Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028738 (nystagmus)
 7,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.
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PMID:Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. 930 78

The SCA6 mutation, a small expansion of a CAG repeat in a calcium channel gene CACNA1A, was identified in three pedigrees. Point mutations in other parts of the gene CACNA1A were excluded and new clinical features of SCA6 reported--namely, central positional nystagmus and episodic ataxia responsive to acetazolamide. The three allelic disorders, episodic ataxia type 2, familial hemiplegic migraine, and SCA6, have overlapping clinical features.
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PMID:Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia. 977 87

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examination was performed in one patient and molecular analysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1-2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This late-onset paroxysmal cerebellar ataxia with neuropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process.
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PMID:Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease? 1262 85

We describe an Italian family with familial hemiplegic migraine (FHM), subtle cerebellar signs and probable linkage to chromosome 1. FHM is genetically heterogeneous; in about 50% of families it is caused by mutations within the CACNA1A gene on chromosome 19. Linkage to 1q31 and 1g21-23 has also been established. Other families do not link either to chromosome 19 or 1. Chromosome 19-linked FHM may display nystagmus and cerebellar ataxia. Affected family members were neurologically examined; linkage analysis was performed with markers for chromosomes 19p13, 1q21-23, and 1q32. Five family members had hemiplegic migraine, and 3 displayed additional cerebellar signs (scanning speech and nystagmus). In 1 patient, episodes of hemiplegic migraine triggered by mild head trauma. Epilepsy and mental retardation were also found in 1 affected relative each. Lod scores for linkage to 19p13 were negative, while the maximum two-point lod score was 1.81 to 1q21-23. This family with FHM and associated subtle cerebellar signs, epilepsy and mental retardation showed probable linkage to 1q21-23.
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PMID:Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family. 1211 14

We report a Japanese family with acetazolamide-responsive episodic ataxia. The proband was a 41-year-old woman with interictal nystagmus. She experienced recurrent attacks of loss of equilibrium and loss of coordination of the extremities accompanied by dysarthria and nausea beginning at about 10 years old. These episodes usually lasted for several hours two or three times a week. Direct sequence of CACNA1A demonstrated a novel insertion mutation in the patient and her father. This mutation is estimated to cause early stop of the gene transcription, producing a truncated protein. This is the first report of episodic ataxia type 2 of which the mutation was identified in a Japanese family.
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PMID:A novel insertion mutation of acetazolamide-responsive episodic ataxia in a Japanese family. 1273 95

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(v)2.1 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.
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PMID:Novel splice site CACNA1A mutation causing episodic ataxia type 2. 1453 Sep 26

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.
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PMID:Periodic alternating nystagmus and rebound nystagmus in spinocerebellar ataxia type 6. 1453 30

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.
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PMID:Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. 1468 82

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.
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PMID:Clinical spectrum of episodic ataxia type 2. 1471 90

Mutations in the gene encoding the ion pore of the P/Q voltage-activated calcium channel (CACNA1A) are predicted to alter synaptic transmission and dendritic excitability within cerebellar granule and Purkinje cells. Determining the relationships between these alterations, neuronal activity, and behavior may yield insight into the relationship between neuronal intrinsic properties and signal processing within the ocular motor system. Toward this end, we compared ocular motor performance in the CACNA1A mutant rocker and C57BL/6 controls. Average vertical eye position was abnormally elevated in the mutants, a finding that may be analogous to downbeat nystagmus seen in human cerebellar disorders. Fast phases of vestibular nystagmus were slowed by approximately 18% of control values. The angular vestibuloocular reflex (VOR) in darkness and light (visual VOR, or VVOR), assessed at 0.1-1.6 Hz, exhibited subnormal gains at the highest stimulus frequencies and increased phase leads at the lowest stimulus frequencies. Horizontal optokinetic responses to constant velocity drum rotation of +/-2.5-40 degrees/s exhibited minimally reduced gains. Attempts to increase VOR gain by concomitant optokinetic and vestibular stimulation were confounded by the tendency of the mice to habituate to repetitive vestibular stimulation, but attempts to induce coupling of vertical eye movements to horizontal vestibular stimulation (cross-axis adaptation) generated rapid plastic changes in controls and little effect in mutants. With the notable exceptions of the vertical elevation and optokinetic gains, the ocular motor abnormalities were stable over a broad range of animal age, a result compatible with the abnormalities arising as direct consequences of the inborn alteration in calcium channel biophysics.
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PMID:Eye movements of the murine P/Q calcium channel mutant rocker, and the impact of aging. 1472 64


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