Rab18 Deficiency
Summary
Clinical characteristics.
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Diagnosis/testing.
The diagnosis of RAB18 deficiency is established in a proband who either has suggestive clinical and neuroimaging findings and biallelic pathogenic variant(s) in RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 identified by molecular genetic testing or meets the clinical diagnostic criteria when molecular genetic testing has not been performed or has not revealed pathogenic variants in one of the four known genes.
Management.
Treatment of manifestations: Treatment is symptomatic and supportive, and is best approached through collaborative multidisciplinary medical specialists and other professionals. Cataracts are usually removed surgically. Management of developmental delay / intellectual disability and feeding difficulties are as per standard practice. Treatment of seizures is by a neurologist based on seizure type. Motor dysfunction due to progressive spasticity may benefit from physical therapy to maximize mobility and use of durable medical equipment. Undescended testes may require surgical correction; hormone supplementation for hypogonadism may occasionally be undertaken.
Surveillance: Routine follow up with an ophthalmologist, neurologist, developmental specialist, feeding team and nutritionist, and endocrinologist is recommended.
Genetic counseling.
RAB18 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
RAB18 deficiency should be suspected in individuals with the following clinical and neuroimaging findings.
Note: Findings indicated with an * are the basis of the diagnosis when molecular genetic testing either has not been performed or has not revealed biallelic pathogenic variants in one of the four known genes.
Clinical Findings
Ophthalmologic
- Bilateral congenital cataracts* (observed in all with a molecularly confirmed diagnosis). Note: To date neither unilateral cataracts nor postnatal cataracts have been observed in persons with molecularly confirmed RAB18 deficiency.
- Bilateral microphthalmia, microcornea* (typically <10 mm in diameter)
- Atonic pupils* (usually constricted and unresponsive to light or mydriatic agents)
- Optic nerve atrophy (usually based on direct inspection of the fundus through a dilated pupil)
- Severe cortical visual impairment. Vision may be light perception only; some may display visual tracking. Electrophysiology confirms cortical visual impairment (see Clinical Description).
Nervous system
- Intellectual disability*. Most affected children do not achieve developmental milestones beyond those of a four-month-old (i.e., they do not achieve independent sitting, crawling, walking, or speech).
- Congenital hypotonia* followed by progressive ascending spasticity associated with contractures of the lower limbs from about 8-12 months; involvement of the upper limbs in later years leads to spastic quadriplegia in most.
- Postnatal microcephaly. Typically in the range of -4 to -6 SD; on occasion may be less pronounced. Congenital microcephaly is rarely observed.
Other
- Short stature
- Hypogonadism. Males: Micropenis and cryptorchidism; females: hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Neuroimaging Findings*
Warburg micro syndrome
- Hypogenesis of the corpus callosum, particularly the splenium.
- Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
- Cortical atrophy: Increased subdural spaces are common.
- Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
Martsolf syndrome. Findings are milder than in Warburg micro syndrome, with preserved cortical structure and polymicrogyria usually confined to the frontal lobes.
Establishing the Diagnosis
The diagnosis of RAB18 deficiency is established in a proband who EITHER:
- Has suggestive clinical and neuroimaging findings together with biallelic pathogenic variant(s) in RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 identified by molecular genetic testing (see Table 1); OR
- Meets the clinical diagnostic criteria outlined under Suggestive Findings when molecular genetic testing has not been performed or when molecular genetic testing has not revealed pathogenic variants in one of the four known genes.
Note that failure to detect biallelic causative pathogenic variant(s) in one of the four genes known to cause RAB18 deficiency does not necessarily exclude a clinical diagnosis of RAB18 deficiency as additional loci may exist.
Molecular testing approaches can include concurrent or serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and neuroimaging findings suggest the diagnosis of RAB18 deficiency, molecular genetic testing approaches can include concurrent or serial single-gene testing or use of a multigene panel.
- Serial single-gene testing by sequence analysis can be considered if history of consanguinity together with homozygosity mapping has implicated one of the disease-associated genes as the probable location of a pathogenic variant.Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
- A multigene panel that includes RAB3GAP1, RAB3GAP2, RAB18, TBC1D20, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of RAB18 deficiency has not been considered or when gene-targeted testing has not identified pathogenic variant(s), comprehensive genomic testing (typically exome sequencing) is likely to be the diagnostic modality selected.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Molecularly Confirmed RAB18 Deficiency
| Gene 1, 2 | Proportion of Molecularly Diagnosed RAB18 Deficiency Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| RAB3GAP1 | 75% | 76/77 6 | Unknown (4 reported) 7 |
| RAB3GAP2 | 11% | 11/11 8 | None reported |
| RAB18 | 9% | 8/9 9 | Unknown (one reported) 10 |
| TBC1D20 | 5% | 4/5 11 | Unknown (one reported) 11 |
Absence of identified biallelic causative pathogenic variant(s) in one of these four genes does not exclude a clinical diagnosis of RAB18 deficiency as additional, as-yet unknown loci may exist.
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Aligianis et al [2005], Abdel-Salam et al [2007], Yüksel et al [2007], Morris-Rosendahl et al [2010], Dursun et al [2012], Yildirim et al [2012], Handley et al [2013], Gillespie et al [2014], Picker-Minh et al [2014], Sawyer et al [2014], Imagawa et al [2015], Tasdemir et al [2015], Asahina et al [2016], Gupta et al [2016], Kabzińska et al [2016], Rump et al [2016], Srivastava et al [2016], Trkova et al [2016], Patel et al [2017]
- 7.
Handley et al [2013], Picker-Minh et al [2014]
- 8.
Aligianis et al [2006], Borck et al [2011], Handley et al [2013]
- 9.
Bem et al [2011], Handley et al [2013], Gillespie et al [2014], Mandarano et al [2017]
- 10.
Bem et al [2011]
- 11.
Liegel et al [2013]
Clinical Characteristics
Clinical Description
RAB18 deficiency describes the molecular deficit underlying Warburg micro syndrome and Martsolf syndrome. Warburg micro syndrome is characterized by eye, nervous system, and endocrine abnormalities [Warburg et al 1993]; Martsolf syndrome is characterized by similar findings, but with a milder presentation [Martsolf et al 1978]. When first described, Warburg micro syndrome and Martsolf syndrome were considered distinct disorders; however, following discovery of the underlying genetic bases of both phenotypes, it became apparent that these phenotypes are a continuum of clinical manifestations: Warburg micro syndrome on the severe end of the spectrum and Martsolf syndrome at the milder end (see Genotype-Phenotype Correlations).
To date Warburg micro syndrome comprises the majority (>96%) of molecularly confirmed RAB18 deficiency reported [Aligianis et al 2005, Abdel-Salam et al 2007, Yüksel et al 2007, Morris-Rosendahl et al 2010, Bem et al 2011, Borck et al 2011, Dursun et al 2012, Yildirim et al 2012, Handley et al 2013, Liegel et al 2013, Gillespie et al 2014, Picker-Minh et al 2014, Sawyer et al 2014, Imagawa et al 2015, Tasdemir et al 2015, Asahina et al 2016, Gupta et al 2016, Kabzińska et al 2016, Rump et al 2016, Srivastava et al 2016, Trkova et al 2016].
Genetically defined Martsolf syndrome has been described in only four families (8 individuals), whose countries of origin are Pakistan, Mexico, Gambia, and Egypt [Aligianis et al 2006, Handley et al 2013].
Eye Findings
Eye abnormalities are often the first presenting features of RAB18 deficiency. Both Warburg micro syndrome and Martsolf syndrome are associated with the hallmark finding of bilateral congenital cataracts. Cataracts have been observed prenatally by ultrasound examination in several instances and in one instance as early as the second trimester [Morris-Rosendahl et al 2010, Trkova et al 2016].
Cataracts are commonly accompanied by microphthalmia and microcornea (diameter <10 mm). Eyes may appear deep set (enophthalmic). Usually the pupils are small and atonic (i.e., unresponsive to light or mydriatic agents). In rare instances, microphthalmia, microcornea, and atonic pupils are absent in Warburg micro syndrome [Handley et al 2013]. Of the eight individuals reported with Martsolf syndrome, six had microphthalmia; several had small pupils [Aligianis et al 2006, Handley et al 2013].
Despite early cataract surgery, the vision of individuals with RAB18 deficiency remains poor, likely due to progressive optic atrophy and cortical visual impairment, both of which are more severe in Warburg micro syndrome than in Martsolf syndrome. The following electrophysiologic findings support the presence of cortical visual impairment:
- Normal electroretinograms (ERGs)
- Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [Aligianis et al 2005, Aligianis et al 2006, Bem et al 2011, Borck et al 2011, Handley et al 2013, Liegel et al 2013].
Neurologic Findings
Intellectual disability (ID). Individuals with Warburg micro syndrome have severe to profound ID. Individuals with Martsolf syndrome have mild to moderate ID. Language acquisition is largely absent in Warburg micro syndrome. Although acquisition of language is delayed in Martsolf syndrome, several affected children are bilingual [Aligianis et al 2006, Handley et al 2013].
Microcephaly. Postnatal microcephaly is a characteristic – but not invariant – feature of RAB18 deficiency. While the head circumference ranges from -4 to -6 SD in most individuals [Handley et al 2013], it can be within the normal range [Handley et al 2013, Trkova et al 2016]. Conversely, prenatal microcephaly has been seen, on occasion, as a severe manifestation of the disorder [Handley et al 2013].
Feeding difficulties. Individuals with Warburg micro syndrome usually have difficulty feeding and may have gastroesophageal reflux disease and/or dysphagia. Gastrostomy tube placement is usually required to improve nutrition.
Epilepsy. Some – but not all – individuals with RAB18 deficiency have epilepsy. Seizure types vary: focal and generalized seizures, tonic and tonic-clonic seizures, and myoclonic absences have been reported [Graham et al 2004, Handley et al 2013, Mandarano et al 2017]. Within the same family, one sib may have seizures while another sib does not.
EEG findings, which may be normal or abnormal in affected individuals, do not appear to demonstrate a consistent pattern.
Motor Dysfunction
Warburg micro syndrome is associated with progressive ascending spastic paraplegia. Affected infants are usually hypotonic with poor postural and head control; however, they may roll and sit with support. Increased deep tendon reflexes in the lower limbs may progress to hyperreflexia and then contractures and spastic diplegia from approximately 8 to 12 months. Involvement of the upper limbs leading to spastic quadriplegia occurs (variably) from about age five years. Later progression may lead to breathing difficulties. It is likely that paraplegia results from impaired motor neuron function.
Clinical findings of a motor and sensory peripheral neuropathy have been reported [Nassogne et al 2000, Graham et al 2004, Kabzińska et al 2016].
Martsolf syndrome is associated with hypotonia and primarily lower-limb spasticity, which progresses more slowly than that of Warburg micro syndrome [Aligianis et al 2006, Handley et al 2013]. Three of the eight individuals reported with Martsolf syndrome were able to walk with assistance.
Hypogonadism
Both Warburg micro syndrome and Martsolf syndrome are frequently associated with hypogonadism. Clinical findings are consistent with hypogonadotropic hypogonadism of hypothalamic origin [Warburg et al 1993, Graham et al 2004, Handley et al 2013, Asahina et al 2016].
In affected males it manifests as micropenis and/or cryptorchidism [Bem et al 2011, Handley et al 2013]. In affected females, it may manifest as hypoplastic labia minora, clitoral hypoplasia, and small introitus [Graham et al 2004, Handley et al 2013].
Untreated hypogonadism may be associated with delayed-onset puberty or lack of puberty.
Other
RAB18 deficiency is often – but not always – associated with short stature (height <-2 SD).
Dysmorphic features associated with RAB18 deficiency are mild but form a recognizable pattern, including deep-set eyes, a wide nasal bridge and prominent nasal root, relatively narrow mouth, and proportionately large anteverted ears (Figure 1).
Figure 1.
Photographs of individuals with Warburg micro and Martsolf syndromes Brothers K2.1 (age 15 years) and K2.2 (age 13 years) with Warburg micro syndrome are homozygous for the RAB3GAP1 p.Thr18Pro variant.
Mild micrognathia, a high-arched palate, and delayed dentition may also be seen [Handley et al 2013, Aligianis & Handley 2016].
Mild hypertrichosis has been reported; see for example Yüksel et al [2007], Morris-Rosendahl et al [2010], Picker-Minh et al [2014], and Mandarano et al [2017].
Osteopenia has been reported as potentially a primary manifestation of Warburg micro syndrome in one family [Picker-Minh et al 2014].
Although secondary complications from RAB18 deficiency can be life-threatening, RAB18 deficiency is not known to directly affect life expectancy.
Phenotype Correlations by Gene
Clinical observations cannot be used to distinguish the genetic basis of RAB18 deficiency.
The strongest suggestion of phenotype correlation by gene comes from comparative analysis of brain MRIs in which it appears that biallelic loss-of-function RAB3GAP2 variants may result in milder malformations than biallelic variants in either RAB3GAP1 or RAB18 [Handley et al 2013].
Of note, several individuals with biallelic loss-of-function pathogenic variants in TBC1D20 have developed glaucoma [Liegel et al 2013], an uncommon finding in RAB18 deficiency caused by biallelic variants in the other three genes (RAB3GAP1, RAB3GAP2, or RAB18).
Genotype-Phenotype Correlations
RAB18 deficiency results from biallelic pathogenic variants in RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 [Aligianis et al 2005, Aligianis et al 2006, Bem et al 2011, Borck et al 2011, Liegel et al 2013]. Biallelic loss-of-function variants in any one of these genes cause Warburg micro syndrome, which corresponds to the severe end of the phenotypic spectrum. Pathogenic variants that diminish but do not completely nullify gene expression or function can cause or contribute to Martsolf syndrome, which corresponds to the milder end of the phenotypic spectrum.
Warburg micro syndrome comprises the majority (98/102 families) of molecularly confirmed RAB18 deficiency reported [Aligianis et al 2005, Abdel-Salam et al 2007, Yüksel et al 2007, Morris-Rosendahl et al 2010, Bem et al 2011, Borck et al 2011, Dursun et al 2012, Yildirim et al 2012, Handley et al 2013, Liegel et al 2013, Gillespie et al 2014, Picker-Minh et al 2014, Sawyer et al 2014, Tasdemir et al 2015, Asahina et al 2016, Gupta et al 2016, Imagawa et al 2015, Kabzińska et al 2016, Rump et al 2016, Srivastava et al 2016, Trkova et al 2016].
- RAB18 deficiency usually results from pathogenic variants likely to completely nullify gene expression (nonsense, frameshift, intragenic deletion or consensus splice sites). The clinical presentation in these individuals is highly consistent, in keeping with the likelihood that the clinical consequences of these loss-of-function variants are equivalent.
- Other variants associated with Warburg micro syndrome that are likely to abrogate the function of the encoded protein (see Molecular Genetics) include:
- RAB3GAP1: Three missense variants [Handley et al 2013, Asahina et al 2016].
- RAB18: Two missense variants, an in-frame deletion, and an extension variant [Bem et al 2011, Handley et al 2013].
Martsolf syndrome. The three pathogenic variants reported in four families with Martsolf syndrome [Aligianis et al 2006, Handley et al 2013] are as follows:
- RAB3GAP1. A homozygous frameshift variant, c.9delC, identified in affected sibs, inactivates the normal RAB3GAP1 transcript but also expresses a novel transcript whose protein product may provide sufficient residual function to result in the milder phenotype of Martsolf syndrome [Handley et al 2013] (see details in Molecular Genetics).
- RAB3GAP2
- The homozygous missense variant c.3154G>T (Gly1052Cys) was identified in three affected individuals from one family [Aligianis et al 2006]. In lymphocyte RNA from two of the affected individuals, this variant was found to promote exon-skipping and to introduce a frameshift into the shortened transcript; however, some full-length transcript was also found in each case, compatible with residual full-length protein expression.
- The homozygous missense variant c.1276C>T (p.Arg426Cys) affects a conserved amino acid residue, and the altered protein may retain some functional activity [Handley et al 2013].
Nomenclature
Although the following naming system has been used – in some instances – to designate the causative gene for Warburg micro syndrome, no clinical purpose is served by this naming system as the causative gene does not influence phenotype.
- Warburg micro syndrome type 1: RAB3GAP1
- Warburg micro syndrome type 2: RAB3GAP2
- Warburg micro syndrome type 3: RAB18
- Warburg micro syndrome type 4: TBC1D20
Prevalence
Data on the prevalence of RAB18 deficiency are limited.
As expected for an autosomal recessive disorder, incidence is known to be higher in isolated communities and in communities with a high rate of consanguinity [Bem et al 2011, Handley et al 2013].
Incidence may be higher in populations in which pathogenic founder variants are present at a high frequency. Notably, loss of function of an essential splice site variant in RAB3GAP1, c.748+1G>A, has been identified as a founder allele in 11 families of Turkish origin [Aligianis et al 2005, Yüksel et al 2007, Dursun et al 2012, Yildirim et al 2012, Handley et al 2013, Tasdemir et al 2015].
Differential Diagnosis
Array CGH may be useful in identifying pathogenic copy number variants associated with clinical findings similar to those in RAB18 deficiency [Arroyo-Carrera et al 2015]. Similarly, TORCH screening may useful in determining whether prenatal infection is a potential cause of the clinical findings [Gupta et al 2016].
Note that in RAB18 deficiency, prenatal onset of cataracts appears to be a consistent feature, a finding in contrast to other inherited conditions in which cataracts are a more variable manifestation or can arise postnatally (Table 2).
Differential diagnosis therefore includes some other syndromes with congenital cataracts.
Table 2.
Disorders to Consider in the Differential Diagnosis of RAB18 Deficiency
| Disorder | Gene(s) | MOI | Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/RAB18 Deficiency | Distinguishing from RAB18 Deficiency | |||
| Prenatal TORCH infection (particularly rubella) | N/A | N/A | CC, microphthalmia | Positive TORCH screen, frequently associated w/SNHL, cardiac defects, rash, hepatosplenomegaly |
| Monosomy 1p36 (OMIM 607872) | N/A | De novo | Microcephaly, DD/ID, genital abnormalities, rarely cataracts | Characteristic dysmorphic features, cardiac defects, hearing loss, skeletal & renal abnormalities often present |
| Monosomy 1q21 | N/A | De novo | Microcephaly, DD/ID, genital abnormalities, hypotonia, seizures, corpus callosum hypogenesis, cataracts | ID present in only ~30% of cases, usually mild-moderate. Cardiac defects, SNHL may be present. |
| Cerebrooculofacioskeletal syndrome (OMIM PS214150), Cockayne syndrome | ERCC1 ERCC2 ERCC5 ERCC6 ERCC8 | AR | CC, microcornea, optic atrophy, microcephaly, ID, short stature, contractures, corpus callosum hypoplasia, cryptorchidism | Cutaneous photosensitivity; cultured cells from affected individuals are hypersensitive to UV radiation. Pigmentary retinopathy, brain calcifications, FTT, arthrogryposis, SNHL may be present. |
| Smith-Lemli-Opitz syndrome | DHCR7 | AR | Microcephaly, short stature, ID, hypotonia, genital abnormalities, CC | ↑ 7-dehydrocholesterol in serum. Characteristic dysmorphic features. Postaxial polydactyly or 2-3 toe syndactyly, cardiac defects, renal defects, & photosensitivity frequently present. Cataracts may appear acutely. |
| Cutis laxa, de Barsy syndrome (OMIM 219150 612940, 614438, 616603) | ALDH18A1 PYCR1 | AR/AD | Microcephaly, ID, corpus callosum hypogenesis, hypotonia, short stature, contractures, cataracts may be present. | Lax, thin, sometimes wrinkled, skin. Progeria-like appearance. Cataracts may develop postnatally. |
| Peroxisome biogenesis disorder 14B (OMIM 614920) | PEX11B | AR | CC, ID, microphthalmia, short stature, hypotonia & spasticity | Normal MRI. Dry skin, SNHL may be present. |
| Epileptic encephalopathy, early infantile, 35 (OMIM 616647) | ITPA | AR | CC, microcephaly, ID, short stature, hypotonia & spasticity, hypogonadism | Characteristic imaging findings, early-onset dilated cardiomyopathy |
| Marinesco-Sjögren syndrome | SIL1 | AR | CC, hypotonia, ID, hypogonadism | Cerebellar ataxia; imaging shows cerebellar atrophy. ↑ serum creatine kinase, myopathy, skeletal abnormalities may be present; cataracts may appear postnatally. |
| Cataract, microcephaly, arthrogryposis, and kyphosis (CAMAK/CAMFAK) syndrome (OMIM 212540) | N/A | N/A | CC, microcephaly, ID, contractures | Kyphosis, arthrogryposis. Brain calcifications may be present. Cataracts may appear postnatally. |
AD = autosomal dominant; AR = autosomal recessive; CC = congenital cataracts; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with RAB18 deficiency, the evaluations in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis of RAB18 Deficiency
| System/Concern | Evaluation | Comment |
|---|---|---|
| Eyes | Ophthalmologic examination | Consultation w/neurologist if spasticity found or seizures suspected |
| Neurologic | Measurement of head size (OFC); assessment of motor function & reflexes | |
| Gastrointestinal | Consultation w/feeding specialist, nutritionist, &/or gastroenterologist for assessment of feeding difficulties & nutritional status | |
| Endocrine | Evaluation by endocrinologist recommended | Consider consultation w/urologist if a male has cryptorchidism. |
| Miscellaneous / Other | Assessment of developmental milestones | |
| Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Treatment is symptomatic and supportive. It is best approached through collaborative care involving medical specialists, and is best coordinated by a pediatrician who is aware of the child's general health and development. Psychosocial support for families is an important component of effective care.