Unravelling the genetics of familial and sporadic Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), a form of motor neuron disease, is a fatal neurodegenerative disease characterised by the selective loss of motor neurons in the cortex, brainstem and spinal cord. Patients suffer from progressive wasting and weakness of limb, bulbar and respiratory muscles, and die on average within 3 years of symptom onset, usually because of respiratory failure. Although ALS can occur anytime during adulthood, the median age of onset is in the mid-fifties. The only therapeutic strategy to slow progression of ALS is currently riluzole, which delays disease development by 3 to 6 months. Global incidence of ALS is about 1 – 2 per 100,000 and lifetime risk of developing ALS is estimated to be 1/600 – 1/2000, which makes it the most common motor neuron disease. About 10% of patients have a family history of ALS (FALS). Over ten different subtypes of FALS are distinguished and mutation in SOD1, ANG, FUS, VAPB and TARDBP have identified. The remaining 90% of ALS cases are sporadic, and are thought to be multifactorial, with both environmental and genetic components contributing to disease susceptibility. On the basis of concordance rates in twin studies, estimates of the heritability of ALS range from 0.38 to 0.85. The aim of this thesis is to confirm and identify novel genetic risk factors for familial and sporadic ALS by performing candidate gene studies and genome-wide association studies. Mutation analysis in Dutch familial ALS patients demonstrated that SOD1 mutations (found in approximately 20% of familial ALS patients) are very rare in The Netherlands, demonstrating genetic heterogeneity of the disease. We further demonstrate segregation of the ANG K17I mutation with disease in a pedigree with FALS. One affected family member was initially diagnosed with Parkinson’s disease, but went on to develop ALS and frontotemporal dementia. This thesis further describes multiple genome-wide association studies in sporadic ALS, in which genetic variation in ITPR2, DPP6, UNC13A and a locus on chromosome 9p are identified as susceptibility factors. We also show that common genetic variation in KIFAP3 is associated with prolonged survival in ALS. Patients who are homozygous for the associated allele have 14.0 month survival advantage. Using a candidate gene approach we show that rare mutation in ANG confer a large risk for both ALS and Parkinson’s disease (odds ratio > 25.0). We also show elevated serum levels in of angiogenin in ALS, but not PD patients.