The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene

Abstract

Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with heterogenous phenotypic manifestations and genetic background. We describe seven patients from five independent families with an isolated myopathic phenotype of CoQ10 deficiency. The clinical, histological and biochemical presentation of our patients was very homogenous. All patients presented with exercise intolerance, fatigue, proximal myopathy and high serum CK. Muscle histology showed lipid accumulation and subtle signs of mitochondrial myopathy. Biochemical measurement of muscle homogenates showed severely decreased activities of respiratory chain complexes I and II + III, while complex IV (COX) was moderately decreased. CoQ10 was significantly decreased in the skeletal muscle of all patients. Tandem mass spectrometry detected multiple acyl-CoA deficiency, leading to the analysis of the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII). All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. Our results indicate that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Since this condition is treatable, correct diagnosis is of the utmost importance and should be considered both in children and in adults. We suggest to give patients both CoQ10 and riboflavin supplementation, especially for long-term treatment.

Fig 1

Histological findings of patient 1 (A–G), patient 2 (H–J), patient 3 (L) and patient 5 (K). Muscle biopsies of all patients show moderate to severe vacuolar myopathy (H&E stain: A, E, K; semithin section, toluidin blue: H); the vacuolar change was most prominent in type 1 fibers (ATPase pH 9.4: B). There are few COX negative fibres (asterixis in C, F). Sudan black (D, G) or Oil-Red-O (J, L) stain shows lipid accumulation in type 1 fibres of all patients. Ragged red fibres were seen rarely (Gomori trichrome stain: I). There is no significant difference between the first and second biopsy specimens of patient 1 (A–D; E–G) Bars in A–L adjusted to 30μm.

Fig 2

Conservation of the ETFDH mutations L377P, P456L, P483L and K590E.

Fig 3

RFLP analysis for the mutation L377P in the family of patient 2. Presence of a homozygous state in muscle DNA (lane 2) and blood DNA (lane 7) of the patient.The mutation is heterozygous in both parents (motherçlane1; fatherçlane 3) and in one healthy sibling (lane 6), and absent in another healthy sibling (lane 4) and in the patients wife (lane 5) as well as in a normal control (lane 8).