hypoglycemia

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

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics

Ocular Features:

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features:

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay. They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age. Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension. Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present. Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia. Hyperreflexia may be present and some infants have seizures. Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

There is no effective treatment. Liver transplantation in one infant was unsuccessful.

References

Article Title:

New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome

Mancuso M, Ferraris S, Pancrudo J, Feigenbaum A, Raiman J, Christodoulou J, Thorburn DR, DiMauro S. New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome. Arch Neurol. 2005 May;62(5):745-7.

PubMed ID:

15883261

The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA

Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet. 2001 Nov;29(3):337-41. Erratum in: Nat Genet 2001 Dec;29(4):491.

PubMed ID:

11687800

You are here

Search For A Disorder