Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, Part 28: NEUROGENETICS, _.

Multiple-system atrophy (MSA) is an adult-onset neurodegenerative disease encompassing various combinations of parkinsonism, autonomic dysfunction, cerebellar ataxia and pyramidal dysfunction. As the neuropathologic diagnosis of MSA requires the finding of cytoplasmic aggregates of alpha-synuclein in oligodendroglia, it is classed among the alpha-synucleinopathies, alongside Parkinson disease and Lewy-body dementia. The disease is generally considered sporadic, though some families showing Mendelian patterns of inheritance have been observed.

A recent study by the Multiple-System Atrophy Research Collaboration1 has, for the first time, identified a monogenic form of MSA by an elegant combination of linkage analysis and whole-genome sequencing in multiplex families. In two of the six families studied, the clinically affected members were homozygous or compound heterozygous for deleterious mutations in COQ2, whose product is involved in coenzyme Q10 biosynthesis. The authors also showed, through a large case-control study, that a common sequence variant and multiple rare variants in COQ2 (in the heterozygous state, in most cases) are associated with sporadic forms of MSA.

This study adds to the literature a new clinical manifestation of coenzyme Q10 deficiency. The authors draw attention to previous studies suggesting the presence of mitochondrial dysfunction or oxidative injury in patients with MSA; other studies have shown that mitochondrial dysfunction and oxidative stress can induce alpha-synuclein oligomerization, and that treatment of Parkinson disease cells with coenzyme Q10 and/or glutathione dampens this mechanism.2 These findings allow a tentative pathophysiological link to be drawn between coenzyme Q10 deficiency and MSA. Potential future studies may focus on the effect of treatment of patients with familial or sporadic MSA with coenzyme Q10.


1  Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med. 2013 Jul 18;369(3):233-44. doi: 10.1056/NEJMoa1212115. Epub 2013 Jun 12. PMID:23758206.

2 Esteves AR et al. Oxidative stress involvement in alpha-synuclein oligomerization in Parkinson’s disease cybrids. Antioxid Redox Signal. 2009 Mar; 11(3):439-48. PMID:18717628.

Posted by Alina Levtova, MD



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