Which of the following genes is involved in familial amyotrophic lateral sclerosis?
(A) Androgen receptor gene
(E) Superoxide dismutase 1 gene
(E) The greatest contribution toward an understanding of amyotrophic lateral sclerosis (ALS) thus far has come from the discovery of mutations in the superoxide dismutase 1 (SOD1) gene on chromosome 21q22.11, which account for 10% to 20% of autosomal dominant ALS cases. Tremendous efforts have been made to understand not only the multiple likely pathogenic mechanisms of SOD1 in eliciting disease but also the genetic profile of the reported mutations in this gene. A number of conclusions can be drawn from this research: (1) SOD1 mutations result in a toxic gain-of-function pathology. Evidence for this arose largely from mouse studies in which the knockout of the SOD1 gene failed to yield a phenotype; conversely, transgenic mice that overexpressed mutant SOD1 did develop a motor neuron phenotype. (2) Loss of the normal function of SOD1 is not the cause of ALS. Mutations in the SOD1 gene have a broad range of effects on the enzymatic activity of SOD1; however, among the mutated SOD1 proteins reported, some noticeably retained full enzymatic activity. The rest of the mutations were shown to influence, among other things, the stability of SOD1, its ability to dimerize, its hydrophobicity, and its ability to chelate copper ions. Different SOD1 mutations may also influence various aspects of the disease, such as its onset or duration, but they nonetheless do not cause ALS. (3) Mutations can occur at almost any position in the SOD1 gene. One of the most remarkable aspects of this gene is that more than 110 mutations have been reported in nearly 50% of the 153 amino acids in the SOD1 protein. The distribution of these mutations is quite uniform: the largest interval without a reported mutation is only nine consecutive amino acids. (4) With some noteworthy exceptions, mutations are primarily dominant. (Amato, 53; Valdmanis, 144–152)
Which of the following disorders is consistently observed in a subset of families with amyotrophic lateral sclerosis?
(B) Frontotemporal dementia
(E) Autonomic dysfunction
(B) Frontotemporal dementia (FTD) is the only reported disease which is consistently observed in a subset of ALS families. Estimates of FTD prevalence in ALS cases range between 5% and 15%. (Valdmanis, 144–152)