delayed myelination

Epileptic Encephalopathy, Early Infantile 58

Clinical Characteristics

Ocular Features:

Infants are noted early to have poor fixation and visual following of targets. Optic nerve hypoplasia is evident on brain MRIs.

Systemic Features:

Epilepsy and development delay are hallmarks of this condition. The seizures are of multiple types and have their onset in the first year of life. The EEG often shows diffuse slowing, multifocal spikes and hypsarrhythmia. These are often difficult to control. Severe intellectual disability is usually present. Feeding difficulties are evident early and slow growth is common. Hypotonia is common but hyperreflexia and spasticity are also reported.

Brain MRIs show delayed or reduced myelination. Acquired microcephaly is often seen.

Genetics

De novo heterozygous mutations in the NTRK2 gene (9p21.33) have been found in 4 unrelated individuals.

Pedigree:

Autosomal dominant

Treatment

Treatment Options:

No treatment has been reported.

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

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics

Ocular Features:

Optic atrophy is sometimes present. Nystagmus, and strabismus are seen in some patients. A pigmentary retinopathy was found in one individual.

Systemic Features:

This is a clinically heterogeneous disorder with extensive neurological deficits. Patients have feeding and swallowing difficulties from the neonatal period. There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities. Some develop seizures and few achieve normal developmental milestones. Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy. However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis. Ataxia eventually develops in most patients.

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination.

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues. Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition. The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No treatment has been reported for the general condition.

References

Article Title:

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID:

28905505

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

Musante L, Puttmann L, Kahrizi K, Garshasbi M, Hu H, Stehr H, Lipkowitz B, Otto S, Jensen LR, Tzschach A, Jamali P, Wienker T, Najmabadi H, Ropers HH, Kuss AW. Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability. Hum Mutat. 2017 Jun;38(6):621-636.

PubMed ID:

28236339

Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy

Theisen BE, Rumyantseva A, Cohen JS, Alcaraz WA, Shinde DN, Tang S, Srivastava S, Pevsner J, Trifunovic A, Fatemi A. Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. Am J Med Genet A. 2017 Sep;173(9):2505-2510.

PubMed ID:

28650581

Spastic Paraplegia, Intellectual Disability, Nystagmus, and Obesity

Clinical Characteristics

Ocular Features:

Patients have deep-set eyes with nystagmus, reduced vision, and often an esotropia perhaps secondary to hypermetropia. In one of 3 reported patients the optic discs were described pale.

Systemic Features:

Prominent foreheads are present at birth along with full cheeks and a prominent forehead. Children grow rapidly in the first year eventually reaching the 90th percentiles in weight, height, and head circumference although neurologically they are developmentally delayed. Speech and walking may be delayed as well. While limbs have increased tone together with hyperreflexia, the trunk exhibits hypotonia.

Brain imaging reveals delayed myelination, dilated lateral ventricles, reduced while matter, and cerebral atrophy.

Genetics

Heterozygous mutations in the KIDINS220 gene (2p25.1) have been identified in 3 unrelated patients.

Pedigree:

Autosomal dominant

Treatment

Treatment Options:

No treatment has been reported.

References

Article Title:

Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity

Josifova DJ, Monroe GR, Tessadori F, de Graaff E, van der Zwaag B, Mehta SG; DDD Study., Harakalova M, Duran KJ, Savelberg SM, Nijman IJ, Jungbluth H, Hoogenraad CC, Bakkers J, Knoers NV, Firth HV, Beales PL, van Haaften G, van Haelst MM. Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity. Hum Mol Genet. 2016 Jun 1;25(11):2158-2167.

PubMed ID:

27005418

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