A number sign (#) is used with this entry because nephronophthisis-12 (NPHP12) is caused by homozygous or compound heterozygous mutation in the TTC21B gene (612014) on chromosome 2q24. Heterozygous mutation in the TTC21B gene has been found in patients with Joubert syndrome-11 (JBTS11), a related cilopathy. For a general phenotypic description and a discussion of genetic heterogeneity of NPHP, see 256100. For a general phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. Molecular Genetics In affected members of 2 unrelated consanguineous families with nephronophthisis-12, Davis et al. (2011) identified a homozygous mutation in the TTC21B gene (P209L; 612014.0001).

A number sign (#) is used with this entry because of evidence that nephronophthisis-13 (NPHP13) is caused by homozygous or compound heterozygous mutation in the WDR19 gene (608151) on chromosome 4p14. For a general phenotypic description and a discussion of genetic heterogeneity of NPHP, see NPHP1 (256100). Clinical Features Bredrup et al. (2011) studied a nonconsanguineous Moroccan family in which 3 of 6 sibs had nephronophthisis, 1 had mild proteinuria and a glomerular filtration rate at the lower limit of normal, and 2 sibs were unaffected. The oldest affected brother and sister had end-stage renal disease by 19 and 20 years of age, respectively, whereas their younger sister had end-stage renal failure at 13 years of age. The affected brother had no skeletal abnormalities, and ophthalmoscopy showed a retinal microaneurysm in the right eye.

A number sign (#) is used with this entry because nephronophthisis-3 is caused by homozygous or compound heterozygous mutation in the NPHP3 gene (608002) on chromosome 3q22. For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features Nephronophthisis, an autosomal recessive cystic kidney disease, is the most frequent monogenic cause of renal failure in childhood. Omran et al. (2000) described a form of this disorder, adolescent nephronophthisis, that they considered clearly distinct by clinical and genetic findings. They evaluated clinical symptoms and renal pathology in a large, 340-member consanguineous Venezuelan kindred.

A number sign (#) is used with this entry because nephronophthisis-2 (NPHP2) is caused by homozygous or compound heterozygous mutation in the inversin gene (INVS; 243305) on chromosome 9q31. For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features Gagnadoux et al. (1989) described observations taken over a 15-year period in 7 children (4 girls, 3 boys) presented within the first months of life with severe renal failure and acidosis, associated with hypertension in 5 patients and polyuria in 4. In addition, 1 patient had a severe cholestatic liver disease. In 2 families, a similarly affected sib had died previously. Four patients were referred with the clinical diagnosis of polycystic kidney disease because of moderate enlargement of kidneys, but renal imaging did not confirm this diagnosis.

A number sign (#) is used with this entry because of evidence that nephronophthisis-like nepropathy-1 (NPHPL1) is caused by homozygous mutation in the XPNPEP3 gene (613553) on chromosome 22q13. Description Nephronophthisis is an autosomal recessive cystic kidney disease characterized by onset of end-stage renal failure in the first 3 decades of life. The disorder is often associated with extrarenal manifestations, including liver fibrosis, retinal degeneration, and central nervous system abnormalities (summary by O'Toole et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features O'Toole et al. (2010) reported 3 sibs, born of consanguineous Finnish parents, with a renal disease reminiscent of nephronophthisis.

Nephronophthisis Nephronophthisis has an autosomal recessive pattern of inheritance. Specialty Medical genetics Symptoms Polyuria [1] Types Infantile, Juvenile and Adult NPH [2] Diagnostic method Renal ultrasound [2] Treatment Hypertension and anemia management [2] Nephronophthisis is a genetic disorder of the kidneys which affects children. [3] It is classified as a medullary cystic kidney disease . The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure. It is a form of ciliopathy . [4] Its incidence has been estimated to be 0.9 cases per million people in the United States, and 1 in 50,000 births in Canada. [5] Contents 1 Signs and symptoms 2 Cause 3 Pathophysiology 3.1 Related rare genetic disorders 4 Diagnosis 4.1 Types 5 Management 6 Epidemiology 7 References 8 Further reading 9 External links Signs and symptoms [ edit ] Infantile, juvenile, and adolescent forms of nephronophthisis have been identified. Although the range of characterizations is broad, people affected by nephronophthisis typically present with polyuria (production of a large volume of urine), polydipsia (excessive liquid intake), and after several months to years, end-stage kidney disease , a condition necessitating either dialysis or a kidney transplant in order to survive. [1] Some individuals that suffer from nephronophthisis also have so-called "extra-renal symptoms" which can include tapetoretinal degeneration, liver problems, ocularmotor apraxia , and cone-shaped epiphysis (Saldino-Mainzer syndrome). [6] [7] Cause [ edit ] Nephronophthisis is characterized by fibrosis and the formation of cysts at the cortico-medullary junction, it is an autosomal recessive disorder which eventually leads to terminal kidney failure. [8] Pathophysiology [ edit ] Ciliopathy (eukaryotic cilium diagram) Mechanism of nephronophthisis indicates that all proteins mutated in cystic kidney diseases express themselves in primary cilia.

A number sign (#) is used with this entry because nephronophthisis-18 (NPHP18) is caused by homozygous or compound heterozygous mutation in the CEP83 gene (615847) on chromosome 12q22. Description Nephronophthisis-18 is an autosomal recessive disorder characterized by chronic tubulointerstitial nephritis resulting in end-stage renal disease in early childhood. Extrarenal manifestations, including intellectual disability or liver changes, may occur in some patients (summary by Failler et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features Failler et al. (2014) reported 8 children from 7 families with early-onset nephronophthisis resulting in end-stage renal disease between 1 and 4 years of age.

Summary Clinical characteristics. The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH , the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years.

A rare, genetic, renal ciliopathy characterized by reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, cystic renal disease and progression to end stage renal disease (ESRD). The three clinical subtypes are characterized by the age of onset of ESRD which includes infantile, juvenile and late onset. Epidemiology The prevalence is unknown; however, at birth it is estimated at 1: 80,000 in Finland. Nephronophthisis (NPHP) is responsible for 2.4 to 15% of ESRD in children. Clinical description Three main forms have been described. Juvenile NPHP, the most frequent form, progresses to end-stage renal failure at median age of 13 and is responsible for 15% of cases of childhood ESRD.

A number sign (#) is used with this entry because of evidence that nephronophthisis-20 (NPHP20) is caused by homozygous or compound heterozygous mutation in the MAPKBP1 gene (616786) on chromosome 15q15. Description Nephronophthisis-20 is an autosomal recessive tubulointerstitial nephritis characterized by progressive renal fibrosis resulting in end-stage renal failure. The age at onset is relatively late compared to other forms of NPHP, and patients develop end-stage renal disease in the second or third decades. Unlike most other forms of NPHP, NPHP20 does not have features of a ciliopathy and patients do not appear to have extrarenal manifestations (summary by Macia et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).

A number sign (#) is used with this entry because of evidence that nephronophthisis-4 (NPHP4) is caused by homozygous or compound heterozygous mutation in the NPHP4 gene (607215) on chromosome 1p36. For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features Three loci had been mapped for nephronophthisis, the leading genetic cause of chronic renal failure in young adults: juvenile NPHP1 (256100) on 2q13; infantile nephronophthisis (NPHP2; 602088) on 9q22-q31; and adolescent nephronophthisis (NPHP3; 604387) on 3q21-q22. By renal histology the 3 forms of the disease are indistinguishable, all 3 exhibiting a triad of interstitial-cell infiltrates, renal tubular-cell atrophy with cysts arising from the corticomedullary junction of the kidneys, and renal interstitial fibrosis (Waldherr et al., 1982). Clinically, there is a statistically different age at onset at end-stage renal disease: terminal renal failure develops at median ages of 1 year, 13 years, and 19 years, in NPHP2, NPHP1, and NPHP3, respectively (Omran et al., 2000).

A number sign (#) is used with this entry because of evidence that nephronophthisis-7 (NPHP7) is caused by homozygous mutation in the GLIS2 gene (608539) on chromosome 16p13. For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100). Clinical Features Attanasio et al. (2007) reported a consanguineous Canadian Oji-Cree family in which 3 members had nephronophthisis. All developed end-stage kidney disease by age 8 years and underwent renal transplantation. Kidney histology of all 3 affected individuals was consistent with the diagnosis.

Johnson and Munson (1990) described infant sibs, a female and male, with aphalangy of the hands and feet, hemivertebrae, and visceral malformations which included, in the female, pulmonary hypoplasia, ventricular septal defect, and dysgenesis of the urogenital tract and rectum. The female died in the neonatal period; the male was in good health with normal psychomotor development at the age of 6 months. The mother and her father and grandfather had symphalangism (185800) of both index fingers. Johnson and Munson (1991) reported the birth of another affected brother. Limbs - Aphalangy, hands and feet - Symphalangism of both index fingers in heterozygotes Lungs - Pulmonary hypoplasia Inheritance - Autosomal recessive Spine - Hemivertebrae GU - Dysgenesis of urogenital tract and rectum Cardiac - Ventricular septal defect ▲ Close

An extremely rare congenital limb malformation syndrome, described in only 3 patients to date,characterized by the association of hypoplasia or aplasia of the hand and foot phalanges, hemivertebrae and various urogenital and/or intestinal abnormalities (i.e. dysgenesis of the urogenital tract and rectum). There have been no further descriptions in the literature since 1991.

Cranio-cervical dystonia with laryngeal and upper-limb involvement is a rare genetic, isolated dystonia characterized by a variable combination of cervical dystonia with tremor, blepharospasm, oromandibular and laryngeal dystonia. Dystonia progresses slowly and might spread to become segmental. Arm tremor and myoclonic jerks in the arms or neck have also been reported.

A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-4 (WARBM4) is caused by homozygous mutation in the TBC1D20 gene (611663) on chromosome 20p13. Description Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). For a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118. Clinical Features Liegel et al. (2013) studied 7 patients from 5 families with Warburg Micro syndrome due to mutations in the TBC1D20 gene who showed the same range of clinical features observed in WARBM patients with mutations in the RAB3GAP1 (602536), RAB3GAP2 (609275), and RAB18 (602207) genes. Shortly after birth, patients presented with congenital cataracts, microphthalmia, microcornea, and small atonic pupils.

A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-3 (WARBM3) is caused by homozygous or compound heterozygous mutation in the RAB18 gene (602207) on chromosome 10p12. Description Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). For a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118. Clinical Features Graham et al. (2004) described a Caucasian sister and brother who had microcephaly, postnatal growth retardation, cataract, microcornea, atonic pupils, optic atrophy, profound mental retardation, hypotonic spastic diplegia, polymicrogyria, hypoplasia of the corpus callosum, and hypogenitalism. A nerve conduction study in the boy was markedly abnormal due to severe loss of neurons, suggesting an axonal peripheral neuropathy.

A number sign (#) is used with this entry because Warburg Micro syndrome-1 (WARBM1) is caused by homozygous mutation in the RAB3GAP1 gene (602536) on chromosome 2q21. Description Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13.

Micro syndrome is an autosomal recessive disorder caracterised by ocular and neurodevelopmental defects and by microgenitalia. It presents with severe intellectual disability, microcephaly, congenital cataract, microcornea, microphthalmia, agenesis/hypoplasia of the corpus callosum, and hypogenitalism. Epidemiology Since its initial description, 26 cases of Micro syndrome have been reported in the literature. Clinical description With exception of the ophthalmologic features, the clinical and dysmorphic findings are either unapparent or subtle in the early postnatal period. Etiology Mutations in RAB3GAP , a gene showing linkage to a region of homozygosity at 2q21.3, have been identified in some families.

Micro syndrome Other names Warburg–Sjo–Fledelius syndrome Warburg Micro syndrome ( WARBM ), also known as Micro syndrome , is a rare autosomal recessive genetic disorder characterized by microcephaly , microcornea , congenital cataract, intellectual or developmental disability, optic atrophy, and hypogenitalism . [1] Contents 1 Genetics 2 Diagnosis 3 Treatment 4 References 5 External links Genetics [ edit ] The rare cases that have been examined are often within families, or the people that have cases of Warburg Micro syndrome have a mutation in their genes. [ citation needed ] It can be associated with RAB3GAP . [2] Diagnosis [ edit ] Warburg Micro syndrome can be identified in people several ways, one of the most common is ocular problems or other physical traits that don't appear natural. It is especially easy to identify micro syndrome in infants and in younger children. Intellectual or developmental disabilities can seriously affect a patient in the way they think and move. So far according to studies all patients have had serious intellectual or developmental disabilities, and hypotonia is found in all the patients during infancy. [ citation needed ] Treatment [ edit ] There is no specific treatment for Warburg Micro syndrome, but there are ways to help the disorders, and illnesses that come with it. Many individuals with Warburg Micro syndrome need permanent assistance from their disorders and inabilities to move and support themselves.

A number sign (#) is used with this entry because some cases of idiopathic pulmonary fibrosis (IPF) are caused by heterozygous mutation in the SFTPA2 gene (178642), encoding pulmonary surfactant protein A2, on chromosome 10q22. Evidence suggests that susceptibility to the disease may also be conferred by a polymorphism in the SFTPA1 gene (178630) on chromosome 10q22 or a promoter mutation in the MUC5B gene (600770) on chromosome 11p15. Description Idiopathic pulmonary fibrosis is one of a family of idiopathic pneumonias sharing clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees in inflammation, fibrosis, or both on lung biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Although older studies included several forms of interstitial pneumonia under the term 'idiopathic pulmonary fibrosis,' the clinical label of 'idiopathic pulmonary fibrosis' should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as usual interstitial pneumonia (Gross and Hunninghake, 2001).

A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure-4 (PFBMFT4) is caused by heterozygous mutation in the PARN gene (604212) on chromosome 16p13. For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742). Clinical Features Stuart et al. (2015) reported 6 unrelated families with pulmonary fibrosis and/or unspecified lung disease. Affected family members had shortened telomeres (less than 1-30% of control length). A few patients had premature graying of the hair, but none were noted to have features of bone marrow failure.

Idiopathic pulmonary fibrosis (IPF) is a condition in which tissues in the lungs become thick and stiff, or scarred, over time. The lungs then lose their ability to move oxygen to the brain and other parts of the body. Common symptoms include shortness of breath and a dry, hacking cough. In some cases fibrosis happens quickly, while in others, the process is much slower. Sometimes the disease stays the same for years. The condition is 'idiopathic' because the cause is unknown.

Acute interstitial pneumonia (AIP) is a rare and serious condition that affects the lungs. The signs and symptoms generally develop and progress rapidly. In the early stages of the condition, affected people may experience upper respiratory and/or viral-like symptoms such as cough, shortness of breath, and fever. This is followed by the rapid onset of respiratory failure and the need for mechanical ventilation in the majority of cases. The underlying cause of AIP is unknown. Most cases occur sporadically in people with no family history of the condition. There is, unfortunately, no proven treatment for AIP. Supportive care is generally recommended to address the signs and symptoms of the condition.

Multicentric carpotarsal osteolysis syndrome is a very rare condition characterized by progressive loss of some of the bones of the hand and feet, usually the carpal (bones of the wrist) and tarsal bones (bones of the ankle), as well as chronic kidney (renal) failure in many cases. The bone problems lead to deformity and disability. Some patients also have intellectual disability and facial abnormalities. It is caused by mutations in the MAFB gene. Autosomal dominant inheritance has been described in many families but most cases are sporadic . Treatment is with long-term immunosuppressive therapy .

A number sign (#) is used with this entry because of evidence that multicentric carpotarsal osteolysis syndrome (MCTO) is caused by heterozygous mutation in the MAFB gene (608968) on chromosome 20q12. Description Multicentric carpotarsal osteolysis syndrome is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bone usually occurs and other bones may also be involved. Chronic renal failure is a frequent component of the syndrome. Mental retardation and minor facial anomalies have been noted in some patients. Autosomal dominant inheritance has been documented in many families (Pai and Macpherson, 1988).

Idiopathic multicentric osteolysis is a very rare syndrome characterized by progressive loss of bone, usually the capsal and tarsal bones, resulting in deformity and disability, as well as chronic renal failure in many cases. The bone and renal disorders are sometimes associated with intellectual deficit and facial abnormalities.

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2C (PCH2C) is caused by homozygous mutation in the TSEN34 gene (608754) on chromosome 19q13. One such patient has been reported. Description Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesia and chorea, epilepsy, and normal spinal cord findings (Barth, 1993). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596). Molecular Genetics In an individual of Turkish origin with PCH2, Budde et al. (2008) identified homozygosity for a missense mutation in the TSEN34 gene (R58W; 608754.0001).

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 2D (PCH2D), also known as progressive cerebellocerebral atrophy (PCCA), is caused by homozygous or compound heterozygous mutation in the SEPSECS gene (613009) on chromosome 4p15. Description PCH2D is an autosomal recessive disorder characterized by progressive microcephaly, postnatal onset of progressive atrophy of the cerebrum and cerebellum, profound mental retardation, spasticity, and variable seizures (summary by Ben-Zeev et al., 2003). For a general phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470). Clinical Features Ben-Zeev et al. (2003) reported 4 unrelated patients with profound mental retardation, postnatal progressive microcephaly, spasticity, and progressive cerebellocerebral atrophy (PCCA). All patients were from nonconsanguineous Sephardic Jewish families: 2 were of Iraqi origin, and 2 were of combined Iraqi and Moroccan origin.

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2F (PCH2F) is caused by homozygous mutation in the TSEN15 gene (608756) on chromosome 1q25. Description Pontocerebellar hypoplasia type 2F is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly and variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity (summary by Breuss et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470). Clinical Features Alazami et al. (2015) reported a boy (13DG0167), born of consanguineous parents, with primary microcephaly and global developmental delay. Breuss et al. (2016) reported follow-up on this patient, who was born to Saudi parents.

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2A (PCH2A) is caused by homozygous mutation in the TSEN54 gene (608755) on chromosome 17q25. Description Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesia and chorea, epilepsy, and normal spinal cord findings (Barth, 1993). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596). Genetic Heterogeneity of Pontocerebellar Hypoplasia Type 2 PCH2B (612389) is caused by mutation in the TSEN2 gene (608753) on chromosome 3p25, and PCH2C (612390) is caused by mutation in the TSEN34 gene (608754) on chromosome 19q13.

Pontocerebellar hypoplasia type 2 (PCH2) is a rare condition that affects the development of the brain. Signs and symptoms vary but may include microcephaly, developmental delay with lack of voluntary motor development, intellectual disability and movement disorders (i.e. chorea , dystonia, and spasticity). Affected people may also experience dysphagia (difficulty swallowing), impaired vision, seizures and an inability to communicate. Children with this condition often pass away prior to age 10 years, although survival beyond age 20 years has been reported. PCH2 is caused by changes (mutations) in the TSEN54 , TSEN2 , TSEN34 , or SEPSECS gene and is inherited in an autosomal recessive manner.

A rare, genetic form of pontocerebellar hypoplasia characterized by pontocerebellar hypoplasia and progressive neocortical atrophy that manifests clinically with uncoordinated sucking and swallowing, and generalized clonus in the neonate. In early childhood, spasticity, chorea/dyskinesia, seizures and progressive microcephaly develop. Voluntary motor development is lacking. Epidemiology Pontocerebellar hypoplasia type 2 (PCH2) is reported in at least 81 families to date. It is the most common form of pontocerebellar hypoplasia. Clinical description After an uneventful pregnancy and birth without dysmorphic features, affected neonates present usually, but not always, with dysphagia due to bucco-pharyngeal incoordination, respiratory and feeding difficulties and generalized clonus. Extrapyramidal dyskinesia with mixed spasticity such as chorea, athetosis and dystonia develop later.