myoclonus

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

Dystonia, Childhood Onset, With Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is often observed during the first decade of life and has been noted as early as 15 months.  It may be congenital.  Nystagmus has been seen in some patients.

Systemic Features: 

Signs of motor dysfunction are seen in the first decade of life, and as early as 15 months of age.  Motor development may be mildly delayed.  Features are variable and include facial dystonia, myoclonus, dyskinesia, dysarthria, dysphagia, limb spasticity, and chorea-like movements all of which may progress.  Some patients lose independent ambulation but cognition is not affected.

Brain imaging reveals hyperintense T2-weighted signals in the basal ganglia.

Genetics

The transmission pattern in 5 reported families is consistent with autosomal recessive inheritance.  Biallelic mutations in the MECR gene (1p35) have been found in 7 affected individuals.

This nuclear gene plays a role in mitochondrial fatty acid synthesis.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Heimer G, Keratar JM, Riley LG, Balasubramaniam S, Eyal E, Pietikainen LP, Hiltunen JK, Marek-Yagel D, Hamada J, Gregory A, Rogers C, Hogarth P, Nance MA, Shalva N, Veber A, Tzadok M, Nissenkorn A, Tonduti D, Renaldo F; University of Washington Center for Mendelian Genomics., Kraoua I, Panteghini C, Valletta L, Garavaglia B, Cowley MJ, Gayevskiy V, Roscioli T, Silberstein JM, Hoffmann C, Raas-Rothschild A, Tiranti V, Anikster Y, Christodoulou J, Kastaniotis AJ, Ben-Zeev B, Hayflick SJ. MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. Am J Hum Genet. 2016 Dec 1;99(6):1229-1244.

PubMed ID: 
27817865

Neuraminidase Deficiency

Clinical Characteristics
Ocular Features: 

A cherry red spot is may be seen in late childhood or early adolescence.  It occurs in nearly 100% of patients with type I while only 75% of type II patients have this feature possibly because their early death from the more severe systemic disease prevents full ascertainment.  Visual acuity is reduced, sometimes severely.  Some but not all individuals have corneal and lens opacities.  A subtle corneal haze has also been seen.  Nystagmus has been reported. 

Systemic Features: 

This is a neurodegenerative disorder with progressive deterioration of muscle and central nervous system functions.  Myoclonus, mental deterioration, hepatosplenomegaly, muscle weakness and atrophy are common.  The defect in neuraminidase activity leads to abnormal amounts of sialyl-oligosaccharides in the urine.  Spinal deformities such as kyphosis are common.  Deep tendon reflexes are exaggerated.  Ataxia and hearing loss may be present.  Coarse facies, a barrel chest, and short stature are characteristic.  Hepatic cells contain numerous vacuoles and numerous inclusions.

Sialidosis types I and II are both caused by mutations in the neuroaminidase gene.  Type I is associated with milder disease than type II which has an earlier age of onset and may present in infancy or even begin in utero.  Early death within two years of age is common in the congenital or infantile forms.  There is, however, significant variability in age of onset and the course of disease among types. 

Genetics

The sialidoses are autosomal recessive lysosomal storage disorders resulting from mutations in the NEU1 gene (6p21.3) which lead to an intracellular accumulation of glycoproteins containing sialic acid residues.  Both types I and II are caused by mutations in the same gene. 

Treatment
Treatment Options: 

Treatment is focused on symptom management. 

References
Article Title: 
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