Dystonia-Ataxia with early handwriting deterioration in COQ8A mutation carriers: A case series and literature review.

Cerebellar ataxia is a hallmark of coenzyme Q10 (CoQ10) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ10 supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.

Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2.

Dihydrolipoamide dehydrogenase (DLD, E3) is a flavoprotein common to pyruvate, α-ketoglutarate and branched-chain α-keto acid dehydrogenases. We found two novel DLD mutations (p.I40Lfs*4; p.G461E) in a 19 year-old patient with lactic acidosis and a complex amino- and organic aciduria consistent with DLD deficiency, manifesting progressive exertional fatigue. Muscle biopsy showed mitochondrial proliferation and lack of DLD cross-reacting material. Riboflavin supplementation determined the complete resolution of exercise intolerance with the partial restoration of the DLD protein and disappearance of mitochondrial proliferation in the muscle. Morphological and functional studies support the riboflavin chaperon-like role in stabilizing DLD protein with rescue of its expression in the muscle.