The electrophysiological footprint of CACNA1A disorders

Journal of Neurology - CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). EEG...     

The molecular biology of the autosomal-dominant cerebellar ataxias.

Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. While the progressive ataxias have been named spinocerebellar ataxias (SCA), the paroxysmal disorders are designated episodic ataxias (EA). Until now, three different mutational mechanisms resulting in distinctive pathogenesis have been identified. The first type of mutation present in SCA1, SCA2, SCA3, and SCA7 is an expanded CAG repeat in genes of unknown function that are translated into proteins with expanded polyglutamine tracts. A common ultrastructural feature of these disorders is the formation of neuronal intranuclear inclusions (NII) harboring the expanded disease proteins and a variety of other proteins. The pathogenic role of these inclusions has yet to be clarified. A second group of disorders is the result of mutations in genes that code for ion channels. In EA-1, a disorder characterized by episodes of ataxia provoked by movement and startle, missense mutations in a potassium channel gene, KCNA1, have been found. Patients with EA-2, another form of paroxysmal ataxia, carry nonsense mutations of the gene encoding the alpha1A voltage-dependent calcium channel subunit, CACNA1A, that are predicted to result in truncated channel proteins. In SCA6, a progressive ataxia, an expanded CAG repeat in the 3' translated region of the CACNA1A gene, has been found. The third type of mutation is an untranslated CTG expansion resembling the mutation found in myotonic dystrophy. It is associated with a progressive ataxia, SCA8.     

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     

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.     

Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder?

Spinocerebellar ataxia type 6 (SCA6) is due to small expansions of a CAG repeat at the 3' end of the CACNA1A gene, coding for the alpha(1A) subunit of voltage-gated calcium channels type P/Q, expressed in the cerebellar Purkinje and granule cells. It is one of three allelic disorders, the other two being episodic ataxia type 2 (EA2), due mostly to protein truncating mutations, and familial hemiplegic migraine, associated with missense mutations. The latter disorders, due to point mutations altering the P/Q channel activity, clearly belong to the group of channelopathies. For SCA6, due to CAGn expansions, a toxic gain of function might, instead, be envisaged homologous to that of glutamine repeat disorders. A comparison between SCA6 and EA2 phenotypes performed on available literature data, shows that the clinical features of the two disorders are widely overlapping and that the differences could be accounted for with the older age of patients in the SCA6 group. A similar phenotype in the two disorders could imply the same pathogenic process. Functional analyses on cells expressing the protein with an expanded polyglutamine stretch have shown, in fact, an altered channel activity. In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders.     

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.     

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.     

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.

     

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.     

Electrophysiological studies in spinocerebellar ataxia type 6: a statistical approach

In spinocerebellar ataxia type 6 (SCA6), the cerebellum is predominantly affected, but several electrophysiological studies have revealed subclinical disorders other than cerebellar lesions. We conducted statistical analyses by comparing SCA6 patients and age-matched normal controls to asses whether electrophysiological abnormalities are directly associated with SCA6 because late onset of SCA6 may involve senile changes. We performed brain stem auditory evoked potentials (BAEP), visual evoked potentials, somatosensory evoked potentials and nerve conduction studies in 10 SCA6 patients. The BAEP latencies of wave I was prolonged and compound muscle action potentials of peroneal nerve and sensory nerve action potentials of sural nerve reduced in SCA6 patients. Our results suggest an existence of peripheral impairment in the auditory pathway and axonal neuropathy in SCA6.     

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.     

Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.

BACKGROUND: Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders. The mutational basis for most of these disorders is an expanded CAG repeat sequence within the coding regions of the genes involved. The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese people. OBJECTIVES: To characterize the prevalence of SCA in the ethnic Chinese on Taiwan, and to specifically characterize Chinese patients with SCA6 in terms of clinical and molecular features. PATIENTS AND METHODS: Using a molecular approach, we investigated SCA in 74 Taiwanese families with dominantly inherited ataxias and in 49 Taiwanese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 12 patients from 8 families and in 2 sporadic cases. Furthermore, the intragenic polymorphic marker D19S1150 was amplified by polymerase chain reaction to analyze for linkage disequilibrium. RESULTS: Machado-Joseph disease-SCA3 was the most common type of autosomal dominant SCA in the Taiwanese cohort, accounting for 35 cases (47.3%), followed by SCA6 (8 [10.8%]), SCA2 (8 [10.8%]), SCA1 (4 [5.4%]), SCA7 (2 [2.7%]), dentatorubropallidoluysian atrophy (1 [1.4%]), and SCA8 (0%). The genes responsible for 16 (21.6%) of Taiwanese dominantly inherited SCA cases remain to be determined. Among the 49 patients with sporadic ataxias in the present series, 2 (4.1%) were found to harbor SCA6 mutations. In the families with SCA6, we found significant anticipation in the absence of genetic instability on transmission, indicating that some other mechanism might account for the anticipation. The same frequent allele of the intragenic DNA marker (D19S1150) was shared by 7 of 10 Taiwanese families with SCA6. CONCLUSIONS: Although SCA6 has, so far, not been reported in mainland Chinese, we found a geographic cluster of families with SCA6 on Taiwan. Genotyping studies suggest a founder effect in the Taiwanese patients with SCA6.     

Regional patterns of cerebral glucose metabolism in spinocerebellar ataxia type 2, 3 and 6

The purpose of this study was to investigate the regional patterns of cerebral metabolic deficits by voxel-based FDGPET analysis in patients with distinct spinocerebellar ataxia (SCA) genotypes, including SCA type 2 (SCA2), SCA3, and SCA6. Nine patients with SCA2, 12 with SCA3, seven with SCA6, and 23 healthy control subjects were recruited. The clinical severity of the patients' cerebellar ataxia was evaluated according to the International Cooperative Ataxia Rating Scale. The brain glucose metabolism was evaluated with 2- [fluorine 18]-fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography. Group data were analyzed and compared by voxelbased analysis. In SCA2, FDG utilization was significantly reduced in the cerebellum, pons, parahippocampal gyrus and frontal cortex. In SCA3, FDG metabolism in the cerebellum, parahippocampal gyrus of the limbic system, and lentiform nucleus was decreased. In SCA6, FDG metabolism was diminished in the cerebellum and the frontal and prefrontal cortices. On group comparisons, while all SCAs have impaired cerebellar functions, the cerebellar FDG metabolism was most severely compromised in SCA2. Instead, the FDG metabolism in the lentiform nucleus and medulla was characteristically worst in SCA3. There was no brainstem involvement in SCA6.     

An autopsy case of spinocerebellar ataxia type 6 with mental symptoms of schizophrenia and dementia.

We herein report the findings of an autopsy case of spinocerebellar ataxia type 6 (SCA6) which revealed a mild CAG-repeat expansion in the alpha1A voltage-dependent calcium channel (CACNL1A4) gene on chromosome 19p13. A 39-year-old man who showed slowly progressive mental disorders and gait ataxia was clinically diagnosed to have cortical cerebellar atrophy (CCA) and schizophrenia. None of his relatives revealed any symptoms such as spinocerebellar disease, however, his younger brother had shown some mental disorders. The patient eventually died at 52 years of age, and an autopsy was thus performed. The main histopathological findings included a severe neuronal cell loss of Purkinje cells and inferior olivary nuclei. The number of Purkinje cells in our case had decreased severely in comparison to that in either OPCA or age-matched control cases, and the Purkinje cells in the cerebellar hemisphere were more affected than those in the cerebellar vermis. The neurons of the dentate nucleus and pontine nuclei were well-preserved, and no pathological changes were seen in cerebral cortices or basal ganglia. The clinicopathological findings were similar to those of late cortical cerebellar atrophy (LCCA), Holmes' cortical cerebellar atrophy (Holmes type) or SCA6 cases reported previously. Using genomic DNA extracted from archival paraffin-embedded sections in the frontal lobe, cerebral basal ganglia and cerebellum, the identical mild CAG-repeat expansions in the CACNL1A4/SCA6 gene were revealed in all samples examined. These findings suggest that in cases with LCCA or Holmes type atrophy, we should thus examine the CAG-repeat expansions in the SCA6 gene, and the genomic DNA extracted from paraffin-embedded sections was thus found to be useful in diagnosing SCA6 retrospectively.     

Molecular epidemiology of spinocerebellar ataxia type 6

We performed a population-based clinical and molecular genetic study of spinocerebellar ataxia type 6 (SCA6) in the northeast of England. The minimum point prevalence of SCA6 was 1.59 in 100,000 (95% confidence interval [CI], 1.04-2.14), and the number of individuals who either had SCA6 or are at risk of developing SCA6 was at least 5.21 in 100,000 (95% CI, 4.31-6.10), or 1 in 19,210. Microsatellite analysis of the CACNA1A gene indicated a founder effect for SCA6 within this region.     

Quantitative assessment of cerebral blood flow in genetically confirmed spinocerebellar ataxia type 6

BACKGROUND: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia caused by CAG trinucleotide expansion. The characteristics of regional cerebral blood flow (rCBF) in SCA6 patients have not been established, whereas it has been reported that decreased rCBF in the cerebrum seems to be a remote effect of cerebellar impairment in other cerebellar disorders. OBJECTIVE: To clarify the characteristics of rCBF, including cerebro-cerebellar relationship, and its correlation with clinical manifestations in patients with genetically confirmed SCA6 using quantitative assessment of rCBF by brain single-photon emission computed tomography (SPECT). DESIGN: Technetium Tc 99m ethyl cysteinate dimer SPECT study using a Patlak plot.Patients Hiroshima University Hospital, Hiroshima, Japan. Ten patients with SCA6 and 9 healthy controls.Main Outcome Measure The rCBF of the cerebellar vermis, cerebellar hemisphere, and frontal lobes. RESULTS: In SCA6 patients, rCBF was decreased only in the cerebellar vermis and hemisphere compared with healthy controls, and this was inversely correlated with duration of illness. The rCBF in the frontal lobes was slightly correlated with duration of illness without statistical significance. The rCBF in the vermis was inversely correlated with severity of dysarthria, but there was no significant correlation with CAG repeated expansions. CONCLUSIONS: Decrease in rCBF was found only in the cerebellum and was associated with duration of illness, dysarthria and ataxia, and cerebellar atrophy. No remote effect of cerebellar hypoperfusion was found in the SCA6 patients.     

Periodic alternating nystagmus and rebound nystagmus in spinocerebellar ataxia type 6.

We report on a family with ataxia type 6 (SCA6) showing peculiar oculomotor symptoms. The proband presented with periodic alternating nystagmus (PAN), and her 2 brothers had rebound nystagmus and gaze-evoked nystagmus. They carried the identical mutation (the number of expanded CAG repeat, 24) in the CACNA1A gene. The intrafamilial variability of oculomotor symptoms may be ascribed to factors other than CAG repeat expansion size in SCA6.     

Clinical and genetic analysis of spinocerebellar ataxia in Mali

Background: Autosomal dominant cerebellar ataxia, currently denominated spinocerebellar ataxia (SCAs), represents a heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. We describe the clinical and molecular findings in 16 patients originating from Malian families, who suffer from progressive cerebellar ataxia syndrome. Methods and results: Molecular analysis allows genetic profiles of SCA to be distinguished. In seven patients, SCA type 2 (CAG) mutation was expanded from 39 to 43 repeats. SCA type 7 (CAG) mutation was confirmed in six patients. Mutations were expanded from 49 to 59 repeats. In three patients, SCA type3 was diagnosed and CAG mutation was expanded to 73 repeats. Conclusions: Our data suggest that the most frequent types of SCA are SCA2 and SCA7. However, further studies are needed to confirm these preliminary results.     

Degeneration of ingestion-related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7

Dysphagia, which can lead to nutritional deficiencies, weight loss and dehydration, represents a risk factor for aspiration pneumonia. Although clinical studies have reported the occurrence of dysphagia in patients with spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3), type 6 (SCA6) and type 7 (SCA7), there are neither detailed clinical records concerning the kind of ingestive malfunctions which contribute to dysphagia nor systematic pathoanatomical studies of brainstem regions involved in the ingestive process. In the present study we performed a systematic post mortem study on thick serial tissue sections through the ingestion-related brainstem nuclei of 12 dysphagic patients who suffered from clinically diagnosed and genetically confirmed spinocerebellar ataxias assigned to the CAG-repeat or polyglutamine diseases (two SCA2, seven SCA3, one SCA6 and two SCA7 patients) and evaluated their medical records. Upon pathoanatomical examination in all of the SCA2, SCA3, SCA6 and SCA7 patients, a widespread neurodegeneration of the brainstem nuclei involved in the ingestive process was found. The clinical records revealed that all of the SCA patients were diagnosed with progressive dysphagia and showed dysfunctions detrimental to the preparatory phase of the ingestive process, as well as the lingual, pharyngeal and oesophageal phases of swallowing. The vast majority of the SCA patients suffered from aspiration pneumonia, which was the most frequent cause of death in our sample. The findings of the present study suggest (i) that dysphagia in SCA2, SCA3, SCA6 and SCA7 patients may be associated with widespread neurodegeneration of ingestion-related brainstem nuclei; (ii) that dysphagic SCA2, SCA3, SCA6 and SCA7 patients may suffer from dysfunctions detrimental to all phases of the ingestive process; and (iii) that rehabilitative swallow therapy which takes specific functional consequences of the underlying brainstem lesions into account might be helpful in preventing aspiration pneumonia, weight loss and dehydration in SCA2, SCA3, SCA6 and SCA7 patients.