SNOMEDCT: 719210007; ORPHA: 98763; DO: 0050964;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.42 | Spinocerebellar ataxia 14 | 605361 | Autosomal dominant | 3 | PRKCG | 176980 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-14 (SCA14) is caused by heterozygous mutation in the PRKCG gene (176980) on chromosome 19q13.
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Yamashita et al. (2000) described a 3-generation Japanese family with autosomal dominant spinocerebellar ataxia. Among affected members, those with an early onset (age 27 years or less) first showed intermittent axial myoclonus followed by ataxia. Neuroimaging studies showed atrophy confined to the cerebellum.
Van de Warrenburg et al. (2003) reported a large 6-generation Dutch family in which 13 members were affected with autosomal dominant spinocerebellar ataxia. Mean age at onset was 40 years (range, 21 to 59 years), and gait disorder was the most common presenting feature. Other features, not found in all patients, included cerebellar dysarthria, slowed saccades, ocular dysmetria, and hyperreflexia. Two patients with onset in their twenties also had focal task-induced dystonia. Brain MRI of 3 affected members showed severe cerebellar atrophy.
Stevanin et al. (2004) reported a family of French origin with SCA14 confirmed by genetic analysis (176980.0006). There were at least 20 affected individuals spanning 4 generations; 14 affected members were included in the study. Age at onset ranged from childhood to 60 years, and cerebellar signs ranged from mild to severe. Additional signs included dysphagia, nystagmus, facial myokymia, and decreased vibration sense at ankles. Rare signs included chorea of the hands and head tremor in 2 patients each. Nine of 14 patients had cognitive deficits, mainly memory loss and attention deficits.
Morita et al. (2006) reported a Japanese woman with slowly progressive pure SCA14 beginning with gait difficulties at age 42 years. By age 62, she was still ambulatory with mild ataxia, saccadic pursuit, scanning speech, and cerebellar atrophy, but no other abnormalities. There was no family history of the disorder. Mutation analysis identified a heterozygous mutation in the PRKCG gene (176980.0003).
Klebe et al. (2007) reported a French mother and son with a pure form of SCA14 confirmed by genetic analysis. The son developed ataxia and cerebellar dysarthria at age 26 years, although he reported unstable gait since age 18. The disorder was slowly progressive; dysarthria was still present at age 35, and he had mildly increased reflexes in the lower limbs without other abnormalities. His mother was found to have dysarthria at age 50. Brain MRI of both patients showed cerebellar atrophy.
Sailer et al. (2012) reported a large 5-generation British family in which 10 individuals had pure cerebellar ataxia inherited in an autosomal dominant pattern. The mean age at symptom onset was 37 years (range 15 to 68 years), and features included cerebellar ataxia predominantly affecting lower limb coordination and speech. The severity was variable; some patients showed ataxia only on neurologic examination. The disorder showed slow symptom progression with an overall benign disease course. Exome sequencing identified a heterozygous mutation in the PRKCG gene, confirming SCA14.
SCA14 is an autosomal dominant cerebellar ataxia; however, probable autosomal recessive inheritance has been reported by Asai et al. (2009) in a family in which the proband was homozygous for a PRKCG mutation (176980.0009) and an affected paternal grandmother was heterozygous.
Sailer et al. (2012) reported successful diagnosis of SCA14 using exome sequencing in a 5-generation British family with autosomal dominant SCA in whom sequencing of 13 of the most common SCA genes failed to find a genetic cause for the disorder. The work demonstrated the utility of exome sequencing to rapidly screen heterogeneous genetic disorders such as ataxia.
Yamashita et al. (2000) performed systematic linkage analysis in a 3-generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter (maximum lod = 4.08, corrected for age-dependent penetrance).
Brkanac et al. (2002) reported a 4-generation family of English and Dutch descent in which 14 members had SCA in an autosomal dominant pattern. Ten members were available for study and showed a mean age of onset in the third decade, presenting with gait ataxia, dysmetria, dysarthria, abnormal eye movements, and hyperreflexia. There was no cognitive impairment, myoclonus, or sensory loss. Linkage analysis mapped the locus to a 22-cM region on chromosome 19q13.4-qter (maximum lod score = 4.72 at D19S926).
In an affected member of the SCA14 family described by Brkanac et al. (2002) and in 2 of 39 unrelated patients with ataxia not attributable to trinucleotide expansions, Chen et al. (2003) identified 3 different mutations in the PRKCG gene, each of which resulted in a nonconservative missense mutation in a highly conserved residue in C1, the cysteine-rich region of the protein (176980.0001-176980.0003). Two mutations occurred in families and cosegregated with the disorder.
In all 11 affected members of a Japanese family with SCA14 first reported by Yamashita et al. (2000), Yabe et al. (2003) identified a mutation in the PRKCG gene (176980.0005). In addition, a 76-year-old asymptomatic obligate carrier and a 44-year-old asymptomatic family member carried the mutation, indicating reduced penetrance.
In a large Dutch family with SCA14, van de Warrenburg et al. (2003) identified a mutation in the PRKCG gene (G118D; 176980.0004) that cosegregated with the disorder. Two unaffected members also carried the mutation. Verbeek et al. (2005) identified the G118D mutation in 8 additional Dutch patients with SCA14. Haplotype analysis indicated a founder effect. Genealogic analysis of these 8 patients and the patients reported by van de Warrenburg et al. (2003) showed that they all derived from a common ancestor from the Dutch province of North Brabant who was born in 1722.
Among 284 index cases of French or German origin with autosomal dominant cerebellar ataxia (ADCA), Klebe et al. (2005) identified 6 different mutations, including 5 novel mutations, in the PRKCG gene in 15 affected members from 6 French families. Combined with a previous study (Stevanin et al., 2004), SCA14 represented 1.5% (7 of 454) of French families with ADCA.
In a family with SCA14, Asai et al. (2009) identified a 102-bp deletion beginning at the termination codon in exon 18 of the PRKCG gene (176980.0009). The proband had early onset of a severe phenotype and was homozygous for the deletion, whereas a paternal grandmother had late onset and was heterozygous for the deletion. The parent's were unrelated and asymptomatic, but declined genetic testing; they were assumed to be obligate carriers.
Asai, H., Hirano, M., Shimada, K., Kiriyama, T., Furiya, Y., Ikeda, M., Iwamoto, T., Mori, T., Nishinaka, K., Konishi, N., Udaka, F., Ueno, S. Protein kinase C-gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin. Hum. Molec. Genet. 18: 3533-3543, 2009. [PubMed: 19561170] [Full Text: https://doi.org/10.1093/hmg/ddp298]
Brkanac, Z., Bylenok, L., Fernandez, M., Matsushita, M., Lipe, H., Wolff, J., Nochlin, D., Raskind, W. H., Bird, T. D. A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter. Arch. Neurol. 59: 1291-1295, 2002. Note: Erratum: Arch. Neurol.: 59: 1972 only, 2002. [PubMed: 12164726] [Full Text: https://doi.org/10.1001/archneur.59.8.1291]
Chen, D.-H., Brkanac, Z., Verlinde, C. L. M. J., Tan, X.-J., Bylenok, L., Nochlin, D., Matsushita, M., Lipe, H., Wolff, J., Fernandez, M., Cimino, P. J., Bird, T. D., Raskind, W. H. Missense mutations in the regulatory domain of PKC-gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am. J. Hum. Genet. 72: 839-849, 2003. [PubMed: 12644968] [Full Text: https://doi.org/10.1086/373883]
Klebe, S., Durr, A., Rentschler, A., Hahn-Barma, V., Abele, M., Bouslam, N., Schols, L., Jedynak, P., Forlani, S., Denis, E., Dussert, C., Agid, Y., Bauer, P., Globas, C., Wullner, U., Brice, A., Riess, O., Stevanin, G. New mutations in protein kinase C gamma associated with spinocerebellar ataxia type 14. Ann. Neurol. 58: 720-729, 2005. [PubMed: 16193476] [Full Text: https://doi.org/10.1002/ana.20628]
Klebe, S., Faivre, L., Forlani, S., Dussert, C., Tourbah, A., Brice, A., Stevanin, G., Durr, A. Another mutation in cysteine 131 in protein kinase C-gamma as a cause of spinocerebellar ataxia type 14. (Letter) Arch. Neurol. 64: 913-914, 2007. [PubMed: 17562946] [Full Text: https://doi.org/10.1001/archneur.64.6.913]
Morita, H., Yoshida, K., Suzuki, K., Ikeda, S. A Japanese case of SCA14 with the gly128asp mutation. J. Hum. Genet. 51: 1118-1121, 2006. [PubMed: 17024314] [Full Text: https://doi.org/10.1007/s10038-006-0063-8]
Sailer, A., Scholz, S. W., Gibbs, J. R., Tucci, A., Johnson, J. O., Wood, N. W., Plagnol, V., Hummerich, H., Ding, J., Hernandez, D., Hardy, J., Federoff, H. J., Traynor, B. J., Singleton, A. B., Houlden, H. Exome sequencing in an SCA14 family demonstrates its utility in diagnosing heterogeneous diseases. Neurology 79: 127-131, 2012. [PubMed: 22675081] [Full Text: https://doi.org/10.1212/WNL.0b013e31825f048e]
Stevanin, G., Hahn, V., Lohmann, E., Bouslam, N., Gouttard, M., Soumphonphakdy, C., Welter, M.-L., Ollagnon-Roman, E., Lemainque, A., Ruberg, M., Brice, A., Durr, A. Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14. Arch. Neurol. 61: 1242-1248, 2004. [PubMed: 15313841] [Full Text: https://doi.org/10.1001/archneur.61.8.1242]
van de Warrenburg, B. P. C., Verbeek, D. S., Piersma, S. J., Hennekam, F. A. M., Pearson, P. L., Knoers, N. V. A. M., Kremer, H. P. H., Sinke, R. J. Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family. Neurology 61: 1760-1765, 2003. [PubMed: 14694043] [Full Text: https://doi.org/10.1212/01.wnl.0000098883.79421.73]
Verbeek, D. S., van de Warrenburg, B. P. C., Hennekam, F. A. M., Dooijes, D., Ippel, P. F., Verschuuren-Bemelmans, C. C., Kremer, H. P. H., Sinke, R. J. Gly118asp is a SCA14 founder mutation in the Dutch ataxia population. Hum. Genet. 117: 88-91, 2005. [PubMed: 15841389] [Full Text: https://doi.org/10.1007/s00439-005-1278-z]
Yabe, I., Sasaki, H., Chen, D.-H., Raskind, W. H., Bird, T. D., Yamashita, I., Tsuji, S., Kikuchi, S., Tashiro, K. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch. Neurol. 60: 1749-1751, 2003. [PubMed: 14676051] [Full Text: https://doi.org/10.1001/archneur.60.12.1749]
Yamashita, I., Sasaki, H., Yabe, I., Fukazawa, T., Nogoshi, S., Komeichi, K., Takada, A., Shiraishi, K., Takiyama, Y., Nishizawa, M., Kaneko, J., Tanaka, H., Tsuji, S., Tashiro, K. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann. Neurol. 48: 156-163, 2000. [PubMed: 10939565] [Full Text: https://doi.org/10.1002/1531-8249(200008)48:2<156::aid-ana4>3.0.co;2-9]