Low Coenzyme Q10 Linked to Multiple System Atrophy

Pauline Anderson

July 13, 2016

Patients with multiple system atrophy (MSA) have decreased levels of plasma coenzyme Q10 (CoQ10), regardless of whether they carry a mutation in the gene encoding for CoQ10 (COQ2), new research reveals.

While researchers know that familial cases of MSA are caused by COQ2 variants, "we don't know anything" about the sporadic form of the neurodegenerative disease, said study author Shoji Tsuji, MD, PhD, professor, neurology, University of Tokyo, Japan.

The new study provides an important clue to the mechanism of this sporadic form, he said.

Dr Shoji Tsuji

The new information also provides a rationale for a clinical trial he and his colleagues are planning for testing of CoQ10 supplementation, he said.

"We know now that the presence of CoQ10 levels are decreased in patients even without COQ2 variants. That means supplementation of CoQ10 may be effective for patients with or without COQ2 mutations, so it may be effective for all MSA patients."

The study was published online June 27 in JAMA Neurology.

MSA is a progressive neurodegenerative disease, with patients often experiencing rapid functional decline and poor response to medical therapy. There are two subtypes: MSA C, in which cerebellar ataxia is predominant, and MSA P, in which parkinsonism, including rigidity and difficulty with movement, is predominant.

This analysis included 44 Japanese patients (mean age, 63.7 years) who had been diagnosed with MSA for a mean of 3.3 years and 39 Japanese control participants free of neurologic disease. There was no significant difference in age or sex distribution between the two groups.

Of the patients, 26 had the cerebellar variant of MSA and 18 had the parkinsonian variant. In this patient group, 26 were ambulatory, 9 required mobility aids (such as a cane or walker), and 9 were wheelchair dependent.

Three patients with MSA (2 with MSA C and 1 with MSA P) and 3 controls had a COQ2 mutation.

Investigators who were blinded to the case or control status of participants measured plasma CoQ10 levels.

The mean plasma level of CoQ10 in patients with MSA was significantly lower than that in controls (0.51 vs 0.72 μg/mL; P = .01; difference between medians: –0.14; 95% confidence interval [CI] –0.25 to –0.03).

The study showed that the COQ2 variants are more significantly associated with the cerebellar variant of MSA than the parkinsonian variant, said Dr Tsuji He noted recent research from the UK showing that CoQ10 levels in the cerebellum are significantly decreased in patients with MSA C but not in those with MSA P. The patients with decreased CoQ10 in the cerebellum did not carry the COQ2 variant.

This suggests that the cerebellum "may be more vulnerable" to decreased coenzyme Q10, said Dr Tsuji.

After adjustment for COQ2 genotype, as well as for age and sex. the association of plasma CoQ10 levels was still significantly associated with MSA. This suggests that lower plasma levels of CoQ10 in patients with MSA are not only attributable to COQ2 mutations.

"We are sure that the COQ2variant is associated with MSA; this is definite and the COQ2variant results in decreased synthesis of COQ10," said Dr Tsuji.

"But the interesting finding is that the patients with MSA who do not carry the COQ2 variant still have a decreased level of coenzyme Q10. We believe that there are several or multiple causal mechanisms, and COQ10 is only one of the multiple causes."

He acknowledged that researchers "still don't understand" the mechanisms of decreased coenzyme Q10 in those without COQ2 mutations. It's possible, he said, that other enzymes or genes are involved in the biosynthesis pathway of coenzyme Q10.

Supplements Safe

Tsuji's and colleagues' phase 1 trial of high-dose coenzyme Q210 supplements has just wrapped up. Although it has yet to be fully analyzed, the results suggest that the dose used was safe in healthy volunteers, he said.

His team is now planning a phase 2 clinical trial of these supplements in patients with MSA "early in the next year."

In an accompanying editorial, Sheng-Han Kuo, MD, and Catarina M. Quinzii, MD, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, outlined several limitations of measuring CoQ10 levels in plasma for diagnostic purposes.

"Because the biosynthetic pathway of CoQ10 is tightly linked to cholesterol homeostasis, blood levels of CoQ10 are affected by diet, hyperlipidemia, and hyperthyroidism, as well as by drugs (ie, statins)."

Further, plasma levels of CoQ10 could vary even in individuals with known mutations in genes encoding CoQ10-synthesizing enzymes, they said, adding that levels of CoQ10 in the muscles and fibroblasts "provide a more reliable measurement."

The editorial writers concluded that recent discoveries of COQ2 mutations in certain patients with MSA, and of CoQ10 deficiency in the brain and blood of some of them, may lead to mechanism-based and rational therapies for MSA, "a rapidly progressive disorder in need of a disease-modifying therapy."

For an additional comment, Medscape Medical News approached Nikolaus McFarland, MD, PhD, assistant professor of neurology and Movement Disorders Division chief, University of Florida College of Medicine, Gainesville.

The study, he said, "presents new data," and the findings are "significant" as CoQ10 plays an important role in mitochondrial function and energy production in cells, in particular neurons in the brain.

"While these findings are intriguing and suggest the possibility that supplementing CoQ10 might be helpful in MSA, making these suggestions may be premature and the findings should be interpreted with caution."

CoQ10 has been "touted" as a potential neuroprotective supplement to treat neurodegenerative disorders, and several small studies showed promising results in disorders such as Huntington's disease and Parkinson's disease, but larger studies demonstrated no benefit, said Dr McFarland.

"Further studies are clearly needed to determine the role of plasma levels CoQ10 in MSA and the relationship to disease pathology."

Dr McFarland also noted the "several limitations" of the study, including the case-control design, limited sample size, and measurement of plasma levels, which do not directly reflect CoQ10 levels in the brain.

This study was supported in part by KAKENHI (grant-in-aid for Scientific Research on Innovative Areas, Dr Tsuji) and a grant-in-aid for Scientific Research (C) (Dr Mitsui) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant-in-aid from the Ministry of Health, Welfare and Labour of Japan (Dr Tsuji). Dr Tsuji and the editorial writers have disclosed no relevant financial relationships.

JAMA Neurol. Published online June 27, 2016. Abstract Editorial

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