BACKGROUND: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6). OBJECTIVE: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation. PATIENTS AND METHODS: A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects. RESULTS: A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed. CONCLUSIONS: This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.
BACKGROUND: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6). OBJECTIVE: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation. PATIENTS AND METHODS: A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects. RESULTS: A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed. CONCLUSIONS: This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.
Authors: Katharina Eikermann-Haerter; Michal Arbel-Ornath; Nilufer Yalcin; Esther S Yu; Kishore V Kuchibhotla; Izumi Yuzawa; Eloise Hudry; Carli R Willard; Mihail Climov; Fatmagul Keles; Arianna M Belcher; Buse Sengul; Andrea Negro; Isaac A Rosen; Andrea Arreguin; Michel D Ferrari; Arn M J M van den Maagdenberg; Brian J Bacskai; Cenk Ayata Journal: Ann Neurol Date: 2015-07-06 Impact factor: 10.422
Authors: Stefan Kipfer; Simon Jung; Johannes R Lemke; Anna Kipfer-Kauer; Jeremy P Howell; Alain Kaelin-Lang; Thomas Nyffeler; Klemens Gutbrod; Angela Abicht; René M Müri Journal: J Neurol Date: 2013-09-18 Impact factor: 4.849
Authors: Hanan E Shamseldin; Eissa Faqeih; Ali Alasmari; Maha S Zaki; Joseph G Gleeson; Fowzan S Alkuraya Journal: Am J Hum Genet Date: 2015-12-17 Impact factor: 11.025