SNOMEDCT: 715824008; ORPHA: 101109; DO: 0050977;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18p11.21 | Spinocerebellar ataxia 28 | 610246 | Autosomal dominant | 3 | AFG3L2 | 604581 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-28 (SCA28) is caused by heterozygous mutation in the AFG3L2 gene (604581) on chromosome 18p11.
Heterozygous mutation in the AFG3L2 gene can also cause optic atrophy-12 (OPA12; 618977), and biallelic mutation in the AFG3L2 gene can cause autosomal recessive spastic ataxia-5 (SPAX5; 614487).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Cagnoli et al. (2006) reported a 4-generation Italian family in which at least 14 members were affected with juvenile-onset spinocerebellar ataxia inherited in an autosomal dominant pattern. The mean age at onset was 19.5 years (range 12 to 36) with unbalanced standing and gait abnormalities. Other features included limb ataxia, dysarthria, slow and lower limb hyperreflexia. Two patterns of eye movement abnormalities were observed: patients with shorter disease duration had gaze-evoked nystagmus, while those with longer disease duration showed dysmetric saccades, slow saccades, ophthalmoparesis, and ptosis. The disorder was slowly progressive, and there was no evidence of sensory involvement or cognitive impairment. Brain MRI showed cerebellar atrophy.
Cagnoli et al. (2010) reported 9 European families, including 8 of French and 1 of Italian origin, with autosomal dominant SCA28 confirmed by genetic analysis. The mean age at onset was 30.7 years (range, 6 to 60 years), and most patients presented with cerebellar ataxia. Other features included dysarthria (68%), ophthalmoplegia (48%) and/or gazed-evoked nystagmus (54%), saccadic pursuit (37%), slow saccades (25%), and ptosis (42%). Six patients had a full pyramidal syndrome, with increased reflexes and Babinski sign, whereas 1 had gait spasticity. Rare individuals had dystonia or parkinsonism. Overall, the disease was slowly progressive and did not result in major functional incapacity.
The transmission pattern of SCA28 in the families reported by Di Bella et al. (2010) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of a large Italian family, Cagnoli et al. (2006) identified a candidate disease locus, termed SCA28, on chromosome 18p11.22-q11.2 (maximum 2-point lod score of 4.20 for marker D18S53; maximum multipoint lod score of 4.77 at D18S453). Haplotype analysis defined a 7.9-Mb region between D18S1418 and D18S1104.
In affected members of 5 unrelated families with SCA28, including the family reported by Cagnoli et al. (2006), Di Bella et al. (2010) identified 5 different heterozygous mutations in the AFG3L2 gene (604581.0001-604581.0005). Studies in yeast showed that the mutations affected mitochondrial respiratory and proteolytic functions of the protein by both dominant-negative (E691K; 604581.0001) and loss of function (see, e.g., S674L; 604581.0002) mechanisms. Di Bella et al. (2010) hypothesized that AFG3L2 or specific substrates of AFG3L2 may have an essential function in protecting the cerebellum from neurodegeneration.
Cagnoli et al. (2010) identified 6 different missense mutations in exons 15 and 16 of the AFG3L2 gene (see, e.g., 604581.0006-604581.0009) in 9 (2.6%) of 366 Caucasian European probands with autosomal dominant SCA who were negative for the most common triplet expansions in other genes. Pathogenic copy number variations of the AFG3L2 gene were not detected.
Cagnoli, C., Mariotti, C., Taroni, F., Seri, M., Brussino, A., Michielotto, C., Grisoli, M., Di Bella, D., Migone, N., Gellera, C., Di Donato, S., Brusco, A. SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain 129: 235-242, 2006. [PubMed: 16251216] [Full Text: https://doi.org/10.1093/brain/awh651]
Cagnoli, C., Stevanin, G., Brussino, A., Barberis, M., Mancini, C., Margolis, R. L., Holmes, S. E., Nobili, M., Forlani, S., Padovan, S., Pappi, P., Zaros, C., Leber, I., Ribai, P., Pugliese, L., Assalto, C., Brice, A., Migone, N., Durr, A., Brusco, A. Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias. Hum. Mutat. 31: 1117-1124, 2010. [PubMed: 20725928] [Full Text: https://doi.org/10.1002/humu.21342]
Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., and 14 others. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nature Genet. 42: 313-321, 2010. [PubMed: 20208537] [Full Text: https://doi.org/10.1038/ng.544]