Mutation Analysis of <i><scp>COQ</scp>2</i> in Chinese Patients with Cerebellar Subtype of Multiple System Atrophy

Wen, Xiao-Dan; Li, Hongfu; Wang, Hongxia; Wang, Ni; Dong, Yi; Wu, Zhi‐Ying

doi:10.1111/cns.12412

Cited by 17 publications

(12 citation statements)

References 18 publications

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“…Unlike PD, no single gene mutation linked to familial forms and no definite risk factors have been identified. A loss-of-function mutation in the COQ2 gene, encoding the coenzyme Q10 (COQ10)-synthesizing enzyme (4-hydroxybenzoate-polyprenyl transferase), was reported in Japanese familial and sporadic cases [ 63–66 ], the association being particularly strong for MSA-C [ 67–69 ]. A case of familial MSA was associated with compound heterocygous nonsense (R387X) and missense (V393A) mutations in COQ2 [ 70 ].…”

Section: Etiology and Geneticsmentioning

confidence: 99%

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Jellinger¹

2018

JAD

151

142

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Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

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Section: Etiology and Geneticsmentioning

confidence: 99%

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Jellinger¹

2018

JAD

151

142

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“…2 Several subsequent case-control association studies in East Asia have consistently shown that the carrier frequency of V393A in COQ2 is higher in patients with MSA than in controls. 2,[5][6][7][8][9] On the basis of these findings, a question is raised regarding the potential role of CoQ10 insufficiency in the pathophysiologic development of MSA. Nevertheless, thus far, little has been known about levels of plasma CoQ10 in patients with MSA carrying either COQ2 mutations or no mutations.…”

mentioning

confidence: 99%

Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy

et al. 2016

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IMPORTANCE Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA. OBJECTIVE To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls. DESIGN, SETTING, AND PARTICIPANTS We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level. MAIN OUTCOMES AND MEASURES Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype. RESULTS Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] μg/mL; P = .01) (difference between medians: −0.14; 95% CI,-0.25 to-0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) μg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02). CONCLUSIONS AND RELEVANCE Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

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“…An association between sporadic MSA and CoQ2 variants was found in Japanese, Taiwanese and Chinese populations, but these results were not replicated in other cohorts. [26][27][28][29][30][31] Further studies have revealed reduction in CoQ10 levels in the cerebellum and serum of patients with MSA. 32,33 These findings may be particularly important in implicating CoQ10 supplementation as a therapeutic option in MSA, though this has not yet been systematically studied.…”

Section: Coenzyme Q2 Genementioning

confidence: 99%

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

Sklerov¹,

Waters²

2016

US Neurology

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Multiple system atrophy (MSA) is a progressive, adult-onset, neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia, autonomic failure, and corticospinal tract dysfunction. It is considered a rare disease, similar in frequency to the more well-known neurodegenerative disease amyotrophic lateral sclerosis or Lou Gehrig’s disease. Though MSA has not traditionally been considered a genetic disease, new evidence is emerging supporting some genetic predisposition in many patients. In this short review, we will discuss advances in the knowledge of genetics in MSA and how this has furthered our understanding of the pathophysiology of the disease. There is still much unknown about this disease, but some of the recent advances made in MSA genetics may give important clues to understanding the pathogenesis and treatment of this disease.

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Mutation Analysis of COQ2 in Chinese Patients with Cerebellar Subtype of Multiple System Atrophy

Abstract: Our results indicated that COQ2 tended to play a population-specific and subtype-depended role in conferring susceptibility to MSA.

Cited by 17 publications

References 18 publications

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

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