Objective: Describe discovery of novel mitochondrial mutations causing ataxia and dystonia syndromes with occurrence in childhood.

Background: An African-American man at 5 years old subacutely developed falls.  Exam found intention tremor, and unsteady gait with poor tandem. Extensive laboratory work was negative except for lactic acidosis. MRI brain showed two foci of high signal in lateral medulla and mild vermis atrophy. He recovered gradually and by age 12 was reported to be normal, though he had learning disability and short stature. At age 18 he developed head and hand tremor, and repeat evaluation found both truncal and appendicular mild ataxia, dystonic neck tremor, and action/intention tremor in the hands.  MRI showed cerebellar atroph, bilateral gliosis and some cavitation of the posterior caudate.  His older sister developed similar gait symptoms and dysarthria at age 5, stabilizing with chronic tremor.  Another similar two cases involve a pair of young siblings from South America with a moderately severe, seemingly monophasic episodes of neurological deterioration during a “flu” in early childhood leaving them with striatal necrosis and generalized dystonia.

Method: Case reports and literature review

Results: After analysis, the NIH Undiagnosed Disease program discovered that the syndrome for the first described siblings was most likely due to a mild complex-I deficiency due to mutations in the gene NDUFS3 (NADH-ubiquinone oxidoreductase Fe-S Protein 3).  The second siblings had a compound heterozygous pair in the gene NDUFAF6 (NADH-ubiquinone oxidoreductase complex assembly factor 6) with one of the variants being an intronic variant affecting splicing. Both are an autosomal recessive mutations affecting the first enzyme complex in the electron transport chain of mitochondria, coding for subunits essential for catalyzing electron transfer from NADH to ubiquinone and for the generation of the proton motive force; these genes highly conserved across species. The abnormal splice products in fibroblasts compared to controls.

Conclusion: These cases are consistent with a “mild” Leigh’s phenotype and adds to the growing description of phenotypes of rare complex-1 mutations. While mitochondrial disease is often suspected, obtaining a specific genetic diagnosis is elusive without access to specialty genetic laboratories, with many novel mutations available for discovery.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-recessive-mitochondrial-mutations-causing-leighs-syndrome-and-movement-disorders/