**Genetics of Familial Amyotrophic Lateral Sclerosis**

Emily F. Goodall, Joanna J. Bury, Johnathan Cooper-Knock, Pamela J. Shaw and Janine Kirby *Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom* 

### **1. Introduction**

516 Amyotrophic Lateral Sclerosis

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patient with sporadic amyotrophic lateral sclerosis. *Amyotrophic Lateral Sclerosis*,

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of motor neurones from the cortex, brainstem and spinal cord. For the patient, this results in a progressive loss of muscle function characterised by muscle weakness, atrophy and spasticity that develops into paralysis. Onset is typically in mid-life around ages 50-60 years, however there are juvenile forms with much earlier symptom onset (below 25 years). Disease duration is heterogeneous; however the majority of patients will only survive 2-3 years following initial symptom onset, with death generally resulting from respiratory muscle failure (Worms 2001).

A recent meta-analysis of population based studies revealed that 5% of ALS cases are familial (FALS) and the remaining 95% are sporadic (SALS) with no reported family history (Byrne et al 2011). There is a broad spectrum of inheritance for FALS ranging from fully penetrant, dominantly inherited Mendelian forms to recessive disease with weak penetrance affecting only a few family members (Simpson & Al-Chalabi 2006). The majority of familial cases are clinically and pathologically indistinguishable from sporadic cases, leading to the hypothesis that they share common pathogenic mechanisms. In addition, mutations in several of the FALS genes have also been identified in apparently sporadic disease, suggesting some degree of genetic overlap (Alexander et al 2002; Chio et al 2010; Kabashi et al 2008).

In ALS, cognitive impairment has been reported in up to 51% of cases, with frontotemporal dementia (FTD) present in up to 15% (Gordon et al 2011; Lillo et al 2011; Ringholz et al 2005). In approximately a third of cases, there is a family history of ALS or FTD or both in the family, and genes initially associated with either ALS or FTD are now being found to be associated with both disease phenotypes. This genetic link, in addition to extensive neuropathological evidence (Mackenzie et al 2010) has led to the widely accepted view that ALS and FTD form part of a spectrum of the same neurodegenerative disease process (Geser et al 2010).
