hypomyelination

Mental Retardation, AD 31

Clinical Characteristics
Ocular Features: 

A variety of ocular dysmorphisms have been described in this disorder including up-slanting lid fissures, epicanthal folds, hypertelorism, and telecanthus.  Ptosis was described in 1 patient.  Strabismus, nystagmus, and disconjugate gaze have been observed.  Visual acuity has not been reported but "variable visual impairment" has been described.  One patient was considered to have cortical visual impairment.

Systemic Features: 

Neonatal hypotonia and feeding difficulties are among the first signs along with seizure-like activity (50%) including infantile spasms.  EEG anomalies are present in the majority of individuals.  Gastroscopy tubes may be required in a significant minority of patients.  Hypotonic or myopathic facies is common.  Apneic episodes may be seen in the neonatal period and most infants have respiratory difficulties in the first year of life which may improve during this period.  Learning difficulties and features of autism are common.  Some patients are unable to walk while others have an ataxic or broad-based gait.  Speech may be absent or severely limited.  The forehead is prominent while the hard palate is usually highly vaulted.

Brain MRIs may show delayed myelination but such scans have been described as normal in other individuals.  Enlarged ventricles, a thin corpus callosum, and periventricular white matter changes may also be present.   Neuropathologic studies have revealed chronic inflammatory changes around the arterioles of deep while matter.

Genetics

Heterozygous mutations in the PURA gene (5q31) have been identified in this disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Expanding the neurodevelopmental phenotype of PURA syndrome

Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, Stodgell C, Bennetto L, Kwon J, Fong CT, Gripp KW, Marsh ED, Smith WE, Huq AM, Coury SA, Tan WH, Solis O, Mehta RI, Leventer RJ, Baralle D, Hunt D, Paciorkowski AR. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 Jan;176(1):56-67.

PubMed ID: 
29150892

De novo mutations in PURA are associated with hypotonia and developmental delay

Tanaka AJ, Bai R, Cho MT, Anyane-Yeboa K, Ahimaz P, Wilson AL, Kendall F, Hay B, Moss T, Nardini M, Bauer M, Retterer K, Juusola J, Chung WK. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000356. doi: 10.1101/mcs.a000356.

PubMed ID: 
27148565

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, McGuire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet AL, Yang Y, Wang MC, Xia F. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet. 2014 Nov 6;95(5):579-83.

PubMed ID: 
25439098

Spastic Ataxia 8, Autosomal Recessive, with Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Reported ocular signs are limited to abnormal eye movements.  In other forms of spastic ataxia, nystagmus is evident in association with optic atrophy but no fundus examinations are reported in the 3 families with SPAX8.  Hypometric saccades and limited upgaze have also been found in these families.

Systemic Features: 

First signs and symptoms occur sometime in the first 5 years of life and often in the first year.   In 6 of 7 reported patients the presenting sign was nystagmus but one individual with reported onset of disease at age 5 years presented with ataxia.  Cerebellar signs, both truncal and limb, are usually present and the majority of individuals have evidence of dystonia.  Likewise, pyramidal signs are nearly always present.  Cerebellar dysarthria and titubation are often present with dystonic posturing and torticollis. 

Brain MRIs usually reveal cerebellar atrophy and widespread hypomyelination.  Two individuals in a single family had severe global psychomotor delays as well.  No sensory deficits were reported.  This disorder is progressive and patients in adulthood may require the use of a wheelchair.

Genetics

Homozygous mutations in the NKX6-2 (NKX6-2) gene (10q26.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Chelban V, Patel N, Vandrovcova J, Zanetti MN, Lynch DS, Ryten M, Botia JA, Bello O, Tribollet E, Efthymiou S, Davagnanam I; SYNAPSE Study Group, Bashiri FA, Wood NW, Rothman JE, Alkuraya FS, Houlden H. Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination. Am J Hum Genet. 2017 Jun 1;100(6):969-977.

PubMed ID: 
28575651

Leukodystrophy, Hypomyelinating, 13

Clinical Characteristics
Ocular Features: 

Several individuals in one family have been observed with optic atrophy, nystagmus and visual impairment.

Systemic Features: 

Head circumference is normal at birth but later in childhood falls behind in growth.  Neurodevelopment seems to plateau without regression.  Feeding difficulties may be present from birth and may require gastroscopy tube placement.  Motor skills are delayed and expressive language may never develop.  General irritability and increased muscle tone with hyperreflexia are usually present eventually resulting in joint contractures. 

EEGs , electromyography, and nerve conduction studies have been normal in 3 patients.  A brain MRI in one patient showed a leukodystrophic pattern in periventricular areas.  Variable cardiac malfunctions such as heart failure, LVH, and pericarditis were observed in several patients.

Sudden death following a short febrile illness has been reported to occur in three of the six affected children before the age of 15 years. 

Genetics

Homozygous mutations in the C11ORF73 gene (11q14.2) are responsible for this disorder.  Three unrelated families of Ashkenazi Jewish descent have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Spastic Paraplegia 11

Clinical Characteristics
Ocular Features: 

Gaze evoked nystagmus and pigmentation in the macula are components of this syndrome and adults have some degree of retinal degeneration with poor vision eventually.  Optic atrophy and ptosis have been reported but rarely.   

Systemic Features: 

his progressive condition nay have its onset in childhood or early adolescence although rarely it first appears in adulthood.  Obesity is a component in older individuals.  Loss of ambulation usually occurs within 10 years of the onset of gait difficulties.  Hyperreflexia and spasticity develop early while ataxia, urinary sphincter disturbances, extensor plantar responses, and dysarthria appear later.  Amyotrophy is frequently seen in the thenar and hypothenar muscles.  Children have learning difficulties while cognitive decline and frank mental retardation occur somewhat later.  

Peripheral nerve biopsy may reveal hypomyelination and loss of unmyelinated nerve fibers.  MRI imaging in some individuals shows a thin or absent corpus callosum and cortical atrophy. 

Genetics

Homozygous mutations in the gene SPG11 (15q21.1) encoding spatacsin are responsible for this disorder. 

See spastic paraplegia 15 (Kjellin syndrome) (270700) and spastic paraplegia 7 (607259) for other disorders with retinal degeneration, optic atrophy, and nystagmus.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known.

References
Article Title: 

Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007 Mar;39(3):366-72.

PubMed ID: 
17322883

Cataracts, Congenital, and Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Bilateral cataracts may be present at birth or later in the first decade of life.  The ERG and flash VEPs are normal.

Systemic Features: 

Psychomotor development is initially normal but signs of delay are usually present during the first year of life.  Patients may be able to walk but only with support.  Pyramidal and cerebellar dysfunction, muscle weakness and wasting, dysarthria, truncal hypotonia, intention tremor, and spasticity are evident during the first decade.  Some have seizures.  Cognitive impairment ranges from mild to moderate.  Most patients become wheelchair-bound late in the first decade of life and some do not survive beyond childhood.

Hypomyelination and mild axonal loss may be seen in peripheral nerve biopsies while neuroimaging shows evidence of diffuse and progressive cerebral white matter atrophy.

Genetics

This is an autosomal recessive disorder caused by homozygous mutations in FAM126A (7p15.3) leading to a deficiency of the neuronal protein hyccin.  The result is deficient myelination in both central and peripheral nervous systems.  No symptoms are evident in heterozygotes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The cataracts may be surgically removed.  There is no known treatment for the progressive neurologic deterioration but physical therapy and special education may be helpful.

References
Article Title: 

Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease

Traverso M, Assereto S, Gazzerro E, Savasta S, Abdalla EM, Rossi A, Baldassari S, Fruscione F, Ruffinazzi G, Fassad MR, El Beheiry A, Minetti C, Zara F, Biancheri R. Novel FAM126A mutations in Hypomyelination and Congenital Cataract disease. Biochem Biophys Res Commun. 2013 Aug 30. [Epub ahead of print] PubMed PMID: 23998934.

PubMed ID: 
23998934

Phenotypic characterization of hypomyelination and congenital cataract

Biancheri R, Zara F, Bruno C, Rossi A, Bordo L, Gazzerro E, Sotgia F, Pedemonte M, Scapolan S, Bado M, Uziel G, Bugiani M, Lamba LD, Costa V, Schenone A, Rozemuller AJ, Tortori-Donati P, Lisanti MP, van der Knaap MS, Minetti C. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol. 2007 Aug;62(2):121-7.

PubMed ID: 
17683097
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