Spinocerebellar ataxia type 6 in relation to CAG repeat length

The purpose of the present study was to assess the relationship between clinical characteristics of spinocerebellar ataxia type 6 (SCA6) and CAG repeat length. MATERIALS AND METHODS: We examined clinical symptoms of 54 patients with SCA6. CAG repeat length was compared among subgroups divided by clinical manifestations. RESULTS: The major symptom was progressive cerebellar ataxia. Truncal or limb ataxia, dysarthria, and nystagmus were observed in more than 80% of the patients. In analysis of CAG repeat length in patients with different types of nystagmus, CAG repeat length was the longest when both upbeat and downbeat nystagmus existed (P < 0.01). In addition, CAG repeat length was longer when the initial symptom was ataxic gait and was shorter when the initial symptom was dysarthria or ocular symptom (P < 0.05). CONCLUSION: Clinical features of SCA6 might be influenced by the length of abnormal CAG repeat.     

Spinocerebellar ataxia type 6: Gaze-evoked and vertical nystagmus,Purkinje cell degeneration,and variable age of onset

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the α1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.     

Meiotic CAG repeat instability in spinocerebellar ataxia type 6: maternally transmitted elongation in a presumed sporadic case

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6.     

Downbeat nystagmus in two siblings with spinocerebellar ataxia type 6 (SCA 6)

We report two siblings with spinocerebellar ataxia type 6 (SCA 6), both showing downbeat nystagmus (DBN) as a predominant clinical feature. Familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA-2) and SCA 6 are allelic disorders, and interestingly, the occasional presence of DBN in EA-2 was reported. Our observations suggest that common molecular mechanisms might underlie DBN in FHM, EA-2 and SCA 6. Then, these disorders should be kept in mind in diagnosing patients with DBN.     

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.     

脊髓小脑性共济失调6型的分子遗传学诊断及临床特点

目的 研究脊髓小脑性共济失调6型(SCA6)的基因诊断方法及临床特点。方法 对临床诊断为脊髓小脑性共济失调(SCA)的36个家系43例患者及38例散发患者，应用聚合酶链反应对SCA6基因含有CAG三核苷酸重复片段进行扩增，并对异常等位基因片段进行DNA测序，计算CAG重复次数；对2例SCA6患者临床资料进行分析。结果 正常人的SCA6等位基因CAG重复数目为10～13。本组检出家族性患者1例，散发患者1例，其异常等位基因内CAG重复数目分别为25、24。患者临床基本特征为缓慢进展的小脑性共济失调、眼震、构音障碍。结论 致病基因内CAG三核苷酸重复异常扩增是SCA6的确诊依据。SCA6的临床表现与其他SCA亚型无明显差别。     

Pontine atrophy in spinocerebellar ataxia type 6

To investigate the clinical range of spinocerebellar ataxia type 6 (SCA6), we screened CAG repeat expansion in the voltage-dependent alpha 1A calcium channel gene (CACNL1A4) in 71 ataxic patients in 60 families; 54 patients in 43 families with hereditary ataxia and 17 sporadic patients. Thirteen patients with SCA6 were detected to have elongated CAG in CACNL1A4. Of these, 7 patients had been diagnosed as having hereditary cerebellar cortical atrophy, and 6 patients had been found to have sporadic occurrence. One patient showed distinct pontine atrophy with prominent horizontal or oblique gaze nystagmus which is an unusual feature in sporadic olivopontocerebellar atrophy. For the efficient screening of SCA6, we would propose testing CAG repeat expansion in CACNL1A4, in patients with one of two markers: (1) horizontal or oblique gaze nystagmus without other eye movement disorders, (2) pure cerebellar atrophy, even if occurrence is sporadic. We should note that the pontine atrophy could also be caused by CAG repeat expansion in CACNL1A4.     

Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6)

To investigate the frequency of positioning nystagmus in degenerative ataxic disorders, we examined downbeat positioning nystagmus (DPN) in 25 patients with spinocerebellar ataxia type 6 (SCA6) and 58 patients with other types of degenerative ataxia. DPN was observed in 21 of the 25 patients with SCA6 (84 %) versus only 3 of the 58 patients (5.2 %) with other types of degenerative ataxia, including multiple system atrophy, SCA1, SCA2, SCA3/Machado-Joseph disease, and non-SCA6 late-onset pure cerebellar ataxia. Our findings indicated that DPN is a distinct part of the clinical presentation of SCA6, showing that vestibular cerebellum is more affected in SCA6 than other types of degenerative ataxia. Received: 11 June 2002, Received in revised form: 24 October 2002, Accepted: 8 November 2002 Correspondence to Hidenao Sasaki, MD, PhD     

Vertigo and vestibular abnormalities in spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is a calcium channelopathy due to a pathological CAG repeat expansion in CACNL1A4. Patients frequently describe paroxysmal vertigo early in the disease course, but it is not clear whether this is central or labyrinthine in origin. To address this issue we studied 21 SCA6 patients. Symptoms of vertigo were defined using a structured questionnaire. Signs were recorded during a standardised bed-side vestibular examination that included systematic positional testing with Frenzel goggles. Brief, recurrent attacks of vertigo occurred in 13 patients, usually preceding the onset of ataxia. Nystagmus was observed behind Frenzel goggles in 14 patients, and was induced either during positional testing, or head shaking in 20 patients. Only one patient had findings typical of benign paroxysmal positional vertigo (BPPV). Combined downbeat and horizontal gaze-evoked nystagmus (“side-pocket”) was the most common form, occurring most commonly in supine and head-hanging positions, and following horizontal head-shaking. Nystagmus beating away from the ground (apogeotropic) occurred in 9 patients as they lay on their side. In conclusion, vertigo and abnormalities on bedside vestibular examination are common in SCA6, with forms of nystagmus typical of cerebellar, rather than labyrinthine, disease. These findings demonstrate phenotypic overlap between SCA6 and episodic ataxia type 2, which are both due to mutations in CACNL1A4.     

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     

Monocular downbeat nystagmus

Summary A patient with sporadic pontocerebellar degeneration and downbeat nystagmus limited to the left eye is described. The nystagmus was not modified by head movements, but was associated with a purely tonic upgaze paresis in the same eye. Absence of internuclear ophthalmoplegia indicated sparing of the medial longitudinal fasciculus. It is suggested that the vertical oculomotor abnormalities are due to dysfunction of the ipsilateral brachium conjunctivum.     

中国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型基因诊断中的应用

目的 探讨我国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型(spinocerebellar ataxias type 6,SCA6)基因诊断中的应用.方法 应用"两步PCR法"、变性聚丙烯酰胺凝胶电泳(DPAGE)和测序等方法对300名健康对照及109例无血缘关系的SCA患者进行CACNA1A基因CAG三核苷酸重复数目分析.结果 300名健康对照的CAG重复次数范围为3～18次,以13次最常见.在109例SCA患者中,发现1例SCA6患者,其CAG异常重复次数为24次,该患者的母亲和哥哥亦为SCA6患者,临床上均表现为缓慢进展的小脑性共济失调、构音障碍、眼震、轻度的振动及本体觉减退,遗传早现现象较明显.结论 SCA6病例在我国较少见,进行CACNA1A基因突变分析有助于临床诊断."两步PCR法"可提高CACNA1A基因突变分析的效率.     

中国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型基因诊断中的应用

目的 探讨我国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型(spinocerebellar ataxias type 6,SCA6)基因诊断中的应用.方法 应用"两步PCR法"、变性聚丙烯酰胺凝胶电泳(DPAGE)和测序等方法对300名健康对照及109例无血缘关系的SCA患者进行CACNA1A基因CAG三核苷酸重复数目分析.结果 300名健康对照的CAG重复次数范围为3～18次,以13次最常见.在109例SCA患者中,发现1例SCA6患者,其CAG异常重复次数为24次,该患者的母亲和哥哥亦为SCA6患者,临床上均表现为缓慢进展的小脑性共济失调、构音障碍、眼震、轻度的振动及本体觉减退,遗传早现现象较明显.结论 SCA6病例在我国较少见,进行CACNA1A基因突变分析有助于临床诊断."两步PCR法"可提高CACNA1A基因突变分析的效率.     

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.     

Slow saccades and other eye movement disorders in spinocerebellar atrophy type 1

In order to study the relation between genotype and phenotype, a detailed study of the course of oculomotor deficits was performed in three patients with autosomal-dominant cerebellar ataxia, subtype spinocerebellar atrophy type 1 (SCA 1) using clinical testing and electrooculography. DNA analysis revealed a CAG repeat expansion of 65 in the SCA 1 gene on chromosome 6p in all patients. A progressive disorder of the saccadic system became obvious, leading to a marked slowing of saccadic eye movements and loss of pathological and physiological nystagmus. An upward gaze palsy developed early, followed by horizontal and downward gaze palsy at a later state of the disease. Smooth pursuit eye movements were disturbed to a lesser extent; the vestibulo-ocular reflex was reduced. As an additional feature, severe loss of visual acuity developed due to progressive optic nerve atrophy. The oculomotor deficits can be explained by progressive damage to the brain stem rather than to the cerebellum. Each combination of oculomotor deficits with or without optic atrophy may occur irrespective of the gene locus of the disease, making a correlation between clinical signs and genetic findings difficult. Received: 24 May 1996 Received in revised form: 9 September 1996 Accepted: 23 September 1996     

Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia

The SCA6 mutation, a small expansion of a CAG repeat in acalcium channel gene CACNA1A, was identified in three pedigrees. Pointmutations in other parts of the gene CACNA1A were excluded and newclinical features of SCA6 reported—namely, central positional nystagmus and episodic ataxia responsive to acetazolamide. The threeallelic disorders, episodic ataxia type 2, familial hemiplegic migraine, and SCA6, have overlapping clinical features.

     

EFNS task force--therapy of nystagmus and oscillopsia.

An overview of possible treatment options for oculomotor disorders that prevent clear vision is given. Downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus, acquired pendular nystagmus, and saccadic oscillations such as opsoclonus/ocular flutter are discussed. In addition, superior oblique myokymia and vestibular paroxysmia are reviewed. All treatment recommendations available in the literature are classified as class C only. In general, only some of the patients benefit from the treatment.     

Clinical features and genetic analysis of a Spanish family with spinocerebellar ataxia 6

Objective - To present the clinical features and DNA analysis of a Spanish SCA6 family. Material and methods - Four symptomatic members of the family (mean age at onset: 53.75 ± 5.21) were examined. SCA6 CAG trinucleotide repeat was analysed in the proband by the polymerase chain reaction (PCR). Results - Early dysphagia, ophthalmoparesis and neck dystonia in the oldest patient, without the loss of vibratory and proprioceptive sensation supporting the theory of phenotypic variability within families with SCA6 . Our results are in accordance with the theory that the size of the repeat pattern correlates with the age at onset of the symptoms. Analysis of the SCA6 CAG trinucleotide repeat at the CACNA1A gene in the patient's DNA demonstrated an expanded allele of 22 CAG repeat units. Conclusions - This study identifies phenotypic differences in the surviving kindred. The diagnosis of SCA6 in family members or single affected patients can be made by direct molecular analysis. This makes predictive testing possible.     

Spinocerebellar ataxia type 17 (SCA17): Oculomotor phenotype and clinical characterization of 15 Italian patients

SCA17 is a rare type of autosomal dominant spinocerebellar ataxia caused by a CAG/CAA expansion in the gene encoding the TATA-binding protein (TBP).We screened for triplet expansion in the TBP gene 110 subjects with progressive cerebellar ataxia and 94 subjects with Huntington-like phenotype negative at specific molecular tests. SCA17 mutation-positive subjects were found in both groups of patients. Expanded alleles with ≥ 44 CAG/CAA repeats were identified in 11 individuals and in 4 non-symptomatic relatives. Eleven de novo diagnosed patients and four patients previously reported underwent extensive clinical, neuroradiological and oculographic examination. Cerebellar signs and symptoms were present in all cases; 80% of the patients had mild to severe cognitive deficits; 66% of patients showed choreic movements; pyramidal signs, bradykinesia and dystonia were observed in approx 50% of the cases. MRI demonstrated cortical and cerebellar atrophy in all patients, whereas neurophysiological examination excluded signs of peripheral nervous system involvement. Oculographic examinations were performed in 9 out of 15 patients and showed a distinct pattern of oculomotor abnormalities, characterized by impairment of smooth pursuit, defects in the saccade accuracy, normal saccade velocity, hyperreflexia of vestibuloocular reflexes, and absence of nystagmus. In summary, this study presents one of the largest series of SCA17 patients in Europe. In our group of patients, SCA17 represents the third most frequent SCA genotype. Our clinical data confirm the large variability in SCA17 phenotypic presentation, and indicate that a peculiar combination of neuroradiological, electrophysiological and oculomotor findings is recognizable in SCA17.