Hereditary Spinocerebellar Degeneration Research Articles

Recent clinical advances in hereditary spinocerebellar degeneration

Spinocerebellar degeneration (SCD) is a neurodegenerative disorder characterized by cerebellar ataxia and other multisystem manifestations, such as Parkinsonism and pyramidal tract symptoms. No effective treatment is available for SCD. Approximately one-third of the cases of SCD are inherited, and the remaining two-third are sporadic, including multiple system atrophy. This article provides an overview of hereditary SCD, its clinical features, recent treatment advances, biomarkers, role of genomic medicine, and future treatment prospects.

Valuable insights into hereditary spinocerebellar degeneration from clusters of homozygosity in Africa.

Valuable insights into hereditary spinocerebellar degeneration from clusters of homozygosity in Africa.

Abnormal saccade profiles in hereditary spinocerebellar degeneration reveal cerebellar contribution to visually guided saccades

ObjectiveTo study how the pathophysiology underlying hereditary spinocerebellar degeneration (spinocerebellar ataxia; SCA) with pure cerebellar manifestation evolves with disease progression using saccade recordings. MethodsWe recorded visually- (VGS) and memory-guided saccade (MGS) task performance in a homogeneous population of 20 genetically proven SCA patients (12 SCA6 and eight SCA31 patients) and 19 normal controls. ResultsFor VGS but not MGS, saccade latency and amplitude were increased and more variable than those in normal subjects, which correlated with cerebellar symptom severity assessed using the International Cooperative Ataxia Rating Scale (ICARS). Parameters with significant correlations with cerebellar symptoms showed an aggravation after disease stage progression (ICARS > 50). The saccade velocity profile exhibited shortened acceleration and prolonged deceleration, which also correlated with disease progression. The main sequence relationship between saccade amplitude and peak velocity as well as saccade inhibitory control were preserved. ConclusionsThe cerebellum may be involved in initiating VGS, which was aggravated acutely during disease stage progression. Dysfunction associated with disease progression occurs mainly in the cerebellum and brainstem interaction but may also eventually involve cortical saccade processing. SignificanceSaccade recording can reveal cerebellar pathophysiology underlying SCA with disease progression.

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations.

Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

Usefulness of an anti-mouse cerebellar tissue-derived antigen antibody test in predicting immunotherapy efficacy in patients with idiopathic cerebellar ataxia

Autoimmune cerebellar ataxia (AICA) is a general term for diseases in which the cerebellum is damaged by an autoimmune mechanism. For the diagnosis of the AICA, anti-thyroid antibodies (anti-thyroid peroxidase antibody and anti-thyroglobulin antibody), anti-glutamic acid decarboxylase (GAD) antibodies, and anti-gliadin antibodies are measured. Immunotherapy is known to be effective for AICA, but some patients with effective immunotherapy lack autoantibodies associated with cerebellar ataxia. The purpose of this study was to clarify whether the effectiveness of immunotherapy in patients with suspected AICA could be predicted by anti-mouse cerebellar tissue-derived antigen antibody tests. This study was conducted on 25 patients with idiopathic cerebellar ataxia (excluding multiple system atrophy, hereditary spinocerebellar degeneration, cancer-bearing patients, and patients taking phenytoin) who received immunotherapy from 2005 to 2016 at Tokyo Medical University Hachioji Medical Center. The patients were suspected of having AICA because they were positive for cerebellar ataxia-related autoantibodies (anti-thyroid antibody, anti-GAD antibody, anti-gliadin antibody, or anti-transglutaminase 6 antibody) or other autoantibodies. Antibodies that bind to mouse cerebellar tissue-derived antigens were defined as "anti-mouse cerebellar tissue-derived antigen antibodies" in this study, and their IgG-class antibodies were comprehensively measured using a slot blot. Anti-mouse cerebellar tissue-derived antigen antibody test results were correlated with immunotherapy efficacy. Furthermore, the combination of anti-mouse cerebellar tissue-derived antigen and anti-GAD antibody tests could predict the effectiveness of immunotherapy with 83% sensitivity and 100% specificity, while the combination of the anti-mouse cerebellar tissue-derived antigen, anti-GAD, and anti-gliadin (IgA class) antibody tests could predict the effectiveness of immunotherapy with 94% sensitivity and 86% specificity. Anti-mouse cerebellar tissue-derived antigen antibody tests could help to provide useful information for immunotherapy administration to patients with idiopathic cerebellar ataxia suspected to be AICA.

The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives.

Hereditary spinocerebellar degeneration (SCD) encompasses an expanding list of rare diseases with a broad clinical and genetic heterogeneity, complicating their diagnosis and management in daily clinical practice. Correct diagnosis is a pillar for precision medicine, a branch of medicine that promises to flourish with the progressive improvements in studying the human genome. Discovering the genes causing novel Mendelian phenotypes contributes to precision medicine by diagnosing subsets of patients with previously undiagnosed conditions, guiding the management of these patients and their families, and enabling the discovery of more causes of Mendelian diseases. This new knowledge provides insight into the biological processes involved in health and disease, including the more common complex disorders. This review discusses the evolution of the clinical and genetic approaches used to diagnose hereditary SCD and the potential of new tools for future discoveries.

Early decrease in intermediate monocytes in peripheral blood is characteristic of multiple system atrophy-cerebellar type

To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes from patients with MSA-C or hereditary spinocerebellar degeneration (hSCD) and from healthy controls (HCs). The percentage of intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs and showed significant positive correlations with disease duration and unified MSA rating scale scores. The percentage of CD62L+ intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs. Early decrease of peripheral blood intermediate monocytes is characteristic of MSA-C and is a biomarker.

Deciphering Cortical Cerebellar Atrophy through Molecular Genetics

Cortical cerebellar atrophy (CCA) contains hereditary spinocerebellar degeneration (hSCD) and genetic testing is necessary for an accurate diagnosis. Screening for frequent hSCDs (triplet repeat disease and SCA31) was performed. Panel analysis and whole exome analysis using a next-generation sequencer were also performed. The Japan Consortium for Ataxias, J-CAT, contributes to the elucidation of the genetic epidemiology of CCA. The elucidation of CCA would be promoted by comprehensive gene analysis, including whole genome analysis.

Exploring the molecular basis of hereditary spinocerebellar degeneration in a large Sudanese family

Spinocerebellar neurodegeneration (SCD) is phenotypically and genetically complex forming a heterogeneous spectrum of disorders with hereditary spastic paraplegias on one end and hereditary ataxias on the other. Genetics of SCD has been a target for extensive researches worldwide, yet little is known about SCD genetics in Sub-Saharan African population. We recruited a large consanguineous Sudanese family with five affected siblings. Extracted genomic DNA was screened for genetic variations using whole exome sequencing (WES). Analysis was done to identify the culprit variations using bioinformatics tools. Clinical results showed a complex phenotype of progressive spastic-ataxia, deafness and microcephaly. Analysis of WES data suggested two homozygous missense variants in two candidate genes (MYO15A and SEMA5D) that were not reported to be linked to similar disease before. The first variant in MYO15A gene (NM_016239.3: c.1634C>T) was reported to cause autosomal recessive hearing loss but was not reported in similar neurological disease. The second variant in SEMA4D gene (NM_006378.3:c.1588G>A) which involved in brain development but not reported to be associated with inherited neurological conditions before. Both variants were extremely rare and highly conserved. They were predicted to be highly pathogenic using bioinformatics tools. The scarcity of genetic data in the highly consanguineous Sudanese population makes whole exome sequencing a powerful and cost effective strategy to identify both known and new pathogenic variations and genes. Sanger sequencing and further functional studies are recommended to prove the association of MYO15A gene and SEMA4D gene with the complex clinical phenotype of deafness, spasticity and ataxia.

S161. Eye-hand coordination in hereditary spinocerebellar degeneration

Gaze and hand movements are known to be closely linked in daily actions (eye-hand coordination), and the cerebellum is implicated in the control of this eye-hand coordination. There are negative reciprocal interactions between the eye and hand movements when patients with cerebellar dysfunction perform a target tracking task. We devised a system which is capable of simultaneously recording the trajectory of hand and eye movements when subjects performed a visually guided reaching task. The aim of this preliminary study was to investigate how cerebellar dysfunction affects the coordination. Subjects were 8 patients with hereditary spinocerebellar degeneration (SCA6 or SCA31) with pure cerebellar symptoms and 9 age-matched normal controls. A video-based eye tracker recorded eye movements while a touch panel recorded the trajectory of finger movements while performing the visually guided reaching task. A fixation spot was presented in the center of the touch panel, which the subjects fixated and touched with the index finger. At a random interval, this fixation spot moved to a peripheral position, selected from positions at an eccentricity of 10 or 20 degrees (in 8 directions separated by 45 degrees), to which the subjects were to move their fingers by sliding their fingers over the monitor. The subjects also performed a visual guided saccade task, in which they made a saccade to the peripheral target without moving the finger. In SCA patients, trajectory of both eye and finger showed hypermetria in comparison with normal controls. Superimposed trajectories of saccades showed a wider distribution than that of finger movements, which implied that the variability of eye movements did not directly translate into that of the hand movements. In most trials, the eyes preceded the finger movements to the target location, and was locked at the target location until the hand was reached the target location. The interval between onsets of the hand and eye movements was larger for SCA patient than for normal subjects. This wider separation between the hand and eye onset was due to the eyes moving to the targets in multiple steps of saccades with changing direction and the hand did not start before the eyes reached the vicinity of the target. Eye-hand coordination was disrupted in hereditary spinocerebellar degeneration. In SCA patients, the multistep saccade and saccades that changed direction toward the target prevented gaze locking at the target required for eye-hand coordination, and led to increased interval between the saccade onset and finger onset.

P1-2-09. Saccadic eye movements in spinocerebellar degeneration – correspondence to clinical manifestation

Objectives The cerebellum is implicated in the control of saccade but saccade abnormality in cerebellar disorders is not fully delineated, especially in the vertical directions. To clarify the role of the cerebellum, we studied saccades in hereditary spinocerebellar degeneration (SCD) with pure cerebellar presentation. Methods Subjects were 20 SCD patients (SCA6, 31) and 19 normal age-matched controls. We used the visual guided (VGS) and memory guided saccade tasks (MGS) in which targets were presented in 8 possible directions with 45 degree separation, and recorded saccades with a video-based eye tracker. Results In SCA patients, latency was significantly delayed mainly in vertical and oblique directions, which correlated with SARA scores. The number of both overshoot and undershoot increased correlatively with SARA scores in all directions. Peak velocity showed no change, but the time from the beginning to the peak velocity of the saccade was shorter, whereas the time from the peak velocity to the end of saccade was longer. Conclusion The change in amplitude and velocity profile may reflect abnormal output from the cerebellar nuclei, whereas the pathophysiology of prolonged latency remains elusive. We hope the saccade analysis paves the way toward objective assessment of SCD and other neurological disorders.

Whole exome sequencing analysis revealed complex genetic architecture of early-onset spinocerebellar degeneration in the Japanese Population

Background: Hereditary spinocerebellar degeneration (hSCD) is genetically heterogeneous group of disorders with more than 50 causative genes. Molecular epidemiology of early-onset SCD in the Japanese population has not been fully delineated.

P2-71. Saccadic eye movements in Spinocerebellar Degeneration – study of saccades in eight directions

Objectives The cerebellum is implicated in the control of saccadic eye movement but it is unknown how it differs for vertical and horizontal saccades, since vertical saccades have been rarely studied. To clarify the role of the cerebellum we studied saccades in hereditary spinocerebellar degeneration in two dimensional directions. Methods We compared saccade performance in 16 patients (SCA31 and SCA6) with that in 19 normal age-matched controls. We used the visual guided (VGS) and memory guided tasks (MGS) in which targets were presented in eight directions with 45 degrees separation, and recorded saccades with a video-based eye tracker. Results In SCA patients, latency of VGS was significantly delayed compared with normal subjects in vertical and oblique directions, which correlated with SARA scores. MGS latency was significantly delayed only in the oblique direction. Hypermetria was prominently detected in the vertical and oblique directions, but less in the horizontal directions. Conclusion Abnormal latency and dysmetria are easily detected for directions having vertical component. The cerebellum may be more involved in vertical than in horizontal saccade system, or vertical saccade system may be more susceptible to diseases than horizontal saccades. Further study of other diseases will be helpful to differentiate between these possibilities.

DAT SPECT may have diagnostic value in prodromal SCA2 patients with parkinsonism

IntroductionAlthough spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia. Methods123I-metaiodobenzyl guanidine (123I-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using 123I-ioflupane (123I-FP-CIT) were performed for the six patients from three SCA2 families. Results123I-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinson's disease, most of the patients had minimal reduction of uptake in the putamen. ConclusionDAT SPECT is expected to be useful in differentiating SCA2 from Parkinson's disease, making an early diagnosis, and allowing early therapeutic intervention.

Overview of Hereditary Spinocerebellar Ataxias in Japan

Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non-cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X-linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non-cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking.

Striatal glucose hypometabolism in preadolescent-onset dentatorubral–pallidoluysian atrophy

Dentatorubral–pallidoluysian atrophy (DRPLA) is hereditary spinocerebellar degeneration presenting various symptoms in association with expansion of the CAG repeat in Atrophin-1 gene. The functional neuroimaging of DRPLA has been poorly investigated. The purpose of this study was to examine 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) findings of DRPLA. We retrospectively investigated the cases of 14 consecutive genetically confirmed DRPLA patients at our institute. Four juvenile-onset patients underwent 18F-FDG-PET because of intractable seizures. Their 18F-FDG-PET images, clinical profiles and MRI findings were evaluated. For quantitative comparison, 3 healthy volunteers also underwent 18F-FDG-PET as controls. All four patients presented progressive myoclonus epilepsy without MRI abnormalities. Both the visual and quantitative assessments of their 18F-FDG-PET findings demonstrated bistriatal hypometabolism in only the two preadolescent-onset patients with larger CAG repeat size, whereas the two other later-onset patients showed no hypometabolism in the striatum. Bistriatal glucose hypometabolism in preadolescent-onset DRPLA patients might reflect more severe degeneration. This finding could contribute to a better understanding of DRPLA.

Dentatorubral‐pallidoluysian atrophy (DRPLA)

Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary spinocerebellar degeneration. Despite the establishment of this disease in 1982, it has been pointed out that DRPLA has an unexplained aspect concerning its clinicopathological features; that is, the discrepancy between the variety of clinical manifestations and the uniformity of the brain lesions. The discovery of a causative gene mutation (abnormal expansion of the CAG repeat in DRPLA gene) triggered the development of novel neuropathology in DRPLA, which has suggested that polyglutamine-related pathogenesis involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. It is now likely that DRPLA has an aspect of neuronal storage disorder and has multiple system degeneration, the lesion distribution of which varies depending on the CAG repeat sizes in the causative gene.

性腺機能低下症を合併した小脳性運動失調症の１例

A 28-year-old man had experienced non-progressive gait disturbance since early childhood. He was admitted because of hypogonadism and cerebellar ataxia. On admission, bilateral vitelliform macular dystrophy, fixation nystagmus, slurred speech, cerebellar ataxia, decreased tendon reflexes, and pes cavus were present. Higher brain function, auditory function, and olfactory function were not disturbed. A gene abnormality related to known hereditary spinocerebellar degeneration and Kallman syndrome was not observed. Brain MRI demonstrated cerebellar atrophy. ECD-SPECT revealed decreased blood flow in the brain stem and cerebellum. Endocrinological tests indicated that the hypogonadism seemed to be due to a primary pituitary disturbance. This is the second case of Boucher-Neuhäuser syndrome in Japan.

Cutaneous accumulation of abnormal polyglutamine proteins of patients with dentatorubral‐pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary spinocerebellar degeneration caused by expansion of a trinucleotide CAG repeat encoding a polyglutamine tract in a disease protein atrophin-1. The clinical features include ataxia, choreoathetosis, and dementia, which result from neural degeneration caused by the mutant atrophin-1. We performed skin biopsy in two patients with DRPLA. We found multiple clear cells in the epidermis, which were positive for proteins containing an expanded polyglutamine stretches. The clear cells were p63 (+), S-100 (-), and cytokeratin 20 (-), showing that they were keratinocytes. Negative or weak signals of pan-cytokeratin were consistent with the finding of decreased tonofilaments at the electron microscopic level. The presence of clear keratincoytes showed that the mutant proteins interfered in cellular functions not only in neural cells but also in keratinocytes. The skin is accessible by biopsy, making it important in the diagnosis. Furthermore, the polyglutamine staining in the skin may be useful for evaluation of therapeutic modalities for DRPLA and other polyglutamine diseases.

Brainstem in Machado–Joseph disease: atrophy or small size?

Machado-Joseph disease (MJD), one of the most common types of hereditary spinocerebellar degeneration caused by abnormal expansion of the CAG repeat in the MJD1 gene, presents atrophy of the infratentorial structures neuropathologically and neuroradiologically. Although a significant positive correlation has been reported between infratentorial atrophy and the number of expanded CAG repeat units, the exact changing course of brainstem size in the individual case remains to be resolved. We investigated seven cases of genetically confirmed MJD longitudinally by magnetic resonance imaging with observation periods of 4.5-10.6 years. Measurement of the midsagittal areas of infratentorial structures disclosed progressive atrophy of the pontine base and cerebellum, which correlated significantly with age, whilst midbrain and pontine tegmentum showed atrophy with no significant progression, suggesting it was better identified as 'small size' and might have mostly been completed before the initial symptoms. Such differences between regions in atrophy progression must be caused by a difference in the neuropathological course.