Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C
- B Dermaut1,2,
- S Seneca3,
- L Dom4,
- K Smets5,6,
- L Ceulemans7,
- J Smet8,
- B De Paepe1,
- S Tousseyn9,
- S Weckhuysen9,
- M Gewillig10,
- P Pals5,
- P Parizel11,
- J L De Bleecker1,
- P Boon1,
- L De Meirleir12,
- P De Jonghe5,6,
- R Van Coster8,
- W Van Paesschen9,
- P Santens1
- 1Department of Neurology, University Hospital Ghent, Ghent University, Ghent Belgium
- 2Laboratory of Developmental Genetics, VIB, Leuven, Belgium
- 3Center for Medical Genetics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- 4Koningin Paola Kinderziekenhuis, Antwerp, Belgium
- 5Department of Neurology, University Hospital Antwerp, University of Antwerp, Antwerp, Belgium
- 6Department of Molecular Genetics, Neurogenetics Research Group, VIB, University of Antwerp, Antwerp, Belgium
- 7Sint-Jozefkliniek, Bornem, Belgium
- 8Department of Pediatrics, Division of Neurology and Metabolism, University Hospital Ghent, Ghent University, Ghent, Belgium
- 9Department of Neurology, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
- 10Department of Pediatric Cardiology, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
- 11Department of Radiology, University Hospital Antwerp, Antwerp, Belgium
- 12Department of Pediatric Neurology and Metabolism, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- Correspondence to Professor P Santens, Department of Neurology, University Hospital Ghent, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; patrick.santens{at}ugent.be
- Received 3 July 2008
- Revised 9 December 2008
- Accepted 23 December 2008
Abstract
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.
Objectives: 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.
Interpretation: 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.
Footnotes
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Funding This work was supported by grants of the Research Council of the Vrije Universiteit Brussel (OZR1216-OZR1145), the University of Antwerp and FWO grants G.0666.06 and G.0399.08. BD is a postdoctoral researcher of the Fund for Scientific Research (FWO).
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Competing interests None.
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Patient consent Obtained.
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Provenance and Peer review Not commissioned; externally peer reviewed.
