Missense CACNA1A mutation causing episodic ataxia type 2

OBJECTIVES: To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. BACKGROUND: Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. METHODS: All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. RESULTS: A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. CONCLUSIONS: The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.     

Novel splice site CACNA1A mutation causing episodic ataxia type 2

Episodic ataxia type 2 (EA-2) is an autosomal dominant neurological disorder, characterized by episodes of ataxia, vertigo, nausea, nystagmus, and fatigue, associated with acetazolamide responsiveness. The disease is caused by mutations in the P/Q-type calcium channel Ca_v2.1 subunit gene, CACNA1A, located on chromosome 19p13.2. We analyzed a family with 13 affected individuals for linkage to this locus and reached a two-point maximum LOD score of 4.48. A novel CACNA1A mutation, IVS36–2A>G, at the 3 acceptor splice site of intron 36 was identified by sequencing. It is the first described CACNA1A acceptor splice site mutation and the most C-terminal EA-2-causing mutation reported to date.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s10048-003-0161-0.     

Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A

Episodic ataxia type 2 (EA2) is caused by calcium channel (CACNA1A) mutations and typically begins before age 20 years. The molecular basis of late-onset EA2 is unclear. The authors describe a case of late-onset EA2 associated with the first multiple-base pair insertion in CACNA1A. Molecular expression revealed evidence of impaired calcium channel function, suggesting that genetically induced reduction in calcium channel function may associate with cases of late-onset EA2.     

Clinical spectrum of episodic ataxia type 2

The authors searched for mutations in CACNA1A in patients with episodic ataxia and describe the clinical spectrum in genetically defined patients. Eighteen families and nine sporadic cases of episodic ataxia were evaluated for mutations in CACNA1A. The families were first genotyped to check for linkage to the chromosome 19p locus of CACNA1A. In families consistent with linkage and in the sporadic cases, the authors screened for polymorphisms in CACNA1A using single-strand conformational polymorphism and denaturing high performance liquid chromatography followed by direct sequencing to identify specific nucleotide changes. Of the 18 families, 11 were linked to 19p and mutations were found in 9. Mutations were detected in four of the nine sporadic cases. Overall, five nonsense mutations, four missense mutations, two deletions, one insertion, and one donor splice mutation were identified. All but two of the 64 genetically defined patients reported episodes of ataxia (two members of one family only had progressive ataxia). All but one had onset before age 20 and all but four had interictal nystagmus. Migraine headaches occurred in more than half, and about two thirds reported a good response to treatment with acetazolamide. Vertigo and weakness accompanied the ataxia in more than half of the genetically defined patients. One family had multiple members with epilepsy. A wide range of mutations in CACNA1A were associated with episodic ataxia. Four of 13 were missense mutations; the remainder predicted truncated proteins. The mutations were scattered throughout the gene, and only 2 of the 13 mutations identified in our laboratory have been reported by other laboratories, so it will not be possible to screen a few "hot spots" in CACNA1A. Overall, the type of mutation, missense versus nonsense, or the location of altered or truncated amino acid residues did not predict the clinical phenotype.     

Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia

BACKGROUND: Episodic ataxia type 2 (EA2) is an autosomal dominant condition that results from mutations in the CACNA1A gene. It is characterized by episodes of ataxia and nystagmus that typically last hours. OBJECTIVE: To describe the clinical and genetic features of 2 unrelated patients who developed EA2 in childhood and late-onset dystonia. DESIGN: Pedigree study. SETTING: University academic teaching hospital. PATIENTS: Two unrelated patients with childhood-onset EA2 and adult-onset dystonia were identified through a neurogenetics clinic. The CACNA1A gene was screened by heteroduplex analysis and sequencing for mutations. MAIN OUTCOME MEASURE: Mutations in the CACNA1A gene. RESULTS: Novel mutations in the pore-forming subunit of the P/Q-type calcium channels were found in both pedigrees. None of the family members carried an expansion of the CAG sequence that is found in the carboxy terminus of the CACNA1A gene. CONCLUSIONS: Truncating mutations are the most common mutations to cause EA2. We have identified 2 novel truncating mutations that are associated with interictal dystonia. The dystonia is a late feature in this disease and may be a manifestation of a degenerative cerebellar process.     

A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia.

OBJECTIVE: To identify the disease-causing mutation and to characterize penetrance and phenotypic variability in a large pedigree with episodic ataxia type 2 (EA-2) previously linked to chromosome 19. BACKGROUND: Mutations in the CACNA1A gene on chromosome 19 encoding a calcium channel subunit cause EA-2, which is characterized by recurrent attacks of imbalance with interictal eye movement abnormalities. METHODS: The authors used single-strand conformation polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing to identify mutations in CACNA1A. Allele-specific oligonucleotides were designed to detect the presence of the diseased allele in members of their pedigree as well as in normal control subjects. RESULTS: Reassessment of members of the pedigree revealed two notable clinical features. Diffuse weakness during attacks of ataxia was a prominent complaint. Two affected individuals had had episodic hemiplegia, one with typical migraine headaches. SSCP analysis revealed aberrant bands in exon 29 in affected members but not in normal control subjects. Direct sequencing of exon 29 identified a C-to-T change at position 4914 of the coding sequence of CACNA1A, predicting an early stop code at codon 1547. Two asymptomatic mutation carriers demonstrated the incomplete penetrance of this mutation. CONCLUSIONS: A nonsense mutation in CACNA1A causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.     

Identification of CACNA1A large deletions in four patients with episodic ataxia

Episodic ataxia is an autosomal dominant ion channel disorder characterized by paroxysmal attacks of incoordination. Episodic ataxia type 2 (EA2) is caused by mutations in CACNA1A. EA2 mutations are mostly nonsense and sometimes missense mutations. However, in some typical EA2 families, CACNA1A sequencing does not detect any point mutation. Herein, we have designed a quantitative multiplex polymerase chain reaction of short fluorescent fragment test to screen the 50 exons of CACNA1A and investigated 27 probands referred for molecular diagnosis of EA2 who did not show any point mutation in CACNA1A. We have identified four different exonic deletions in four patients with a typical EA2 phenotype. These results establish the need to complete sequencing analysis by a screening for deletions to ensure an accurate molecular diagnosis of EA2.     

Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits

Episodic ataxia type 2 (EA2) is a dominantly inherited disorder, characterized by spells of ataxia, dysarthria, vertigo, and migraines, associated with mutations in the neuronal calcium-channel gene CACNA1A. Ataxic spells lasting minutes to hours are provoked by stress, exercise, or alcohol. Some patients exhibit nystagmus between spells and some develop progressive ataxia later in life. At least 21 distinct CACNA1A mutations have been identified in EA2. The clinical and genetic complexities of EA2 have offered few insights into the underlying pathogenic mechanisms for this disorder. We identified a novel EA2 kindred in which members had ataxic spells induced by fevers or high environmental temperature. We identified a novel CACNA1A mutation (nucleotides 1253+1 G-->A) that was present in all subjects with febrile spells or ataxia. Moreover, we found that, regardless of age or interictal clinical status, all affected subjects had objective evidence of abnormal saccades, ocular fixation, and postural stability. These findings suggest that early cerebellar dysfunction in EA2 results from the intrinsically abnormal properties of the CACNA1A channel rather than a degenerative process.     

Vestibular impairments in episodic ataxia type 2

Journal of Neurology - Episodic ataxia type 2 (EA2) can present diverse ocular motor abnormalities, but few studies have systematically evaluated vestibular function during the interictal periods....     

Progressive cerebellar ataxia with variable episodic symptoms--phenotypic diversity of R1668W CACNA1A mutation

We describe a family with an R1668W mutation in the CACNA1A gene who presented with a broader clinical spectrum and more variable features than previously reported. The mother had a pure progressive cerebellar ataxia of late onset with downbeat nystagmus, whereas her daughter suffered from episodic ataxia, hemiplegic migraine, and progressive cerebellar ataxia with horizontal gaze-evoked and rebound nystagmus. In both patients, treatment with acetazolamide was ineffective and worsened baseline ataxia, whereas flunarizine ameliorated episodic symptoms. Our report highlights profound phenotypic variability that can be associated with CACNA1A mutations and adds important therapeutic considerations.     

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.     

Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene

We analysed the CACNA1A gene, located on chromosome 19p13, in three unrelated families and one sporadic case with episodic ataxia type 2 (EA–2). In two of the families and the sporadic patient, novel truncating mutations, which disrupt the reading frame and result in a premature stop of the CACNA1A protein, were identified in exons 14, 16 and 26. In the remaining family, a novel missense mutation (H253Y) was found. Of the twenty two EA–2 mutations identified thus far, including those of the present study, seventeen are truncating mutations and five are missense mutations, all resulting in an EA–2 clinical phenotype. Received: 20 December 2001, Received in revised form: 15 April 2002, Accepted: 22 April 2002 Correspondence to M. D. Ferrari, MD PhD     

Deficits in ocular and manual tracking due to episodic ataxia type 2.

Four patients with a novel mutation leading to episodic ataxia type 2 were studied in a task that required them to track target motion either with the eyes or with the index finger of the right hand. The target initially moved in a straight line and then changed direction at an unpredictable time by an unpredictable amount. On the day of testing, 3 of the patients were evaluated as normal on a neurological exam, whereas the fourth was severely ataxic. Nevertheless, all 4 showed deficits in tracking behavior with common features. Ocular tracking tended to result in hypermetric saccades at longer than normal latencies. Smooth pursuit tracking was absent in 1 patient and had lower than normal gain in the others. Deficits in manual tracking showed similarities to the deficits in ocular tracking, with hypermetric compensations for changes in target direction. The similarities in the deficits in manual and ocular tracking suggest that they are subject to similar control by the cerebellar structures.