cortical blindness

Epileptic Encephalopathy, Infantile or Early Childhood 2

Clinical Characteristics
Ocular Features: 

Cortical visual impairment or blindness was reported in 3 0f 11 patients.

Systemic Features: 

The hallmark signs of this disorder consist of developmental delay and epilepsy.  Onset of seizures occur in the first decade of life, between birth and 6 years, and consist of a variety of types including focal, multifocal, generalized tonic-clonic, febrile, myoclonic, and atonic.  EEG patterns range from normal, to slow waves, spike waves, and burst suppression patterns.  Seizures may respond to treatment in some individuals whereas others are unresponsive.

Microcephaly, both acquired and congenital, was seen in 7 individuals.  MRI scans are usually normal but some patients have nonspecific white matter abnormalities.  Developmental milestones are seldom achieved but some patients are able to walk and speak with difficulty.   Hypotonia, spasticity, and dyskinesias such as myoclonia, dystonia and ataxia are variably present.

Genetics

Heterozygous missense mutations in the GABRB2 gene (5q34) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general condition has been reported.  Seizures may not respond to the usual pharmacologic treatments.

References
Article Title: 

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G; Deciphering Developmental Disorders Study, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Ounap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafreniere RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017 Nov 2;101(5):664-685.

 

PubMed ID: 
291000083

Pontocerebellar Hypoplasia 3

Clinical Characteristics
Ocular Features: 

Optic atrophy is an inconsistent feature (sometimes even unilateral) of patients with PCH.  Cortical blindness has also been described.  There may be dysmorphic facial features such as wide palpebral fissures, epicanthal folds, and prominent eyes. 

Systemic Features: 

Infants are generally small and hypotonic at birth.  The skull is small and often brachycephalic.  The ears are large and low-set and  facial dysmorphism (full cheeks, long philtrum) is present.  Infants have poor head control and truncal ataxia.  Later, hyperreflexia and spasticity become evident.  Seizures are common.  Developmental delays, both somatic and mental, are nearly universal and large joint contractures are often seen. Many of these signs are progressive.  

Brain imaging generally reveals cerebral and cerebellar atrophy, a hypoplastic corpus callosum, a small cerebellar vermis, and a hypoplastic brainstem.  Short stature is a feature and early death often occurs.

Genetics

PCH3 is one of at least 10 syndromes belonging to a clinically and genetically heterogeneous group of conditions known as pontocerebellar hypoplasias.  Members of this group, while individually rare, nevertheless collectively account for a significant proportion of what was once labeled cerebral palsy.

PCH3 results from homozygous mutations in the PCLO gene (7q21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general disorder.

References
Article Title: 

Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH, Mochida GH. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28;84(17):1745-50.

PubMed ID: 
25832664

Cerebral Atrophy, Autosomal Recessive

Clinical Characteristics
Ocular Features: 

Severe visual impairment is noted before one year of age when infants cease following objects in their environment.  Cortical visual impairment has been diagnosed although 'atrophic optic fundi' and hypotrophic optic nerves and fovea have also been described.  Nystagmus has been observed as well.

Systemic Features: 

Microcephaly relative to age norms is evident usually by 2 months of age and there is little subsequent growth of the skull.  Regression of developmental milestones is noted by 4 months of age with signs of irritability, akathisia, spasticity, visual impairment, seizures, and increased startle responses.  Sucking responses and eye-to-eye contact are usually lost by 6 months of age.  Repetitive body stiffening and extension of arms in older individuals consistent with seizure activity has been confirmed by EEG in at least one infant.  Imaging consistently reveals cerebral atrophy with ventriculomegaly and general loss of brain volume. Progressive muscle weakness is evident after about 1 year of age and oral feeding is impaired. There is complete lack of responsive interaction beyond irritability and agitation while motor function is limited to involuntary responses.  Two individuals have lived into the second decade of life.

Genetics

This condition has been described in 4 individuals who were products of consanquineous Amish couples.  Homozygous mutations in the TMPRSS4 gene (11q23.3), whose product is a serine transmembrane protease, seems to be responsible.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Optic Atrophy with Intellectual Disability

Clinical Characteristics
Ocular Features: 

Optic atrophy is the primary ocular abnormality but visual deficits are said to originate from cortical impairment.  The optic discs are pale and may be small with excavation.  Strabismus and latent nystagmus are often present. Up slanting palpebral fissures and epicanthal folds have been noted. Visual acuity levels have not been reported.

Systemic Features: 

Facial dysmorphism of a non-specific pattern can be present as evidenced by protruding ears with helical anomalies, and a small, sometimes elevated nasal bridge. The fingers are small and tapered.  Developmental delay is common.  Obsessive-compulsive behavior and autistic features have been reported in a single individual.  Hypotonia may be present.

Genetics

This is an autosomal dominant disorder resulting from heterozygous mutations in the NR2F1 gene (5q15), a transcription regulator.   Six persons with this condition have so far been reported.  The gene product is a nuclear protein active in transcription regulation during neurodevelopment.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Only symptomatic treatment is available.  Low vision aids and special education may be of benefit.

References
Article Title: 

NR2F1 mutations cause optic atrophy with intellectual disability

Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S, Wiszniewski W, Muzny DM, Yntema HG, Pfundt R, Vissers LE, Spruijt L, Blokland EA, Chen CA; Baylor-Hopkins Center for Mendelian Genomics, Lewis RA, Tsai SY, Gibbs RA, Tsai MJ, Lupski JR, Zoghbi HY, Cremers FP, de Vries BB, Schaaf CP. NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet. 2014 Feb 6;94(2):303-9.

PubMed ID: 
24462372

MELAS Syndrome

Clinical Characteristics
Ocular Features: 

This progressive mitochondrial disorder primarily affects muscles and the CNS, including the visual system.  The pattern of ocular deficits is not consistent and those that are present are not specific, requiring the clinician to take the entire neurological picture into consideration.  Hemianopsia, cortical blindness and ophthalmoplegia may be present.  The ERG can show reduced b-wave amplitudes and VEPs may be absent.  The optic nerve head has been described as normal without the atrophy often seen with other mitochondrial disorders.  A pigmentary retinopathy may be present.

Systemic Features: 

The clinical picture is highly variable.  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures.  The headaches may simulate migraines.  Weakness, lethargy, and apathy may be present early.  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities.  Neurosensory deafness is often seen and peripheral neuropathy is usually evident.  MRIs may show cerebellar hypoplasia and infarctions in the cerebral hemispheres.  Some patients have calcifications in the basal ganglia.  Patients may develop lactic acidosis.  Muscle biopsies often show ragged, red fibers.  The heart is commonly involved with both structural and rhythm defects.  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia.  Morbidity and mortality are high.

Genetics

MELAS syndrome is a group of disorders caused by mutations in mitochondrial genes (at least 9 have been identified) that alter transfer RNA molecules resulting in disruption of intramitochondrial synthesis of proteins involved in oxidative phosphorylation pathways.  It is both clinically and genetically heterogeneous.  One can expect that any familial occurrence would result from maternal transmission but the occurrence of heteroplasmy results in considerable variability in the severity of clinical disease.

Treatment
Treatment Options: 

There is no effective treatment that prevents development of disease or that slows its progress.

References
Article Title: 
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