Which cytogenic findings are characteristic of amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)?

Updated: Apr 28, 2014
  • Author: Hidehiro Takei, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Answer

Most forms of amyotrophic lateral sclerosis (ALS) are sporadic and considered to be multifactorial diseases, but about 10% of patients have an inherited familial form of the disease with a clear family history. In many instances, however, the disease is not transmitted in a typical dominant or recessive manner. [51]

Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, DAO, OPTN, VCP,UBQLN2, and VAPB genes, are known to cause familial ALS.

Mutations in C9orf72, a gene of unknown function, are responsible for as many as 50% of familial ALS cases in individuals of European descent and approximately 5% of apparently sporadic ALS cases. This gene alteration is characterized by expanded GGGGCC hexanucleotide repeats in the promotor. The gene is autosomal dominantly inherited. [52, 53]

Dominant causative mutations in the Cu/Zn superoxide dismutase–1 gene (SOD1) on chromosome 21q22.11 are seen in about 20% of familial ALS cases (genetic nomenclature: ALS1) and 1% of sporadic cases. SOD1 mutations, which can occur at almost any position in the gene, result in a toxic gain-of-function pathology. The loss of normal SOD1 function is not the cause of ALS. [51] However, no consensus on the exact mechanisms as to how SOD1 mutations lead to selective premature death of motor neurons has yet emerged.

Homozygous loss-of-function mutations in the ALSIN gene on chromosome 2q33, which encodes the protein alsin, produce either an autosomal recessive juvenile-onset ALS or a juvenile-onset upper motor neuron (UMN)-predominant ALS (genetic nomenclature: ALS2). [54]

Mutations in the transactive response (TAR) DNA–binding protein gene (TARDBP) on chromosome 1 (1p36.22), which codes for TDP-43, have been identified in patients with both familial and sporadic ALS. A total of 30 different mutations are now known in 22 unrelated families (about 3% of familial ALS cases) and in 29 sporadic cases of ALS (about 1.5% of sporadic cases). [55] All TARDBP mutations exhibit an autosomal dominant pattern of inheritance.

Mutations in fused-in-sarcoma (FUS)/translocation in liposarcoma (TLS) protein have been identified. These mutations were reportedly detected in approximately 4% of familial ALS (about 0.4% of all ALS cases). [55] TDP-43 and FUS/TLS are DNA/RNA-binding proteins with striking structural and functional similarities, implicating alterations in RNA processing as a pathogenesis of ALS.


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