#612539
Table of Contents
A number sign (#) is used with this entry because of evidence that spastic paraplegia-42 (SPG42) is caused by heterozygous mutation in the SLC33A1 gene (603690) on chromosome 3q25.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Lin et al. (2008) reported a large Chinese family in which at least 20 individuals diagnosed with autosomal dominant spastic paraplegia were found to have a mutation in the SLC33A1 gene. There was at least 1 case of incomplete penetrance in an obligate carrier. Age at onset varied widely, ranging from 4 to 42 years, although most affected individuals had onset in the first 2 decades of life. Classic features included spastic gait, increased lower limb tone, hyperreflexia, weakness and atrophy of the lower limb muscles, extensor plantar responses, and pes cavus. None of the patients became wheelchair-bound, and there were no additional neurologic symptoms.
Radziwonik et al. (2022) reported 2 unrelated Polish patients with SPG42. Patient SA had cerebellar atrophy, a pyramidal syndrome, and peripheral neuropathy. Neuroimaging demonstrated cerebellar atrophy. Patient BJ had ataxia, a cerebellar syndrome, impaired tandem gait, intention tremor, vertigo, dysarthria, and nystagmus, among other features. Neuroimaging demonstrated cortical and subcortical atrophy of the cerebellum and cerebellar vermis.
By linkage analysis of a large Chinese family with autosomal dominant SPG, Lin et al. (2008) mapped the disease locus, SPG42, to chromosome 3q24-q26 (maximum lod score of 5.085 at D3S1746).
In affected members of a Chinese family with SPG42, Lin et al. (2008) identified a heterozygous mutation in the SLC33A1 gene (603690.0001). The authors postulated haploinsufficiency as the disease mechanism.
In a cohort of 29 Polish patients with hereditary ataxia who did not have a molecular diagnosis, Radziwonik et al. (2022) identified 2 unrelated patients with a heterozygous mutation in the SLC33A1 gene (I520T; 603690.0007). The mutations were identified by next-generation sequencing of a panel of 152 genes associated with hereditary ataxias and spastic paraplegias and were confirmed by Sanger sequencing.
Exclusion Studies
Schlipf et al. (2010) did not find pathogenic mutations in the SLC33A1 gene in 220 patients with autosomal dominant SPG who were negative for mutations in the SPAST gene (604277). The patients were of German, French, and Norwegian descent. The findings suggested that SLC33A1 mutations are not a common cause of SPG in the European population.
Lin, P., Li, J., Liu, Q., Mao, F., Li, J., Qiu, R., Hu, H., Song, Y., Yang, Y., Gao, G., Yan, C., Yang, W., Shao, C., Gong, Y. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am. J. Hum. Genet. 83: 752-759, 2008. [PubMed: 19061983, images, related citations] [Full Text]
Radziwonik, W., Elert-Dobkowska, E., Klimkowicz-Mrowiec, A., Ziora-Jakutowicz, K., Stepniak, I., Zaremba, J., Sulek, A. Application of a custom NGS gene panel revealed a high diagnostic utility for molecular testing of hereditary ataxias. J. Appl. Genet. 63: 513-525, 2022. [PubMed: 35588347, related citations] [Full Text]
Schlipf, N. A., Beetz, C., Schule, R., Stevanin, G., Erichsen, A. K., Forlani, S., Zaros, C., Karle, K., Klebe, S., Klimpe, S., Durr, A., Otto, S., Tallaksen, C. M. E., Riess, O., Brice, A., Bauer, P., Schols, L. A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42). Europ. J. Hum. Genet. 18: 1065-1067, 2010. [PubMed: 20461110, related citations] [Full Text]
SNOMEDCT: 763070001; ORPHA: 171863; DO: 0110794;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q25.31 | Spastic paraplegia 42, autosomal dominant | 612539 | Autosomal dominant | 3 | SLC33A1 | 603690 |
A number sign (#) is used with this entry because of evidence that spastic paraplegia-42 (SPG42) is caused by heterozygous mutation in the SLC33A1 gene (603690) on chromosome 3q25.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Lin et al. (2008) reported a large Chinese family in which at least 20 individuals diagnosed with autosomal dominant spastic paraplegia were found to have a mutation in the SLC33A1 gene. There was at least 1 case of incomplete penetrance in an obligate carrier. Age at onset varied widely, ranging from 4 to 42 years, although most affected individuals had onset in the first 2 decades of life. Classic features included spastic gait, increased lower limb tone, hyperreflexia, weakness and atrophy of the lower limb muscles, extensor plantar responses, and pes cavus. None of the patients became wheelchair-bound, and there were no additional neurologic symptoms.
Radziwonik et al. (2022) reported 2 unrelated Polish patients with SPG42. Patient SA had cerebellar atrophy, a pyramidal syndrome, and peripheral neuropathy. Neuroimaging demonstrated cerebellar atrophy. Patient BJ had ataxia, a cerebellar syndrome, impaired tandem gait, intention tremor, vertigo, dysarthria, and nystagmus, among other features. Neuroimaging demonstrated cortical and subcortical atrophy of the cerebellum and cerebellar vermis.
By linkage analysis of a large Chinese family with autosomal dominant SPG, Lin et al. (2008) mapped the disease locus, SPG42, to chromosome 3q24-q26 (maximum lod score of 5.085 at D3S1746).
In affected members of a Chinese family with SPG42, Lin et al. (2008) identified a heterozygous mutation in the SLC33A1 gene (603690.0001). The authors postulated haploinsufficiency as the disease mechanism.
In a cohort of 29 Polish patients with hereditary ataxia who did not have a molecular diagnosis, Radziwonik et al. (2022) identified 2 unrelated patients with a heterozygous mutation in the SLC33A1 gene (I520T; 603690.0007). The mutations were identified by next-generation sequencing of a panel of 152 genes associated with hereditary ataxias and spastic paraplegias and were confirmed by Sanger sequencing.
Exclusion Studies
Schlipf et al. (2010) did not find pathogenic mutations in the SLC33A1 gene in 220 patients with autosomal dominant SPG who were negative for mutations in the SPAST gene (604277). The patients were of German, French, and Norwegian descent. The findings suggested that SLC33A1 mutations are not a common cause of SPG in the European population.
Lin, P., Li, J., Liu, Q., Mao, F., Li, J., Qiu, R., Hu, H., Song, Y., Yang, Y., Gao, G., Yan, C., Yang, W., Shao, C., Gong, Y. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am. J. Hum. Genet. 83: 752-759, 2008. [PubMed: 19061983] [Full Text: https://doi.org/10.1016/j.ajhg.2008.11.003]
Radziwonik, W., Elert-Dobkowska, E., Klimkowicz-Mrowiec, A., Ziora-Jakutowicz, K., Stepniak, I., Zaremba, J., Sulek, A. Application of a custom NGS gene panel revealed a high diagnostic utility for molecular testing of hereditary ataxias. J. Appl. Genet. 63: 513-525, 2022. [PubMed: 35588347] [Full Text: https://doi.org/10.1007/s13353-022-00701-3]
Schlipf, N. A., Beetz, C., Schule, R., Stevanin, G., Erichsen, A. K., Forlani, S., Zaros, C., Karle, K., Klebe, S., Klimpe, S., Durr, A., Otto, S., Tallaksen, C. M. E., Riess, O., Brice, A., Bauer, P., Schols, L. A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42). Europ. J. Hum. Genet. 18: 1065-1067, 2010. [PubMed: 20461110] [Full Text: https://doi.org/10.1038/ejhg.2010.68]
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