Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 102;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q21.23 | {Multiple system atrophy, susceptibility to} | 146500 | Autosomal dominant; Autosomal recessive | 3 | COQ2 | 609825 |
A number sign (#) is used with this entry because of evidence that susceptibility to multiple system atrophy-1 (MSA1) can be conferred by heterozygous, homozygous, or compound heterozygous mutation in the COQ2 gene (609825) on chromosome 4q21.
Multiple system atrophy (MSA) is a distinct clinicopathologic entity that manifests as a progressive adult-onset neurodegenerative disorder causing parkinsonism, cerebellar ataxia, and autonomic, urogenital, and pyramidal dysfunction in various combinations. Two main subtypes are recognized: 'subtype C,' characterized predominantly by cerebellar ataxia, and 'subtype P,' characterized predominantly by parkinsonism. MSA is characterized pathologically by the degeneration of striatonigral and olivopontocerebellar structures and glial cytoplasmic inclusions (GCIs) that consist of abnormally phosphorylated alpha-synuclein (SNCA; 163890) or tau (MAPT; 157140) (Gilman et al., 1998; Gilman et al., 2008; Scholz et al., 2009). 'Subtype C' of MSA has been reported to be more prevalent than 'subtype P' in the Japanese population (65-67% vs 33-35%), whereas 'subtype P' has been reported to be more prevalent than 'subtype C' in Europe (63% vs 34%) and North America (60% vs 13%, with 27% of cases unclassified) (summary by The Multiple-System Atrophy Research Collaboration, 2013).
MSA is similar clinically and pathologically to Parkinson disease (PD; 168600) and Lewy body dementia (127750). See also PARK1 (168601), which is specifically caused by mutation in the SNCA gene.
Pure autonomic failure manifests as orthostatic hypotension and other autonomic abnormalities without other neurologic involvement. Although there is some phenotypic overlap, the relationship of pure autonomic failure to MSA is unclear (Vanderhaeghen et al., 1970; Schatz, 1996).
MSA typically shows onset in middle age. Parkinsonian features include bradykinesia, rigidity, postural instability, hypokinetic speech, and tremor; response to L-DOPA is poor. Cerebellar dysfunction includes gait ataxia, dysarthria, and disorders of extraocular movement. Autonomic insufficiency results in orthostatic hypotension, erectile dysfunction, constipation, and decreased sweating. Urinary symptoms include urgency, frequency, incomplete bladder emptying, nocturia, and incontinence. Less commonly, corticospinal dysfunction may manifest as hyperreflexia (Gilman et al., 1998).
Shy and Drager (1960) described a syndrome of adult-onset orthostatic hypotension, bladder and bowel incontinence, anhidrosis, iris atrophy, amyotrophy, ataxia, rigidity and tremor; intellect was unaffected.
Vanderhaeghen et al. (1970) reported a 71-year-old woman with severe orthostatic hypotension and urinary incontinence. A year later, she developed parkinsonism, amyotrophy of the small hand muscles, and hyperreflexia. She died following cardiopulmonary complications. Neuropathologic examination showed pallor of the substantia nigra, neuronal rarefaction, and cytoplasmic hyaline inclusions. An unrelated male patient, with a history of radiotherapy to the neck, presented at age 73 with orthostatic hypotension. He had absence of ankle reflexes, but no ataxia or extrapyramidal signs. After death, postmortem exam showed increased microglia and concentric hyaline bodies within some neurons. Vanderhaeghen et al. (1970) concluded that there are 2 forms of orthostatic hypotension: one accompanied by neurologic features consistent with MSA, and another devoid of additional neurologic signs.
Wullner et al. (2004) reported a German mother and daughter with probable MSA. The mother presented at age 68 with akinetic parkinsonism that responded to L-DOPA treatment for 7 years. She later developed urinary incontinence and orthostatic hypotension, as well as gait ataxia. At age 77, she had severe ataxia, dysarthria, smooth expressionless face, brisk tendon reflexes, and cogwheel rigidity. The daughter presented at age 46 with gait ataxia. Within 2 years, she developed urge incontinence, orthostatic dysfunction, and mild unilateral parkinsonism. Other features included limb ataxia, dysarthria, and mild cogwheel rigidity. Neither patient had cognitive impairment. Brain MRI of both patients showed brainstem and cerebellar atrophy. Single photon emission CT (SPECT) of both patients showed asymmetric massive reduction of presynaptic dopamine transporter and a moderate loss of dopamine D2 receptors (DRD2; 126450). Wullner et al. (2004) noted that whereas MSA is usually considered to be a sporadic disorder, their family suggested a rare instance of autosomal dominant inheritance. Wullner et al. (2009) reported postmortem examination of the German mother with MSA described by Wullner et al. (2004). The brain showed severe atrophy of the putamen, depigmentation of the substantia nigra, and pontine and cerebellar atrophy. Microscopic analysis showed profound neuronal loss and gliosis in the striatum, globus pallidus, substantia nigra, pontine nuclei, and inferior olivary nuclei, as well as marked loss of Purkinje cells and demyelination of cerebellar white matter. There were widespread SNCA-positive cytoplasmic inclusions. The neuropathologic findings confirmed the diagnosis of MSA.
Hara et al. (2007) reported 4 unrelated Japanese families in each of which 2 sibs had findings consistent with MSA. One of the families was consanguineous, suggesting autosomal recessive inheritance. Among the 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The mean age at onset was 65.9 years. The most frequent clinical feature was parkinsonism, observed in 5 patients. All had a poor response to L-DOPA treatment. Six patients showed pontine atrophy with 'cross sign' or 'slitlike' signal changes at the posterolateral pontine margin on brain MRI. The patterns were consistent with autosomal recessive inheritance. No mutations were found in several genes for hereditary ataxia or in the SNCA gene.
Gilman et al. (1998) reported the conclusions of a consensus report for the diagnosis of MSA. Clinical criteria for inclusion centered on 4 domains: autonomic failure/urinary dysfunction, parkinsonism, cerebellar ataxia, and corticospinal dysfunction. Definitive diagnosis requires pathologic confirmation, with the findings of glial cytoplasmic inclusions and degenerative changes in various brain regions.
Gilman et al. (2008) reported the conclusions of a second consensus report for the diagnosis of MSA, which falls into 3 groups. Definite MSA requires neuropathologic demonstration of SNCA-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Autonomic failure can manifest as genitourinary dysfunction or orthostatic hypotension. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least 1 feature suggesting autonomic dysfunction plus 1 other feature that may be a clinical or a neuroimaging abnormality.
Shahnawaz et al. (2020) showed that the alpha-synuclein (163890)-protein misfolding cyclic amplification (PMCA) assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson disease (168600) and samples from patients with MSA, with an overall sensitivity of 95.4%. Shahnawaz et al. (2020) used a combination of biochemical, biophysical, and biologic methods to analyze the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson disease and MSA. They also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggested that alpha-synuclein aggregates that are associated with Parkinson disease and MSA corresponded to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA, and may enable the development of a biochemical assay to discriminate between Parkinson disease and MSA.
Although multiple system atrophy is generally considered to be a sporadic disorder, genetic factors may influence the pathogenesis and development of the disease (Scholz et al., 2009).
Lewis (1964) described a family in which 6 persons in 3 generations had orthostatic hypotension, with 2 instances of possible male-to-male transmission. Two affected family members had ataxia and parkinsonism. Walton (1969) also observed male-to-male transmission.
Nee et al. (1991) found higher frequencies of neurologic diseases and autonomic symptoms among 148 first-degree relatives of 33 MSA patients compared to control subjects. However, no secondary cases of MSA were identified. Of note, patients with MSA had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population, suggesting that environmental factors may also play a role.
Wenning et al. (1993) reported a higher frequency of parkinsonism among first-degree or second-degree relatives of 38 patients with autopsy-proven MSA. However, there were no familial cases of MSA, and the authors believed that the parkinsonism could be a chance occurrence. Wenning et al. (1993) concluded that MSA is most likely a sporadic disease.
Bannister et al. (1983) noted that the pathologic feature of MSA is a unique degeneration of both pigmented catecholamine-containing cells in the brainstem and cholinergic cells in the intermediolateral columns, with distal ganglionic and postganglionic degeneration. A subgroup, the parkinsonian variety, shows hyaline eosinophilic cytoplasmic neuronal inclusions (Lewy bodies) in the brainstem. Degeneration of melanin-containing and catecholamine-containing cells in the brainstem suggests a genetic metabolic defect.
Chalmers and Swash (1987) described electrophysiologic studies in patients with MSA that revealed selective damage to the somatic efferent innervation of the external urinary sphincter musculature. The findings implied selective vulnerability of the motor neurons of Onuf's nucleus in the sacral cord. This nucleus is known to innervate the striated components of the anal and urinary sphincter muscles.
Aggregated alpha-synuclein (163890) proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress is implicated in the pathogenesis of some of these disorders. Giasson et al. (2000) used antibodies to specific nitrated tyrosine residues in alpha-synuclein to demonstrate extensive and widespread accumulation of nitrated alpha-synuclein in the signature inclusions of Parkinson disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer disease (127750), and multiple system atrophy brains. The authors also showed that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selected and specific nitration of alpha-synuclein in these disorders provides evidence to link oxidative and nitrative damage directly to the onset and progression of neurodegenerative synucleinopathies.
Using detailed biochemical studies, Anderson et al. (2006) found that the predominant form of alpha-synuclein within Lewy bodies isolated from brains of patients with Lewy body dementia, multiple system atrophy, and PARK1 was phosphorylated at ser129. A much smaller amount of ser129-phosphorylated alpha-synuclein was found in the soluble fraction of both control and diseased brains, suggesting that ser129-phosphorylated alpha-synuclein shifts from the cytosol to be deposited in Lewy bodies, and that phosphorylation enhances inclusion formation. Other unusual biochemical characteristics of alpha-synuclein in Lewy bodies included ubiquitination and the presence of several C-terminally truncated alpha-synuclein species.
In Lewy body diseases, including Parkinson disease with or without dementia, dementia with Lewy bodies, and Alzheimer disease with Lewy body copathology, alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy, alpha-synuclein accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs). Peng et al. (2018) reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. Peng et al. (2018) found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments.
In a genomewide association study of 413 patients with MSA and 3,974 controls, followed by replication in 108 MSA patients and 537 controls, Scholz et al. (2009) found the most significant associations between MSA and SNPs rs3857059 in intron 4 of the SNCA gene on chromosome 4q22.1 (combined p value = 2.1 x 10(-10); OR, 5.9) and rs11931074 located downstream of the SNCA locus (combined p value = 5.5 x 10(-12); OR, 6.2). The findings were significant because the genetic factors overlap those found in Parkinson disease, which shows similar pathologic and clinical features.
Among 100 Korean patients with MSA and 100 Korean controls, Yun et al. (2010) did not find a significant association between MSA and rs11931074. The frequency of the T risk allele was 58% in both patient and control groups, which was significantly higher than that reported by Scholz et al. (2009) in Caucasian patients (10%) and controls (8%). The findings indicated that population-specific variation in the frequency needs to be considered when assessing the genetic risk for MSA.
Using whole-genome copy number variation (CNV) microarray analysis of a pair of monozygotic twins discordant for MSA, Sasaki et al. (2011) found that the affected twin had a 350-kb heterozygous deletion of the subtelomere of chromosome 19p13.3, whereas this change was not seen in the unaffected twin. Whole-genome CNV analysis found heterozygous loss of this region in 10 (30%) of 31 unrelated patients with MSA, although the breakpoints differed in each patient. CNV of this region was not seen in 2 control cohorts totaling 125 individuals, yielding an odds ratio (OR) of 8.98 (p = 1.04 x 10(-8)). The region identified in the twins encompasses 4 genes, including SHC2 (605217); SHC2 was deleted in the affected twin and in the MSA patients with 19p deletions, suggesting that it may be a candidate gene for predisposition to the disorder.
The association between variation in the COQ2 gene and susceptibility to multiple system atrophy is controversial.
In affected members of 2 unrelated Japanese families with multiple system atrophy, one of which was reported by Hara et al. (2007), The Multiple-System Atrophy Research Collaboration (2013) identified homozygous or compound heterozygous mutations in the COQ2 gene (609825.0006-609825.0008). The mutations were found in the first family by linkage analysis combined with whole-genome sequencing. Subsequent sequencing of the COQ2 gene in 363 Japanese patients with sporadic MSA and 2 sets of controls (520 individuals and 2,383 individuals) identified putative heterozygous or biallelic pathogenic variants in 33 patients (see, e.g., 609825.0009). The most common variant was V393A (609825.0007), which was also found in heterozygous state in 17 controls. Rare pathogenic variants were also found in 4 of 223 European patients with sporadic disease and in 1 of 172 North American patients with sporadic disease. In vitro functional expression assays in yeast Coq2-null strains showed that the mutations caused variable growth defects and variably low COQ2 activities in patient cell lines. The findings suggested that mutations in the COQ2 gene may cause susceptibility to the disorder. Patients with COQ2 mutations had increased frequency of the cerebellar variant compared to the parkinsonism variant. Four additional families with MSA, including the German family reported by Wullner et al. (2009), did not have COQ2 mutations, indicating genetic heterogeneity.
Quinzii et al. (2014) commented that 2 Japanese sibs with COQ2 mutations reported by The Multiple-System Atrophy Research Collaboration (2013) had retinitis pigmentosa and low levels of COQ10 in the cerebellum, similar to that observed in patients with primary COQ10 deficiency (607426).
Jeon et al. (2014) did not find an association between the V393A variant in the COQ2 gene (609825.0007) and multiple system atrophy among 299 Korean patients with the disorder and 365 controls (minor allele frequency 2.7% of cases versus 2.6% of controls). Sharma et al. (2014) did not find the V393A variant in a large cohort of 788 European patients with MSA or 600 European controls. Schottlaender and Houlden (2014) did not find the V393A variant in more than 300 European patients with MSA or 262 European controls. These authors suggested that variation in the COQ2 gene may not represent a risk factor for the development of multiple system atrophy.
Exclusion Studies
Among 47 patients with MSA, Morris et al. (2000) excluded pathogenic mutations and association with variation in the SNCA (163890), MAPT (157140), synphilin (SNCAIP; 603779), and APOE (107741) genes.
The Multiple-System Atrophy Research Collaboration (2013) excluded COQ2 mutations in 3 of the Japanese families reported by Hara et al. (2007) and in the German family reported by Wullner et al. (2004, 2009), indicating genetic heterogeneity.
In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000; of these, 7% were thought to have the Shy-Drager syndrome.
Schatz (1996) pointed out that a consensus statement generated by the American Autonomic Society and the American Academy of Neurology, defining the various neurogenic causes of autonomic dysfunction, suggested abandonment of the term 'Shy-Drager' syndrome. The consensus statement suggested that the nosology for autonomic disorders include: (1) primary pure autonomic failure (previously called idiopathic orthostatic hypotension or the Bradbury-Eggleston syndrome) in which no neurologic defects other than autonomic dysfunction are present; and (2) multiple system atrophy, a sporadic, progressive, adult-onset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. Secondary autonomic failure can occur in diabetes mellitus, amyloidosis, dopamine beta-hydroxylase deficiency (223360), and drug toxicity.
Another report from a consensus conference on MSA (Gilman et al., 1998) also concluded that the term 'Shy-Drager' syndrome had been misused and should no longer be used. They recommended the term 'multiple system atrophy,' which could also be subgrouped into MSA-P, if parkinsonian features predominate, or MSA-C, if cerebellar symptoms predominate. MSA-P and MSA-C replace the previous terms 'striatonigral degeneration' and 'olivopontocerebellar atrophy,' respectively. Another confusing term, 'multisystem degeneration,' was deemed inappropriate and its use discouraged.
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