Hiroyuki Soma

Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

BACKGROUND Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

MSA-C is the predominant clinical phenotype of MSA in Japan: Analysis of 142 patients with probable MSA

We investigated the clinical features and mode of disease progression in 142 patients with probable multiple system atrophy (MSA) according to the Consensus Criteria. The subjects included 84 men and 58 women with a mean age at onset of 58.2+/-7.1 years (range: 38-79 years). Cerebellar signs were detected in 87.3% of these patients at the time of initial examination, and were found in 95.1% of them at latest follow-up. MSA-C was diagnosed in 83.8% of the patients at their first examination. Parkinsonism was initially detected in 28.9% of the patients, increasing to 51.4% at the latest follow-up. Among all of the subjects, only 16.2% were classified as having MSA-P on initial examination. At the latest follow-up, parkinsonian features had become predominant over cerebellar features in 24.6% of the 65 patients with MSA-C who were followed for more than 3 years. Although parkinsonism usually masked the signs of cerebellar involvement in MSA-C patients, none of the patients with MSA-P at an early stage showed predominance of cerebellar features at the latest follow-up. Parkinsonism is the predominant feature of MSA among Western patients, even at an early stage, but this study showed that cerebellar deficits are the main feature in Japanese patients. This difference of disease manifestations between ethnic groups suggests that genetic factors may influence the clinical phenotype of MSA.

Usefulness of the Scale for Assessment and Rating of Ataxia (SARA)

In this study, we examined the usefulness and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in assessing cerebellar ataxia in 27 patients with spinocerebellar degeneration. The inter-rater reliability of the SARA scores between the two neurologists was high. The scores on SARA correlated significantly with the Barthel index and scores on the International Cooperative Ataxia Rating Scale (ICARS). Scores on ICARS and SARA did not correlate with the total length traveled (TLT) or the root mean square area (RMS) of body sways measured by body stabilometry. The time required to examine each patient for SARA was approximately 4 min, one-third the time required for ICARS. Our results indicate that SARA is useful for the evaluation of cerebellar ataxic patients in daily examinations and that body sway analysis by stabilometry is influenced by factors other than cerebellar ataxia, such as muscle weakness, which should be taken into account when body sway analysis is used to evaluate the severity of cerebellar ataxia.

Heredity in Multiple System Atrophy

We investigated the family histories of 157 Japanese patients with probable or possible multiple system atrophy (MSA). A family history of neurodegenerative disorders was only detected in three MSA patients (1.9%). We evaluated these patients by careful neurological examination, neuroimaging studies, and genetic studies to exclude hereditary spinocerebellar ataxia with a similar clinical phenotype to MSA. The results indicated that one of them had a family history of MSA. Although the familial presence of neurodegenerative disorders is rare in MSA patients, the existence of such cases suggests that MSA may have a genetic background.

Microstructural White Matter Abnormalities of Multiple System Atrophy: In Vivo Topographic Illustration by Using Diffusion-Tensor MR Imaging

PURPOSE To determine whether diffusion-tensor (DT) imaging can demonstrate microstructural white matter abnormalities of multiple system atrophy (MSA) and to correlate these imaging findings with clinical signs and symptoms. MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained. DT imaging was performed in 16 patients with MSA with predominant cerebellar symptoms (MSA-C) (mean age, 60.0 years + or - 5.1 [standard deviation]; range, 51-69 years) and 16 age-matched healthy subjects. Fractional anisotropy (FA) and mean diffusivity (MD) were compared voxel-by-voxel between the two groups by using a two-sample t test. Overlap maps were created to illustrate areas with FA and MD alterations. Correlation between DT imaging indexes and Barthel index score, scale for assessment and rating of ataxia (SARA) score, severity of orthostatic hypotension, age of disease onset, and disease duration was tested by using Spearman rank or Pearson product-moment correlation analysis. T2-weighted and proton density-weighted images of the patients were visually assessed. RESULTS Widespread areas of FA reduction and MD elevation were observed in supra- and infratentorial white matter structures in patients with MSA (P < .05, false discovery rate corrected). Significant correlation (P < .01) between DT imaging indexes and Barthel index score, SARA score, severity of orthostatic hypotension, and disease duration was observed for multiple areas with FA and/or MD alterations. T2-weighted and proton density-weighted images showed no significant abnormality in supratentorial white matter. CONCLUSION DT imaging may help identify the microstructural white matter abnormalities of MSA-C. DT imaging may be useful for severity assessment of MSA-C.

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families.

AbstractAutosomal dominant cerebellar ataxia (ADCA) is a genetically heterogeneous group of neurodegenerative disorders. To shed further light on the clinical and genetic spectrum of ADCA in Japan, we conducted a study to determine the frequency of a new variety of different subtypes of SCAs among ADCA patients. This current study was carried out from April 1999 to December 2006 on the basis of patients with symptoms and signs of ADCA disorders. PCR and/or direct sequencing were evaluated in a total of 113 families. Among them, 35 families were found to have the mutation associated with SCA6, 30 with SCA3, 11 with SCA1, five with SCA2, five with DRPLA, and one with SCA14. We also detected the heterozygous −16C → T single nucleotide substitution within the puratrophin-1 gene responsible for 16q22.1-linked ADCA in ten families. In this study, unusual varieties of SCA, including 27, 13, 5, 7, 8, 12, 17, and 16 were not found. Of the 113 patients, 14% had as yet unidentified ADCA mutations. The present study validates the prevalence of genetically distinct ADCA subtypes based on ethnic origin and geographical variation, and shows that 16q-linked ADCA has strong hereditary effects in patients with ADCAs in Japan.

Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes.

Multiple system atrophy (MSA) is an adult‐onset sporadic neurodegenerative disease. Although the etiology of MSA remains obscure, recent studies suggest that oxidative stress is associated with the pathogenesis of MSA. The aim of this study was to evaluate genetic associations between the candidate genes involved in oxidative stress and MSA in a case‐control study. We examined 119 Japanese patients with MSA and 123 controls, and genotyped single‐nucleotide polymorphisms (SNPs) of the following eight genes: CCAAT/enhancer‐binding protein homologous protein, activating transcription factor 3, CCAAT/enhancer‐binding protein‐β, sequestosome 1 (SQSTM1), cysteinyl‐tRNA synthetase, solute carrier family 1A4 (SLC1A4), activating transcription factor 4, and eukaryotic translation initiation factor 4E‐binding protein 1 (EIF4EBP1). SLC1A4 SNP +28833 (V398I, rs759458, genotype: Pc = 0.0186, allele: Pc = 0.0303, Pc: P‐value with Bonferroni correction), two major haplotypes of SLC1A4 “T‐C‐C‐G” and “T‐C‐T‐A” (Pc = 0.0261 and 0.000768), two‐SNP haplotypes of SQSTM1 “C‐T” and “A‐T” (Pc = 0.0136 and 0.0369), and the most common haplotype of EIF4EBP1 “C‐T‐G‐C” (Pc = 0.0480) showed significant associations. This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA.

Hyperintense putaminal rim at 1.5 T: prevalence in normal subjects and distinguishing features from multiple system atrophy

BackgroundHyperintense putaminal rim (HPR) is an important magnetic resonance imaging (MRI) sign for multiple system atrophy (MSA). Recent studies have suggested that it can also be observed in normal subjects at 3 T. Whether it can be observed in normal subjects at 1.5 T is not known. This study aimed to determine whether HPR could be observed in normal subjects at 1.5 T; and if so, to establish its prevalence, the MRI characteristics, and the features which distinguish from HPR in MSA patients.MethodsAxial T2-weighted images of 130 normal subjects were evaluated for the prevalence of HPR, its age and gender distribution, laterality, maximum dimension, association with hypointensity of nearby putamen, and presence of discontinuity. To distinguish from that observed in MSA, axial T2-weighted images of 6 MSA patients with predominant parkinsonism (MSA-P) and 15 MSA patients with predominant cerebellar symptoms (MSA-C) were also evaluated. The characteristics of HPR were compared between these patients and age-matched normal subjects. The mean diffusivity (MD) values of putamen were also compared. Fisher’s exact test, t-test, and one way analysis of variance were used to determine significance at corrected p < 0.05.ResultsHPR was observed in 38.5% of normal subjects. Age and gender predilection and laterality were not observed. In most cases, it occupied the full length or anterior half of the lateral margin of putamen, and was continuous throughout its length. Maximum transverse dimension was 2 mm. There was no association with hypointensity of nearby putamen. However, in MSA-P, HPR was located predominantly at the posterolateral aspect of putamen, and associated with putaminal atrophy. Discontinuity of HPR was more frequently observed in MSA-P. On visual analysis, the characteristics of HPR were similar between MSA-C patients and normal subjects. Patients with MSA of either type had significantly higher MD values of putamen than normal subjects.ConclusionsHPR can be observed in 38.5% of normal subjects at 1.5 T. Thin linear hyperintensity without discontinuity, occupying the full length or anterior half of the lateral margin of the putamen, is suggestive of “normal.” In doubtful cases, measurement of the MD values of nearby putamen may be valuable.

Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family

Clinical examinations and mutational analyses were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.

Four mutations of the spastin gene in Japanese families with spastic paraplegia

AbstractHereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A→G, 1207C→G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.