# 616208
AMYOTROPHIC LATERAL SCLEROSIS 22 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS22
ORPHA: 803; DO: 0060355;
Phenotype-Gene Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q35 | Amyotrophic lateral sclerosis 22 with or without frontotemoral dementia | 616208 | Autosomal dominant | 3 | TUBA4A | 191110 |
TEXT
A number sign (#) is used with this entry because of evidence that amyotrophic lateral sclerosis-22 with or without frontotemporal dementia (ALS22) is caused by heterozygous mutation in the TUBA4A gene (191110) on chromosome 2q35.
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
Clinical Features
In their study of familial ALS caused by mutations in the TUBA4A gene, Smith et al. (2014) found that all patients carrying TUBA4A mutations had spinal-onset classical ALS with upper and lower motor neuron signs. Two cases also developed a cognitive decline of frontal type, consistent with a diagnosis of frontotemporal dementia (FTD; 600274), and another had a first-degree relative with FTD.
Molecular Genetics
Smith et al. (2014) performed an exomewide rare variant burden analysis in 363 index cases with familial ALS (FALS) from 6 countries. In this discovery cohort, Smith et al. (2014) identified 5 nonsynonymous TUBA4A changes, all localized in exon 4 and confirmed by Sanger sequencing. None of the mutations was observed in 4,300 controls from the Exome Variant Server database, and all occurred at highly conserved positions. The mutations included 2 missense mutations in the same residue (R320C, 191110.0001 and R320H, 191110.0002) a nonsense mutation (W407X; 191110.0003) removing the last 41 amino acids, and 2 additional missense mutations (R215C, 191110.0004 and A383T, 191110.0005). Because no relatives of the affected patients were available to test segregation, Smith et al. (2014) sequenced an independent replication cohort comprising 272 index FALS cases and 5,510 internal European American controls for rare damaging exon 4 variants. In the replication cohort, 2 cases (0.65%) were identified versus 2 controls (0.04%, p = 1.5 x 10(-2)). A combined analysis of the discovery and replication cohorts resulted in a statistically significant overabundance of rare variants after multiple test correction (odds ratio = 36, 95% confidence interval: 10-210, corrected p = 4.2 x 10(-3)).
REFERENCES
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Smith, B. N., Ticozzi, N., Fallini, C., Gkazi, A. S., Topp, S., Kenna, K. P., Scotter, E. L., Kost, J., Keagle, P., Miller, J. W., Calini, D., Vance, C., and 54 others. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84: 324-331, 2014. [PubMed: 25374358] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(14)00847-2]
alopez : 1/30/2015