Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3

Forty-six patients suffering from autosomal dominant cerebellar ataxia type I (ADCA I) underwent to a genotype-phenotype correlation analysis by molecular genetic assignment to the spinocerebellar ataxia type 1, 2, or 3 (SCA1, SCA2, SCA3) genetic locus and electro-oculography. Oculomotor deficits that are attributed to dysfunction of cerebellar structures occurred in all three mutations without major differences between the groups. Gaze-evoked nystagmus, however, was not found to be associated with SCA2. Square wave jerks were exclusively observed in SCA3. The gain in vestibulo-ocular reflex was significantly impaired in SCA3 and SCA1. In SCA3 the severity of vestibular impairment increased with CAG repeat length. Severe saccade slowing was a highly characteristic feature of SCA2. In SCA3 saccade velocity was normal to mildly reduced while SCA1 fell into an intermediate range. The present data show that each mutation is associated with a distinct syndrome of oculomotor deficits. Reduced saccade velocity and the absence of both square-wave jerks and gaze-evoked nystagmus allow one SCA2 to be distinguished from SCA3 patients in almost all cases. The eye movement disorder of SCA1 patients, however, overlaps with both SCA2 and SCA3. Received: 9 September 1998 Received in revised form: 18 February 1999 Accepted: 23 February 1999     

Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes

We clinically and genetically evaluated 73 Italian families with autosomal dominant cerebellar ataxia (ADCA) type I. Spinocerebellar ataxia (SCA) type 1 was the most common genotype (SCA1), accounting for 41% of cases (30 families), SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. In SCA1 and SCA2 families there was a significant inverse correlation between expansion size and age at onset. Analysis of triplet repeat numbers in parent-offspring pairs showed greater meiotic instability, which was associated with an earlier onset of the disease in SCA2 families than in SCA1 families. Received: 23 April 1998 Received in revised form: 14 September 1998 Accepted: 13 October 1998     

Spinocerebellar ataxia type 28: A novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis

We have recently mapped the spinocerebellar ataxia type 28 (SCA28) locus on chromosome 18p11.22 in a four-generation Italian family. The clinical phenotype in affected individuals of this family was characterized by juvenile onset, slowly progressive gait and limb ataxia, dysarthria, hyperreflexia at lower limbs, nystagmus, and ophthalmoparesis. The mean age at onset was 19.5 years, and no evidence of anticipation between generations was observed. The disease locus on chromosome 18p11.22-q11.2 was found to span a region of 7.9 Mb of genomic DNA. Direct sequencing of candidate genes within the critical interval led to the identification of a heterozygous point mutation in one of them. The mutation was located in a highly conserved domain with proposed functional properties in the protein product of the SCA28 gene, and segregated with the disease phenotype in all affected members of this family. Thereafter we have screened 105 patients with autosomal dominant spinocerebellar ataxia who had resulted negative for mutations in known SCA genes. Genetic screening allowed the identification in a second Italian family of a distinct missense mutation located in the very same functional domain of the protein. The affected members of this second family exhibited a neurological phenotype similar to that of the original family. Both mutations, not found in more than 500 chromosomes, are associated with amino acid changes (Glu→Lys and Ser→Leu, respectively) in evolutionarily conserved residues of the alleged SCA28 gene. Our data point to a putative pathogenic role of these mutations, and indicate SCA28 as the sixth recognized SCA genotype caused by point mutations.     

Spinocerebellar ataxia type 3 presenting with writer's cramp without ataxia

Aim of the study: Spinocerebellar ataxia type 3 is the most common cause of autosomal dominant inherited ataxia worldwide.

Material and methods: Clinically, it exhibits wide phenotypic variability. Presentation as isolated dystonia is exceptional.

Results: Here, the case of a woman with writers cramp without ataxia is presented as a paucisymptomatic manifestation of this disease.

Conclusions: This association has not been described to date and extends the clinical variability of the disease.     

马查多-约瑟夫病/脊髓小脑型共济失调Ⅲ型患者(CAG)n拷贝数与临床特征

目的探讨马查多约瑟夫病基因１（ＭＪＤ１）ＣＡＧ三核苷酸动态突变及其拷贝数与ＭＪＤ／脊髓小脑型共济失调Ⅲ型（ＳＣＡ３）患者临床特征的相关关系。方法应用聚合酶链式反应、变性聚丙烯酰胺凝胶电泳和银染技术,对９个ＭＪＤ／ＳＣＡ３家系１０９名成员进行ＭＪＤ１基因（ＣＡＧ）ｎ拷贝数分析。结果发现异常扩增的（ＣＡＧ）ｎ拷贝数与发病年龄呈负相关,并在一定程度上影响病情严重程度;主要临床症状、体征与异常扩增的（ＣＡＧ）ｎ拷贝数无关,而是受病程影响。同时发现１７例症状前患者。结论异常扩增的（ＣＡＧ）ｎ拷贝数对疾病表型有影响,但不能完全作为临床特征的预测指标     

Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3

To identify the prevalence and determinants of restless legs syndrome (RLS) in spinocerebellar ataxia (SCA) we studied 58 patients with a molecular diagnosis of SCA1, SCA2 and SCA3. Data on the symptoms of RLS were collected by a standardized questionnaire, and RLS was diagnosed when patients met the four minimal criteria of the syndrome as recently defined by an international study group. In addition, we studied the relationship between RLS and age, age at ataxia onset, CAG repeat length, and nerve conduction and evoked potentials data. RLS was significantly more frequent in SCA patients than in controls (28 % vs. 10 %). Age at RLS onset in SCA was 49.0 ± 10.9 years. There were no significant differences in nerve conduction or evoked potentials between RLS and non-RLS SCA patients. The probability of developing RLS increased with age but not with CAG repeat length or higher age of ataxia onset. The data provide evidence that patients with SCA1, SCA2 and SCA3 are per se more susceptible to RLS than non-affected individuals. The probability of developing RLS is related principally to the period over which the CAG repeat mutation exerts its effect and not to CAG repeat length or age of ataxia onset. Received: 18 July 2000, Received in revised form: 10 November 2000, Accepted: 15 November 2000     

Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus

The detailed clinical, electrophysiological and imaging data of three German autosomal dominant cerebellar ataxia (ADCA) families are reported. Linkage to SCA2 was established using microsatellite markers D12S105, D12S1339(1328), D12S1340(1329) yielding a lod score exceeding +3.0 for the combined data. Analysis of the pedigree data provided evidence of anticipation as observed in other neurodegenerative disorders due to polyglutamine expansion encoded by a CAG repeat. This hypothesis was confirmed by the detection of the SCA2-specific pathological protein using the 1C2 monoclonal antibody which selectively recognizes large polyglutamine expansions and the characterization of a CAG expansion in the patients. Clinically, the families were characterized by progressive ataxia of stance, gait and limbs. Saccade velocity was markedly reduced in SCA2. Further oculomotor findings were gaze palsy, impaired smooth pursuit and reduced optokinetic reflex. Dementia and pyramidal tract signs were rather rare, while peripheral involvement (reduced or absent ankle reflexes, fasciculation-like movements, amyotrophy) was a prominent feature. Electrophysiological investigations provided evidence of sensory neuropathy of the axonal type and degeneration of the posterior columns. Imaging studies demonstrated severe shrinkage of brain-stem structures even in early stages of the disease. Received: 10 September 1996 Accepted: 8 December 1996     

脊髓小脑性共济失调3型一家系的临床表现分析

目的 探讨1个脊髓小脑性共济失调3型(SCA3)家系中患者的临床表现,分析影响其特征、异质性及严重程度的原因。方法 采用PCR、琼脂糖凝胶电泳的方法对1个脊髓小脑性共济失调家系进行基因检测明确分型并获得等位基因内CAG三核苷酸重复扩增次数; 对比该家系中5例患者的典型症状、非典型症状,了解其临床异质性并分析产生原因。结果 确定该家系为脊髓小脑性共济失调SCA3型,发现3名表现正常的女性携带者。CAG重复次数与病程长短呈负相关(r=-0.942,P<0.05); 病程与共济失调严重程度呈正相关(r=1.000,0.913,P<0.01)。结论 该家系所有患者以明显共济失调及构音障碍为临床特征,特别是躯干及下肢的共济失调; CAG重复次数、病程及共济失调严重程度之间有明显相关性; 认知功能障碍随着疾病的进展逐渐显现; 眼肌麻痹、括约肌功能障碍或吞咽困难与CAG重复次数之间无明显关系但增加疾病持续时间; 锥体束受损及严重程度可能提示预后不良。     

CAG repeat length and clinical features in three Italian families with spinocerebellar ataxia type 2 (SCA2): early impairment of Wisconsin Card Sorting Test and saccade velocity

We report on the clinical, neuropsychological, neurophysiological, computerized eye movement, magnetic resonance imaging (MRI) and molecular findings from 17 individuals affected with spinocerebellar ataxia type 2 (SCA2) belonging to three families. The average age at onset of the symptoms was 35.6, 11.9 (mean, SD) years. The mean age at onset of the symptoms in the parents was 44.8, 8.2 years, and in the offspring it was 28.7, 7.2 years. In 12 parent-child pairs, the mean anticipation was –15.75, 9.1 years (range –8.1 to –23.3 years, t = –4.9, P = < 0.002). The mutated SCA2 alleles ranged from 38 to 42 CAG repeats, while the normal alleles ranged from 22 to 24 repeats, with 97% of the alleles having 22 repeats. Small differences in the number of CAG repeats influenced the age at onset and rate of progression of the disease considerably. Indeed, patients presenting with their first symptom at an age of 35 years or later with a slower course of the disease harboured between 38 and 39 repeats. In contrast, patients carrying ≥ 40 CAG repeats manifested the disease prior to 30 years of age and had a faster disease progression toward incapacity. The presenting symptom was always gait ataxia. Slow saccades occured from the beginning of the disease despite normal delay, accuracy and smooth pursuit eye movements. The neuropsychological study showed early and selective impairment of conceptual reasoning ability, as detected by the Wisconsin Card Sorting Test (WCST). It is noteworthy that a significant mutual relationship was observed between performance on the WCST and saccade velocity. All of these findings favour the hypothesis that the disease process of SCA2 in regions other than the cerebellum and brain stem affects severely and early those cortical structures involved in the control of both visually guided saccades and WCST performance. Received: 13 October 1997 Received in revised form: 23 February 1998 Accepted: 20 March 1998     

Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6)

SCA6 is an autosomal dominant spinocerebellar ataxia (SCA) caused by a small CAG repeat expansion of the gene encoding an α-1a-voltage-dependent Ca channel gene subunit on chromosome 19p13. A Japanese woman with SCA6, with a 7-year history of progressive pure cerebellar ataxia, died of malignant lymphoma. Systematic neuropathological examination showed that neuronal degeneration was confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without any involvement of other central nervous system structures. Such pathological selectivity correlates with the localized expression of the responsible gene, and coincides with the neurological manifestation. These findings might contribute to establishing the phenotype of the SCA6 via comparison with other dominant ataxias. Received: 7 July 1997 / Revised, accepted: 14 August 1997     

Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis

INTRODUCTION: The genetic and clinical profile of autosomal dominant cerebellar ataxias (ADCA) displays marked geographical and ethnical variability. MATERIALS AND METHODS: We have analysed the molecular and clinical correlations in an ethnically homogeneous sample of 30 Spanish ADCA kindreds. Minimal point prevalence for the region of Cantabria was estimated. RESULTS: Seventy per cent of the families harboured known mutations. Areflexia, slow saccades and hypopallesthesia predominated in SCA2; nystagmus, pyramidal signs or areflexia restricted to the legs in SCA 3; and retinal degeneration, pyramidal signs and slow saccades in SCA 7. Anticipation and intergenerational instability were greater in SCA 7. Length of expansions and age at onset were inversely correlated in all SCA subtypes. Larger expansions correlated with areflexia in SCA 2, with pyramidal signs in SCA 3 and with early visual impairment in SCA 7. Survival was similar among the different SCA subtypes. Prevalence of ADCA in Cantabria was 1.6 cases per 100,000 population. CONCLUSIONS: This report shows the epidemiological, clinical and genetic profile of ADCA in Spain, providing additional data regarding the broad clinical heterogeneity of these disorders and the variability of the genotype-phenotype correlations.     

Autophagic vacuolar myopathy involving the phenotype of spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a form of autosomal dominant cerebellar ataxia with a wide range of clinical manifestations, including ataxia and pyramidal and extrapyramidal signs. A few SCA3 patients have been noticed to be predisposed to the development of inclusion body myositis. It is still unknown whether muscle can be primarily involved in the pathogenesis of SCA3. This study reported an SCA3 family in which the index patient initially presented with parkinsonism, sensory ataxia, and distal myopathy but the absence of cerebellar and pyramidal symptoms. The clinical and electrophysiological studies implied a possible combination of distal myopathy and sensory–motor neuropathy or neuronopathy. MRI muscle showed selective fat infiltration and absence of denervated edema-like changes, indicating the distal muscle weakness had a myopathic origin. Muscle pathology showed the myopathic involvement, besides neurogenic involvement, characterized by chronic myopathic changes with multiple autophagic vacuoles. Genetic screening revealed expanded CAG of 61 repeats in the ATXN3 gene, which showed co-segregation in the family. Besides the neurogenic origin, the myopathic origin may be partly attributed to the limb weakness of SCA3 patients, which expands the spectrum of the clinical manifestation of SCA3.     

Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.     

Clinical and genetic epidemiological study of 16q22.1-linked autosomal dominant cerebellar ataxia in western Japan

OBJECTIVE: Autosomal dominant cerebellar ataxia (ADCA) is a heterogeneous neurodegenerative disorder. A single nucleotide substitution in the puratrophin-1 gene is associated with 16q22.1-linked ADCA showing pure cerebellar ataxia. We screened patients with spinocerebellar degeneration (SCD) to investigate the frequency and clinical features of 16q22.1-linked ADCA. MATERIALS AND METHODS: We examined 91 SCD patients from a 1998 community-based prevalence study of Tottori Prefecture in western Japan. We also analyzed samples from 176 patients with SCD collected from a 1996 to 2006 laboratory-based study. RESULTS: In the community-based study, the prevalence of spinocerebellar ataxia 6 (SCA6) and 16q22.1-linked ADCA was 2.4 and 1.12 per 100,000 individuals, respectively. In the laboratory-based study, the frequency of SCA6 and 16q22.1-linked ADCA was 28% and 17%, respectively. We found two cases of 16q22.1-linked ADCA among 26 SCD patients with no family history. CONCLUSION: In this area in Japan, 16q22.1-linked ADCA was the second most common type of hereditary SCD.     

A family with mild clinical manifestations of spinocerebellar ataxia type 1 (SCA1): correlation with smaller CAG repeats

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat. We analyzed CAG repeat expansion in one Japanese SCA1 family with mild clinical manifestations. Clinically, this SCA1 family showed less frequent nystagmus (p = 0.045, Fisher's exact-test) in comparison with duration-matched control patients with larger numbers of CAG repeats (48.4 ± 4.2, p < 0.01). Some patients showed no other signs than cerebellar ataxia in the earlier stage. All six patients had expanded alleles for SCA1 with relatively small CAG repeats (41.5 ± 1.0, mean ± SD), which may be related to the mild clinical symptoms of the disease. The present results also suggest that slow saccades and amyotrophy are constantly observed in 30–40% of SCA1 patients without regard to the size of CAG repeats, while the frequency of nystagmus decreases with reduction in size of the CAG expansion.     

Psychological consequences of genetic testing for spinocerebellar ataxia in the Japanese

To evaluate the psychological consequences of genetic testing for spinocerebellar ataxia (SCA), state and trait anxiety inventories (SAI and TAI) and social desirability scale (SDS) were assessed and analyzed in patients and their family members diagnosed with spinocerebellar ataxias such as spinocerebellar ataxia type 1 and Machado—Joseph disease (MJD). The results obtained prior to and after the genetic testing were compared to a control group that included more severe hereditary neurological disorders such as Huntington's disease and familial amyotrophic lateral sclerosis. Genetic counseling was undertaken during the study. Of the 62 total participants, 37 were diagnosed with SCA, and 25 as asymptomatic family members. The SCA patients had higher baseline SAI, TAI and SDS scores than their asymptomatic family members. Genetic testing did not significantly increase the scores for all the patients and their asymptomatic family members, whereas the SAI value was greatly reduced in those subjects who received negative results and were not carriers of the defective gene. Similar results were obtained even in the control group with more severe diseases except for a reduction of SAI values in the patients. Patients, their SCA asymptomatic family members, and the disease control generally had some apprehension for the testing, but, at the same time, were not so anxious if remedial or curative therapy was available. Furthermore, most participants in this study showed a high degree of acceptance and did not express much regret in undergoing the genetic testing regardless of having the disease or finding out the results of the predictive testing. These results suggest that the psychological health of the asymptomatic family members with negative results for SCA gene abnormality recovered after genetic testing, and genetic testing was not disadvantageous for the psychological well-being of the patients and even for those with positive predictive results.     

Serum insulin‐like system alterations in patients with spinocerebellar ataxia type 3

Spinocerebellar ataxias (SCAs) constitute a group of autosomal dominant neurodegenerative disorders with no current treatment. The insulin/insulin‐like growth factor 1 (IGF‐1) system (IIS) has been shown to play a role in the neurological dysfunction of SCAs and other polyglutamine disorders. We aimed to study the biomarker profile of serum IIS components in SCA3. We performed a case–control study with 46 SCA3 patients and 42 healthy individuals evaluating the peripheral IIS profile (insulin, IGF‐1, IGFBP1 and 3) and the correlation with clinical, molecular, and neuroimaging findings. SCA3 patients presented lower insulin and IGFBP3 levels and higher insulin sensitivity (HOMA2), free IGF‐I, and IGFBP1 levels when compared with controls. IGFBP‐1 levels were directly associated with CAG expanded repeat length; IGF‐1 was associated with the volumetries of specific brainstem regions on magnetic resonance imaging (MRI). Insulin levels and sensitivity were related to age at onset of symptoms. Our findings indicate an involvement of IIS components in SCA3 neurobiology and IGFBP‐1 as a potential biomarker of the disease. © 2010 Movement Disorder Society     

MJD1基因单个碱基多态性与CAG重复序列不稳定性的关系

马查多－约瑟夫病患者的ＭＪＤ１基因存在ＣＡＧ三核苷酸不稳定扩展突变，为探讨这种不稳定扩展突变的分子机制。方法对５８名正常人和２０名ＭＪＤ患者的ＭＪＤ１基因内ＣＡＧ／ＣＡＡ、ＣＧＧ／ＧＧＧ两个位点的多态性进行检测。结果正常染色体中，具有ＣＧＧ等位基因的ＣＡＧ重复数目（２７．３２±０．６１，ｎ＝２８）较具有ＧＧＧ等位基因的ＣＡＧ重复数目（１５．９０±０．６９，ｎ＝３０）明显大（Ｐ＜０．０１）。ＣＧＧ等位基因在患者中的分布频率（１００％）明显高于正常人（４８．３％）。结论ＭＪＤ１基因内单个碱基置换影响ＣＡＧ重复序列的稳定性。     

Autosomal dominant cerebellar ataxia (SCA6): clinical, genetic and neuropathological study in a family

We describe a family with dominantly inherited ataxia of late adult onset. Expansion of a CAG repeat in the gene encoding the α_1A voltage-dependent calcium channel was identified at autopsy in one patient, a 65-year-old woman with a disease duration of 11 years. In this patient, pathological changes were confined to the cerebellar cortex and inferior olivary complex. The cerebellar cortex showed severe loss of Purkinje cells with proliferation of Bergmann’s glia, being more pronounced in the superior parts of the vermis and hemispheres. In the inferior olivary complex, a reduced neuronal cell population, which could be interpreted as a change secondary to the cerebellar cortical lesion, was evident. We conclude that the pathological phenotype of this newly classified autosomal dominant cerebellar ataxia, SCA6, is cerebello-olivary atrophy, or more strictly cerebellar cortical atrophy. Received: 27 May 1997 / Revised, accepted: 27 October 1997     

Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal

Background and purpose:  The relative frequency of the different autosomal dominant cerebellar ataxia (ADCA) varies widely amongst different geographic locations. Here we describe a series of 45 ADCA families from Portugal.
Methods:  Patients with progressive cerebellar dysfunction of autosomal dominant transmission underwent a clinical examination protocol and genetic testing for spinocerebellar ataxia (SCA)1 to Machado-Joseph disease (MJD)/SCA3, SCA6, SCA7, SCA10, SCA12, SCA17 and dentatorubral-pallidoluysian atrophy (DRPLA). We registered the clinical characteristics and frequency of each type of ataxia.
Results:  MJD/SCA3 was the most frequent ADCA (26 families, 57.8% of all families), followed by DRPLA (5 families, 11.2%), SCA7 (2 families, 4.4%), SCA2 and SCA1 (1 family each, 2.2% each); 10 families (22.2%) had no molecular diagnosis. SCA1 and SCA7 patients had African ancestry. DRPLA patients had Portuguese ancestry and were characterized by prominent anticipation and a variable combination of epilepsy, extra-pyramidal symptoms and dementia. Ophtalmoparesis, slow saccades and retinopathy were most distinctive of SCA3, SCA2 and SCA7 cases, respectively.
Conclusions:  MJD/SCA3 was the most common ADCA in this group of families. The high frequency of DRPLA and presence of SCA1 and SCA7 cases was unexpected. The presence of these rarer ADCA types probably reflects migration phenomena, posing a challenge for differential diagnosis.