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Purpose: Muscular dystrophy is a group of heterogeneous diseases causing progressive muscle weakness and atrophy. Many types have been defined, including Duchenne/Becker, myotonic, limb-girdle, congenital, and facioscapulohumeral muscular dystrophies. This study aims to present the first patient with both a homozygous CAPN3 mutation and a CCTG expansion in the CNBP gene, which suggests the co-occurrence of two diseases in a single patient. Case description: Homozygous pathogenic variant c.550delA (p.Thr184ArgfsTer36) in the CAPN3 gene, as well as a heterozygous expansion of a CCTG repeat of the CNBP gene, were identified in a single patient. Segregation analysis showed both maternal and paternal heterozygous carriers for CAPN3 mutation, and a maternally inherited CNBP expansion. Comment: In general, the co-occurrence of two diseases in a single patient is considered as uncommon, although possible, and therefore it should be taken into consideration in the populations with a relatively high prevalence of myotonic dystrophy type 2.
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Since 1991, several genetic disorders caused by unstable trinucleotide repeats (TNRs) have been identified, collectively referred to as triplet repeat diseases (TREDs). They share a common mutation mechanism: the expansion of repeats (dynamic mutations) due to the propensity of repeated sequences to form unusual DNA structures during replication. TREDs are characterized as neurodegenerative diseases or complex syndromes with significant neurological components. Spinocerebellar ataxia type 17 (SCA17) falls into the former category and is caused by the expansion of mixed CAA/CAG repeats in the TBP gene. To date, a five-unit organization of this region [(CAG)3 (CAA)3] [(CAG)n] [CAA CAG CAA] [(CAG)n] [CAA CAG], with expansion in the second [(CAG)n] unit being the most common, has been proposed. In this study, we propose an alternative organization scheme for the repeats. A search of the PubMed database was conducted to identify articles reporting both the number and composition of GAC/CAA repeats in TBP alleles. Nineteen reports were selected. The sequences of all identified CAG/CAA repeats in the TBP locus, including 67 cases (probands and b relatives), were analyzed in terms of their repetition structure and stability in inheritance, if possible. Based on the analysis of three units [(CAG)3 (CAA)2] [CAA (CAG)n CAA CAG] [CAA (CAG)n CAA CAG], the organization of repeats is proposed. Detailed analysis of the CAG/CAA repeat structure, not just the number of repeats, in TBP-expanded alleles should be performed, as it may have a prognostic value in the prediction of stability/instability during transmission and the possible anticipation of the disease.
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Mutación , Proteína de Unión a TATA-Box , Expansión de Repetición de Trinucleótido , Humanos , Alelos , Ataxias Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/genética , Proteína de Unión a TATA-Box/genética , Expansión de Repetición de Trinucleótido/genética , Repeticiones de Trinucleótidos/genéticaRESUMEN
The most common form of hereditary spastic paraplegia (HSP), SPG4 is caused by single nucleotide variants and microrearrangements in the SPAST gene. The high percentage of multi-exonic deletions or duplications observed in SPG4 patients is predisposed by the presence of a high frequency of Alu sequences in the gene sequence. In the present study, we analyzed DNA and RNA samples collected from patients with different microrearrangements in SPAST to map gene breakpoints and evaluate the mutation mechanism. The study group consisted of 69 individuals, including 50 SPG4 patients and 19 healthy relatives from 18 families. Affected family members from 17 families carried varying ranges of microrearrangements in the SPAST gene, while one individual had a single nucleotide variant in the 5'UTR of SPAST. To detect the breakpoints of the SPAST gene, long-range PCR followed by sequencing was performed. The breakpoint sequence was detected for five different intragenic SPAST deletions and one duplication, revealing Alu-mediated microhomology at breakpoint junctions resulting from non-allelic homologous recombination in these patients. Furthermore, SPAST gene expression analysis was performed using patient RNA samples extracted from whole blood. Quantitative real-time PCR tests performed in 14 patients suggest no expression of transcripts with microrearrangements in 5 of them. The obtained data indicate that nonsense-mediated decay degradation is not the only mechanism of hereditary spastic paraplegia in patients with SPAST microrearrangements.
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Haploinsuficiencia , Paraplejía Espástica Hereditaria , Espastina , Humanos , Espastina/genética , Paraplejía Espástica Hereditaria/genética , Masculino , Femenino , Haploinsuficiencia/genética , Linaje , Variaciones en el Número de Copia de ADN , Adulto , Elementos Alu/genética , Persona de Mediana Edad , Adolescente , Adulto Joven , Degradación de ARNm Mediada por Codón sin SentidoRESUMEN
Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals.
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Calpaína , Canales de Cloruro , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas Musculares , Enfermedades Neuromusculares , Fenotipo , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Masculino , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/diagnóstico , Femenino , Pruebas Genéticas/métodos , Adulto , Persona de Mediana Edad , Calpaína/genética , Canales de Cloruro/genética , Proteínas Musculares/genética , Adolescente , Mutación , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adulto Joven , Niño , Genotipo , Anciano , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Miotónica/genética , Distrofia Miotónica/diagnóstico , PreescolarRESUMEN
The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6 years (SCA1 +) aged 27.8 ± 8.1 years; 12 with expected disease onset > 6 years (SCA1-) aged 26.6 ± 3.1 years and 26 age and sex matched healthy controls (HCs) underwent static posturography during 5 years of observation. The movements of the centre of feet pressure (COP) during quiet standing with eyes open (EO) and closed (EC) were quantified by calculating the mean radius (R), developed surface area (A) and mean COP movement velocity (V). Ataxia was evaluated by use of the Scale for Assessment and Rating of Ataxia (SARA).SCA1 + exhibited significantly worse quality of stance with EC vs. SCA1- (p < 0.05 for V) and HCs (p < 0.001) even 5 to 6 years before estimated disease onset. There were no statistically significant differences between SCA1- and HCs. A slow increase in Cohen's d effect size was observed for VEO up to the clinical manifestation of ataxia. VEO and AEC recorded in preclinical SCA1 individuals correlated slightly but statistically significantly with SARA (r = 0.47).The study confirms that static posturography detects COP sway changes in SCA1 preclinical gene carriers even 5 to 6 years before estimated disease onset. The quantitative evaluation of stance in preclinical SCA is a sensitive biomarker for the monitoring of the disease progression and may be useful in clinical trials.
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INTRODUCTION: We present the first two Polish families diagnosed with spinocerebellar ataxia type 7 (SCA7) and draw attention to cardiac involvement as a new potential manifestation of this disease. MATERIAL AND METHODS: Two well-documented kindreds are presented. RESULTS: The proband from Family 1 presented aged 54 years with vision worsening followed by progressive imbalance. Brain MRI demonstrated cerebellar atrophy. Genetic testing confirmed CAG repeat expansion (42/10) in ATXN7 gene. The proband from Family 2 developed imbalance at age 20, followed by progressive deterioration of vision. Brain MRI revealed cerebellar atrophy. Additionally, she developed chronic congestive heart failure and, at age 38, had cardiomyopathy with an ejection fraction of 20% and significant mitral and tricuspid regurgitation. Genetic analysis found abnormal CAG expansion in the ATXN7 (46/10). CONCLUSIONS AND CLINICAL IMPLICATIONS: Vision loss due to pigmentary retinal degeneration is the distinguishing feature of SCA7 and often the initial manifestation. Although SCA7 is one of the most common SCAs in Sweden, it has never been reported in neighbouring Poland. Until now, cardiac abnormalities have only been described in infantile-onset SCA7 with large CAG repeats. The observed cardiac involvement in Family 2 may be coincidental, albeit a new possible manifestation of SCA7 cannot be excluded.
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Ataxias Espinocerebelosas , Femenino , Humanos , Adulto Joven , Adulto , Polonia , Ataxina-7/genética , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/genética , Pruebas Genéticas , AtrofiaRESUMEN
BACKGROUND: The present study assessed the influence of recurrent social isolation stress on the aversive memory extinction and dopamine D2 receptors (D2R) expression in the amygdala and the hippocampus subnuclei. We also analyzed the expression of epigenetic factors potentially associated with fear extinction: miRNA-128 and miRNA-142 in the amygdala. METHODS: Male adult fear-conditioned rats had three episodes of 48 h social isolation stress before each fear extinction session in weeks intervals. Ninety minutes after the last extinction session, the D2R expression in the nuclei of the amygdala and the hippocampus (immunocytochemical technique), and mRNA levels for D2R in the amygdala were assessed (PCR). Moreover, we evaluated the levels of miRNA-128 and miRNA-142 in the amygdala. RESULTS: It was found that recurrent social isolation stress decreased the fear extinction rate. The extinguished isolated rats were characterized by higher expression of D2R in the CA1 area of the hippocampus compared to the extinguished and the control rats. In turn, the isolated group presented higher D2R immunoreactivity in the CA1 area compared to the extinguished, the control, and the extinguished isolated animals. Moreover, the extinguished animals had higher expression of D2R in the central amygdala than the control and the extinguished isolated rats. These changes were accompanied by the increase in miRNA-128 level in the amygdala in the extinguished isolated rats compared to the control, the extinguished, and the isolated rats. Moreover, the extinguished rats had lower expression of miRNA-128 compared to the control and the isolated animals. CONCLUSIONS: Our results suggest that social isolation stress impairs aversive memory extinction and coexists with changes in the D2R expression in the amygdala and hippocampus and increased expression of miRNA-128 in the amygdala.
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Miedo , MicroARNs , Receptores de Dopamina D2 , Animales , Masculino , Ratas , Amígdala del Cerebelo/metabolismo , Extinción Psicológica , Hipocampo/metabolismo , MicroARNs/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
Spinocerebellar ataxia type 3 (SCA3; Machado-Joseph disease, MJD) is the most common autosomal-dominant form of genetic ataxia worldwide. However, it has never been reported in Eastern Europe. This letter presents the first three families with SCA3 from Poland and discusses the practical implications of the disease for clinicians.
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Enfermedad de Machado-Joseph , Humanos , Enfermedad de Machado-Joseph/genética , PoloniaRESUMEN
INTRODUCTION: In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis. MATERIAL AND METHODS: We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC. RESULTS: Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.
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Miotonía Congénita , Femenino , Humanos , Masculino , Miotonía Congénita/diagnóstico , Miotonía Congénita/genética , Caracteres Sexuales , Electromiografía , Potenciales de Acción/fisiología , MutaciónRESUMEN
INTRODUCTION: The expansion of a hexanucleotide GGGGCC repeat (G4C2) in the C9orf72 locus is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, C9orf72 expansion has also been detected in patients with a clinical manifestation of Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), and ataxic disorders. MATERIAL AND METHODS: A total of 1,387 patients with clinically suspected ALS, HD or spinal and bulbar muscular atrophy (SBMA) were enrolled, and the prevalence of C9orf72 expansions was estimated. RESULTS: The hexanucleotide expansion accounted for 3.7% of the ALS patients, 0.2% of the HD suspected patients with excluded HTT mutation, and 1.3% of the suspected SBMA patients with excluded mutation in AR gene. CONCLUSIONS: This is the first report revealing the presence of C9orf72 expansion in patients with a suspected SBMA diagnosis. Consequently, we advise testing for C9orf72 expansion in patients presenting with the SBMA phenotype and a genetically unsolved diagnosis.
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Esclerosis Amiotrófica Lateral , Atrofia Bulboespinal Ligada al X , Demencia Frontotemporal , Esclerosis Amiotrófica Lateral/genética , Atrofia Bulboespinal Ligada al X/genética , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genética , Demencia Frontotemporal/genética , Humanos , Proteínas/genéticaRESUMEN
BACKGROUND: Recent discoveries show that high-intensity interval training (HIIT) can bring many positive effects such as decreases in fat tissue, lower blood sugar levels, improved learning and memory, and lower risk of cardiac disease. Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the dopaminergic neurons, accompanied by chronic inflammation and neuroinflammation. Previous research shows that interval training can bring a beneficial effect on the inflammation and neuroplasticity in PD. OBJECTIVES: The objective of this study was to investigate the effect of 12 weeks of HIIT on the inflammation levels and antioxidant capacity in the serum of PD patients. METHODS: Twenty-eight people diagnosed with PD were enrolled in this study. Fifteen PD patients performed 12 weeks of HIIT on a cycloergometer. Thirteen non-exercised PD patients constitute the control group. Concentrations of inflammation markers and antioxidants' capacity in the serum were measured at 3 sampling points (a week before, a week after, and 3 months after the HIIT). RESULTS: Twelve weeks of HIIT decreases the level of TNF-α (p = 0.034) and increases the level of IL-10 (p = 0.024). Those changes were accompanied by a decreased level of neutrophils (p = 0.03), neutrophil/lymphocyte ratio (p = 0.048) and neutrophil/monocyte ratio (p = 0.0049) with increases in superoxide dismutase levels (p = 0.04). CONCLUSIONS: Twelve weeks of HIIT can decrease systemic inflammation in PD patients and improve the antioxidant capacity in their serum, which can slow down the progression of the disease.
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Entrenamiento de Intervalos de Alta Intensidad , Inflamación , Enfermedad de Parkinson , Antioxidantes/metabolismo , Femenino , Humanos , Inflamación/terapia , Masculino , Enfermedad de Parkinson/terapia , Superóxido Dismutasa/metabolismoRESUMEN
Hereditary ataxias (HA) are a rare group of heterogeneous disorders. Here, we present the results of molecular testing of a group of ataxia patients using a custom-designed next-generation sequencing (NGS) panel. Due to the genetic and clinical overlapping of hereditary ataxias and spastic paraplegias (HSP), the panel encompasses together HA and HSP genes. The NGS libraries, comprising coding sequences for 152 genes, were performed using KAPA HyperPlus and HyperCap Target Enrichment Kit, sequenced on the MiSeq instrument. The results were analyzed using the BaseSpace Variant Interpreter and Integrative Genomics Viewer. All pathogenic and likely pathogenic variants were confirmed using Sanger sequencing. A total of 29 patients with hereditary ataxias were enrolled in the NGS testing, and 16 patients had a confirmed molecular diagnosis with diagnostic accuracy rate of 55.2%. Pathogenic or likely pathogenic mutations were identified in 10 different genes: POLG (PEOA1, n = 3; SCAE, n = 2), CACNA1A (EA2, n = 2), SACS (ARSACS, n = 2), SLC33A1 (SPG42, n = 2), STUB1 (SCA48, n = 1), SPTBN2 (SCA5, n = 1), TGM6 (SCA35, n = 1), SETX (AOA2, n = 1), ANO10 (SCAR10, n = 1), and SPAST (SPG4, n = 1). We demonstrated that an approach based on the targeted use of the NGS panel can be highly effective and a useful tool in the molecular diagnosis of ataxia patients. Furthermore, we highlight the fact that a sequencing panel targeting both ataxias and HSP genes increases the diagnostic success level.
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Paraplejía Espástica Hereditaria , Degeneraciones Espinocerebelosas , Ataxia/diagnóstico , Ataxia/genética , ADN Helicasas/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Técnicas de Diagnóstico Molecular , Enzimas Multifuncionales/genética , Espasticidad Muscular , Mutación , ARN Helicasas/genética , Paraplejía Espástica Hereditaria/genética , Espastina/genética , Ataxias Espinocerebelosas/congénito , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: Establishing the diagnosis of Huntington's disease (HD) involves molecular genetic testing and estimation of the number of CAG repeats. MATERIAL AND METHODS: We report a 42-year-old patient with clinical phenotype suggestive of HD, who was repeatedly negative on genetic testing for HD at a reference laboratory. He had positive history of similar symptoms in his father, but not in other family members. During a 2-year follow-up his symptoms slowly deteriorated (videos attached). The family history was misleading, as we discovered that patient's father was adopted as infant. Having excluded HD-like disorders and other causes of the symptoms we hypothesized that the primer could not bind to the mutated allele. RESULTS: The PCR reaction with primers HD1 and Hu3 revealed homozygosity of the other adjacent microsatellite tract consisting of the CCG repeats. The newly designed set of primers, located outside of the CAG tract (HD6extF, HD7extR) was used and enabled amplification of the mutant allele and detection of the abnormal range of CAG repeats. CONCLUSIONS: As application of the novel primers led to the diagnosis of HD in other 5 patients previously tested negative, we propose their incorporation into routine genetic testing in patients suspected of HD displaying homoallelism in the standard protocol.
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Enfermedad de Huntington , Adulto , Alelos , Pruebas Genéticas , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Masculino , Reacción en Cadena de la Polimerasa , Repeticiones de TrinucleótidosRESUMEN
Background: One purpose of the training conducted by people is to lose bodyweight and improve their physical condition. It is well-known that endurance training provides many positive changes in the body, not only those associated with current beauty standards. It also promotes biochemical changes such as a decreased inflammatory status, memory improvements through increased brain-derived neurotrophic factor levels, and reduced stress hormone levels. The positive effects of training may provide a novel solution for people with Parkinson's disease, as a way to reduce the inflammatory status and decrease neurodegeneration through stimulation of neuroplasticity and improved motor conditions. Aim: This narrative review aims to focus on the relationship between an acute bout of endurance exercise, endurance training (continuous and interval), brain-derived neurotrophic factor and inflammatory status in the three subject groups (young adults, older adult, and patients with Parkinson's disease), and to review the current state of knowledge about the possible causes of the differences in brain-derived neurotrophic factor and inflammatory status response to a bout of endurance exercise and endurance training. Furthermore, short practical recommendations for PD patients were formulated for improving the efficacy of the training process during rehabilitation. Methods: A narrative review was performed following an electronic search of the database PubMed/Medline and Web of Science for English-language articles between January 2010 and January 2020. Results: Analysis of the available publications with partial results revealed (1) a possible connection between the brain-derived neurotrophic factor level and inflammatory status, and (2) a more beneficial influence of endurance training compared with acute bouts of endurance exercise. Conclusion: Despite the lack of direct evidence, the results from studies show that endurance training may have a positive effect on inflammatory status and brain-derived neurotrophic factor levels. Introducing endurance training as part of the rehabilitation in Parkinson's disease might provide benefits for patients in addition to pharmacological therapy supplementation.
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AIM OF THE STUDY: The aim of this study was to explore genetic findings and the phenotype in Polish patients with Unverricht-Lundborg disease (ULD). MATERIALS AND METHODS: We retrospectively evaluated mutations in the cystatin B (CSTB) gene and clinical presentation in a cohort of patients with ULD. The study population consisted of 19 (14 males) patients with genetically confirmed disease. RESULTS: Sixteen patients were homozygous for the expanded dodecamer repeat mutation alleles, one subject was compound heterozygous for the dodecamer repeat expansion and other mutation, in two, the type of mutation has not yet been established. The numbers of repeats in the CSTB gene varied from 60 to 81. Clinical information was available for 16 subjects. The disease course was progressive in all patients, leading to severe disability, mainly due to myoclonus, in nine. CONCLUSIONS AND CLINICAL IMPLICATIONS: Genetic findings and the clinical picture of our patients with ULD were in accordance with available studies. The most common genetic defect underlying ULD was homozygosity for an unstable expansion of a dodecamer repeat in the CSTB gene. Patients with action or/and stimulus sensitive myoclonus or intractable myoclonus epilepsy, especially with onset in late childhood/adolescence should be screened for ULD.
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Síndrome de Unverricht-Lundborg , Adolescente , Niño , Estudios de Cohortes , Cistatina B/genética , Pruebas Genéticas , Humanos , Masculino , Fenotipo , Polonia , Estudios Retrospectivos , Síndrome de Unverricht-Lundborg/genéticaAsunto(s)
Atrofia Muscular Espinal , Humanos , Atrofia Muscular , Atrofia Muscular Espinal/genética , SíndromeRESUMEN
INTRODUCTION: Myotonia congenita (MC) is caused by pathogenic variants in the CLCN1 gene coding the chloride channel protein. METHODS: To test the hypothesis that needle EMG could be helpful in distinguishing between the recessive and dominant MC, we performed EMG examination in 36 patients (23 men) aged 4-61â¯years with genetically proven MC: in 30 patients with autosomal recessive MC (Becker MC) and in 6 with autosomal dominant MC (Thomsen MC). RESULTS: Myotonic discharges were recorded in 95.8% of examined muscles. For the whole MC group we observed a significant positive correlation between parameters of motor unit activity potentials (MUAPs) in vastus lateralis and tibialis anterior muscles and the duration of the disease. Similar correlation for biceps brachii also was found in Becker MC subgroup only. DISCUSSION: EMG could still be helpful in diagnosis of MC and together with provocative tests might be useful in differentiation between recessive and autosomal MC.
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Electromiografía/métodos , Potenciales Evocados Motores , Mutación , Miotonía Congénita/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Genes Dominantes , Genes Recesivos , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Miotonía Congénita/diagnóstico , Miotonía Congénita/genéticaRESUMEN
BACKGROUND: Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. OBJECTIVE: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. METHODS: Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. RESULTS: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. CONCLUSION: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society.