Diagnosis: familial amyotrophic lateral sclerosis (FALS)
Genetic testing for chromosome 9 open reading frame 72 (C9ORF72) showed repeat numbers of >44 and 8 (normal <30).
Although FALS constitutes about 10% of ALS patients (the other 90% are termed sporadic ALS), knowledge of the pathogenesis of ALS has significantly increased through the identification of mutations that cause FALS.
The most common inheritance pattern of FALS is autosomal-dominant; however, autosomal-recessive and X-linked pattern have also been reported. Cu/Zn superoxide dismutase 1 (SOD1) was the first gene identified as a cause of FALS and account for approximately 20% of FALS cases. The number of genes associated with ALS has been growing since (http://alsod.iop.kcl.ac.uk/als_ftd.aspx) . Some FALS cases are caused by mutations in two RNA binding proteins, TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS).
Recent discovery of expansions of a GGGGCC hexanucleotide repeat in a noncoding region of chromosome 9 (C9ORF72) has been identified as the most frequent cause of FALS. The latter expansion is present in 37% to 46% of FALS and 6% to 20% of sporadic ALS of European descent. Furthermore, C9ORF72 expansion is associated with up to 48% and 25% of familial and sporadic frontotemporal dementias respectively, as well as a large proportion of patients with combined ALS and frontotemporal dementia. C9ORF72 related FALS may resemble sporadic ALS clinically, but the former has an earlier mean age of onset (56–59 vs 61–62 years old); shorter survival (20 vs 26 months); and more frequent family history of dementia and parkinsonism. It should be noted that the lifetime risk of ALS and/or frontotemporal dementia secondary to C9ORF72 mutation is estimated to be around 1 in 2000, whereas the prevalence of pathological expansion in normal population is 0.15- 0.6; therefore this mutation has an incomplete penetrance (Wollacott 2014).
Other less common causes of FALS include mutations in alsin, angiogenin, senataxin, optineurin, ubiquilin 2, VAMP-associated protein type B, polyphosphoinositide phosphatase, and valosin-containing protein.
Suggested readings:
1. Al-Chalabi A, Visscher PM. Motor neuron disease: Common genetic variants and the heritability of ALS. Nature reviews Neurology. 2014;10(10):549-50.
2. Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues. Acta neuropathologica. 2014;127(3):319-32.