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

Mitochondrial disorders of oxidative phosphorylation (OXPHOS disorders) affect ~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 (ND6), a complex I subunit of the mitochondrial
respiratory chain, and has thus far 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 (between 8 and 35 % in blood) in adult patients with clinical features including migraine with aura, Leber Hereditary Optic Neuropathy (LHON), sensorineural hearing loss and Diabetes Mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue.
Conclusions: 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.