GM28411

GM28411 LCL from B-Lymphocyte

Description:

MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH ATAXIA
CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A

Affected:

Yes

Sex:

Female

Age:

14 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
PIGI Consented Sample

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Ethnicity

Not Hispanic/Latino

Ethnicity

German-English

Country of Origin

USA

Family History

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; see "Phenotypic Data" tab.

Characterizations

Gene

CACNA1A

Chromosomal Location

19p13.13

Allelic Variant 1

601011.0018; MIGRAINE, FAMILIAL HEMIPLEGIC 1, WITH ATAXIA

Identified Mutation

ARG583GLN; c.1748(isoform 1)G>A; In 2 Italian sisters with familial hemiplegic migraine (FHM1; 141500) and late-onset cerebellar ataxia and cerebellar atrophy, Battistini et al. (1999) identified an arg583-to-gln (R583Q) mutation in a putative voltage sensor domain of the CACNA1A gene. The frequency and severity of the attacks increased near the sixth decade for both patients, when the cerebellar signs developed. Acetazolamide was effective prophylactic therapy. Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the R583Q mutation in a 16-year-old boy with no cerebellar signs. In a large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive cerebellar ataxia-6 (SCA6; 183086), Alonso et al. (2003) found that all patients shared a common haplotype and carried the R583Q mutation. Mean age at onset for hemiplegic migraine symptoms was in the second decade and onset of cerebellar signs was approximately 20 years later. Four patients, all under the age of 18 years, had only hemiplegic migraine, 8 patients had isolated progressive cerebellar ataxia, and 5 patients had both hemiplegic migraine and cerebellar ataxia. Several patients reported symptoms triggered by minor head trauma. Alonso et al. (2003) postulated that the mutation, which occurs in a transmembrane segment of the voltage sensor of the channel, may cause a shift in the voltage dependence of the channel, leading to an increase in intracellular calcium. They suggested that episodic ataxia-2 (EA2; 108500), SCA6, and familial hemiplegic migraine are not only allelic disorders, but may be the same disorder with great phenotypic variability. De Vries et al. (2007) identified a 2021G-A transition in the CACNA1A gene, resulting in an R583Q substitution, in a patient who developed FHM at age 13 years. The mutation was also identified in his mother, who had migraine with aura. The findings suggested either reduced penetrance or a common pathogenetic mechanism for both hemiplegic and nonhemiplegic migraine.

Phenotypic Data

Demographic Data

Relation to Proband

proband

Age at Sampling

14 YR

Sex

Female

Age of Onset(If not a control)

12 YR

Age at Diagnosis(If not a control)

12 YR

Hispanic or Latino/Not Hispanic or Latino

Not Hispanic/Latino

Racial Category

White

Country

USA

Data Elements

Clinical Element Type: General NIGMS Catalog Remarks

(Baseline)

Mutation Information

Gene, variant, consequence, and exon number:

NEXT GENERATION SEQUENCING (NGS) USING GENOMIC DNA REVEALED AN AUTOSOMAL DOMINANT HETEROZYGOUS PATHOGENIC MISSENSE MUTATION IN CACNA1A: C.1748(ISOFORM1)G>A (P.ARG583GLN); ALIGNMENT TO GRCH37/HG19 GENOMIC BUILD; GENOME ANALYSIS TOOLKIT 2.3-9

Zygosity:

Heterozygous

Age of Symptom Onset and Age at Diagnosis

Age of Symptom Onset:

12 YEARS

Age at Diagnosis:

12 YEARS

In Utero History Information

Birth History Information

Dysmorphic Features

Neurological Symptoms

Optical and Audiological Symptoms