Spinocerebellar ataxia type 8: clinical features in a large family

OBJECTIVE: To compare the clinical and genetic features of the seven-generation family (MN-A) used to define the spinocerebellar ataxia 8 (SCA8) locus. BACKGROUND: The authors recently described an untranslated CTG expansion that causes a novel form of SCA (SCA8) characterized by reduced penetrance and complex patterns of repeat instability. METHODS: Clinical and molecular features of 82 members of the MN-A family were evaluated by neurologic examination, quantitative dexterity testing, and, in some individuals, MRI and sperm analyses. RESULTS: SCA8 is a slowly progressive, predominantly cerebellar ataxia with marked cerebellar atrophy, affecting gait, swallowing, speech, and limb and eye movements. CTG tracts are longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90, p < 10-8). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. Surprisingly, all 21 affected MN-A family members inherited an expansion from their mothers. The maternal penetrance bias is consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (>107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) are significantly shorter than in the blood (116) of an affected man. CONCLUSIONS: The biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. Diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.     

Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred

The authors report a German family with autosomal dominant cerebellar ataxia tightly linked to the spinocerebellar ataxia type 5 (SCA5) locus (multipoint lod score 5.76). The phenotype is characterized by a purely cerebellar syndrome with a downbeat nystagmus occurring prior to the development of other features. Imaging studies demonstrated cortical cerebellar atrophy. Progression is slow even in patients with a disease onset during the second decade. The age at onset varies from 15 to 50 years.     

Spinocerebellar ataxia type 8 in Scotland: frequency, neurological, neuropsychological and neuropsychiatric findings

Objectives –  The objectives of this study were to: (i) establish whether the spinocerebellar ataxia type 8 (SCA 8) expansion is associated with ataxia in Scotland; (ii) test the hypothesis that SCA 8 is associated with neuropsychological impairment; and (iii) review neuroradiological findings in SCA 8.
Methods –  The methods included: (i) measurement of SCA 8 expansion frequencies in ataxic patients and healthy controls; (ii) comprehensive neuropsychological assessment of patients with SCA 8 and matched controls, neuropsychiatric interview; and (iii) comparison of patient and matched control magnetic resonance imaging (MRI) scans.
Results –  (i) 10/694 (1.4%) unrelated individuals with ataxia had combined CTA/CTG repeat expansions >100 compared to 1/1190 (0.08%) healthy controls ( P  < 0.0005); (ii) neuropsychological assessment revealed a dysexecutive syndrome among SCA 8 patients, not readily explained by motor or mood disturbance; neuropsychiatric symptoms occurred commonly; (iii) cerebellar atrophy was the only salient MRI abnormality in the patient group.
Conclusions –  The SCA 8 expansion is associated with ataxia in Scotland. The disorder is associated with a dysexecutive syndrome.     

Spinocerebellar ataxia type 1: clinical and neurophysiological characteristics in German kindreds

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of an unstable (CAG)_n repeat on chromosome 6p. We investigated 36 German families suffering from hereditary ataxias for the SCA1 mutation and elaborated clinical and neurophysiological characteristics. SCA1 accounts for 10 - 15% of dominant cerebellar ataxias in German kindreds. The clinical presentation is characterized by broad, even intrafamilial variability and multiple system involvement already in early stages. Slowed saccades, ptosis and facial weakness are more prevalent in SCA1 but were unspecific differences compared to non-SCAl ataxias. Two electrophysiological parameters characterize SCA1: markedly prolonged central motor conduction time in motor evoked potentials and predominantly demyelinating polyneuropathy. Molecular genetic analyses are indispensable to diagnose SCA patients precisely. Extensive neurophysiological studies are recommendable in the clinical approach as they are suitable to discover subclinical damage of the nervous system. In contrast to the enormous variability of clinical signs in SCA1 neurophysiological findings are rather constant.     

Spinocerebellar ataxia type 7 mimicking Kearns-Sayre syndrome: a clinical diagnosis is desirable

Spinocerebellar ataxias are a group of autosomal dominant cerebellar degenerative disorders, which are characterized by clinical and genetic variability. Spinocerebellar ataxia type 7 (SCA7) is less variable in clinical presentation than other SCAs. We present a pediatric patient with 13 and 70 trinucleotide CAG repeats within SCA7 gene and no family history, whose presentation mimicked Kearns-Sayre syndrome (KSS). We review the differential diagnosis of cerebellar ataxia with vision loss secondary to retinal pigmentary dystrophy. This paper supports concept of a desirable clinical diagnosis to avoid multiple genetic or invasive testing in children with neurodegenerative disorders.     

Spinocerebellar ataxia type 2 in a Turkish family

Autosomal dominant spinocerebellar ataxias are neurodegenerative disorders that generally present in adulthood. Due to extreme expansion of the repeat size during spermatogenesis, they can also be observed in childhood. The diagnosis in childhood is very difficult in the absence of family history. Here we describe an 8-year-old girl with spinocerebellar ataxia type 2 who presented with progressive ataxia, cognitive deficits, and dysarthria. A detailed family history exhibited similarly affected cases on the paternal side. Molecular testing for spinocerebellar ataxia type 2 revealed abnormal "cytosineadenine-guanosine" expansion in all affected family members. The number of cytosine-adenine-guanosine repeats in the index case was 70. The mean size of expansion in the relatives of the patient was 42 (39-46). This finding explains the early onset of symptoms in the index case.     

Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families

Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 ± 3.3 in 85 expanded alleles, with a range of 34–52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range –3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy. Received: 24 November 1997 Received in revised form: 26 October 1998 Accepted: 8 November 1998     

Spinocerebellar ataxia: a critical review of cognitive and socio-cognitive deficits

Purpose: The primary aim of this contribution is to provide a critical discussion on cognitive and sociocognitive implications of spinocerebellar ataxias (SCAs) subtypes. The term SCA refers to a group of neurodegenerative disorders that have been increasingly investigated in the last years, sharing the characteristic of progressive ataxia resulting from degeneration of cerebellum and its connections. In past decades only involvement of cerebellum in behaviour and timing has been investigated, bringing to the belief about its central role in timing of movement and sensation, particularly for short intervals of time. Only very recently the cerebellum has been considered as a potentially important centre for cognitive processing and related spheres of social cognition, so that several studies with SCA patients have been carried out on these topics: as a consequence a section of this review will be dedicated to this important aspect.

Results: After a brief discussion on most commonly used methods to assess cognitive and socio-cognitive abilities in SCAs, cognitive and socio-cognitive profiles of principal SCA subtypes have been thoroughly reviewed and critically discussed. Due to the very poor literature in this field the most common SCA variants have been fully included (i.e. SCA1, SCA2, SCA3, SCA6 and SCA7).Conclusions: A comparative summary of the main characteristics of cognitive and social cognition deficit in SCA subtypes has been proposed together with a research agenda for future investigation in this field principally aimed at using measures of cognition and/or social cognition as potential predictors of the extent and progression of disease.     

Spinocerebellar ataxia 8: Variable phenotype and unique pathogenesis

Spinocerebellar ataxia 8 (SCA8), a triplet repeat expansion disorder, is genetically distinct from the other inherited ataxias, but its unusually variable phenotype can make its diagnosis difficult. In this review we describe 3 new cases of genetically verified SCA8 to highlight the broad clinical spectrum of symptoms observed with this disorder and to draw attention to the features of myoclonus and migraine headaches, which in the context of cerebellar ataxia warrants the clinician to consider SCA8 as a potential diagnosis. We also address the controversy surrounding the genetic testing approach for diagnosing SCA8. Finally, we evaluate the evidence that SCA8 may affect calcium channel function and that the presentation of episodic ataxia and migraines suggests a clinical and pathogenic overlap of SCA8 with the channelopathies.     

Spinocerebellar ataxia type 6: CAG trinucleotide expansion, clinical characteristics and sperm analysis

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by CAG repeat expansions in the human α1A voltage-dependent calcium channel subunit gene. We analyzed 16 SCA6 patients in 14 unrelated Japanese families, and documented the clinical and molecular properties correlating with the CAG repeat expansion. Three of them were sporadic. The CAG repeat number of the expanded and normal alleles was 22.7 ± 2.0 (mean ± SD, n = 15) and 13.8 ± 2.0 (n = 15), respectively, and the repeat size of the expanded alleles correlated inversely with age at onset. The patients presented here were clinically characterized by a slowly progressive cerebellar ataxia and nystagmus. In leukocytes, the strict pattern of the peak in the expanded allele on polyacrylamide gel electrophoresis did not show the presence of cell mosaicism in SCA6, in contrast to other trinucleotide disorders. Moreover, in each patient, the number of CAG repeats in sperm was the same as in leukocytes, and the expanded alleles in sperm indicated uniform peaks as well. In our geographic area, the frequency of SCA6 was as high as MJD, in contrast to the low frequency of other autosomal dominant cerebellar ataxias. Thus, a geographic difference in the frequency of autosomal dominant spinocerebellar ataxias may be present in Japan.     

Friedreich''s ataxia: a clinical review of 20 childhood cases

The authors report the clinical review of 20 childhood cases with Friedreich's ataxia. The mean age at onset of symptoms was 6.1 years. The main presenting symptom was abnormal gait (100%). Ataxia of gait and limbs and depressed or absent tendon reflexes were found in all cases. Clinical findings are in accordance with the findings of Harding and Werdelin. Neurophysiological studies (especially sensory) are important in the confirmation of the diagnosis. Of the 10 cases in which sensory nerve conduction velocity measurements were performed, 7 had absent sensory action potentials, 2 had decreased potentials and one was normal. In our study, it is shown that in patients having ataxic gait, ataxia of limbs and tendon reflexes depression or loss, Friedreich's ataxia may be diagnosed with the help of electrophysiological studies.     

Spinocerebellar ataxia type 6: founder effect in Western Japan

An accumulation of SCA6 cases has been observed in the Chugoku area of Western Japan. In the Tottori prefecture, located in the northeastern part of the Chugoku district, we observed a cluster of SCA6 families within the eastern area, suggesting that there may be a founder in the Japanese SCA6 population. Genotyping with DNA microsatellite markers linked to the CACNL1A4 gene on chromosome 19p13 demonstrated shared allelic characteristics and revealed a common haplotype in the majority of Japanese families. The common haplotype of the shared (CAG)(22) repeat found in this study may indicate the meiotic stability of CAG repeats in SCA6 patients.     

Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds

OBJECTIVE—Spinocerebellar ataxia type 6 (SCA6) isan autosomal dominant cerebellar ataxia (ADCA) of which the mutationcausing the disease has recently been characterised as an expanded CAGtrinucleotide repeat in the gene coding for theα_1A-subunit of the voltage dependent calcium channel. Theaim was to further characterise the SCA6 phenotype
METHODS—The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadiccerebellar ataxia and the CAG repeat length of the expanded allele wascorrelated with the disease phenotype.
RESULTS—Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Diseaseonset ranged from 30 to 71 years of age and was significantlylater than in other forms of ADCA. Age at onset correlated inverselywith repeat length. The SCA6 phenotype comprises predominantlycerebellar signs in concordance with isolated cerebellar atrophy onMRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAGrepeat length.
CONCLUSIONS—This study provides the first detailedcharacterisation of the SCA6 phenotype. Clinical features apart fromcerebellar signs were highly variable in patients with SCA6. Bycomparison with SCA1, SCA2, and SCA3 no clinical orelectrophysiological finding was specific for SCA6. Therefore, themolecular defect cannot be predicted from clinical investigations. InGermany, SCA6 accounts for about 13% of families with ADCA. However,up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadicdisease due to late manifestation in apparently healthy parents.Genetic testing is therefore recommended for the SCA6 mutation also inpatients with putative sporadic ataxia.

     

Spinocerebellar ataxia type 7: Report of an Indian family

Spinocerebellar ataxia type 7 (SCA7) is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries. The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients.Key Words: Autosomal dominant cerebellar ataxia, neurogenetics, pigmentary retinal degeneration, spinocerebellar ataxia type 7     

Pronator syndrome: clinical and electrophysiological features in seven cases.

The clinical and electrophysiological picture of seven patients with the pronator syndrome is contrasted with other causes of median nerve neuropathy. In general, these patients have tenderness over the pronator teres and weakness of flexor pollicis longus as well as abductor pollicis brevis. Conduction velocity of the median nerve in the proximal forearm is usually slow but the distal latency and sensory nerve action potential at the wrist are normal. Injection of corticosteroids into the pronator teres has produced relief of symptoms in a majority of patients.