 affected individuals. A prominent upper sternum and/or a blind-ending inverted U-shaped sinus in the chest wall was also present in 14 cases. Dundar et al. (2001) pointed out the similarity between this phenotype and acropectorovertebral dysplasia (F syndrome; 102510) but noted that in this syndrome the carpal, tarsal, and metatarsal synostoses and vertebral anomalies present in F syndrome were not seen. In addition, the soft tissue syndactyly was more marked than that seen in F syndrome, and the preaxial polydactyly occurred in the feet as well as in the hands.

Prashanth et al. (2012) reported features suggestive of acropectoral syndrome in members of a nonconsanguineous family from southern India. The 13-year-old proposita had pectus carinatum, moderate mental retardation, and preaxial polydactyly on one hand and bifid thumb on the other. Her brother, who had died of traumatic head injury at age 2, reportedly had similar features. The deceased maternal grandfather reportedly had similar defects of the hands and upper chest. The lower limbs of all of those affected were normal.

Mapping

Dundar et al. (2001) demonstrated that the phenotype in the Turkish family is linked to a 6.4-cM region of 7q36 flanked by the EN2 gene (131310) and the marker D7S2423. Dundar et al. (2001) noted that preaxial polydactyly type II (174500) and type III (174600), and triphalangeal thumb-polysyndactyly (see 174500), have been mapped to 7q36. The haplotype in the affected individuals reported by Dundar et al. (2001) is different from those found in the related phenotypes.

Symptoms

INHERITANCE: Autosomal dominant

CHEST: [Ribs and sternum]; Pectus carinatum; Pectus excavatum

SKELETAL: [Limbs]; [Hands]; Preaxial polydactyly; Bifid thumb; Triphalangeal thumb; Soft tissue syndactyly between all fingers (in 1 family); [Feet]; Soft tissue syndactyly between all toes (in 1 family); Preaxial polydactyly

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate (in 1 patient)

MISCELLANEOUS: Variable phenotype; F syndrome (102510) has many overlapping features; Two families reported (last curated September 2012)
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Mental retardation, autosomal recessive 43

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-43 (MRT43) is caused by homozygous mutation in the KIAA1033 gene (615748) on chromosome 12q23. One such family has been reported.Ropers et al. (2011) reported a large consanguineous Omani family in which 7 individuals had moderate to severe intellectual disability (IQ, 35-50). They had severe learning impairment, poor language skills, poor adaptive skills, and delayed fine motor development. They had short stature, but no other dysmorphic features. Brain MRI showed no significant abnormalities. One patient had signs of spasticity.

Inheritance

The transmission pattern in the family with MRT43 reported by Ropers et al. (2011) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of a consanguineous Omani family with mental retardation, Ropers et al. (2011) identified a 12.5-Mb candidate region on chromosome 12q23-q24 (lod score of 3.5).

Molecular genetics

In affected members of a family with MRT43, Ropers et al. (2011) identified a homozygous missense mutation in the KIAA1033 gene (P1019R; 615748.0001). In vitro functional expression studies and analysis of patient cells showed that the mutation destabilized the protein and interfered with the stability of the WASH (613632) complex. The findings implicated a role for abnormal actin dynamics and endosomal trafficking in this form of intellectual disability. The patients also carried a homozygous H362L variant in the LHX5 gene (605992), which was not thought to be pathogenic.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

NEUROLOGIC: [Central nervous system]; Delayed development; Mental retardation, moderate to severe (IQ 35-50); Poor language; Poor adaptive skills; Poor fine motor skills; Spasticity (1 patient)

MISCELLANEOUS: One consanguineous family has been reported (last curated May 2014)

MOLECULAR BASIS: Caused by mutation in the KIAA1033 gene (KIAA1033, 615748.0001)
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Bilateral frontoparietal polymicrogyria

Retrieved: 27-07-2015
Source: GARD (Original article)
Associated genes: gpr56, kiaa0319
Bilateral frontoparietal polymicrogyria

Bilateral frontoparietal polymicrogyria

Bilateral frontoparietal polymicrogyria (BFPP) is a rare neurological disorder that affects the cerebral cortex (the outer surface of the brain). BFPP specifically affects the frontal and parietal lobes on both sides of the brain (bilateral). Signs and symptoms typically include moderate to severe intellectual disability, developmental delay, seizures, cerebellar ataxia, strabismus, and dysconjugate gaze (eyes that are not aligned). Some cases are caused by mutations in the GPR56 gene and are inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each person
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Polymicrogyria, bilateral frontoparietal

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: gpr56, kiaa0319
Polymicrogyria, bilateral frontoparietal

Clinical features

A number sign (#) is used with this entry because bilateral frontoparietal polymicrogyria (BFPP) is caused by homozygous mutation in the GPR56 gene (604110) on chromosome 16q21. Mutation in a cis-regulatory region of GPR56 causes bilateral perisylvian polymicrogyria (BPPR; 615752).

See also unilateral polymicrogyria (610031).In 2 sisters, aged 7 and 10 years, Harbord et al. (1990) described developmental delay and a nonprogressive cerebellar ataxia with similar neurophysiologic and neuroradiologic findings of an extensive neuronal migration defect. There were no dysmorphic features, metabolic abnormalities, chromosomal defects or evidence of prenatal environmental toxins. Harbord et al. (1990) considered that these sibs had an autosomal recessive neuronal migration defect that had not previously been recorded. It appeared that other recognized causes of neuronal migration defects such as the Miller-Dieker syndrome (247200), the Norman-Roberts syndrome (257320), the Neu-Laxova (256520) and Joubert syndrome (213300) could be excluded on the basis of clinical and radiologic features. The absence of muscle disease differentiated these patients from children with migration defects associated with congenital muscular dystrophy, e.g., Fukuyama type (253800).

Piao et al. (2002) studied 2 consanguineous Palestinian pedigrees with an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP) using linkage analysis. The first pedigree was originally reported by Straussberg et al. (1996) and was described as having pachygyria, but improved magnetic resonance imaging (MRI) clearly showed that the core disorder was polymicrogyria. The parents were first cousins and 3 of 4 children were affected. They all had normal prenatal and perinatal history and normal head growth but showed gross developmental delay and moderate mental retardation. At ages 14, 9, and 7.5 years they could speak a few words and walk independently. All 3 developed medically refractory seizures. All 3 had esotropia, increased muscle tone, mild truncal ataxia, and finger dysmetria, without dysmorphic features or other congenital...

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Eyes]; Dysconjugate gaze; Esotropia; Nystagmus; Strabismus; Exotropia

MUSCLE, SOFT TISSUE: Increased muscle tone

NEUROLOGIC: [Central nervous system]; Developmental delay; Psychomotor delay; Mental retardation, moderate to severe; Increased muscle tone; Hyperreflexia; Extensor plantar responses; Ankle clonus; Seizures; Cerebellar signs; Pyramidal signs; Wide-based gait; Truncal ataxia; Finger dysmetria; Polymicrogyria, most severe in the frontoparietal regions; Polymicrogyria, anterior to posterior gradient; Areas of dysmyelination on MRI; Brainstem hypoplasia; Cerebellar hypoplasia

MOLECULAR BASIS: Caused by mutation in the G protein-coupled receptor 56 gene (GPR56, 604110.0001)
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X-linked intellectual disability - cubitus valgus - dysmorphism

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2, cvmrf

This syndrome is characterised by moderate intellectual deficit, marked cubitus valgus, mild microcephaly, a short philtrum, deep-set eyes, downslanting palpebral fissures and multiple nevi. Less than ten individuals have been described so far. Transmission is thought to be X-linked recessive. Last update: May 2007
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Cubitus valgus with mental retardation and unusual facies

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, cvmrf

Clinical features

Jones and Smith (1973) described 2 male maternal first cousins with a similar pattern of malformation, including mental retardation, cubitus valgus, and unusual facies. Jones et al. (2003) described 3 additional cases, a 10-year-old male, his 30-year-old maternal uncle, and an unrelated 15-year-old boy, bringing to 5 the number of individuals with this disorder. The principal features included moderate mental retardation, mild microcephaly, a short philtrum, deep-set and downslanting palpebral fissures, multiple nevi, and striking cubitus valgus, which was defined as 'deviation of the long axis of the supinated forearm away from the midline of the body when the elbow is fully extended.' As illustrated by the patient photographs, the forearms angled out at the elbow so that when the arms were hanging beside the body the hands were a distance from the side. Syndromes associated with cubitus valgus were tabulated.

Inheritance

Jones et al. (2003) suggested that the pattern of inheritance of this disorder is consistent with X-linked recessive transmission.

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Weight]; Truncal obesity, mild

HEAD AND NECK: [Head]; Microcephaly (occipitofrontal head circumference, OFC, at or below 3rd centile); [Eyes]; Deep-set eyes; Downslanting palpebral fissures; [Mouth]; Short philtrum; Inverted V-shaped mouth

SKELETAL: [Limbs]; Cubitus valgus

SKIN, NAILS, HAIR: [Skin]; Nevi, multiple

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate; Seizures
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X-linked intellectual disability, Shashi type

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2, mrxs11

This syndrome is characterised by moderate intellectual deficit, obesity, macroorchidism and a characteristic facies (large ears, a prominent lower lip and puffy eyelids). It has been described in nine boys from two families. Transmission is X-linked and the causative gene has been localised to the q21.3-q27 region of the X chromosome. Last update: February 2007
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Mental retardation, x-linked, syndromic 11

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, mrxs11

Clinical features

In a large family from North Carolina, Shashi et al. (2000) studied a seemingly novel X-linked mental retardation syndrome with characteristic facial dysmorphic features. Only males were affected over 4 generations. Clinical findings in the 7 living affected males included a moderate degree of mental retardation, coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, prominent lower lip, large ears, obesity, and large testes. Cephalometric measurements suggested that the affected males had a distinctive craniofacial skeletal structure, when compared with normative measurements. Obligate-carrier females had no mental retardation, but the results of cephalometric analysis suggested craniofacial dysmorphism intermediate between that of affected males and that of normative control individuals. Unaffected male relatives showed no clinical or cephalometric resemblance to affected males. The blood-lymphocyte karyotype and the results of DNA analysis for fragile X syndrome (300624) and of other routine investigations were normal.

Castro et al. (2003) described a family with mental retardation in 2 brothers. The pedigree was consistent with either X-linked mental retardation or autosomal recessive inheritance. The diagnosis of Shashi X-linked mental retardation syndrome was suggested by the clinical features of coarse facies, prominent lower lip, large testes, and obesity.

Mapping

By linkage analysis with polymorphic DNA markers spanning the X chromosome in a large family with an X-linked mental retardation syndrome, Shashi et al. (2000) established linkage to Xq26-q27. A maximum lod score of 3.1 was obtained at marker DXS1047 (recombination fraction of 0.0). Shashi et al. (2000) concluded that the features in this family were not consistent with those seen in any previously delineated forms of X-linked mental retardation, including those with a similar phenotype and those that had been mapped in close proximity.

Haplotype analysis in the family with mental retardation described by Castro et al. (2003) was consistent with the localization of Shashi X-linked mental retardation syndrome to chromosome Xq26-q27. Castro et al. (2003) concluded that the family represented a second occurrence of Shashi X-linked mental retardation.

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Weight]; Obesity

HEAD AND NECK: [Face]; Coarse facies; [Ears]; Large ears; [Eyes]; Periorbital fullness; Narrow palpebral fissures; [Nose]; Bulbous nose; [Mouth]; Prominent lower lip

GENITOURINARY: [External genitalia, male]; Macroorchidism

SKELETAL: [Skull]; Prominent supraorbital ridges

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate

MISCELLANEOUS: Carrier females show no phenotypic abnormalities, but may have learning difficulties

Congenital muscular dystrophy type 1D

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: large

This disease has been moved to Congenital muscular dystrophy due to dystroglycanopathy

Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type b, 6

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: large

Description

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B6; MDDGB6), previously designated CMD1D, is caused by homozygous or compound heterozygous mutation in the LARGE gene (603590) on chromosome 22q12. LARGE is a novel member of the N-acetylglucosaminyltransferase gene family.

Mutation in the LARGE gene can also cause a severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A6; MDDGA6; 613154).MDDGB6 is an autosomal recessive congenital muscular dystrophy with mental retardation and structural brain abnormalities (Longman et al., 2003). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009).

For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).

Clinical features

Longman et al. (2003) identified 1 patient with LARGE-related congenital muscular dystrophy (CMD) among 36 patients with congenital muscular dystrophy and either mental retardation, structural brain changes, or abnormal alpha-dystroglycan immunolabeling. The affected 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, and white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabeling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced mole...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Face]; Facial weakness, mild; [Eyes]; Nystagmus, horizontal; Decreased electroretinogram (ERG) response; [Mouth]; Tongue hypertrophy

SKELETAL: [Limbs]; Elbow contractures, mild; Achilles tendon contractures, mild; [Hands]; Flexed fingers

MUSCLE, SOFT TISSUE: Hypotonia; Muscle weakness, predominantly proximal; Lower limbs more affected than upper limbs; Delayed motor development; Acquire ability to walk and jump in childhood, but motor regression occurs later; Muscle hypertrophy; EMG shows myopathic changes; Decreased glycosylation of alpha-dystroglycan

NEUROLOGIC: [Central nervous system]; Developmental delay, global; Mental retardation, moderate to profound; Lower limb hyperreflexia (reported in 1 patient); Extensor plantar responses (reported in 1 patient); Periventricular white matter changes; Abnormal neuronal migration; Hypoplastic brainstem; Pachygyria, frontoparietal; Cerebellar hypoplasia

LABORATORY ABNORMALITIES: Increased serum creatine kinase

MISCELLANEOUS: Onset within first 6 months of life; Three unrelated families have been reported (as of June 2011)

MOLECULAR BASIS: Caused by mutation in the acetylglucosaminyltransferase-like protein (LARGE, 603590.0001)
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Atkin-flaitz syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Atkin et al. (1985) reported a 3-generation family with 11 moderately to severely retarded males and 3 mildly retarded females. Phenotypic manifestations included short stature, macrocephaly, 'coarse' facial features with prominent forehead and supraorbital ridges, hypertelorism, broad nasal tip with anteverted nostrils, and thick lips. All postpubertal males had macroorchidism, and moderate obesity was noted in 6 males and all 3 women. All but one of the affected family members had a diastema between the maxillary central incisors. Although noting similarities, the authors distinguished the syndrome from Coffin-Lowry syndrome (CLS; 303600) and fragile X mental retardation (300624).

Clark and Baraitser (1987) and Baraitser et al. (1995) described mentally retarded patients who shared many features with the patients described by Atkin et al. (1985); see 300602. The distinguishing features were short stature and hypertelorism in the patients reported by Atkin et al. (1985).

Symptoms

INHERITANCE: X-linked dominant

GROWTH: [Height]; Short stature; [Weight]; Obesity

HEAD AND NECK: [Head]; Macrocephaly; [Face]; Coarse facial features; Prominent forehead; Heavy supraorbital ridges; [Eyes]; Hypertelorism; Downslanting palpebral fissures; [Nose]; Broad nasal tip; Anteverted nostrils; [Mouth]; Thick lips; Prominent lower lip; Prominent median palatal raphe; Exaggerated median tongue furrow; [Teeth]; Central incisor gap; Microdontia (maxillary lateral incisors)

GENITOURINARY: [Internal genitalia, male]; Macroorchidism

SKELETAL: Joint laxity; [Spine]; Scoliosis; Hyperkyphosis; [Limbs]; Genu valga; Genu recurvata; [Hands]; Tapered fingers; Short, broad hands

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Seizures; Mental retardation, mild (carrier females)
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Atkin-Flaitz syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)

Atkin-Flaitz syndrome is characterised by moderate to severe intellectual deficit, short stature, macrocephaly, and characteristic facies. It has been described in 11 males and three females from three successive generations of the same family. The males also presented with postpubertal macroorchidism. Transmission is X-linked. Last update: October 2006
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Mental retardation, x-linked, syndromic, chudley-schwartz type

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2

Clinical features

Chudley et al. (1999) reported a family in which 3 males spanning 2 generations had a syndromic form of moderate mental retardation with seizures and dysmorphic facial features. Common dysmorphic features included prominent glabella, prognathism, synophrys, and hirsutism; hypertelorism and large ears were each noted in 2 patients. The 2 older patients, who were in their forties, showed slowly progressive unsteady gait and progressive weakness, and 1 of them was found to have cerebellar atrophy and electrophysiologic evidence of a peripheral neuropathy. All had low serum immunoglobulins and 2 had specific absence of plasma and secretory IgA, although only 1 patient had recurrent infections.

Mapping

Using microsatellite markers on the X chromosome to evaluate a family with X-linked syndromic mental retardation, Chudley et al. (1999) found linkage to a region on chromosome Xq21.33-q23 between DXS1170 and DXS8067 (maximum 2-point lod score of 2.23 at DXS1120). Haplotype analysis delineated a region either 16 or 20 Mb in size.

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Face]; Prominent glabella; Prognathism; [Ears]; Prominent ears; [Eyes]; Synophrys; Hypertelorism

SKELETAL: [Spine]; Kyphosis; Scoliosis; [Hands]; Single palmar creases

SKIN, NAILS, HAIR: [Hair]; Hirsutism

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate; Poor speech; Seizures; Unsteady gait; Ataxia; Cerebellar atrophy, mild (1 patient); [Peripheral nervous system]; Peripheral neuropathy (1 patient)

IMMUNOLOGY: Decreased IgG; Decreased IgA, plasma and secretory; Decreased IgM

MISCELLANEOUS: One family with 3 affected males has been reported (as of October 2011)
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Hypertryptophanemia, familial

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Snedden et al. (1982, 1983) described a brother and sister with tryptophanuria as well as a marked increase in plasma tryptophan levels. Martin et al. (1995) provided additional details of these patients and also described abnormal urinary tryptophan metabolites in their mother and a half sib. The brother was a 23-year-old male, the offspring of a Micmac Indian mother and a French Canadian father, who was examined for evaluation of widespread joint pains, emotional lability, defective vision, and a stutter. He had developed normally until the age of 14 years when he began to complain of fleeting pains in his abdomen and joints, precipitated by exertion. At the same time he noticed increasing ulnar drift of the fingers and inability to extend the elbows fully. Generalized joint laxity was noted at the age of 18. A strabismus in the left eye which had almost no vision and high myopia in the right eye were other features. Psychiatric complaints had included aggressive outbursts. Physical examination showed ocular hypertelorism, marked correctable ulnar drift of all the fingers, adduction of the thumbs, and slight contractures of the distal interphalangeal joints of the fingers and intraphalangeal joints of the thumbs. Pes planus was present. The sister was evaluated at the age of 22 years. All her milestones had been delayed; she could not walk until the age of 3 and never acknowledged auditory stimuli or learned to talk. She was institutionalized where she showed hyperactive and aggressive behavior. The mother had had a fever and rash labeled as rubella in the fourth month of pregnancy; the auditory defect in the sister was probably the result of in utero exposure to rubella. Plasma tryptophan estimates were approximately 475 micromole/l in both sibs (normal 25-73). Tryptophanuria and massive excretion of indoleic acids in the urine were also found.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Ears]; Hearing loss, sensorineural (in sister); [Eyes]; Strabismus (in brother); Myopia (in brother); Hypertelorism (in brother)

SKELETAL: [Limbs]; Widespread joint pain; Generalized joint laxity; Limited elbow extension; [Hands]; Ulnar drift of fingers; Slight contractures of distal interphalangeal joints; [Feet]; Pes planus

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate (in sister); [Behavioral/psychiatric manifestations]; Emotional lability, extreme; Delayed milestones; Stuttering, severe (in brother); No verbal language development (in sister); Aggressive outbursts; Hypersexuality; Depression

LABORATORY ABNORMALITIES: Tryptophanuria; Hypertryptophanemia

MISCELLANEOUS: One brother and sister of Micmac Indian and French-Canadian ancestry have been reported (last curated September 2014); Mother had rubella infection during pregnancy with daughter
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Spinocerebellar ataxia, autosomal recessive 2

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, scar2

Clinical features

Norman (1940) described 3 sibs in 1 family and 2 sibs in another who had cerebellar ataxia and mental deficiency since early life. Postmortem examinations showed severe cerebellar granule cell loss. One child showed delayed motor development and mental deficiency in infancy. Other features included small head, cataracts, increased knee jerks, and intention tremor. He died at age 20 years. Postmortem examination showed marked cerebellar atrophy with complete absence of granule cells in the lateral lobes of the cerebellum and the superior part of the vermis. There were heterotopic Purkinje cells and gliosis (Weiner and Konigsmark, 1971).

Scherer (1933) described 2 affected sibs, and Jervis (1950) 3 affected sibs. Jervis (1954) also observed the disorder in monozygotic Italian twin sisters.

In many members of an inbred Christian Maronite family originating from a village in the northeast of Lebanon, Megarbane et al. (1999) described hereditary congenital nonprogressive cerebellar ataxia. The 12 affected members were thought to have the autosomal recessive Norman type of cerebellar atrophy, also known as primary granular cell atrophy of the cerebellum. The patients in the Lebanese family were of short stature varying from 136 cm in a 44-year-old female to 164 cm in a 40-year-old male.

Mapping

By genomewide analysis of the large consanguineous Lebanese family reported by Megarbane et al. (1999), Delague et al. (2001) found linkage to a 12.1-cM interval on chromosome 9q34-qter between markers D9S67 and D9S312.

Animal model

Weiner and Konigsmark (1971) noted that infection of the fetal rat by rat virus (Margolis and Kilham, 1968) and of the fetal kitten by panleukopenia virus (Kilham and Margolis, 1966) can result in granule cell hypoplasia.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature (1 family)

HEAD AND NECK: [Eyes]; Nystagmus (1 patient)

SKELETAL: [Feet]; Pes cavus (1 family)

MUSCLE, SOFT TISSUE: Hypotonia

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Ataxia; Unsteady gait; Incoordination; Delayed speech development; Dysarthria; Spasticity; Hypotonia; Dysmetria; Cerebellar hypoplasia; Atrophy of the granular cell layer of the cerebellum; Abnormal Purkinje cells; Reactive gliosis; [Peripheral nervous system]; Hyperreflexia; Hyporeflexia (less common)

MISCELLANEOUS: Onset in infancy; Nonprogressive; Some patients do not achieve independent ambulation
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Autosomal recessive cerebelloparenchymal disorder type 3

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2, scar2

The disorders involving primarily the cerebellar parenchyma have been classified into six forms. In cerebelloparenchymal disorder III, cerebellar ataxia is congenital (non-progressive) and characterized by cerebellar symptoms such as incoordination of gait often associated with poor coordination of hands, speech and eye movements. The other features are congenital mental retardation and hypotonia, in addition to other neurological and non-neurological features. MRI or CT scan show marked atrophy of the vermis and hemispheres. A severe loss of granule cells with heterotopic Purkinje cells is observed. The mode of inheritance in the few reported families is autosomal recessive. In one family, cerebellar ataxia was associated to albinism.: In a large inbred Lebanese family the disease locus was assigned to a 12.1-cM interval on chromosome 9q34-qter between markers D9S67 and D9S312. The primary biochemical defect remains unknown. Up to now, the only treatment has consisted in early interventional therapies including intensive speech therapy and adequate stimulation and/or training. Expert reviewer(s) Pr André MEGARBANE Last update: February 2005
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Armfield x-linked mental retardation syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, mrxsa

Clinical features

Armfield et al. (1999) reported a family with 6 males with mental retardation in 3 generations, consistent with X-linked inheritance. Other features included short stature (6 of 6), small hands and feet (5 of 5), seizures (6 of 6), cleft palate (2 of 6), and cataracts/glaucoma (3 of 6). Carrier females were unaffected.

Inheritance

In the family described by Armfield et al. (1999), X-linked recessive inheritance was suggested by the presence of mental retardation in males, absence of manifestations in females, and the absence of male-to-male transmission.

Mapping

Linkage studies performed by Armfield et al. (1999) localized this apparently novel syndromic form of X-linked mental retardation to the terminal 8 Mb of Xq28, with a lod score of 2.11 at zero recombination at marker p39.

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Head]; Prominent forehead; Midface hypoplasia (in some patients); [Eyes]; Cataracts (in some patients); Glaucoma (in some patients); Strabismus (in some patients); [Mouth]; Cleft palate (in some patients)

SKELETAL: [Hands]; Small hands; [Feet]; Small feet

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Seizures

MISCELLANEOUS: One family with 6 probands described (as of September 2000)
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X-linked intellectual disability, Armfield type

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2, mrxsa

This syndrome is characterised by intellectual deficiency, short stature, seizures, and small hands and feet. It has been described in six males from three generations of one family. Three of them also had cataracts/glaucoma and two of them had cleft palate. The locus has been mapped to the terminal 8 Mb of Xq28. Last update: January 2007
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Microcephaly 6, primary, autosomal recessive

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cenpj

Clinical features

A number sign (#) is used with this entry because primary microcephaly-6 (MCPH6) is caused by homozygous mutation in the gene encoding centromeric protein J (CENPJ; 609279).

For a phenotypic description and discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).Darvish et al. (2010) reported 2 affected individuals from a consanguineous Iranian family with autosomal recessive primary microcephaly. In addition to severe mental retardation and microcephaly (-4 to -6 SD), the patients had additional features, including small ears, hypertelorism, strabismus, notched nasal tip, seizures, joint stiffness, and wheelchair requirement.

Sajid Hussain et al. (2013) reported 10 patients from 3 consanguineous Pakistani families with primary microcephaly (-8 to -17 SD) between ages 7 and 30 years. Most of the patients were unable to speak or write.

Inheritance

The transmission pattern in the families with MCPH6 reported by Darvish et al. (2010) and Sajid Hussain et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

Leal et al. (2003) reported a novel locus, MCPH6, for autosomal recessive primary microcephaly, mapping to 13q12.2, in a Brazilian family. The minimal critical regions spanned 6 Mb between 2 markers with a maximum 2-point lod score of 6.25.

By homozygosity mapping, Darvish et al. (2010) found linkage to the MCPH6 locus in 5 of 112 consanguineous Iranian families with primary microcephaly.

Molecular genetics

In affected members of 3 families with MCPH6, of which 1 was the Brazilian family previously described by Leal et al. (2003) and 2 were Pakistani, Bond et al. (2005) identified a homozygous mutation in the CENPJ gene (609279.0001-609279.0002, respectively). Each mutation was absent from 380 northern Pakistani control chromosomes, showed the expected disease segregation in families, and was not present in chimpanzee, gorilla, orangutan, gibbon, mouse, or rat.

In affected members of a Pakistani family with MCPH6, Gul et al. (2006) identified homozygosity for a 4-bp deletion in the CENPJ gene (609279.0003).

In 2 affected members of a consanguineous Iranian family with primary microcephaly, Darvish et al. (2010) identified a homozygous mutation in the CENPJ gene (T821M; 609279.0005).

In 10 patients from 3 consanguineous Pakistani families with MCPH6, Sajid Hussain et al. (2013) identified a homozygous truncating mutation in the CENPJ gene (609279.0001). The mutations, which were found by linkage analysis followed by Sanger sequencing of the candidate gene, segregated with the disorder in the families. The families were ascertained from a larger cohort of 57 consan...

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Head]; Microcephaly (head circumference -7 to -17 S.D.)

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate; Small cerebral cortex

MISCELLANEOUS: Onset at birth

MOLECULAR BASIS: Caused by mutation in the centromeric protein J gene (CENPJ, 609279.0001)
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Mental retardation, autosomal recessive 15

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: man1b1

Clinical features

A number sign (#) is used with this entry because autosomal recessive nonsyndromic mental retardation-15 (MRT15) is caused by homozygous mutation in the MAN1B1 gene (604346) on chromosome 9q34.3.Rafiq et al. (2010) reported 3 consanguineous Pakistani families with nonsyndromic mental retardation. The patients were severely mental retarded, all but 1 with an IQ less than 40 and all with delayed speech. Two of 3 sibs in 1 family had truncal obesity, and 2 other patients had epilepsy. None had microcephaly or autistic features. The families belonged to the same clan and were from the same village. Rafiq et al. (2011) provided follow-up of these families, who were from the Punjab province. Two patients had delayed psychomotor development and began walking at age 4 years. Both had hyperphagia and were overweight. Some patients achieved speaking in sentences and toilet training; aggression was a common feature. Mild dysmorphic features, such as dolichocephaly, downslanted palpebral fissures, broad nose, and small chin, were noted.

Rafiq et al. (2011) reported another consanguineous Pakistani family from the Sindh province with a similar, but less severe, form of intellectual disability. In addition to mental retardation, these patients showed dysmorphic features, including downslanting palpebral fissures, hypertelorism, long face, flattened malar region, short philtrum, broad nasal root, and small chin. Rafiq et al. (2011) also described 3 members of an Iranian family with nonsyndromic mental retardation. Overall intellectual disability varied, with 1 patient able to speak and count money and the others more severely affected. Seizures were variable. Dysmorphic features were mild and variable, but included dolichocephaly, long face, flat philtrum, downslanting palpebral fissures, hypertelorism, thin upper lip, triangular and pointed chin, and prominent nose.

Inheritance

The transmission pattern in the families reported by Rafiq et al. (2010) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of 3 consanguineous Pakistani families with autosomal recessive...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Weight]; Obesity (in 1 family)

HEAD AND NECK: [Head]; Dolichocephaly, mild; [Face]; Long face; Flat philtrum; Short philtrum; Malar flattening; Pointed chin; Triangular chin; [Eyes]; Downslanting palpebral fissures; Hypertelorism; Broad eyebrows; Long eyebrows; [Nose]; Broad nasal root; Prominent nose; [Mouth]; Thin upper lip

SKIN, NAILS, HAIR: [Hair]; Broad eyebrows; Long eyebrows

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to profound; Delayed psychomotor development; Seizures (variable); [Behavioral/psychiatric manifestations]; Aggressive behavior

MISCELLANEOUS: Dysmorphic features are variable

MOLECULAR BASIS: Caused by mutation in the mannosidase, alpha, class 1B, member 1 gene (MAN1B1, 604346.0001).
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Polymicrogyria with seizures

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: rttn

Clinical features

A number sign (#) is used with this entry because polymicrogyria with seizures (PMGYS) is caused by homozygous mutation in the RTTN gene (610436) on chromosome 18q22.Kheradmand Kia et al. (2012) reported a consanguineous Turkish family in which 2 sibs were demonstrated to have diffuse asymmetric polymicrogyria extending from the frontal to the temporal, parietal, and occipital lobes on brain MRI. Other imaging findings included mild ventricular enlargement and thin or short corpus callosum. One patient had mild cerebellar atrophy. The patients were 12 and 14 years old at the time of the report. Both had microcephaly, moderate to severe mental retardation, poor speech, dysarthria, and seizures. One had pyramidal signs. Another family member had moderate mental retardation and seizures, but detailed clinical features were not available. An unrelated 16-year-old boy with diffuse polymicrogyria had microcephaly, severe mental retardation with lack of speech, seizures, and spastic tetraparesis. Two of the patients had normal abdominal ultrasound with situs solitus; 1 had small kidney volume.

Inheritance

The transmission pattern in the family with polymicrogyria reported by Kheradmand Kia et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By autozygosity mapping on the basis of a while-genome search of 3 affected members of a family segregating polymicrogyria with seizures, Kheradmand Kia et al. (2012) found shared homozygous regions on chromosomes 14q24.3-q31.1 and 18q22.

Molecular genetics

In 3 members of a consanguineous Turkish family with polymicrogyria with seizures, Kheradmand Kia et al. (2012) identified a homozygous mutation in the RTTN gene (L932F; 610436.0001). The mutation was identified by autozygosity mapping followed by candidate gene sequencing. Another unrelated patient with a similar disorder carried a different homozygous mutation (C27Y; 610436.0002). Mutant L932F RTTN correctly localized to the basal bodies in patient fibroblasts, but there was a higher percentage of ciliary abnormalities, including short cilia with bulbous tips, compared to control. No ciliary abnormalities were apparent in cells from the patient with the C27Y mutation. However, gene expression profiling in patient fibroblasts with bot...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature, mild

HEAD AND NECK: [Head]; Microcephaly, mild (-2 SD)

ABDOMEN: Situs solitus

GENITOURINARY: [Kidneys]; Decreased kidney volume (1 patient)

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Lack of speech or poor speech; Dysarthria; Seizures; Pyramidal signs (in some); Spasticity (in some); Abnormal EEG; Polymicrogyria, diffuse, asymmetric; Abnormal corpus callosum; Cerebellar atrophy, mild (1 patient)

MISCELLANEOUS: Two unrelated families have been reported (last curated September 2012)

MOLECULAR BASIS: Caused by mutation in the rotatin gene (RTTN, 610436.0001)
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Mental retardation, autosomal recessive 39

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: tti2

Clinical features

A number sign (#) is used with this entry because autosomal recessive mental retardation-39 (MRT39) is caused by homozygous mutation in the TTI2 gene (614426) on chromosome 8p12.Langouet et al. (2013) reported 3 sibs, born of consanguineous Algerian parents, with mental retardation and behavioral problems. All had a normal neonatal period, but showed delayed psychomotor development and severe speech delay. Examination at ages 30 to 36 years revealed microcephaly (-3 to -4 SD), short stature, kyphoscoliosis, and dysmorphic facial features, including sloping forehead, deep-set eyes, synophrys, prominent nose, anteverted large ears, and dental anomalies. Behavioral abnormalities included hyperactivity, aggression, and stereotypic movements. Seizures were not reported. Laboratory analysis showed mild lymphopenia of naive T cells, but increased susceptibility to infection was not reported.

Inheritance

The transmission pattern in the family with mental retardation reported by Langouet et al. (2013) was consistent with autosomal recessive inheritance.

Molecular genetics

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M100, they identified homozygosity for a missense mutation in the TTI2 gene (P367L; 614426.0001) in 4 sibs with moderate nonsyndromic mental retardation. The parents were first cousins and had 4 healthy children.

In 3 sibs, born of consanguineous Algerian parents, with mental retardation and dysmorphic features, Langouet et al. (2013) identified a homozygous missense mutation in the TTI2 gene (I436N; 614426.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed almost undetectable levels of mutant TTI2 compared to controls, although mRNA levels wer...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Head]; Microcephaly (-3 to -4 SD); [Face]; Sloping forehead; [Ears]; Anteverted ears; Large ears; [Eyes]; Deep-set eyes; Strabismus; Synophrys; [Nose]; Prominent nose; [Teeth]; Malposition of the teeth

SKELETAL: [Spine]; Kyphoscoliosis

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Speech delay, severe; [Behavioral/psychiatric manifestations]; Hyperactivity; Aggression; Stereotyped behavior

IMMUNOLOGY: Decreased circulating naive T cells (1 family)

MISCELLANEOUS: Onset in infancy; Dysmorphic facial features reported in 1 family; Two unrelated families have been reported (last curated November 2013)

MOLECULAR BASIS: Caused by mutation in the TELO2-interacting protein 2 gene (TTI2, 614426.0001)
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Fragile X syndrome

Retrieved: 27-07-2015
Source: GARD (Original article)
Fragile X syndrome

Fragile X syndrome

Fragile X syndrome is a genetic condition involving changes in part of the X chromosome. This condition causes a range of developmental problems including learning disabilities and cognitive impairment. It is the most common form of inherited intellectual disability in males and a significant cause of intellectual disability in females. Other signs and symptoms may include symptoms of autism spectrum disorders, seizures, and characteristic physical features. Fragile X syndrome is caused by a change (mutation) in the FMR1 gene and is inherited in an X-linked dominant manner
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Hypomyelination with atrophy of basal ganglia and cerebellum

Retrieved: 27-07-2015
Source: GARD (Original article)
Associated genes: tubb4a

Hypomyelination with atrophy of basal ganglia and cerebellum

Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) is a disease that affects certain parts of the brain.  Symptoms usually begin in infancy or early childhood and vary in severity; they include movement difficulties and delay in mental development or learning problems.  These symptoms occur because certain brain cells in individuals with H-ABC are not fully covered by myelin (hypomyelination), a substance that usually surrounds nerve cells to help them work better.  Also, this condition causes the breakdown (atrophy) of two parts of the brain that help to coordinate movement - the basal ganglia and cerebellum.  H-ABC is is caused by a mutation in the TUBB4A gene
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Hypomyelination with atrophy of basal ganglia and cerebellum

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: tubb4a

Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) is characterized by slowly progressive spasticity, extrapyramidal movement disorders (dystonia, choreoathetosis and rigidity), cerebellar ataxia, moderate to severe cognitive deficit, and anarthria/dysarthria. So far, around 20 cases have been reported in the literature. The syndrome affects both males and females and onset occurs in infancy or early childhood. All of the reported cases were sporadic and the mode of inheritance remains unclear. The etiology is unknown. H-ABC is diagnosed on the basis of the distinctive MRI findings of diffuse but partial hypomyelination of the cerebral hemispheres, mild to severe cerebellar atrophy and atrophy of the basal ganglia. Last update: September 2008
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22q13.3 deletion syndrome

Retrieved: 27-07-2015
Source: GARD (Original article)

22q13.3 deletion syndrome

22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a chromosome abnormality caused by the loss (deletion) of a small piece of chromosome 22. The deletion occurs near the end of the long arm (or q arm) at a location designated as q13.3. The signs and symptoms of this condition vary widely from person to person. Common symptoms include low muscle tone (hypotonia), intellectual disability, delayed or absent speech, abnormal growth, tendency to overheat, large hands, and abnormal toenails. Affected individuals may have characteristic behaviors, such as mouthing or chewing on non-food items, decreased perception of pain, and autistic-like behaviors. The loss of a particular gene on chromosome 22, called the SHANK3 gene, is likely responsible for many of the signs and symptoms of 22q13.3 deletion syndrome. Additional genes within the deleted region probably contribute to the variable features of the syndrome
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Mental retardation, autosomal recessive 37

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: ank3

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-37 (MRT37) is caused by homozygous mutation in the ANK3 gene (600465) on chromosome 10q21. One such family has been reported.Iqbal et al. (2013) reported 3 sibs, born of consanguineous Pakistani parents, with moderate intellectual disability (IQ less than 50). The patients were 25, 22, and 18 years of age at the time of the report. All had delayed global development with speech delay, hypotonia, spasticity, and a sleep disorder. All had severe behavioral abnormalities, including aggression, hyperactivity, and grinding of the teeth. One had seizures. They did not have dysmorphic features. CT scans of 2 patients were unremarkable.

Inheritance

The transmission pattern in the family with MRT37 reported by Iqbal et al. (2013) was consistent with autosomal recessive inheritance.

Molecular genetics

In 3 Pakistani sibs, born of consanguineous parents, with MRT37 and behavioral abnormalities, Iqbal et al. (2013) identified a homozygous frameshift mutation in the ANK3 gene (600465.0001). The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

Symptoms

INHERITANCE: Autosomal recessive

MUSCLE, SOFT TISSUE: Hypotonia

NEUROLOGIC: [Central nervous system]; Intellectual disability, moderate; Spasticity; Hypotonia; Sleep disturbances; Seizures (in 1 patient); [Behavioral/psychiatric manifestations]; Aggressive behavior; Hyperactivity; Teeth grinding

MISCELLANEOUS: One family has been reported (last curated October 2013)

MOLECULAR BASIS: Caused by mutation in the ankyrin 3 gene (ANK3, 600465.0001)
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Clark-baraitser syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Clark and Baraitser (1987) described 2 mentally retarded brothers who also had macrocephaly, 'square' forehead, prominent supraorbital ridges, broad nasal tip, prominent lower lip, large ears, obesity, and macroorchidism.

Baraitser et al. (1995) described a family in which 2 male first cousins related through their mothers had features similar to those in the family reported by Clark and Baraitser (1987). The boys had nonspecific mental retardation with macrocephaly and obesity. The authors compared the disorder in both these families to the Atkin-Flaitz syndrome (300431) described by Atkin et al. (1985). The main difference at the clinical level lay in the short stature and hypertelorism of the Atkin-Flaitz patients. The obesity in both conditions suggested Prader-Willi syndrome (176270); however, there was never congenital hypotonia, early feeding difficulties, or nocturnal searching for food.

Monteiro de Pina-Neto and Andreotti de Molfetta (1998) reported a 14-year-old Brazilian boy, born to nonconsanguineous parents, who had mental retardation, macrocephaly, tall stature and large hands, obesity, square forehead, prominent supraorbital ridges, prominent lower lip, large ears, a gap between the central incisors, and normal eye spacing. CT scan of the brain showed macrocrania with no abnormalities of the brain. Bone age was compatible with chronologic age, and there were no inborn errors of metabolism. He had a normal karyotype by GTG banding. Macroorchidism that had been noted at age 10 disappeared after puberty.

Tabolacci et al. (2005) reported 2 brothers, born of nonconsanguineous parents, who had moderate to severe mental retardation, severe macrocephaly, obesity, characteristic face, big hands and feet, advanced bone age, and brain abnormalities, including frontal cortical atrophy. The height of both brothers, aged 24 and 15 years, respectively, was at the 10th centile, below the midparental target. They both exhibited autistic-like behavior in which they would stand still for several minutes with a fixed facial expression in an almost catatonic state; the p...

Symptoms

INHERITANCE: X-linked

GROWTH: [Height]; Tall stature; [Weight]; Obesity

HEAD AND NECK: [Head]; Macrocephaly; [Face]; Coarse facial features; Prominent forehead; Heavy supraorbital ridges; [Eyes]; Downslanting palpebral fissures; [Nose]; Broad nasal tip; Anteverted nostrils; [Mouth]; Thick lips; Prominent lower lip; Prominent median palatal raphe; Exaggerated median tongue furrow; [Teeth]; Central incisor gap; Microdontia (maxillary lateral incisors)

GENITOURINARY: [Internal genitalia, male]; Macroorchidism

SKELETAL: Joint laxity; [Spine]; Scoliosis; Hyperkyphosis; [Limbs]; Genu valga; Genu recurvata; [Hands]; Tapered fingers; Short, broad hands

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Seizures
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Alopecia, neurologic defects, and endocrinopathy syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: rbm28

Clinical features

A number sign (#) is used with this entry because of evidence that alopecia, neurologic defects, and endocrinopathy syndrome (ANES) is caused by homozygous mutation in the RBM28 gene (612074) on chromosome 7q32. One such family has been reported.Nousbeck et al. (2008) reported a consanguineous family of Arab Moslem descent in which 5 brothers had a complex phenotype characterized by alopecia, neurologic defects, and endocrinopathy (ANE syndrome). The patients had hair loss of variable severity, ranging from complete alopecia to near-normal scalp hair with absence of body hair. A scalp skin biopsy showed absence of mature hair follicles, rudimentary infundibula, and epithelial cysts. All patients had moderate to severe mental retardation and progressive motor deterioration during the second decade of life. Extensive endocrinologic studies showed central hypogonadotropic hypogonadism with delayed or absent puberty and central adrenal insufficiency. Brain MRI of 1 patient showed a hypoplastic pituitary. Additional features included short stature, microcephaly, gynecomastia, pigmentary anomalies, hypodontia, kyphoscoliosis, ulnar deviation of the hands, and loss of subcutaneous fat.

Spiegel et al. (2010) restudied the 5 affected brothers with ANES reported by Nousbeck et al. (2008). All 5, aged 20 to 39 years, displaye...

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Head]; Decreased head circumference; [Teeth]; Dental caries; Hypodontia; Early teeth loss

CHEST: [Breasts]; Gynecomastia

SKELETAL: Joint contractures; [Spine]; Kyphoscoliosis; [Hands]; Ulnar deviation of the hands

SKIN, NAILS, HAIR: [Skin]; Hyperpigmentation in flexure areas; Pigmented nevi; [Hair]; Alopecia, variable severity; Scalp biopsy shows absence of mature hair follicles

MUSCLE, SOFT TISSUE: Muscle atrophy; Decreased subcutaneous fat

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Motor deterioration in second decade; Upper motor neuron dysfunction; Lower motor neuron dysfunction; Brain MRI shows hypoplastic pituitary

ENDOCRINE FEATURES: Hypogonadotropic hypogonadism; Absent or delayed puberty; Central adrenal insufficiency; Low insulin-like growth factor-1 (IGF1) concentration; Lack of growth hormone (GH) response to stimulation; Low testosterone levels; Low gonadotropin levels; Absent or low response to gonadotropin-releasing hormone stimulation; Adrenocorticotropic hormone (ACTH) deficiency; Abnormal thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) stimulation, variable; Low prolactin (PRL) levels (in some patients)

MISCELLANEOUS: Endocrine defects evolve over time; Based on report of 5 brothers of Arab-Moslem descent (last curated February 2015)

MOLECULAR BASIS: Caused by mutation in the RNA-binding motif protein 28 gene (RBM28, 612074.0001)
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Mental retardation, autosomal dominant 24

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because autosomal dominant mental retardation-24 (MRD24) is caused by heterozygous mutation in the DEAF1 gene (602635) on chromosome 11p15.Vulto-van Silfhout et al. (2014) reported 4 unrelated children with MRD24, including 2 patients previously identified by Vissers et al. (2010) and Rauch et al. (2012). All patients had delayed psychomotor development with absent or very poor expressive speech and gait abnormalities. Three had poor eye contact. Dysmorphic features were mild, but included thin and/or fair hair, straight eyebrows, full nasal tip, tented upper lip, full lower lip, and prominent chin. Three patients had skin syndactyly of toes 2-3, 2 had a sacral dimple, and 2 had hyperlaxity. All also had recurrent infections and a high pain threshold. The patients were described as having a happy disposition, but 3 had severe behavioral abnormalities consisting of autistic, compulsive, hyperactive, and aggressive behavior with striking mood swings.

Molecular genetics

In 1 of 10 patients with mental retardation, Vissers et al. (2010) identified a de novo heterozygous missense mutation in the DEAF1 gene (I228S; 602635.0001). The mutation was found by exome sequencing. In a girl with nonsyndromic intellectual disability, Rauch et al. (2012) identified a de novo heterozygous missense mutation in the DEAF1 gene (Q264P; 602635.0002). The patient was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing.

In 2 unrelated patients with MRD24, Vulto-van Silfhout et al. (2014) identified 2 different missense mutations in the DEAF1 gene (R224W, 602635.0003 and R254S, 602635.0004). The patients were ascertained from a cohort of over 2,300 individuals with intellectual disability who underwent targeted resequencing of the DEAF1 gene. In vitro functional expression assays using a luciferase reporter indicated that all 4 of the mutations, including those reported by Vissers et al. (2010) and Rauch et al. (2012), resulted in a loss of the ability of DEAF1 to repress its own promoter, ...

Symptoms

INHERITANCE: Autosomal dominant

HEAD AND NECK: [Face]; Prominent chin; [Eyes]; Straight eyebrows; Poor eye contact; [Nose]; Full nasal tip; [Mouth]; Tented upper lip; Full lower lip

SKELETAL: [Feet]; Skin syndactyly, 2-3

SKIN, NAILS, HAIR: [Skin]; Sacral dimple (2 patients)

NEUROLOGIC: [Central nervous system]; Developmental delay; Mental retardation, moderate to severe; Gait abnormalities; High pain threshold; Lack of expressive speech; Very poor expressive speech; [Behavioral/psychiatric manifestations]; Happy disposition; Autistic features; Mood swings; Aggressive behavior; Compulsive behavior

IMMUNOLOGY: Recurrent infections

MISCELLANEOUS: De novo mutation

MOLECULAR BASIS: Caused by mutation in the deformed epidermal autoregulatory factor 1 homolog gene (DEAF1, 602635.0001)

Polyendocrine-polyneuropathy syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because of evidence that the polyendocrine-polyneuropathy syndrome (PEPNS) is caused by homozygous mutation in the DMXL2 gene (612186) on chromosome 15q21.2. One such family has been reported.Tata et al. (2014) described a consanguineous Senegalese family in which 3 of 5 children had a progressive endocrine and neurodevelopmental disorder. The 3 affected brothers displayed growth retardation and had recurrent episodes of asymptomatic profound hypoglycemia with incomplete suppression of insulin concentration that appeared between 2 and 5 years of age. At 14 to 16 years of age, all 3 gradually developed nonautoimmune insulin-dependent diabetes mellitus. Their puberty was incomplete and they had low testicular volumes; all had a normal sense of smell. During adolescence, the brothers exhibited dysarthria and ataxia, and neurologic examination revealed polyneuropathy, with a motor deficit predominantly affecting the proximal lower limbs, as well as pes cavus, claw toes, and cerebellar and pyramidal signs. Electrophysiologic analysis was consistent with demyelinating polyneuropathy, with a diffuse homogeneous pattern of slowing motor conduction in peripheral nerves, and greater preservation of sensory conduction in the legs than in the arms. Brain MRI showed moderate subcortical temporal white matter disease, and 1 brother also showed mild hypoplasia of the cerebellum and a small anterior pituitary gland. Hormone assessment in adulthood showed an increase in HbA1c levels, with low insulin levels in an intravenous glucose tolerance test and subnormal basal C-peptide ...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature; [Other]; Postnatal growth retardation

HEAD AND NECK: [Head]; Partial frontal alopecia; [Ears]; Progressive hearing loss; [Nose]; Normal sense of smell

GENITOURINARY: [External genitalia, male]; Small testicular volume

SKIN, NAILS, HAIR: [Hair]; Partial frontal alopecia

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate; Dysarthria; Dystonia; Ataxia; Pyramidal syndrome; Subcortical temporal white matter disease, moderate; Cerebellar hypoplasia, mild (in some patients); Hypoplastic pituitary gland (in some patients); [Peripheral nervous system]; Peripheral demyelinating polyneuropathy; Motor delay

ENDOCRINE FEATURES: Hypogonadotropic hypogonadism; Low testosterone levels; Low luteinizing hormone levels; Low follicle-stimulating hormone levels; Central hypothyroidism; Low free-T4 levels; Normal thyroid-stimulating hormone level; Episodic asymptomatic severe hypoglycemia in childhood; Nonautoimmune insulin-dependent diabetes in second decade of life

MISCELLANEOUS: One consanguineous Senegalese family has been reported (last curated December 2014)

MOLECULAR BASIS: Caused by mutation in the DMX-like 2 gene (DMXL2, 612186.0001)
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Mental retardation and microcephaly with pontine and cerebellar hypoplasia

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Associated genes: cask
Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH), also known as Mental retardation, X-linked, syndromic, Najm type (MRXSNA), is a rare genetic disorder of infants characterised by intellectual disability and pontocerebellar hypoplasia. The disorder is associated with a mutation in the CASK gene which is transmitted in an X-linked manner. As with the vast majority of genetic disorders, there is no known cure to MICPCH.

See also

Pontocerebellar hypoplasia X-linked mental retardation
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X-linked intellectual disability, Najm type

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cask

Najm type X-linked intellectual deficit is a rare cerebellar dysgenesis syndrome characterized by variable clinical manifestations ranging from mild intellectual deficit with or without congenital nystagmus, to severe cognitive impairment associated with cerebellar and pontine hypoplasia/atrophy and abnormalities of cortical development. Prevalence of this rare neurological syndrome is unknown. Up to 35 families have been reported to date. Patients (mostly females) have been reported to have variable clinical manifestations including intellectual deficit, severe developmental delay, seizures, unsteady gait, sensorineural hearing loss and postnatal microcephaly (in most cases). Minor facial anomalies include: low or broad forehead, hypertelorism, long philtrum and micrognathia. Ocular findings are also variable and include congenital nystagmus, strabismus, cataracts, myopia or reduced visual acuity. Males appear to be more severely affected. Point mutations and deletions in the CASK gene (Xp11.4) have been found in patients with this syndrome. Magnetic resonance imaging (MRI) generally shows pontocerebellar hypoplasia/atrophy and simplified cortical gyri. Molecular genetic testing is needed to confirm diagnosis. Transmission follows an X-linked dominant pattern. Expert reviewer(s) Dr Ginevra ZANNI Last update: February 2013
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Mental retardation, x-linked 21

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: il1rapl1

Description

A number sign (#) is used with entry because X-linked mental retardation-21 (MRX21) is caused by mutation in the IL1RAPL1 gene (300206) on chromosome Xp21.This form of nonsyndromic X-linked mental retardation is characterized by a spectrum of cognitive neurologic impairments or disabilities ranging from moderate mental retardation to high-functioning autism. Males are typically severely affected, but some carrier females may manifest milder deficits (summary by Piton et al., 2008).

Clinical features

Kozak et al. (1993) reported a 3-generation Italian family in which 4 male patients had moderate mental retardation without any specific or consistent phenotypic abnormalities. One obligate female carrier had mild retardation and another 2 had normal intelligence, suggesting incomplete penetrance in females.

Piton et al. (2008) reported a family in which 3 brothers had mental retardation with variable autistic features. The 8-year-old proband had mental retardation and showed some autistic signs, but was too impaired to be formally tested. The proband's 2 brothers had a less severe cognitive phenotype: one had pervasive developmental disorder, not otherwise specified (PDDNOS), and the other had mild mental retardation with repetitive behaviors, but no other signs of autism. Their carrier mother was unaffected.

Franek et al. (2011) reported 2 unrelated families with X-linked mental retardation resulting from deletions encompassing the immunoglobulin domain of the IL1RAPL1 gene. Three affected males in the first family had low IQ and other variable features, including hypotonia (2), pectus excavatum (2), prominent jaw (2), synophrys (2), and hyperextensible joints (2). Two had behavioral abnormalities, including impulsivity, oppositional disorder, and hyperactivity. One had pigmentary skin changes. Genetic analysis identified a 635-kb deletion spanning exons 2-5 in the IL1RAPL1 gene (see 300206.0003), although exact deletion breakpoints were not mapped. In the second family, there were 5 affected males, but only 2 brothers were described in detail. Both had moderate intellectual disability and seizures. Both had prominent jaw, strabismus, and hyperextensible el...

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Face]; Mild dysmorphic features; Hypotonic midface; Prominent jaw; [Ears]; Thick ears; Upturned lobes; [Eyes]; Hypertelorism; Upslanted palpebral fissures; Synophrys; [Nose]; Short nose; Thickened alae nasi and columella; [Mouth]; Open mouth; Tented upper lip; [Teeth]; Crowded dentition

SKELETAL: Hyperextensible joints

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate; Seizures (1 family); [Behavioral/psychiatric manifestations]; Autistic features; Hyperactivity

MISCELLANEOUS: Carrier females may have mild features

MOLECULAR BASIS: Caused by mutation in the IL1 receptor accessory protein-like 1 gene (IL1RAPL, 300206.0001)
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Marden-Walker syndrome

Retrieved: 27-07-2015
Source: GARD (Original article)

Marden-Walker syndrome

Marden-Walker syndrome is a connective tissue disorder characterized by a mask-like face with blepharophimosis (a narrowing of the eye opening), micrognathia, cleft or high-arched palate, low-set ears, congenital joint contractures, decreased muscular mass, failure to thrive and psychomotor retardation (a generalized slowing down of physical reactions, movements, and speech). While the underlying cause has not been clearly established, it is believed to be a developmental disorder of the central nervous system which is inherited in an autosomal recessive manner
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Recombinant chromosome 8 syndrome

Retrieved: 27-07-2015
Source: GARD (Original article)
Associated genes: slc50a1

Recombinant chromosome 8 syndrome

Recombinant chromosome 8 syndrome is a condition that involves heart and urinary tract abnormalities, moderate to severe intellectual disability, and a distinctive facial appearance. Many children with recombinant chromosome 8 syndrome do not survive past early childhood, usually due to complications related to their heart abnormalities. Most people with this condition are descended from a Hispanic population originating in the San Luis Valley area of southern Colorado and northern New Mexico. Recombinant chromosome 8 syndrome is caused by a rearrangement of chromosome 8 that results in a missing piece of the short (p) arm and an extra piece of the long (q) arm. Most affected individuals have at least one parent with a change in chromosome 8 called an inversion
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Hypotonia-cystinuria syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)

Hypotonia-Cystinuria syndrome (HCS) is a rare syndrome including neonatal and infantile hypotonia and failure to thrive, cystinuria type 1 and nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. HCS has been described in 14 families to date. Dysmorphic features mainly include dolichocephaly and ptosis. Nephrolithiasis occurs at variable ages. The syndrome is caused by homozygous deletion of two contiguous genes on chromosome 2: SLC3A1 and PREP (2p21). Last update: November 2010
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X-linked intellectual disability - cerebellar hypoplasia

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: ophn1

X-linked intellectual deficit-cerebellar hypoplasia, also known as OPHN1 syndrome, is a rare syndromic form of cerebellar dysgenesis characterized by moderate to severe intellectual deficit and cerebellar abnormalities. OPHN1 syndrome is very rare. To date, up to 12 families have been reported. Affected male patients present moderate to severe intellectual disability, hypotonia, severe developmental delay, early-onset complex partial or tonic-clonic seizures, strabismus, dysmetria and occasionally ataxia. Cryptorchidism and genital hypoplasia have been reported. Some patients have abnormal behavior and a characteristic facial phenotype (long face, prominent forehead, infraorbital creases, deep-set eyes, upturned philtrum and large ears). Carrier females have been reported to have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes. Various mutations including deletions and splice site mutations in the OPHN1 gene (Xq12) have been reported in patients with this syndrome. Neuroradiological findings include posterior vermis dysgenesis, vermian parasagittal cleft, cerebellar hypoplasia, cortical atrophy, and enlargement of the cerebral ventricles. Molecular genetic testing is needed to confirm diagnosis. Transmission appears to follow an X-linked semi-dominant pattern. Expert reviewer(s) Dr Ginevra ZANNI Last update: February 2013
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Mental retardation, x-linked, with cerebellar hypoplasia and distinctive facial appearance

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: ophn1

Clinical features

A number sign (#) is used with this entry because this form of syndromic X-linked mental retardation is caused by mutation in the oligophrenin-1 gene (OPHN1; 300127).Billuart et al. (1998) reported a large family in which 4 males had X-linked mental retardation. Des Portes et al. (2004) performed clinical and 3-dimensional brain MRI evaluations on the affected males of the family studied by Billuart et al. (1998) and an unrelated female patient with an X;12 balanced translocation described by Bienvenu et al. (1997) (see 300127). Clinical features shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early-onset complex partial seizures, and moderate to severe mental retardation. Brain MRIs in 2 brothers and the unrelated female patient revealed a complex cerebellar dysgenesis including incomplete sulcation of the anterior and posterior vermis with the most prominent defect in lobules VI and VII. Nonspecific cerebral corticosubcortical atrophy was also observed.

Philip et al. (2003) reported 2 families in which 4 males and 1 male, respectively, had X-linked mental retardation associated with subtle facial dysmorphism and cerebellar anomalies, including hypoplasia of the vermis, expansion of the cisterna magna, and retrocerebellar cysts.

Bergmann et al. (2003) reported a family of German descent in which 5 brothers had moderate to severe mental retardation associated with enlargement of the lateral ventricles and cerebellar hypoplasia. Other features included seizures, ataxia, strabismus, and hypogenitalism with cryptorchidism, hypoplastic scr...

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Head]; Macrocephaly; [Face]; Prominent forehead; Prominent supraorbital ridges; Long face; Short philtrum; Upturned philtrum; Marked infraorbital creases; Prominent chin; [Ears]; Large ears; [Eyes]; Hypotelorism; Deep-set eyes; Strabismus; Nystagmus; [Nose]; Long, tubular nose; [Mouth]; Thin upper lip

GENITOURINARY: [External genitalia, male]; Hypoplastic scrotum; Microphallus; [Internal genitalia, male]; Cryptorchidism

NEUROLOGIC: [Central nervous system]; Psychomotor delay; Mental retardation, moderate to severe (IQ 40 to 60); Mental retardation, mild, in most carrier females; Hypotonia; Speech delay; Seizures; Ataxic gait; Spasticity; Cerebellar signs; Cerebellar hypoplasia; Disorganization of the anterior cerebellar vermis; Enlarged ventricles; Enlarged cisterna magna; Retrocerebellar cyst; Decreased cerebral volume, especially of the frontal lobes; [Behavioral/psychiatric manifestations]; Hyperactivity; Autistic features

MISCELLANEOUS: Onset in infancy; Most carrier females have mild mental retardation and subtle facial changes

MOLECULAR BASIS: Caused by mutation in the oligophrenin 1 gene (OPHN1, 300127.0001)
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Lenz-Majewski hyperostotic dwarfism

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: ptdss1

Lenz-Majewski hyperostotic dwarfism is an extremely rare syndrome associating dwarfism, characteristic facial appearance, cutis laxa and progressive bone sclerosis. Nine cases have been reported in the literature. Marked hypertelorism and broad forehead are noted in all patients as well as large ears. Loose and wrinkled atrophic skin with prominent veins is also apparent, giving the patient a progeroid appearance. Increasing generalized osteosclerosis of tubular bones, vertebrae and cranial bones is a characteristic feature. Cutaneous syndactyly of 2nd to 5th fingers was observed in all patients, as well as brachydactyly (see this term) and proximal symphalangism (see this term). All patients have moderate to severe intellectual deficit. The elevated age of some patient's fathers of the reported families is suggestive of an autosomal dominant de novo mutation. Last update: March 2010
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Lenz–Majewski syndrome

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Associated genes: ptdss1
Lenz–Majewski syndrome is a skin condition characterized by hyperostosis, craniodiaphyseal dysplasia, dwarfism, cutis laxa, proximal symphalangism, syndactyly, brachydactyly, mental retardation, enamel hypoplasia, and hypertelorism.James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. In 2013, whole-exome sequencing showed that a [missense mutation] resulting in overactive phosphatidylserine synthase 1 was the cause of LMS, making it the first known human disease to be caused by disrupted phosphatidylserine metabolism. The researchers suggested a link between the condition and bone metabolism.http://www.nature.com/ng/journal/v46/n1/full/ng.2829.html

See also

Skin lesion
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Mental retardation, autosomal recessive 5

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: nsun2

Clinical features

A number sign (#) is used with this entry because autosomal recessive mental retardation-5 (MRT5) is caused by homozygous mutation in the NSUN2 gene (610916) on chromosome 5p15.Najmabadi et al. (2007) reported a large consanguineous Iranian family in which 3 individuals had nonsyndromic moderate to severe mental retardation. Abbasi-Moheb et al. (2012) reported follow-up of the families reported by Najmabadi et al. (2007) and Kuss et al. (2011) with MRT5, and reported an additional family of Iranian descent. Affected individuals had some mild dysmorphic features, including microcephaly, long and narrow face, bushy eyebrows with synophrys, hypotelorism, large nose with long columella and hypoplastic alae nasi, short philtrum, and full upper lip. Many had short stature, and some had later onset of muscular hypertonia and spasticity. Brain malformations were not observed.

Khan et al. (2012) reported a consanguineous Pakistani family in which 3 sisters had MRT5. All had delayed psychomotor development with limited speech, dysarthria, and poor somatic growth. Dysmorphic features included a long face and nose with protruding nasal tip and short philtrum. All also had signs of a distal myopathy, with variable increased muscle tone in the limbs, brisk reflexes, and equivocal plantar responses. Two showed a broad-based gait with pes cavus and tight Achilles tendons....

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature; [Weight]; Low birth weight; Postnatal growth retardation

HEAD AND NECK: [Head]; Microcephaly; [Face]; Long face; Narrow face; Small chin; Short philtrum; Smooth philtrum; [Eyes]; Hypotelorism; Bushy eyebrows; Synophrys; Strabismus; Blepharophimosis (in 1 family); Telecanthus (in 1 family); Hypertelorism (in 1 family); [Nose]; Large nose; Long columella; Hypoplastic alae nasi; High nasal bridge (in 1 patient); Broad nasal bridge (in 1 family); [Mouth]; Full upper lip; Downturned upper lip

SKELETAL: [Feet]; Pes cavus (in 1 family); Tight Achilles tendon (in 1 family)

SKIN, NAILS, HAIR: [Skin]; Eczema (in 1 patient); [Hair]; Sparse hair (in 1 family)

MUSCLE, SOFT TISSUE: Hypertonia; Distal myopathy (in 1 family)

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Axial hypotonia; Delayed speech; Limited speech; Dysarthria; Seizures (rare); Spasticity (later onset); Broad gait; Hyperreflexia; Equivocal plantar responses; [Behavioral/psychiatric manifestations]; Autistic features (in 1 family)

LABORATORY ABNORMALITIES: Increased serum lactate dehydrogenase (in 1 family); Increased serum creatine kinase (1 family)

MISCELLANEOUS: Dysmorphic features are variable

MOLECULAR BASIS: Caused by mutation in the NOL1/NOP2/SUN domain family, member 2 gene NSUN2 (610916.0001)
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Mental retardation, autosomal recessive 13

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: trappc9

Clinical features

A number sign (#) is used with this entry because this form of autosomal recessive mental retardation (MRT13) is caused by homozygous mutation in the TRAPPC9 gene (611966) on chromosome 8q24.3.Mochida et al. (2009) reported a consanguineous Israeli Arab pedigree in which 3 girls had moderate to severe mental retardation and postnatal microcephaly. One girl, at age 7 years 10 months, had severe cognitive delay and could speak only a few words. She had normal motor development and could walk, but showed bruxism and hand-flapping movements. Brain MRI scans at age 2 and 4 years showed a thin corpus callosum and reduced volume of the cerebral white matter. Brain MRI of her 4-year-old affected sister also showed a thin but fully formed corpus callosum, decreased volume of the cerebral white matter, and hypoplasia of the inferior cerebellar vermis. Brain MRI was not reported for the third child. None of the patients had dysmorphic features, autistic features, or seizures, and there was no evidence of developmental regression.

Philippe et al. (2009) reported 3 brothers, born of consanguineous Tunisian parents, with autosomal recessive mental retardation associated with mild microcephaly, myelination defect, and truncal obesity in the first year of life. One child, first examined at age 10 years, had severe mental retardation with significant speech delay and a friendly personality. He had mild microcephaly, truncal obesity, hypertelorism, short neck, and prominent upper central incisors. Examination at age 19 showed progressive microcephaly and short, smooth philtrum, and brain MRI showed unusual white matter abnormalities. The second child had unilateral cleft lip, delayed speech, hypotelorism, short neck, prominent upper central incisors, short, smooth philtrum, and long, thin fingers. He understood simple commands and had a happy disposition and hyperactivity. The third affected child had global developmental delay, but was less severely affected. At age 4, h...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Weight]; Truncal obesity (variable)

HEAD AND NECK: [Head]; Microcephaly, postnatal; [Face]; Short, smooth philtrum; [Eyes]; Hypertelorism (rare); Hypotelorism (rare); [Mouth]; Cleft lip (rare); [Teeth]; Prominent central incisors; [Neck]; Short neck

SKELETAL: [Hands]; Long, thin fingers (rare)

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Language development limited to a few words; Seizures (rare); Delayed walking (less common); Thin corpus callosum; Decreased volume of the cerebral white matter; White matter abnormalities; Hypoplasia of the inferior cerebellar vermis; [Behavioral/psychiatric manifestations]; Happy disposition; Hyperactivity

MISCELLANEOUS: Onset in infancy

MOLECULAR BASIS: Caused by mutation in the trafficking protein particle complex, subunit 9 gene (TRAPPC9, 611966.0001)

Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: cyp11b2

Clinical features

Kuss et al. (2011) reported a consanguineous Iranian family (8700017) in which 4 individuals had moderate to severe nonsyndromic mental retardation.

Mapping

By homozygosity mapping in a consanguineous Iranian family (8700017) in which 4 individuals had moderate to severe nonsyndromic mental retardation, Kuss et al. (2011) found linkage to a 10.5-Mb region on proximal chromosome 4q between SNPs dbSNP rs11944876 and dbSNP rs6551838 (lod score of 4.8).

Symptoms

INHERITANCE: Autosomal recessive

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe

MISCELLANEOUS: One family reported (last curated November 2011)


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Bremer et al. (1976) described a female infant (the offspring of a probably incestuous mating of a mentally retarded mother) who was a typical 'collodion baby.' The skin cleared, but retarded development and floppiness with edema of the dorsum of the hands and feet later became evident. The mother was said to have shown similar features as a baby. The urine showed alpha-ketoadipicacid (COOH-CH(O)-(CH2)3-COOH). The infant's fibroblasts showed a defect in degradation of alpha-ketoadipicacid. The mother also secreted this substance in the urine. This may be an instance of pseudodominance. See aminoadipicaciduria (204750).

Symptoms

INHERITANCE: Autosomal recessive

RESPIRATORY: [Lung]; Bronchiectasis due to chronic upper respiratory tract infections

CHEST: [External features]; Barrel chest

SKELETAL: [Hands]; Clubbed fingers

SKIN, NAILS, HAIR: [Skin]; Neonatal collodion skin

MUSCLE, SOFT TISSUE: Edema of dorsum of hands and feet; Hypotonia

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Delayed motor development; Seizures; [Behavioral/psychiatric manifestations]

LABORATORY ABNORMALITIES: Alpha-ketoadipic aciduria; Alpha-hydroxyadipic aciduria Alpha-aminoadipic aciduria


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

Ramirez et al. (2004) described 3 sibs, born to nonconsanguineous Mexican parents, who had bilateral frontotemporal pachygyria without polymicrogyria. The 2 sisters and their brother shared the additional features of moderate mental retardation, esotropia, telecanthus or hypertelorism, and normal or slightly decreased neuromuscular tone and deep tendon reflexes. There were 2 unaffected brothers in the family.

Inheritance

Ramirez et al. (2004) suggested that this syndrome is most likely inherited as an autosomal recessive trait.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Eyes]; Esotropia; Telecanthus; Hypertelorism

NEUROLOGIC: [Central nervous system]; Pachygyria, bilateral frontotemporal; Mental retardation, moderate; Seizure, febrile (2/3 children); [Peripheral nervous system]; Neuromuscular tone slightly decreased; Deep tendon reflexes slightly decreased


Retrieved: 27-07-2015
Source: WIKIPEDIA (original)
Associated genes: inpp5e, pmpca
MORM syndrome is an autosomal recessive congenital disorder characterized by mental retardation, truncal obesity, retinal dystrophy, and micropenis". It is associated with INPP5E.

External links

MORM syndrome - WrongDiagnosis.org


Retrieved: 27-07-2015
Source: Orphanet (original)
Associated genes: cyp11b2, acrps

Acro-pectoral syndrome is characterized by a combination of distal limb abnormalities (syndactyly of all fingers and toes, preaxial polydactyly in the feet and/or hands) and upper sternum malformations. It has been described in 22 patients from a six-generation Turkish family. It is transmitted as an autosomal dominant trait and the causative gene is located at 7q36. Last update: January 2007


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-43 (MRT43) is caused by homozygous mutation in the KIAA1033 gene (615748) on chromosome 12q23. One such family has been reported.Ropers et al. (2011) reported a large consanguineous Omani family in which 7 individuals had moderate to severe intellectual disability (IQ, 35-50). They had severe learning impairment, poor language skills, poor adaptive skills, and delayed fine motor development. They had short stature, but no other dysmorphic features. Brain MRI showed no significant abnormalities. One patient had signs of spasticity.

Inheritance

The transmission pattern in the family with MRT43 reported by Ropers et al. (2011) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of a consanguineous Omani family with mental retardation, Ropers et al. (2011) identified a 12.5-Mb candidate region on chromosome 12q23-q24 (lod score of 3.5).

Molecular genetics

In affected members of a family with MRT43, Ropers et al. (2011) identified a homozygous missense mutation in the KIAA1033 gene (P1019R; 615748.0001). In vitro functional expression studies and analysis of patient cells showed that the mutation destabilized the protein and interfered with the stability of the WASH (613632) complex. The findings implicated a role for abnormal actin dynamics and endosomal trafficking in this form of intellectual disability. The patients also carried a homozygous H362L variant in the LHX5 gene (605992), which was not thought to be pathogenic.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

NEUROLOGIC: [Central nervous system]; Delayed development; Mental retardation, moderate to severe (IQ 35-50); Poor language; Poor adaptive skills; Poor fine motor skills; Spasticity (1 patient)

MISCELLANEOUS: One consanguineous family has been reported (last curated May 2014)

MOLECULAR BASIS: Caused by mutation in the KIAA1033 gene (KIAA1033, 615748.0001)


Retrieved: 27-07-2015
Source: GARD (original)
Associated genes: gpr56, kiaa0319

Bilateral frontoparietal polymicrogyria

Bilateral frontoparietal polymicrogyria (BFPP) is a rare neurological disorder that affects the cerebral cortex (the outer surface of the brain). BFPP specifically affects the frontal and parietal lobes on both sides of the brain (bilateral). Signs and symptoms typically include moderate to severe intellectual disability, developmental delay, seizures, cerebellar ataxia, strabismus, and dysconjugate gaze (eyes that are not aligned). Some cases are caused by mutations in the GPR56 gene and are inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each person


Retrieved: 27-07-2015
Source: Orphanet (original)
Associated genes: cyp11b2, cvmrf

This syndrome is characterised by moderate intellectual deficit, marked cubitus valgus, mild microcephaly, a short philtrum, deep-set eyes, downslanting palpebral fissures and multiple nevi. Less than ten individuals have been described so far. Transmission is thought to be X-linked recessive. Last update: May 2007


Retrieved: 27-07-2015
Source: Orphanet (original)
Associated genes: cyp11b2, mrxs11

This syndrome is characterised by moderate intellectual deficit, obesity, macroorchidism and a characteristic facies (large ears, a prominent lower lip and puffy eyelids). It has been described in nine boys from two families. Transmission is X-linked and the causative gene has been localised to the q21.3-q27 region of the X chromosome. Last update: February 2007


Retrieved: 27-07-2015
Source: Orphanet (original)
Associated genes: large

This disease has been moved to Congenital muscular dystrophy due to dystroglycanopathy


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

Atkin et al. (1985) reported a 3-generation family with 11 moderately to severely retarded males and 3 mildly retarded females. Phenotypic manifestations included short stature, macrocephaly, 'coarse' facial features with prominent forehead and supraorbital ridges, hypertelorism, broad nasal tip with anteverted nostrils, and thick lips. All postpubertal males had macroorchidism, and moderate obesity was noted in 6 males and all 3 women. All but one of the affected family members had a diastema between the maxillary central incisors. Although noting similarities, the authors distinguished the syndrome from Coffin-Lowry syndrome (CLS; 303600) and fragile X mental retardation (300624).

Clark and Baraitser (1987) and Baraitser et al. (1995) described mentally retarded patients who shared many features with the patients described by Atkin et al. (1985); see 300602. The distinguishing features were short stature and hypertelorism in the patients reported by Atkin et al. (1985).

Symptoms

INHERITANCE: X-linked dominant

GROWTH: [Height]; Short stature; [Weight]; Obesity

HEAD AND NECK: [Head]; Macrocephaly; [Face]; Coarse facial features; Prominent forehead; Heavy supraorbital ridges; [Eyes]; Hypertelorism; Downslanting palpebral fissures; [Nose]; Broad nasal tip; Anteverted nostrils; [Mouth]; Thick lips; Prominent lower lip; Prominent median palatal raphe; Exaggerated median tongue furrow; [Teeth]; Central incisor gap; Microdontia (maxillary lateral incisors)

GENITOURINARY: [Internal genitalia, male]; Macroorchidism

SKELETAL: Joint laxity; [Spine]; Scoliosis; Hyperkyphosis; [Limbs]; Genu valga; Genu recurvata; [Hands]; Tapered fingers; Short, broad hands

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Seizures; Mental retardation, mild (carrier females)


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: cyp11b2

Clinical features

Chudley et al. (1999) reported a family in which 3 males spanning 2 generations had a syndromic form of moderate mental retardation with seizures and dysmorphic facial features. Common dysmorphic features included prominent glabella, prognathism, synophrys, and hirsutism; hypertelorism and large ears were each noted in 2 patients. The 2 older patients, who were in their forties, showed slowly progressive unsteady gait and progressive weakness, and 1 of them was found to have cerebellar atrophy and electrophysiologic evidence of a peripheral neuropathy. All had low serum immunoglobulins and 2 had specific absence of plasma and secretory IgA, although only 1 patient had recurrent infections.

Mapping

Using microsatellite markers on the X chromosome to evaluate a family with X-linked syndromic mental retardation, Chudley et al. (1999) found linkage to a region on chromosome Xq21.33-q23 between DXS1170 and DXS8067 (maximum 2-point lod score of 2.23 at DXS1120). Haplotype analysis delineated a region either 16 or 20 Mb in size.

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Face]; Prominent glabella; Prognathism; [Ears]; Prominent ears; [Eyes]; Synophrys; Hypertelorism

SKELETAL: [Spine]; Kyphosis; Scoliosis; [Hands]; Single palmar creases

SKIN, NAILS, HAIR: [Hair]; Hirsutism

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate; Poor speech; Seizures; Unsteady gait; Ataxia; Cerebellar atrophy, mild (1 patient); [Peripheral nervous system]; Peripheral neuropathy (1 patient)

IMMUNOLOGY: Decreased IgG; Decreased IgA, plasma and secretory; Decreased IgM

MISCELLANEOUS: One family with 3 affected males has been reported (as of October 2011)


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

Snedden et al. (1982, 1983) described a brother and sister with tryptophanuria as well as a marked increase in plasma tryptophan levels. Martin et al. (1995) provided additional details of these patients and also described abnormal urinary tryptophan metabolites in their mother and a half sib. The brother was a 23-year-old male, the offspring of a Micmac Indian mother and a French Canadian father, who was examined for evaluation of widespread joint pains, emotional lability, defective vision, and a stutter. He had developed normally until the age of 14 years when he began to complain of fleeting pains in his abdomen and joints, precipitated by exertion. At the same time he noticed increasing ulnar drift of the fingers and inability to extend the elbows fully. Generalized joint laxity was noted at the age of 18. A strabismus in the left eye which had almost no vision and high myopia in the right eye were other features. Psychiatric complaints had included aggressive outbursts. Physical examination showed ocular hypertelorism, marked correctable ulnar drift of all the fingers, adduction of the thumbs, and slight contractures of the distal interphalangeal joints of the fingers and intraphalangeal joints of the thumbs. Pes planus was present. The sister was evaluated at the age of 22 years. All her milestones had been delayed; she could not walk until the age of 3 and never acknowledged auditory stimuli or learned to talk. She was institutionalized where she showed hyperactive and aggressive behavior. The mother had had a fever and rash labeled as rubella in the fourth month of pregnancy; the auditory defect in the sister was probably the result of in utero exposure to rubella. Plasma tryptophan estimates were approximately 475 micromole/l in both sibs (normal 25-73). Tryptophanuria and massive excretion of indoleic acids in the urine were also found.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Ears]; Hearing loss, sensorineural (in sister); [Eyes]; Strabismus (in brother); Myopia (in brother); Hypertelorism (in brother)

SKELETAL: [Limbs]; Widespread joint pain; Generalized joint laxity; Limited elbow extension; [Hands]; Ulnar drift of fingers; Slight contractures of distal interphalangeal joints; [Feet]; Pes planus

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate (in sister); [Behavioral/psychiatric manifestations]; Emotional lability, extreme; Delayed milestones; Stuttering, severe (in brother); No verbal language development (in sister); Aggressive outbursts; Hypersexuality; Depression

LABORATORY ABNORMALITIES: Tryptophanuria; Hypertryptophanemia

MISCELLANEOUS: One brother and sister of Micmac Indian and French-Canadian ancestry have been reported (last curated September 2014); Mother had rubella infection during pregnancy with daughter


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: cyp11b2, scar2

Clinical features

Norman (1940) described 3 sibs in 1 family and 2 sibs in another who had cerebellar ataxia and mental deficiency since early life. Postmortem examinations showed severe cerebellar granule cell loss. One child showed delayed motor development and mental deficiency in infancy. Other features included small head, cataracts, increased knee jerks, and intention tremor. He died at age 20 years. Postmortem examination showed marked cerebellar atrophy with complete absence of granule cells in the lateral lobes of the cerebellum and the superior part of the vermis. There were heterotopic Purkinje cells and gliosis (Weiner and Konigsmark, 1971).

Scherer (1933) described 2 affected sibs, and Jervis (1950) 3 affected sibs. Jervis (1954) also observed the disorder in monozygotic Italian twin sisters.

In many members of an inbred Christian Maronite family originating from a village in the northeast of Lebanon, Megarbane et al. (1999) described hereditary congenital nonprogressive cerebellar ataxia. The 12 affected members were thought to have the autosomal recessive Norman type of cerebellar atrophy, also known as primary granular cell atrophy of the cerebellum. The patients in the Lebanese family were of short stature varying from 136 cm in a 44-year-old female to 164 cm in a 40-year-old male.

Mapping

By genomewide analysis of the large consanguineous Lebanese family reported by Megarbane et al. (1999), Delague et al. (2001) found linkage to a 12.1-cM interval on chromosome 9q34-qter between markers D9S67 and D9S312.

Animal model

Weiner and Konigsmark (1971) noted that infection of the fetal rat by rat virus (Margolis and Kilham, 1968) and of the fetal kitten by panleukopenia virus (Kilham and Margolis, 1966) can result in granule cell hypoplasia.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature (1 family)

HEAD AND NECK: [Eyes]; Nystagmus (1 patient)

SKELETAL: [Feet]; Pes cavus (1 family)

MUSCLE, SOFT TISSUE: Hypotonia

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Ataxia; Unsteady gait; Incoordination; Delayed speech development; Dysarthria; Spasticity; Hypotonia; Dysmetria; Cerebellar hypoplasia; Atrophy of the granular cell layer of the cerebellum; Abnormal Purkinje cells; Reactive gliosis; [Peripheral nervous system]; Hyperreflexia; Hyporeflexia (less common)

MISCELLANEOUS: Onset in infancy; Nonprogressive; Some patients do not achieve independent ambulation


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: cyp11b2, mrxsa

Clinical features

Armfield et al. (1999) reported a family with 6 males with mental retardation in 3 generations, consistent with X-linked inheritance. Other features included short stature (6 of 6), small hands and feet (5 of 5), seizures (6 of 6), cleft palate (2 of 6), and cataracts/glaucoma (3 of 6). Carrier females were unaffected.

Inheritance

In the family described by Armfield et al. (1999), X-linked recessive inheritance was suggested by the presence of mental retardation in males, absence of manifestations in females, and the absence of male-to-male transmission.

Mapping

Linkage studies performed by Armfield et al. (1999) localized this apparently novel syndromic form of X-linked mental retardation to the terminal 8 Mb of Xq28, with a lod score of 2.11 at zero recombination at marker p39.

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Head]; Prominent forehead; Midface hypoplasia (in some patients); [Eyes]; Cataracts (in some patients); Glaucoma (in some patients); Strabismus (in some patients); [Mouth]; Cleft palate (in some patients)

SKELETAL: [Hands]; Small hands; [Feet]; Small feet

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Seizures

MISCELLANEOUS: One family with 6 probands described (as of September 2000)


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: cenpj

Clinical features

A number sign (#) is used with this entry because primary microcephaly-6 (MCPH6) is caused by homozygous mutation in the gene encoding centromeric protein J (CENPJ; 609279).

For a phenotypic description and discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).Darvish et al. (2010) reported 2 affected individuals from a consanguineous Iranian family with autosomal recessive primary microcephaly. In addition to severe mental retardation and microcephaly (-4 to -6 SD), the patients had additional features, including small ears, hypertelorism, strabismus, notched nasal tip, seizures, joint stiffness, and wheelchair requirement.

Sajid Hussain et al. (2013) reported 10 patients from 3 consanguineous Pakistani families with primary microcephaly (-8 to -17 SD) between ages 7 and 30 years. Most of the patients were unable to speak or write.

Inheritance

The transmission pattern in the families with MCPH6 reported by Darvish et al. (2010) and Sajid Hussain et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

Leal et al. (2003) reported a novel locus, MCPH6, for autosomal recessive primary microcephaly, mapping to 13q12.2, in a Brazilian family. The minimal critical regions spanned 6 Mb between 2 markers with a maximum 2-point lod score of 6.25.

By homozygosity mapping, Darvish et al. (2010) found linkage to the MCPH6 locus in 5 of 112 consanguineous Iranian families with primary microcephaly.

Molecular genetics

In affected members of 3 families with MCPH6, of which 1 was the Brazilian family previously described by Leal et al. (2003) and 2 were Pakistani, Bond et al. (2005) identified a homozygous mutation in the CENPJ gene (609279.0001-609279.0002, respectively). Each mutation was absent from 380 northern Pakistani control chromosomes, showed the expected disease segregation in families, and was not present in chimpanzee, gorilla, orangutan, gibbon, mouse, or rat.

In affected members of a Pakistani family with MCPH6, Gul et al. (2006) identified homozygosity for a 4-bp deletion in the CENPJ gene (609279.0003).

In 2 affected members of a consanguineous Iranian family with primary microcephaly, Darvish et al. (2010) identified a homozygous mutation in the CENPJ gene (T821M; 609279.0005).

In 10 patients from 3 consanguineous Pakistani families with MCPH6, Sajid Hussain et al. (2013) identified a homozygous truncating mutation in the CENPJ gene (609279.0001). The mutations, which were found by linkage analysis followed by Sanger sequencing of the candidate gene, segregated with the disorder in the families. The families were ascertained from a larger cohort of 57 consan...

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Head]; Microcephaly (head circumference -7 to -17 S.D.)

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate; Small cerebral cortex

MISCELLANEOUS: Onset at birth

MOLECULAR BASIS: Caused by mutation in the centromeric protein J gene (CENPJ, 609279.0001)


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: man1b1

Clinical features

A number sign (#) is used with this entry because autosomal recessive nonsyndromic mental retardation-15 (MRT15) is caused by homozygous mutation in the MAN1B1 gene (604346) on chromosome 9q34.3.Rafiq et al. (2010) reported 3 consanguineous Pakistani families with nonsyndromic mental retardation. The patients were severely mental retarded, all but 1 with an IQ less than 40 and all with delayed speech. Two of 3 sibs in 1 family had truncal obesity, and 2 other patients had epilepsy. None had microcephaly or autistic features. The families belonged to the same clan and were from the same village. Rafiq et al. (2011) provided follow-up of these families, who were from the Punjab province. Two patients had delayed psychomotor development and began walking at age 4 years. Both had hyperphagia and were overweight. Some patients achieved speaking in sentences and toilet training; aggression was a common feature. Mild dysmorphic features, such as dolichocephaly, downslanted palpebral fissures, broad nose, and small chin, were noted.

Rafiq et al. (2011) reported another consanguineous Pakistani family from the Sindh province with a similar, but less severe, form of intellectual disability. In addition to mental retardation, these patients showed dysmorphic features, including downslanting palpebral fissures, hypertelorism, long face, flattened malar region, short philtrum, broad nasal root, and small chin. Rafiq et al. (2011) also described 3 members of an Iranian family with nonsyndromic mental retardation. Overall intellectual disability varied, with 1 patient able to speak and count money and the others more severely affected. Seizures were variable. Dysmorphic features were mild and variable, but included dolichocephaly, long face, flat philtrum, downslanting palpebral fissures, hypertelorism, thin upper lip, triangular and pointed chin, and prominent nose.

Inheritance

The transmission pattern in the families reported by Rafiq et al. (2010) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of 3 consanguineous Pakistani families with autosomal recessive...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Weight]; Obesity (in 1 family)

HEAD AND NECK: [Head]; Dolichocephaly, mild; [Face]; Long face; Flat philtrum; Short philtrum; Malar flattening; Pointed chin; Triangular chin; [Eyes]; Downslanting palpebral fissures; Hypertelorism; Broad eyebrows; Long eyebrows; [Nose]; Broad nasal root; Prominent nose; [Mouth]; Thin upper lip

SKIN, NAILS, HAIR: [Hair]; Broad eyebrows; Long eyebrows

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to profound; Delayed psychomotor development; Seizures (variable); [Behavioral/psychiatric manifestations]; Aggressive behavior

MISCELLANEOUS: Dysmorphic features are variable

MOLECULAR BASIS: Caused by mutation in the mannosidase, alpha, class 1B, member 1 gene (MAN1B1, 604346.0001).


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: rttn

Clinical features

A number sign (#) is used with this entry because polymicrogyria with seizures (PMGYS) is caused by homozygous mutation in the RTTN gene (610436) on chromosome 18q22.Kheradmand Kia et al. (2012) reported a consanguineous Turkish family in which 2 sibs were demonstrated to have diffuse asymmetric polymicrogyria extending from the frontal to the temporal, parietal, and occipital lobes on brain MRI. Other imaging findings included mild ventricular enlargement and thin or short corpus callosum. One patient had mild cerebellar atrophy. The patients were 12 and 14 years old at the time of the report. Both had microcephaly, moderate to severe mental retardation, poor speech, dysarthria, and seizures. One had pyramidal signs. Another family member had moderate mental retardation and seizures, but detailed clinical features were not available. An unrelated 16-year-old boy with diffuse polymicrogyria had microcephaly, severe mental retardation with lack of speech, seizures, and spastic tetraparesis. Two of the patients had normal abdominal ultrasound with situs solitus; 1 had small kidney volume.

Inheritance

The transmission pattern in the family with polymicrogyria reported by Kheradmand Kia et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By autozygosity mapping on the basis of a while-genome search of 3 affected members of a family segregating polymicrogyria with seizures, Kheradmand Kia et al. (2012) found shared homozygous regions on chromosomes 14q24.3-q31.1 and 18q22.

Molecular genetics

In 3 members of a consanguineous Turkish family with polymicrogyria with seizures, Kheradmand Kia et al. (2012) identified a homozygous mutation in the RTTN gene (L932F; 610436.0001). The mutation was identified by autozygosity mapping followed by candidate gene sequencing. Another unrelated patient with a similar disorder carried a different homozygous mutation (C27Y; 610436.0002). Mutant L932F RTTN correctly localized to the basal bodies in patient fibroblasts, but there was a higher percentage of ciliary abnormalities, including short cilia with bulbous tips, compared to control. No ciliary abnormalities were apparent in cells from the patient with the C27Y mutation. However, gene expression profiling in patient fibroblasts with bot...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature, mild

HEAD AND NECK: [Head]; Microcephaly, mild (-2 SD)

ABDOMEN: Situs solitus

GENITOURINARY: [Kidneys]; Decreased kidney volume (1 patient)

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate to severe; Lack of speech or poor speech; Dysarthria; Seizures; Pyramidal signs (in some); Spasticity (in some); Abnormal EEG; Polymicrogyria, diffuse, asymmetric; Abnormal corpus callosum; Cerebellar atrophy, mild (1 patient)

MISCELLANEOUS: Two unrelated families have been reported (last curated September 2012)

MOLECULAR BASIS: Caused by mutation in the rotatin gene (RTTN, 610436.0001)


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: tti2

Clinical features

A number sign (#) is used with this entry because autosomal recessive mental retardation-39 (MRT39) is caused by homozygous mutation in the TTI2 gene (614426) on chromosome 8p12.Langouet et al. (2013) reported 3 sibs, born of consanguineous Algerian parents, with mental retardation and behavioral problems. All had a normal neonatal period, but showed delayed psychomotor development and severe speech delay. Examination at ages 30 to 36 years revealed microcephaly (-3 to -4 SD), short stature, kyphoscoliosis, and dysmorphic facial features, including sloping forehead, deep-set eyes, synophrys, prominent nose, anteverted large ears, and dental anomalies. Behavioral abnormalities included hyperactivity, aggression, and stereotypic movements. Seizures were not reported. Laboratory analysis showed mild lymphopenia of naive T cells, but increased susceptibility to infection was not reported.

Inheritance

The transmission pattern in the family with mental retardation reported by Langouet et al. (2013) was consistent with autosomal recessive inheritance.

Molecular genetics

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M100, they identified homozygosity for a missense mutation in the TTI2 gene (P367L; 614426.0001) in 4 sibs with moderate nonsyndromic mental retardation. The parents were first cousins and had 4 healthy children.

In 3 sibs, born of consanguineous Algerian parents, with mental retardation and dysmorphic features, Langouet et al. (2013) identified a homozygous missense mutation in the TTI2 gene (I436N; 614426.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed almost undetectable levels of mutant TTI2 compared to controls, although mRNA levels wer...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Head]; Microcephaly (-3 to -4 SD); [Face]; Sloping forehead; [Ears]; Anteverted ears; Large ears; [Eyes]; Deep-set eyes; Strabismus; Synophrys; [Nose]; Prominent nose; [Teeth]; Malposition of the teeth

SKELETAL: [Spine]; Kyphoscoliosis

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Speech delay, severe; [Behavioral/psychiatric manifestations]; Hyperactivity; Aggression; Stereotyped behavior

IMMUNOLOGY: Decreased circulating naive T cells (1 family)

MISCELLANEOUS: Onset in infancy; Dysmorphic facial features reported in 1 family; Two unrelated families have been reported (last curated November 2013)

MOLECULAR BASIS: Caused by mutation in the TELO2-interacting protein 2 gene (TTI2, 614426.0001)

Fragile X syndrome

Fragile X syndrome is a genetic condition involving changes in part of the X chromosome. This condition causes a range of developmental problems including learning disabilities and cognitive impairment. It is the most common form of inherited intellectual disability in males and a significant cause of intellectual disability in females. Other signs and symptoms may include symptoms of autism spectrum disorders, seizures, and characteristic physical features. Fragile X syndrome is caused by a change (mutation) in the FMR1 gene and is inherited in an X-linked dominant manner