Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to the m.14487T>C mutation in ND6

Mitochondrial disorders of the oxidative phosphorylation (OXPHOS) system effect ~1/5000 individuals in the general population and present with a surprisingly wide range of multisystemic and neuromuscular phenotypes. The m.14487T>C mutation is a known pathogenic mtDNA mutation resulting in an amino acid substitution (p.M63V) in NADH dehydrogenase 6 (MT ND), a complex I subunit of the mitochondrial respiratory chain. Thus far it has been found in isolated cases with infantile Leigh syndrome and progressive dystonia. We report here adult and late-onset phenotypes as it was seen in a 5-generation Belgian family with 12 affected family members. Clinical and mutation load data were available for 9 family members, while biochemical analysis of the respiratory chain was performed in 3 muscle biopsies. Heteroplasmic m.14487T>C levels (36-52% in leukocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leukocytes, 100 % in muscle). We found lower mutation loads (8-35% in blood) in adult patients with clinical features including migraine with aura, Leber Hereditary Optic Neuropathy (LHON), sensoneural hearing loss and Diabetes Mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue of these patients. Conclusion: The m.14487T>C mutation resulted in a broad spectrum of phenotypes in our family. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.