Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C.
BACKGROUND
m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported.


OBJECTIVE
To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family.


METHODS
A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies.


RESULTS
Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 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 leucocytes, 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, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue.


CONCLUSIONS
m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.
Dermaut
B
B
Department of Neurology, University Hospital Ghent, Ghent University, Ghent, Belgium.
Seneca
S
S
Dom
L
L
Smets
K
K
Ceulemans
L
L
Smet
J
J
De Paepe
B
B
Tousseyn
S
S
Weckhuysen
S
S
Gewillig
M
M
Pals
P
P
Parizel
P
P
De Bleecker
J L
JL
Boon
P
P
De Meirleir
L
L
De Jonghe
P
P
Van Coster
R
R
Van Paesschen
W
W
Santens
P
P
D000328:Adult; D017668:Age of Onset; D001530:Belgium; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D020821:Dystonic Disorders / Q000235:genetics; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
D004272:DNA, Mitochondrial; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase