Background
Multiple system atrophy (MSA) is a rare sporadic neurodegenerative disorder, with an estimated prevalence ranging from approximately 2–5 cases per 100,000 people [
1]. This devastating and rapidly progressive disease is characterized clinically by combinations of poor levodopa responsive parkinsonism, autonomic failure, cerebellar ataxia, and pyramidal symptoms [
1,
2]. Widespread presence of glial cytoplasmic inclusions is the neuropathologic hallmark of MSA [
3]. To date, there are no effective therapies for MSA and our understanding of the disease etiology remains limited.
Recently, a homozygous mutation p.M128V-V393A/p.M128V-V393A (referred to by Tsuji and colleagues as p.M78V-V343A/p.M78V-V343A) and compound heterozygous mutations p.R387X/p.V393A (referred to by Tsuji and colleagues p.R337X/p.V343A) in the
coenzyme Q2 4-hydroxybenzoate polyprenyltransferase gene (
COQ2; OMIM 609825) were identified in affected members of two unrelated Japanese families with MSA [
4]. This is the first report of recessive
COQ2 pathogenic mutations in adults, however recessive
COQ2 mutations are known to cause primary coenzyme Q10 (CoQ10) deficiency-1 (COQ10D1; OMIM 607426) which includes phenotype of infantile multisystem disorder or nephrotic syndrome [
5‐
12]; COQ2 is involved in the synthesis of CoQ10. Interestingly, it was also reported that specific heterozygous variation (p.V393A) in the
COQ2 gene may affect susceptibility to MSA [
4]. Given these findings, we screened the Mayo Clinic Florida series of 155 MSA patients to assess the frequency of
COQ2 variants in disease. Given the proposed loss-of-function mechanism we also investigated exon dosage as a possible disease-related phenomenon.
Discussion
Our study examined the relevance of
COQ2 variation (and subsequent CoQ10 deficiency) in susceptibility to MSA. The absence of pathogenic recessive
COQ2 mutations or copy number variants within our series of clinical and pathologically-confirmed MSA patients means further screening of case–control series and functional studies are likely required to confirm the role of this candidate gene in MSA. We identified two heterozygous
COQ2 variant, p.S54W and c.403 + 10G > T, of unknown significance, although cDNA study for c.403 + 10G > T did not show any alternate splicing. Recently, three independent case–control studies also reported an absence of recessive
COQ2 mutations in MSA supporting the rarity of this as a potential cause of disease [
13,
17,
18]. In addition, Jeon and colleagues noted the Asian-specific genetic risk factor p.V393A was observed at the same frequency in cases and controls (~2.6%). These reports question the role of
COQ2 variants in risk of MSA but do not rule out the potential for rare variants in disease.
Interestingly, we found one heterozygous COQ2 p.S146N variant. Clinical and pathological presentation of our Caucasian patient harboring the heterozygous p.S146N variant was MSA-C with severe pathological changes. This mutation has been previously reported as a pathogenic homozygous mutation in infantile multisystem disorder (a major phenotype of primary CoQ10 deficiency-1) [
6,
7] or as part of a compound heterozygous state [
8] (Table
2). The pathogenicity of this mutation is supported by the high conservation at this amino acid position, by the prediction as probably damaging by PolyPhen-2 and SIFT, and by the finding of abnormal mitochondria proliferation and low CoQ10 levels in the skeletal muscle of carriers [
6].
The study of Bujan and colleagues demonstrated that a patient carrying the homozygous p.S146N mutation showed significant CoQ10 deficiency in fibroblasts and presented deficient CoQ10 biosynthesis [
7]. Collectively, these reports suggest that the p.S146N substitution functionally impairs CoQ10 activity and therefore it is possible that in the heterozygous state p.S146N might increase susceptibility to MSA. Our patient with heterozygous p.S146N was clinically diagnosed as MSA-C. Fitting with this, it was reported that patients with
COQ2 mutations have increased frequency of MSA-C compared to MSA-P (the parkinsonian variant of MSA) and the cerebellum is more vulnerable to compromised COQ2 function than other regions of the central nervous system [
4]. A previous study has also revealed that the cerebellum in both rats and humans contains the lowest concentration of CoQ10 in the brain [
20]. Recessive
COQ2 mutations are known to cause primary CoQ10 deficiency-1, including infantile multisystem disorder, it remains unresolved why the same gene would cause MSA in an adult [
5‐
12]. One possible explanation would be that the decrease in COQ2 activity associated with the recessive mutations in patients with MSA is milder than that observed in patients with primary CoQ10 deficiency-1 [
4].
This report is the third time a mutation known to cause primary CoQ10 deficiency-1 has been observed in an MSA case. Recently Tsuji and colleagues found R387X (referred to R337X by Tsuji et al.) in one of the original multiple families (Family 12) and Schottlaender and Houlden (MSA Brain Bank Collaboration) reported one heterozygous p.R197H carrier in 300 pathologically-confirmed MSA [
13].
COQ2 mutations found in CoQ10 deficiency-1 were associated with MSA (3/2268 vs 0/6356, p value =0.019, Table
3), especially pathologically-diagnosed MSA (p value =0.0029). Although primary CoQ10 deficiency-1 due to
COQ2 mutations is rare, it may be worth reassessing family history in these patients for the possible increased occurrence of MSA.
Previously, several genetic risk factors for MSA have been reported. For instance, a common variant in the α-synuclein gene (
SNCA rs11931074) was associated with MSA in an initial study (Odds ratio [OR] = 6.2, 95% confidence interval [CI]: 3.4 – 11.2, p value under recessive model =5.5 × 10
−12) [
21] and this result was subsequently replicated in an independent set of pathologically-confirmed MSA cases (OR: 4.7, 95% CI: 1.0 – 21.7, p value =0.06) [
22]. Another common variant, the microtubule-associated protein tau (
MAPT) H1 haplotype (rs1052553) has also been associated with risk of MSA (OR: 1.9, 95% CI: 1.1 – 3.2, p
=0.016) [
23]. On the other hand, rare variants (MAF < 1%) have not been reported to be associated with MSA, probably due to the low disease frequency of MSA. Copy number loss of “src homology 2 domain containing-transforming protein 2 gene” was reported as a risk of MSA [
24] but a replication study from another institute failed to show the association [
25]. Further studies of rare variants and copy number variation are warranted to elucidate further genetic risks for MSA.
Conclusions
MSA due to recessive
COQ2 mutations (including exon dosage) was not observed in our study. We did detect the presence of a single heterozygous pathogenic
COQ2 variant, which causes infantile multisystem disorder (primary CoQ10 deficiency-1) in a homozygous condition. Given the lack of therapeutic options in MSA, more work is warranted to resolve the role, if any, of
COQ2 variants in disease. Primary CoQ10 deficiencies, with early treatment, respond well to CoQ10 supplementation [
26]. Whether this is a viable option for treatment or prevention of MSA, or within in a small subset of individuals carrying
COQ2 mutations, remains to be determined. Further studies on the etiology of MSA will lead to more rational and improved drug discovery.
Acknowledgements
We would like to thank all those who have contributed to our research, particularly the patients and families who donated Brain tissue and DNA samples for this work. This work was supported by the National Institutes of Health [grant numbers R01 NS078086 (OAR), Morris K. Udall Parkinson's Disease Research Center of Excellence P50 NS072187 (OAR, RR, RU, ZKW and DWD), Mayo Clinic Center for Regenerative Medicine (ZKW), The Michael J. Fox Foundation for Parkinson's Research (ZKW), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (ZKW and SF).
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
KO carried out the molecular genetic studies and drafted the manuscript. MGH, SR, AIS-O, CL, RLW, OLB, XW and YA carried out the molecular genetic studies and data analysis. MGH performed all statistical analysis. SF, NG-R, RU, RR, WPC, ZKW and DWD made substantial contributions to acquisition of patient material and data. OAR conceived of the study, obtained study funding, participated in its design and coordination and drafted the manuscript. All authors participated in the interpretation of results, read and approved the final manuscript.