Spinocerebellar ataxia type 2 presenting with cognitive regression in childhood

Spinocerebellar ataxia type 2 typically presents in adulthood with progressive ataxia, dysarthria, tremor, and slow saccadic eye movements. Childhood-onset spinocerebellar ataxia type 2 is rare, and only the infantile-onset form has been well characterized clinically. This article describes a girl who met all developmental milestones until age 3(1/2) years, when she experienced cognitive regression that preceded motor regression by 6 months. A diagnosis of spinocerebellar ataxia type 2 was delayed until she presented to the emergency department at age 7 years. This report documents the results of her neuropsychologic evaluation at both time points. This case broadens the spectrum of spinocerebellar ataxia type 2 presentation in childhood, highlights the importance of considering a spinocerebellar ataxia in a child who presents with cognitive regression only, and extends currently available clinical information to help clinicians discuss the prognosis in childhood spinocerebellar ataxia type 2.     

A clinical trial of acetazolamide for SCA6]

Spinocerebellar ataxia type 6 (SCA 6) is an allelic disorder of episodic ataxia type 2 (EA 2) and is caused by a small CAG repeat expansion in the gene encoding the alpha 1A-voltage-dependent-Ca channel subunit (CACNA 1 A) on chromosome 19p13.1. The disorder starts at adulthood with progressive cerebellar ataxia, and the symptoms often fluctuate at early stage. These clinical features overlap with those of EA 2, which has been known as acetazolamide-responsive ataxia. On this background, we studied the clinical effectiveness of acetazolamide for SCA 6 in 9 consecutive patients. Their clinical severity was serially evaluated by ARS (ataxia rating scale) and gravimetric test, over 32 weeks of oral administration of acetazolamide (250-500 mg/day). Consequently, a significant improvement was observed in ARS and postural sway. Our results indicate that acetazolamide is temporally effective for ameliorating the symptoms of SCA 6. However, its effects for the disease progression need to be examined in more large scales in number and duration.     

A case of spinocerebellar ataxia type 6 with its initial symptom of episodic ataxia-like phenotype]

We reported a Japanese case of spinocerebellar ataxia type 6 (SCA6) with episodic ataxia type 2 (EA2) phenotype. A 28-year-old woman was admitted to our hospital because of episodic unsteadiness of gait and dysarthria for 4 years. Neurological examination revealed truncal ataxia and dysarthria during attacks, but no abnormal findings in interictal phases. A brain MRI showed no obvious cerebellar atrophy, whereas proton MR spectroscopy (1H-MRS) disclosed decrease of the N-acetylaspartate/ceatine (NAA/Cr) ratio in the cerebellar hemisphere. We identified the expanded 22 CAG repeats without a missense mutation in the CACNA1A gene. After one year from the discharge, her gait ataxia became gradually obvious even in the interictal phase. To our knowledge, although a few foreign papers had reported the SCA6 cases with EA2 phenotype, there is no particular report on such cases in Japan. 1H-MRS, in addition to CAG repeats analysis, might enable us to differentiate SCA6 from EA2, because the latter showed no decrease of NAA/Cr ratio in cerebellar hemisphere according to the previous reports.     

Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene

Mutations in the brain-specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2), and familial hemiplegic migraine type 1 (FHM1). SCA6 is associated with small expansions of a CAG repeat at the 3' end of the gene, while point mutations are mostly responsible for its two allelic disorders, FHMI and EA2. From the electrophysiological point of view, while FHMI mutations lead to a gain of function [Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, et al. Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci 99 (20) (2002) 13284-13289.], EA2 mutations usually generate a loss of channel function [Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, et al. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 68 (3) (2001) 759-764, Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 277 (9) (2002) 6960-6966.]. In the present study, we describe a child affected by permanent non-fluctuating limb and trunk ataxia with a quite early age of onset. Interestingly, the size of the CACNA1A triplet repeat region in the patient is within the normal range while he carries a novel de novo missense mutation in this gene, p.R1664Q. Although functional data are not available, based on the literature data indicating that severe reductions in P/Q-type channel activity favour episodic and/or progressive ataxic symptoms [Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 2002;277(9):6960-6966.], we hypothesize that the functional consequence of the mutation here identified is a partial loss of the Ca channel function. In conclusion, the clinical and molecular findings reported here suggest the opportunity to screen for point mutation in this gene, even patients with a clinical phenotype for some aspects slightly different from the typical picture more commonly associated to SCA6, EA2 or FHM1 diseases.     

Phosphorus and proton magnetic resonance spectroscopy in episodic ataxia type 2.

Localized phosphorus (31P) and proton (1H) magnetic resonance spectroscopy was performed in the cerebellum and the occipital lobe of 6 patients with episodic ataxia type 2. From use of 31P magnetic resonance spectroscopy, untreated patients showed decreased high-energy phosphate ratios in the cerebrum, and increased pH in the cerebellum and cerebrum, which normalized under acetazolamide. 1H magnetic resonance spectra demonstrated high lactate peaks in 3 of the 6 patients. These metabolic alterations, probably induced by the calcium channelopathy, may characterize episodic ataxia type 2.     

Comparison of cerebellar ataxias: A three‐year prospective longitudinal assessment

We quantitatively investigated the clinical severity and progression of diseases with ataxia, as measured with the Scale for the Assessment and Rating of Ataxia, and examined the potential application of the Scale for the Assessment and Rating of Ataxia for future therapeutic trials. Severity of ataxia was assessed in 238 patients with spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 17, multiple system atrophy‐cerebellar variant, or Gerstman‐Sträussler‐Scheinker disease. Among them, 119 (50%) were longitudinally examined three to seven times, in a period of 8 to 38 months, resulting in a total set of 535 assessments. The differences between spinocerebellar ataxia and multiple system atrophy‐cerebellar variant were ascertained cross‐sectionally and longitudinally. Gerstman‐Sträussler‐Scheinker disease had the fastest progression, followed by multiple system atrophy‐cerebellar variant, spinocerebellar ataxia type 17, spinocerebellar ataxia type 3, spinocerebellar ataxia type 2, and spinocerebellar ataxia type 6. Patients with multiple system atrophy‐cerebellar variant had a faster progression in gait, sitting, speech, and total score than patients with spinocerebellar ataxias. For a randomized, case‐control trial, a sample size of 47 for spinocerebellar ataxia and 85 for multiple system atrophy‐cerebellar variant in the treatment or placebo arms would have a sufficient statistical power to demonstrate the efficacy of a new therapy that would retard ataxia progression by 1 point per year as measured by the Scale for the Assessment and Rating of Ataxia. The results will have a significant impact on the planning and implementation of future therapeutic trials of spinocerebellar ataxia and multiple system atrophy‐cerebellar variant. © 2011 Movement Disorder Society     

Degree of cerebellar ataxia correlates with three-dimensional mri-based cerebellar volume in pure cerebellar degeneration

The aim of the present study was to compare the severity of cerebellar ataxia as measured by the International Cooperative Ataxia Rating Scale (ICARS) by Trouillas et al. [ J Neurol Sci 1997;145:205-211] with the cerebellar volume in chronic cerebellar disease. Fifteen patients with pure cerebellar degeneration were investigated. Seven patients suffered from spinocerebellar ataxia type 6, 5 from idiopathic late-onset cerebellar ataxia, 2 from autosomal dominant cerebellar ataxia type III and 1 from episodic ataxia type 2. Volumetric analysis was based on individual three-dimensional MR images. Total ICARS score significantly inversely correlated with the cerebellar volume (r = -0.805, p < 0.0001), correlations between ICARS subscores and cerebellar volume were significant for upper and lower limb ataxia, ataxia of posture and gait, and dysarthria, but not for the oculomotor subscore. The results suggest that the degree of cerebellar atrophy in pure cerebellar degenerative disorders is accompanied by comparable functional impairment (i.e. degree of cerebellar ataxia).     

Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds

OBJECTIVE: To assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, and DRPLA (dentatorubropallidoluysian atrophy) CAG trinucleotide repeat expansions [(CAG)n] among persons diagnosed with hereditary SCA from Chinese families. PATIENTS AND METHODS: Spinocerebellar ataxia type 1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA (CAG)n mutation were detected with the polymerase chain reaction, highly denaturing polyacrylamide gel electrophoresis, and silver staining technique in 167 patients with autosomal dominant SCA from 85 Chinese families and 37 patients with sporadic SCA. RESULTS: Spinocerebellar ataxia type 1 (CAG)n mutation in 7 patients from 4 kindreds (4.70%) was expanded to 53 to 62 repeats. Spinocerebellar ataxia type 2 (CAG)n mutation in 12 patients from 5 kindreds (5.88%) was expanded to 42 to 47 repeats. Spinocerebellar ataxia type 3/Machado-Joseph disease (CAG)n mutation in 83 patients from 41 kindreds (48.23%) was expanded to 68 to 83 repeats. Sixty-five patients from 35 kindreds (41.19%) and 37 patients with sporadic SCA did not test positive for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, or DRPLA. There was a predictable inverse relationship between the number of CAG repeats and the age at onset for SCA3/MJD and SCA2. Clinically, dementia and hyporeflexia were more frequent in patients with SCA2, while spasticity, hyperreflexia, and Babinski signs were more frequent in patients with SCA3/ MJD, and those might be helpful in clinical work to primarily distinguish patients with SCA3/MJD and SCA2 from others with different types of SCA. CONCLUSIONS: The frequency of SCA3/MJD is substantially higher than that of SCA1 and SCA2 in patients with autosomal dominant SCA from Chinese kindreds, who are non-Portuguese. Clinical expressions of the various types of SCAs overlap one another; therefore, for clinical study it is important to make a gene diagnosis and genetic classification for patients with SCA.     

CAG repeat expansions in patients with sporadic cerebellar ataxia

CAG repeat expansions cause spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6 and dentatorubral-pallidoluysian atrophy (DRPLA). So far these expansions have been examined mainly in ataxia patients with a family history. However, some sporadic cases with SCA have recently been reported. To elucidate the frequency and characteristics of sporadic SCAs, we screened 85 Japanese ataxia patients without a family history for the SCA1, SCA2, SCA3, SCA6 and DRPLA mutations. As a result, 19 patients (22%) were found to have expanded CAG repeats. Among sporadic SCAs, the SCA6 mutation was most frequently observed. The sporadic SCA6 patients had smaller CAG repeats and a later age of onset than SCA6 patients with an established family history. We also identified one father-child pair in which intermediate sized CAG repeats expanded into the SCA2 disease range during transmission. These findings suggest that patients with ataxia even without a family history should be examined for a CAG repeat expansion.     

Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia

BACKGROUND: The small-conductance calcium-activated potassium channel gene (hSKCa3) contains 2 CAG repeats, 1 of which is highly polymorphic. Although this repeat is not pathologically expanded in patients with schizophrenia, some studies have suggested an allelic association with schizophrenia. CAG expansions in other genes such as the alpha1 subunit of a brain-specific P/Q-type calcium channel gene cause spinocerebellar ataxia type 6, whereas the length of the CAG repeat in the RAI1 gene modifies the age of onset of spinocerebellar ataxia type 2. OBJECTIVES: To evaluate expansions in the hSKCa3 polyglutamine domain as causative for ataxia, and to study the association between the length of the polyglutamine repeat and the presence of ataxia. METHODS: We analyzed this repeat in 122 patients with autosomal dominant cerebellar ataxia, or sporadic ataxia, and compared allele distribution with 750 alleles seen in 2 healthy control groups and 172 alleles in patients with Parkinson disease. RESULTS: The distribution of alleles in ataxia patients and controls was significantly different by Wilcoxon rank test (P <.001). Twenty-two or more polyglutamine tracts were more common in ataxia patients compared with controls by chi2 analysis (P<.001). CONCLUSION: Longer stretches of polyglutamines in a human potassium channel are not causative for ataxia, but they are associated with the presence of ataxia. There is no association with the presence of Parkinson disease.     

Stepwise developmental regression associated with novel CACNA1A mutation

Mutations in CACNA1A were previously described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. We report on an 11-year-old girl with episodes of seizures, ataxia, headache, a decreased level of consciousness, and motor regression, with a background of mental retardation and mild cerebellar atrophy. Sequence analysis of the CACNA1A gene revealed a de novo Ile712Val sequence variant, which was not reported previously.     

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).     

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.     

Early-onset cerebellar atrophy associated with mutation in the CACNA1A gene

Mutations in the CACNA1A gene were described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. Familial hemiplegic migraine and episodic ataxia type 2 are caused by point mutations in the CACNA1A gene, and spinocerebellar ataxia type 6 develops as a result of a CAG triple expansion in exon 1 of the gene. Phenotypic variability and clinical overlap are well recognized. We describe a 3-year-old child with clinical and radiologic signs of early-onset cerebellar atrophy. The family history was significant for migraine, and in some members of the family, a diagnosis of hemiplegic migraine was established. The combination of cerebellar atrophy in our patient and the family history suggested involvement of the CACNA1A gene. The sequence analysis of genomic DNA from the proband identified heterozygosity for a mutation (Thr666Met) in the CACNA1A gene. Subsequently, his father, who was mildly affected, and two other relatives were demonstrated to carry the same mutation. Therefore, CACNA1A gene mutations should be considered in the differential diagnosis of congenital cerebellar atrophy.     

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     

Type 1 ataxia with oculomotor apraxia with aprataxin gene mutations in two American children

Ataxia and oculomotor apraxia are seen in ataxia-telangiectasia, type 1 ataxia with oculomotor apraxia, and type 2 ataxia with oculomotor apraxia; however, only type 1 ataxia with oculomotor apraxia is associated with aprataxin gene mutation. We report two American children, a sister and a brother, with type 1 ataxia with oculomotor apraxia and aprataxin gene mutations and briefly review type 1 ataxia with oculomotor apraxia.     

Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy

We investigated a family with a new type of autosomal dominant cerebellar ataxia (ADCA) in which pure cerebellar ataxia is often accompanied with epilepsy. No CAG repeat expansions were detected at the spinocerebellar ataxia (SCA) type 1, 2, 3, 6, or 7 locus, and SCAs 4 and 5 were excluded by linkage analysis. We found linkage between the disease locus and D22S274 (Zmax = 3.86 at theta = 0.00) and two other makers in 22q13-qter. Haplotype analysis of the crossover events and the multipoint linkage mapping localized the disease locus to an 8.8-cM region between D22S1177 and D22S1160.     

Difference in the Effects of Tandospirone on Ataxia in Various Types of Spinocerebellar Degeneration: An Open-Label Study

The aim of this study was to investigate the effects of tandospirone on ataxia in various types of spinocerebellar degeneration (SCD). Fifteen milligram per day of tandospirone was administered to 39 patients with SCD (spinocerebellar atrophy (SCA) 1, five patients; SCA2, six patients; Machado–Joseph disease (MJD), 14 patient; SCA6, five patients; multiple system atrophy-cerebellar type (MSA-C), seven patients; and multiple system atrophy–Parkinson type (MSA-P), two patients). All patients were assessed before and 4 weeks after administration of the drug using the international cooperative ataxia rating scale total score (ARS), total length traveled (TLT) of body stabilometry, and a self-rating depression scale. Statistically, ARS showed a significant difference in MJD (p?=?0.005) and SCA6 (p?=?0.043). TLT also showed a significant difference in MJD (p?=?0.002) and SCA6 (p?=?0.043). Eight of 39 patients (SCA1, 1/5; SCA2, 0/6; MJD, 4/14; SCA6, 3/5; MSA-C, 0/7; and MSA-P, 0/2) showed more than a five point reduction in ARS, and 13 of 39 patients (SCA1, 0/5; SCA2, 1/6; MJD, 8/14; SCA6, 4/5; MSA-C, 0/7; and MSA-P, 0/2) showed a reduction of TLT. Our data indicate that the effects of tandospirone on ataxia are different between types of SCD. Therefore, tandospirone is useful for cerebellar ataxia in patients with MJD and SCA6.