#616795
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant spinocerebellar ataxia-42 (SCA42) is caused by heterozygous mutation in the CACNA1G gene (604065) on chromosome 17q21.
Heterozygous mutation in the CACNA1G gene can also cause early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087).
Spinocerebellar ataxia-42 (SCA42) is an autosomal dominant neurologic disorder characterized predominantly by gait instability and additional cerebellar signs such as dysarthria, nystagmus, and saccadic pursuits. The age at onset and severity of the disorder is highly variable. The disorder is slowly progressive (Coutelier et al., 2015).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Coutelier et al. (2015) reported 10 patients from 3 unrelated French families with spinocerebellar ataxia. The age at symptom onset was highly variable, ranging from 9 to 78 years, although most had onset in mid-adulthood. Gait instability was the most common manifestation, and additional features included dysarthria, saccadic eye movements, diplopia, and nystagmus. Less common features included decreased distal vibration sense and urinary symptoms. Five patients had mild pyramidal signs, such as hyperreflexia and spasticity. Brain imaging showed cerebellar atrophy of the cerebellar vermis. The progression of the disorder was relatively slow. Three patients had depression and 2 had cognitive impairment. Neuropathologic studies, available for one 83-year-old affected individual who also had dementia, showed cerebellar atrophy with Purkinje cell loss and loss of neurons in the inferior olive. There was also microscopic evidence of Alzheimer disease (AD; 104300).
Morino et al. (2015) reported 2 unrelated, large multigenerational Japanese families with slowly progressive SCA42. The age at onset ranged from 18 to 70 years, and the main features included ataxic gait, dysarthria, and gaze-evoked horizontal nystagmus. Cognitive impairment, seizures, muscle atrophy, involuntary movements, and parkinsonism were not observed. However, 2 patients in one family had prominent resting tremor. Brain imaging showed cerebellar atrophy.
The transmission pattern of SCA42 in the families reported by Coutelier et al. (2015) was consistent with autosomal dominant inheritance.
In affected members of 3 unrelated French families with SCA42, Coutelier et al. (2015) identified a heterozygous missense mutation in the CACNA1G gene (R1715H; 604065.0001). The mutation in the first family was found by linkage analysis combined with whole-exome sequencing; the mutations in the other 2 families were found by screening of a large number of probands with a similar disorder. The mutation segregated with the phenotype in all families, and haplotype analysis excluded a founder effect. The substitution occurred in the voltage-sensing region. In vitro electrophysiologic studies and computer modeling simulations suggested that the mutation results in decreased neuronal excitability.
In affected members of 2 unrelated Japanese families with SCA42, Morino et al. (2015) identified heterozygosity for the same R1715H mutation in the CACNA1G gene. The mutations were found by linkage analysis and exome sequencing, and there was a shared haplotype containing the mutation between these 2 families. Electrophysiologic studies showed that the mutation shifted the activation to more positive (depolarized) membrane potentials. Inactivation potentials were also shifted to more positive membrane potentials, although the slope factor was not significantly different. The findings indicated that SCA42 is a channelopathy.
Coutelier, M., Blesneac, I., Monteil, A., Monin, M.-L., Ando, K., Mundwiller, E., Brusco, A., Le Ber, I., Anheim, M., Castrioto, A., Duyckaerts, C., Brice, A., Durr, A., Lory, P., Stevanin, G. A recurrent mutation in CACNA1G alters Cav3.1 T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am. J. Hum. Genet. 97: 726-737, 2015. [PubMed: 26456284, images, related citations] [Full Text]
Morino, H., Matsuda, Y., Mugurama, K., Miyamoto, R., Ohsawa, R., Ohtake, T., Otobe, R., Watanabe, M., Maruyama, H., Hashimoto, K., Kawakami, H. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Molec. Brain 8: 89, 2015. Note: Electronic Article. [PubMed: 26715324, images, related citations] [Full Text]
SNOMEDCT: 1208513005; ORPHA: 458803; DO: 0111742;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
17q21.33 | Spinocerebellar ataxia 42 | 616795 | Autosomal dominant | 3 | CACNA1G | 604065 |
A number sign (#) is used with this entry because of evidence that autosomal dominant spinocerebellar ataxia-42 (SCA42) is caused by heterozygous mutation in the CACNA1G gene (604065) on chromosome 17q21.
Heterozygous mutation in the CACNA1G gene can also cause early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087).
Spinocerebellar ataxia-42 (SCA42) is an autosomal dominant neurologic disorder characterized predominantly by gait instability and additional cerebellar signs such as dysarthria, nystagmus, and saccadic pursuits. The age at onset and severity of the disorder is highly variable. The disorder is slowly progressive (Coutelier et al., 2015).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Coutelier et al. (2015) reported 10 patients from 3 unrelated French families with spinocerebellar ataxia. The age at symptom onset was highly variable, ranging from 9 to 78 years, although most had onset in mid-adulthood. Gait instability was the most common manifestation, and additional features included dysarthria, saccadic eye movements, diplopia, and nystagmus. Less common features included decreased distal vibration sense and urinary symptoms. Five patients had mild pyramidal signs, such as hyperreflexia and spasticity. Brain imaging showed cerebellar atrophy of the cerebellar vermis. The progression of the disorder was relatively slow. Three patients had depression and 2 had cognitive impairment. Neuropathologic studies, available for one 83-year-old affected individual who also had dementia, showed cerebellar atrophy with Purkinje cell loss and loss of neurons in the inferior olive. There was also microscopic evidence of Alzheimer disease (AD; 104300).
Morino et al. (2015) reported 2 unrelated, large multigenerational Japanese families with slowly progressive SCA42. The age at onset ranged from 18 to 70 years, and the main features included ataxic gait, dysarthria, and gaze-evoked horizontal nystagmus. Cognitive impairment, seizures, muscle atrophy, involuntary movements, and parkinsonism were not observed. However, 2 patients in one family had prominent resting tremor. Brain imaging showed cerebellar atrophy.
The transmission pattern of SCA42 in the families reported by Coutelier et al. (2015) was consistent with autosomal dominant inheritance.
In affected members of 3 unrelated French families with SCA42, Coutelier et al. (2015) identified a heterozygous missense mutation in the CACNA1G gene (R1715H; 604065.0001). The mutation in the first family was found by linkage analysis combined with whole-exome sequencing; the mutations in the other 2 families were found by screening of a large number of probands with a similar disorder. The mutation segregated with the phenotype in all families, and haplotype analysis excluded a founder effect. The substitution occurred in the voltage-sensing region. In vitro electrophysiologic studies and computer modeling simulations suggested that the mutation results in decreased neuronal excitability.
In affected members of 2 unrelated Japanese families with SCA42, Morino et al. (2015) identified heterozygosity for the same R1715H mutation in the CACNA1G gene. The mutations were found by linkage analysis and exome sequencing, and there was a shared haplotype containing the mutation between these 2 families. Electrophysiologic studies showed that the mutation shifted the activation to more positive (depolarized) membrane potentials. Inactivation potentials were also shifted to more positive membrane potentials, although the slope factor was not significantly different. The findings indicated that SCA42 is a channelopathy.
Coutelier, M., Blesneac, I., Monteil, A., Monin, M.-L., Ando, K., Mundwiller, E., Brusco, A., Le Ber, I., Anheim, M., Castrioto, A., Duyckaerts, C., Brice, A., Durr, A., Lory, P., Stevanin, G. A recurrent mutation in CACNA1G alters Cav3.1 T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am. J. Hum. Genet. 97: 726-737, 2015. [PubMed: 26456284] [Full Text: https://doi.org/10.1016/j.ajhg.2015.09.007]
Morino, H., Matsuda, Y., Mugurama, K., Miyamoto, R., Ohsawa, R., Ohtake, T., Otobe, R., Watanabe, M., Maruyama, H., Hashimoto, K., Kawakami, H. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Molec. Brain 8: 89, 2015. Note: Electronic Article. [PubMed: 26715324] [Full Text: https://doi.org/10.1186/s13041-015-0180-4]
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