Dominant Spinocerebellar Ataxia Research Articles

Chapter 10 - Spinocerebellar ataxias

There are over 40 autosomal dominant spinocerebellar ataxias (SCAs) now identified. In this chapter we delineate the phenotypes of SCAs 1-44 and dentatorubral-pallidoluysian atrophy (DRPLA) and highlight the clinical and genetic features of the well characterised SCAs in detail in the main section of the chapter, along with their frequency and age at onset. We have included a section on the key phenotypic features of rare spinocerebellar ataxias and discuss rare and unusual presentations and genetic mechanisms of the ataxias and show differences between adult and paediatric presentations. We look at unusual mechanisms where knowledge is evolving in some dominant ataxias. For ease of reference we have tabulated historical aspects of the ataxias, major neurological diagnostic features, ataxias with predominant paediatric and infantile onset and list recognisable nerve conduction features. We comment on the anti-sense ataxia gene mechanisms and we discuss potential developments including exome sequencing and potential therapeutic options. A gene table listing all of the identified SCAs and DRPLA is also included with key references and gene locations and symbols with OMIM reference numbers for further reading.

Origins and Spread of Machado-Joseph Disease Ancestral Mutations Events.

Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia reported worldwide, but it shows marked geographic differences in prevalence. The study of ancestral origins and spreading routes of MJD mutational events has contributed to explain such differences. During human evolution, at least two independent de novo MJD expansions occurred in distinct haplotype backgrounds: TTACAC and GTGGCA (named Joseph and Machado lineages). The most ancient Joseph lineage, probably of Asian origin, has been introduced recently in Europe, where founder effects are responsible for the high MJD prevalence, as occurs in the Portuguese/Azorean island of Flores and Northeastern mainland. The Machado lineage is geographically more restricted, with most known families in Portugal (island of São Miguel and along the Tagus valley). The hypothesis of other mutational origins has been raised, namely to explain the disease among Australian aborigines; however, a comprehensive haplotype study suggested the introduction of the Joseph lineage in that community via Asia. Also, additional SNP-based haplotypes (TTAGAC, TTGGAC and GTGCCA) were observed in other MJD families, but phylogenetic analysis with more polymorphic flanking markers did not point to independent mutational events, reinforcing the hypothesis of a very low mutation rate underlying this repeat expansion locus.

Epidemiological, clinical, and genotype characterization of spinocerebellar ataxia type in families in Buriram province, northeast Thailand

Abstract Background In Thais, the most prevalent type of spinocerebellar ataxia (SCA) is type 3, most commonly known as Machado–Joseph disease (MJD), followed by SCA type 1 (SCA1), SCA2, and SCA6. Objectives To describe the epidemiological, clinical, and genotypic features of SCA in northeastern Thailand and to study 2 associations: between syndromic features and the genotype of SCA, and between health determinants and scores on the scale for the assessment and rating of ataxia (SARA). Methods We conducted a cross-sectional study of 24 patients with autosomal dominant SCA from 13 families recruited from Buriram province in northeast Thailand between December 2009 and January 2014. Patients provided a clinical history and were examined by a neurologist. DNA was extracted from the peripheral blood of each patient. We analyzed associations between the type of SCA and sex, age, family history, clinical features, any underlying disease, age at onset, body weight, smoking status, family history, alcohol consumption, head injury history, and SARA. Results Seven of the families were positive for SCA1 and 6 for MJD. There were 24 index patients from these autosomal dominant SCA families, including 13 with SCA1 and 11 with MJD. Their average age was 43.7 years (range 20–72 years), whereas their average age at disease onset was 36.9 years (range 18–59 years). Pyramidal signs between MJD and SCA1 were not significantly different. Extrapyramidal features appeared uncommon. Horizontal nystagmus and upward gaze paresis were significantly associated with MJD. There were no significant differences in demographic data between the groups with SARA scores ≥15 or <15. Conclusions MJD and SCA1 were the 2 adult-onset cerebellar degenerative diseases found in Buriram province. Clinical clues for differentiating between them were upward gaze paresis and horizontal nystagmus, which were significantly more common in MJD.

Microstructural Alterations in Asymptomatic and Symptomatic Patients with Spinocerebellar Ataxia Type 3: A Tract-Based Spatial Statistics Study.

Spinocerebellar ataxia type 3 (SCA3) is the most commonly occurring type of autosomal dominant spinocerebellar ataxia. The present study aims to investigate progressive changes in white matter (WM) fiber in asymptomatic and symptomatic patients with SCA3. A total of 62 participants were included in this study. Among them, 16 were asymptomatic mutation carriers (pre-SCA3), 22 were SCA3 patients with clinical symptoms, and 24 were normal controls (NC). Group comparison of tract-based spatial statistics was performed to identify microstructural abnormalities at different SCA3 disease stages. Decreased fractional anisotropy (FA) and increased mean diffusivity (MD) were found in the left inferior cerebellar peduncle and superior cerebellar peduncle (SCP) in the pre-SCA3 group compared with NC. The symptomatic SCA3 group showed brain-wide WM tracts impairment in both supratentorial and infratentorial networks, and the mean FA value of the WM skeleton showed a significantly negative correlation with the International Cooperative Ataxia Rating Scale (ICARS) scores. Specifically, FA of the bilateral posterior limb of the internal capsule negatively correlated with SCA3 disease duration. We also found that FA values in the right medial lemniscus and SCP negatively correlated with ICARS scores, whereas FA in the right posterior thalamic radiation positively correlated with Montreal Cognitive Assessment scores. In addition, MD in the middle cerebellar peduncle, left anterior limb of internal capsule, external capsule, and superior corona radiate positively correlated with ICARS scores in SCA3 patients. WM microstructural changes are present even in the asymptomatic stages of SCA3. In individuals in which the disease has progressed to the symptomatic stage, the integrity of WM fibers across the whole brain is affected. Furthermore, abnormalities in WM tracts are closely related to SCA3 disease severity, including movement disorder and cognitive dysfunction. These findings can deepen our understanding of the neural basis of SCA3 dysfunction.

Clinical and magnetic resonance imaging features of elderly onset dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar ataxia caused by CAG triplet expansion in atrophin 1 and is frequently associated with cerebral white matter lesions. To elucidate the clinical features of elderly onset DRPLA and the key radiological findings for differentiating DRPLA from physiological white matter lesions in healthy elderly subjects, we reviewed the clinical and magnetic resonance imaging (MRI) features of ten patients with elderly onset genetically confirmed DRPLA (>60years) and compared their MRI findings with those of age- and sex-matched ten healthy subjects with asymptomatic cerebral white matter lesions. The initial symptom was cerebellar ataxia in all DRPLA patients, and five of them did not have any symptoms other than ataxia at the time of MRI examination. Atrophy of the brainstem, superior cerebellar peduncle, and cerebellum was detected in all DRPLA patients and none of the healthy subjects. Abnormal signals in the brainstem (inferior olive, pons, and midbrain), thalamus, and cerebellar white matter were frequently observed in elderly onset DRPLA patients but not in healthy subjects. In conclusion, elderly onset DRPLA presents as cerebellar ataxia alone in the early stage of disease. Atrophy of the brainstem, superior cerebellar peduncle, and cerebellum and abnormal signals in the brainstem, cerebellum, and thalamus are key findings for differentiating elderly onset DRPLA from asymptomatic cerebral white matter lesions in healthy subjects.

Clinical and genetic analysis of spinocerebellar ataxia type 7 (SCA7) in Zambian families

BackgroundTo date, 43 types of Spinocerebellar Ataxias (SCAs) have been identified. A subset of the SCAs are caused by the pathogenic expansion of a CAG repeat tract within the corresponding gene. Ethnic and geographic differences are evident in the prevalence of the autosomal dominant SCAs. Few descriptions of the clinical phenotype and molecular genetics of the SCAs are available from the African continent. Established studies mostly concern the South African populations, where there is a high frequency of SCA1, SCA2 and SCA7. The SCA7 mutation in South Africa (SA) has been found almost exclusively in families of indigenous Black African ethnic origin.ObjectiveTo present the results of the first clinical description of seven Zambian families presenting with autosomal dominant SCA, as well as the downstream molecular genetic analysis of a subset of these families.MethodsThe study was undertaken at the University Teaching Hospital in Lusaka, Zambia. Ataxia was quantified with the Brief Ataxia Rating Scale derived from the modified international ataxia rating scale. Molecular genetic testing for 5 types of SCA (SCA1, SCA2, SCA3, SCA6 and SCA7) was performed at the National Health Laboratory Service at Groote Schuur Hospital and the Division of Human Genetics, University of Cape Town, SA. The clinical and radiological features were evaluated in seven families with autosomal dominant cerebellar ataxia. Molecular genetic analysis was completed on individuals representing three of the seven families.ResultsAll affected families were ethnic Zambians from various tribes, originating from three different regions of the country (Eastern, Western and Central province). Thirty-four individuals from four families had phenotypic features of SCA7. SCA7 was confirmed by molecular testing in 10 individuals from 3 of these families. The age of onset of the disease varied from 12 to 59 years. The most prominent phenotypic features in these families were gait and limb ataxia, dysarthria, visual loss, ptosis, ophthalmoparesis/ophthalmoplegia, pyramidal tract signs, and dementia. Affected members of the SCA7 families had progressive macular degeneration and cerebellar atrophy. All families displayed marked anticipation of age at onset and rate of symptom progression. The pathogenic SCA7 CAG repeat ranges varied from 47 to 56 repeats. Three additional families were found to have clinical phenotypes associated with autosomal dominant SCA, however, DNA was not available for molecular confirmation. The age of onset of the disease in these families varied from 19 to 53 years. The most common clinical picture in these families included a combination of cerebellar symptoms with slow saccadic eye movements, peripheral neuropathy, dementia and tremor.ConclusionSCA is prevalent in ethnic Zambian families. The SCA7 families in this report had similar clinical presentations to families described in other African countries. In all families, the disease had an autosomal dominant pattern of inheritance across multiple generations. All families displayed anticipation of both age of onset and the rate of disease progression. Further clinical and molecular investigations of the inherited ataxias in a larger cohort of patients is important to understand the natural history and origin of SCAs in the Zambian population.

Challenges in sleep stage R scoring in patients with autosomal dominant spinocerebellar ataxias (SCA1, SCA2 and SCA3) and oculomotor abnormalities: a whole night polysomnographic evaluation

ObjectivesSpinocerebellar ataxias are progressive neurodegenerative disorders characterized by progressive cerebellar features with additional neuro-axis involvement. Oculomotor abnormality is one of the most frequent manifestations. This study was done to assess the polysomnographic abnormalities in patients with Spinocerebellar ataxia (SCA1, SCA2 and SCA3) and also to evaluate whether oculomotor abnormalities interfere with sleep stage R scoring. MethodsThe study was carried out using 36 genetically positive SCA patients. All patients underwent neurological examination with special focus on oculomotor function (optokinetic nystagmus-OKN and extraocular movement restriction-EOM). The sleep quality was measured with Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Disease severity was assessed with International Cooperative Ataxia Rating Scale (ICARS). All the patients underwent over-night video-polysomnography (VPSG). ResultsOut of 36 patients studied, the data of 34 patients [SCA1 (n = 12), SCA2 (n = 13), SCA3 (n = 9)] were used for final analysis. Patients from SCA1, SCA2, and SCA3 category did not show significant differences in age and diseases severity (ICARS). All patients had vertical OKN impairment. Oculomotor impairment was higher in SCA2 patients. Sleep macro-architecture analysis showed absent stage R sleep, predominantly in SCA2 (69%) followed by SCA3 (44%) and SCA1 (8%). Patients showed a strong negative correlation of stage R sleep percentage with disease severity and oculomotor dysfunction. ConclusionVoluntary saccadic eye movement velocity and rapid eye movements (REMs) in sleep are strongly correlated. The more severe the saccadic velocity impairment, the less likely was it to generate REMs (rapid eye movements) during stage R. Accordingly 69% of SCA2 patients with severe occulomotor impairments showed absent stage R as per the AASM sleep scoring. We presume that the impaired REMs generation in sleep could be due to oculomotor abnormality and has resulted in spuriously low or absent stage R sleep percentage in SCA patients with conventional VPSG scoring rules. The present study recommends the modification of AASM scoring rules for stage R in patients with oculomotor abnormalities.

Chinese herbal medicine extracts targeting ubiquitin proteasome pathway to reduce polyq aggregation in cell models of spinocerebellar ataxia 3

Background: Autosomal dominant spinocerebellar ataxias (SCA) are caused by the abnormal expansions of CAG trinucleotide repeats and associated polyglutamine (polyQ) tract. Accumulation of aggregated disease proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and degeneration. SCA type 3 (SCA3), the most common form of SCA worldwide, is characterized by a CAG triplet expansion in chromosome 14q32.1 ATXN3 gene, with 13-36 repeats in normal individuals and 68-79 repeats in clinically diagnosed patients.

AB065. Genetic testing and counseling in family with late onset autosomal dominant spinocerebellar ataxia

AB065. Genetic testing and counseling in family with late onset autosomal dominant spinocerebellar ataxia

A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.

The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.

A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study

The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. Eleven adult patients with a confirmed genetic diagnosis of autosomal dominant spinocerebellar ataxia or Friedreich's ataxia were asked to wear an active device for 3weeks. Assessments were performed at baseline, after the device use (T1), and 3weeks after (T2). SARA, 9-HPT, PATA, 6MWT, and spatial and temporal gait parameters, measured with a BTS-G-Walk inertial sensor, were used as study endpoints. As expected, no adverse effects were reported. Statistically significant improvements in SARA, 9HPT dominant hand, PATA test, 6MWT, cadence, length cycle, support right/cycle, support left/cycle, flight right/cycle, flight left/cycle, double support right/cycle, double support left/cycle, single support right/cycle, and single support left/cycle were observed between T0 and T1. All parameters improved at T1 did not show statistically significant differences a T2, with the exception of length of cycle. This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.

Clinical features of Chinese patients with Gerstmann–Sträussler–Scheinker identified by targeted next-generation sequencing

Gerstmann–Sträussler–Scheinker (GSS) is an autosomal dominant neurodegenerative disease due to mutations within prion protein (PRNP) gene. Clinically, it is not easy to distinguish GSS from spinocerebellar ataxia (SCA), especially in the early stage of disease. We aimed to identify genetic mutations in 8 Chinese pedigrees with dominant ataxia but excluded dynamic mutations of SCA genes. Targeted next-generation sequencing was performed in the 8 probands. A customized panel was designed to capture 24 known causative genes, including 15 autosomal dominant SCA genes and 9 dementia-related genes. A 2-year follow-up was performed in these patients who harbored mutation. Of the 8 probands, 5 were identified to harbor the p.P102L mutation within PRNP. All these 5 cases had progressive ataxia with age at onset ranging from 48 to 52 years (49.5 ± 4.51). Remarkable phenotypic heterogeneity was observed in them. Cognitive decline was found in 4/5 probands. The average duration from initial symptoms to cognitive decline is 32.5 months, ranging from 22 to 48 months. In this study, we presented the detailed clinical features of 5 GSS pedigrees with PRNP p.P102L mutation. The variable phenotypes among these GSS patients indicated other genetic or environmental factors might be involved in the phenotypic heterogeneity of GSS. Our findings also support the proposal that screening of PRNP mutations should be performed for the patients with dominant ataxia if dynamic mutations of SCA genes were excluded.

Cellular and circuit mechanisms underlying spinocerebellar ataxias.

Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease.

Determination of Genotypic and Phenotypic Characteristics of Friedreich's Ataxia and Autosomal Dominant Spinocerebellar Ataxia Types 1, 2, 3, and 6.

This study aimed to analyze the genotypic characteristics of Friedreich's ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings. The study included 129 indexed cases, who applied to the neurology department and were diagnosed with hereditary cerebellar ataxia through clinical, laboratory, and electrophysiological findings, and 15 sibling patients who were diagnosed through family scanning (144 cases in total); their genetic analyses were also performed. Detailed physical and neurological examinations, pedigree analyses, electroneurography, evoked potentials, cerebral-spinal magnetic resonance imaging, and echocardiographic analyses were performed for all cases. Blood samples were collected from patients, and the genotypic characteristics of autosomal dominant SCA types 1, 2, 3, and 6 were investigated. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS Inc; Chicago, IL, USA) 17.0. Almost 50% of patients were defined as FA. Moreover, two SCA1 cases and one SCA6 case were detected. In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA.

Spinocerebellar ataxia type 21 exists in the Chinese Han population.

Recently, mutations in transmembrane protein 240 (TMEM240) were identified as the cause of spinocerebellar ataxia type 21 (SCA21) in several French families. Clinically, SCA21 is characterized as an early-onset, slowly progressive cerebellar syndrome typically associated with cognitive impairment. To date, molecular screening of SCA21 has not been reported among patients of other ethnic origins or in other areas. Here we used Sanger sequencing to detect mutations in exons of TMEM240 in 340 unrelated probands with spinocerebellar ataxia for whom commonly known causative mutations have been excluded (96 probands of autosomal dominant spinocerebellar ataxia families and 244 patients with sporadic spinocerebellar ataxia). As a result, a de novo missense mutation (c.509C > T/p.P170L) was identified in one sporadic SCA patient. The condition manifested as early-onset (30 years old), slowly progressive cerebellar ataxia accompanied by mild early evidenced mental retardation, mild frontal behavior disorders and intentional hand tremors. Although rare, a SCA21 case was identified and described in mainland China, thus broadening the ethnic distribution of SCA21 beyond French families.

Genetic and clinical analysis of spinocerebellar ataxia type 36 in Mainland China.

Spinocerebellar ataxia type 36 (SCA36) is a new SCA subtype recently reported in Japanese and Spanish pedigrees. To assess the frequency and clinical characteristics of SCA36 in patients from Mainland China, we combined the repeat-primed polymerase chain reaction method and Southern blot analysis to detect the GGCCTG hexanucleotide repeats of NOP56 in 364 probands with SCA, 126 probands with hereditary spastic paraplegia and 99 probands with amyotrophic lateral sclerosis (ALS). Systematic and targeted clinical evaluations and investigations were conducted in the SCA36 patients. As a result, eight autosomal dominant spinocerebellar ataxia (ADCA) pedigrees (a total of 13 patients) and one sporadic SCA (S-SCA) patient were identified as SCA36 in the SCA cohort, accounting for approximately 1.60% of the cases in the ADCA group and 0.32% of those in the S-SCA group in Mainland China. The characteristics include late onset and slow progression accompanied by acoustic impairments and 'possible' ALS phenotype in patients from Mainland China.

Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2

Background/Aims: Inherited, autosomal dominant spinocerebellar ataxia type 11 (SCA11) is caused by loss of function mutations of TTBK2 (tau tubulin kinase 2). Mutations observed in patients with SCA11 include truncated TTBK2(450). The present study explored the possibility that TTBK2 influences the function of the glutamate receptor GluK2. Methods: GluK2 was expressed in Xenopus oocytes without and with additional expression of wild type TTBK2, the truncated mutant TTBK2(450), or the kinase dead mutants TTBK2(KD) and TTBK2(450/KD). GluK2 current was determined by dual electrode voltage clamp and GluK2 protein abundance in the cell membrane utilizing confocal microscopy. Results: Glutamate exposure of GluK2 expressing oocytes generated a current, which was significantly lower in oocytes expressing GluK2 together with TTBK2 wt or TTBK2(KD) than in oocytes expressing GluK2 alone or together with either TTBK2(450) or TTBK2(450/KD). According to confocal microscopy of EGFP-tagged GluK2, TTBK2 wt decreased the GluK2 protein abundance in the cell membrane. Overexpression of an inactive RAB5(N133I) mutant but not RAB5wt could reverse the TTBK2 effect on GluK2 suggesting that RAB5 function is required for the effect. Conclusions: TTBK2 down-regulates GluK2 activity by decreasing the receptor protein abundance in the cell membrane via RAB5-dependent endocytosis, an effect that may protect against neuroexcitotoxicity.

Diagnosing REM sleep behaviour disorder in patients with Parkinson's disease: The role of screening questionnaires and of measures of REM sleep without atonia

s for the 6th World Congress on Sleep Medicine, 23 March to 25 March 2015 Altered sleep architecture in autosomal dominant spinocerebellar ataxias: A polysomnographic based study S. Donilparthi 1, R. Yadav 1, A. Sasidharan 2, P. Pal 1, S. Jain 3, B. Kutty 2 1 Department of Neurology, NIMHANS, Bangalore, India 2 Department of Neurophysiology, NIMHANS, Bangalore, India 3 Molecular Genetics Laboratory, NIMHANS, Bangalore, India Introduction: Spinocerebellar ataxias (SCAs), are tri nucleotide repeat length progressive neurodegenerative disorders in which the cerebellum slowly degenerates, often accompanied by degenerative changes in the brainstem. Sleep disturbances have been reported in few studies. Materials and methods: Objective: To identify and to characterize the sleep disturbances in patients with genetically positive spinocerebellar ataxias (SCA 1, 2, 3). Methods: Patients with progressive ataxia were identified and assessed clinically. All the patients were interviewed with sleep questionnaire. Disease severity was measured with International Ataxia Rating Scale (ICARS) scale. Sleep quality was assessed with Pittsburgh Sleep Quality Index (PSQI), Mayo Sleep Questionnaire (MSQ), Epworth Sleepiness Scale (ESS). Genetically confirmed cases (20 patients) underwent overnight polysomnography (PSG) using 40 channel Galileo Mizar-40 Polysomnography sytem (EB Neuro, Italy). The sleep scoring was carried out according to AASM-2012 using POLYMAN v1.15 (Marco Roessen and Bob Kemp) and sleep variables were analysed across sleep cycles using custom scripts written in MATLAB 2012b (Mathworks, USA). Results: Patients of SCA1, 2, 3 (n = 20; 11 males) were recruited. SCA1 = 8; SCA2 = 7; SCA3 = 5; Mean age = 35.49 ± 7.75; Mean ICARS = 35.15 ± 18.75; Mean PSQI =3.8 ± 3.6, Mean ESS =2.1 ± 1.7. All patients (8/8) of SCA1 reported no sleep distrubances; 3/7 patients of SCA 2 reported delayed sleep onset; 3/5 patients of SCA3 reported delayed sleep onset and intermittent awakening. And none of them gave a history suggestive of REM sleep behaviour disorder (RBD), rest less leg syndrome (RLS), excessive day time somnolence (EDS). Polysomnographic analysis showed significant alteration of sleep architecture predominantly affecting REM sleep states. Average Sleep Efficiency = 75.6 ± 17.6; N1% = 17.6 ± 12; N2% = 52 ± 14.6; N3% = 24.5 ± 12.5; REM% = 5.6 ± 6.8. Absent REM sleep states in 70% of SCA2 patients, 60% of SCA3 patients, present in all patients in SCA1 but with significant reduction. There is negative correlation between disease severity (ICARS) and REM percentage (p = 0.028). Conclusion: In SCAs as the degeneration progresses brain stem structures are involved apart from the cerebellum. The more severe affection of REM sleep States in SCA2 patients and SCA3 supports early affection of brain stem structures. This needs further exploration by neuroimaging and pathology studies. Acknowledgements: Department of Neurology, NIMHANS, Department of Neurophysiology, NIMHANS. http://dx.doi.org/10.1016/j.sleep.2015.02.003 Diagnosing REM sleep behaviour disorder in patients with Parkinson’s disease: The role of screening questionnaires and of measures of REM sleep without atonia M. Figorilli 1, R. Ferri 2, B. Pereira 3, P. Beudin 4, F. Marrosu 5, M. Puliggheddu 5, F. Durif 6, M. Fantini 6 1 Sleep Disorder Center, Department of Public Health & Clinical and Molecular Medicine, University of Cagliari, Italy 2 Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Italy 3 Biostatistics Unit (DRCI) Clermont-Ferrand, France 4 Neurology Department, Chu Clermont-Ferrand, France 5 Sleep Disorder Center, Department of Public Health & Clinical and Molecular Medicine, Italy 6 EA 7980, UFR Medicine, University of Clermont, Clermont-Ferrand,

Altered sleep architecture in autosomal dominant spinocerebellar ataxias: A polysomnographic based study

s for the 6th World Congress on Sleep Medicine, 23 March to 25 March 2015 Altered sleep architecture in autosomal dominant spinocerebellar ataxias: A polysomnographic based study S. Donilparthi 1, R. Yadav 1, A. Sasidharan 2, P. Pal 1, S. Jain 3, B. Kutty 2 1 Department of Neurology, NIMHANS, Bangalore, India 2 Department of Neurophysiology, NIMHANS, Bangalore, India 3 Molecular Genetics Laboratory, NIMHANS, Bangalore, India Introduction: Spinocerebellar ataxias (SCAs), are tri nucleotide repeat length progressive neurodegenerative disorders in which the cerebellum slowly degenerates, often accompanied by degenerative changes in the brainstem. Sleep disturbances have been reported in few studies. Materials and methods: Objective: To identify and to characterize the sleep disturbances in patients with genetically positive spinocerebellar ataxias (SCA 1, 2, 3). Methods: Patients with progressive ataxia were identified and assessed clinically. All the patients were interviewed with sleep questionnaire. Disease severity was measured with International Ataxia Rating Scale (ICARS) scale. Sleep quality was assessed with Pittsburgh Sleep Quality Index (PSQI), Mayo Sleep Questionnaire (MSQ), Epworth Sleepiness Scale (ESS). Genetically confirmed cases (20 patients) underwent overnight polysomnography (PSG) using 40 channel Galileo Mizar-40 Polysomnography sytem (EB Neuro, Italy). The sleep scoring was carried out according to AASM-2012 using POLYMAN v1.15 (Marco Roessen and Bob Kemp) and sleep variables were analysed across sleep cycles using custom scripts written in MATLAB 2012b (Mathworks, USA). Results: Patients of SCA1, 2, 3 (n = 20; 11 males) were recruited. SCA1 = 8; SCA2 = 7; SCA3 = 5; Mean age = 35.49 ± 7.75; Mean ICARS = 35.15 ± 18.75; Mean PSQI =3.8 ± 3.6, Mean ESS =2.1 ± 1.7. All patients (8/8) of SCA1 reported no sleep distrubances; 3/7 patients of SCA 2 reported delayed sleep onset; 3/5 patients of SCA3 reported delayed sleep onset and intermittent awakening. And none of them gave a history suggestive of REM sleep behaviour disorder (RBD), rest less leg syndrome (RLS), excessive day time somnolence (EDS). Polysomnographic analysis showed significant alteration of sleep architecture predominantly affecting REM sleep states. Average Sleep Efficiency = 75.6 ± 17.6; N1% = 17.6 ± 12; N2% = 52 ± 14.6; N3% = 24.5 ± 12.5; REM% = 5.6 ± 6.8. Absent REM sleep states in 70% of SCA2 patients, 60% of SCA3 patients, present in all patients in SCA1 but with significant reduction. There is negative correlation between disease severity (ICARS) and REM percentage (p = 0.028). Conclusion: In SCAs as the degeneration progresses brain stem structures are involved apart from the cerebellum. The more severe affection of REM sleep States in SCA2 patients and SCA3 supports early affection of brain stem structures. This needs further exploration by neuroimaging and pathology studies. Acknowledgements: Department of Neurology, NIMHANS, Department of Neurophysiology, NIMHANS. http://dx.doi.org/10.1016/j.sleep.2015.02.003 Diagnosing REM sleep behaviour disorder in patients with Parkinson’s disease: The role of screening questionnaires and of measures of REM sleep without atonia M. Figorilli 1, R. Ferri 2, B. Pereira 3, P. Beudin 4, F. Marrosu 5, M. Puliggheddu 5, F. Durif 6, M. Fantini 6 1 Sleep Disorder Center, Department of Public Health & Clinical and Molecular Medicine, University of Cagliari, Italy 2 Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Italy 3 Biostatistics Unit (DRCI) Clermont-Ferrand, France 4 Neurology Department, Chu Clermont-Ferrand, France 5 Sleep Disorder Center, Department of Public Health & Clinical and Molecular Medicine, Italy 6 EA 7980, UFR Medicine, University of Clermont, Clermont-Ferrand,

A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia.

BackgroundSpinocerebellar ataxia (SCA) is a genetically heterogeneous disease. To date, 36 dominantly inherited loci have been reported, and 31 causative genes have been identified.ResultsIn this study, we analyzed a Japanese family with autosomal dominant SCA using linkage analysis and exome sequencing, and identified CACNA1G, which encodes the calcium channel CaV3.1, as a new causative gene. The same mutation was also found in another family with SCA. Although most patients exhibited the pure form of cerebellar ataxia, two patients showed prominent resting tremor in addition to ataxia. CaV3.1 is classified as a low-threshold voltage-dependent calcium channel (T-type) and is expressed abundantly in the central nervous system, including the cerebellum. The mutation p.Arg1715His, identified in this study, was found to be located at S4 of repeat IV, the voltage sensor of the CaV3.1. Electrophysiological analyses revealed that the membrane potential dependency of the mutant CaV3.1 transfected into HEK293T cells shifted toward a positive potential. We established induced pluripotent stem cells (iPSCs) from fibroblasts of the patient, and to our knowledge, this is the first report of successful differentiation from the patient-derived iPSCs into Purkinje cells. There was no significant difference in the differentiation status between control- and patient-derived iPSCs.ConclusionsTo date, several channel genes have been reported as causative genes for SCA. Our findings provide important insights into the pathogenesis of SCA as a channelopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0180-4) contains supplementary material, which is available to authorized users.