Genetics of Amyotrophic Lateral Sclerosis

Introduction

Studies of disease concordance rates among monozygotic and dizygotic twins suggest that 53–84% of amyotrophic lateral sclerosis (ALS) population risk is genetically determined. *

* Refers to the proportion of disease risk that is genetically determined both within and across all individuals of a population, not the proportion of cases for which genetic risk factors are involved.

Ten percent of patients exhibit a readily identifiable family history of the disorder, and the first-degree relatives of ALS patients develop disease at ~10 times the rate seen in the general population. The majority of ALS cases are believed to result from the combined effects of multiple genetic and nongenetic risk factors that individually confer only minor to modest increases of risk. Despite this, much of the current understanding of ALS etiopathogenesis comes from the study of very rare Mendelian subtypes, where disease appears primarily, if not exclusively, attributable to single gene defects that segregate with disease in families.

The presence or absence of a prior family history is used to divide ALS into familial (FALS) and sporadic (SALS) forms. Strict criteria for this division, in terms of minimal level of relatedness or consistency of phenotype, are not in place but the majority of observable FALS pedigrees would include only a small number of affected persons and are not usually associated with striking patterns of Mendelian segregation. In keeping with the elevated recurrence rate among relatives, mutations of major effect are believed to make a more significant contribution to FALS than to SALS burden. However, high-impact mutations are also observed within an important proportion of SALS cases. In these instances, the absence of a prior family history might reflect the small patient family size (providing limited opportunity for the observation of affected relatives), variant penetrance, ^†

† Proportion of individuals carrying a mutation that present with the associated clinical phenotype.

and associated age of disease onset. Alternatively, patients might develop disease due to the presence of de novo mutations, which refers to mutations of patient DNA that are absent from the germline of both parents. Examples of ALS-associated de novo mutations have been reported, but are quite rare so far. In general, variants of minor to modest effect, or variants that exert high-risk effects only in the context of compounding environmental or genetic risk factors, are thought to make a greater contribution to the SALS burden than high-impact variants. Owing to their lower independent risk effects, such variants need not necessarily be very rare among the general population, and best estimates put the proportion of ALS genetic risk explained by common genetic variation as 12%.

Amyotrophic Lateral Sclerosis Genes

Since the discovery of the first ALS gene in 1993, over 100 disease loci have been proposed to influence ALS susceptibility or clinical phenotype ( http://alsod.iop.kcl.ac.uk ). The pathogenic relevance of many of these is well supported ( Table 3.1 ), but whether and how most contribute to the ALS burden is far from certain. The difficulty in establishing clinical relevance is multifactorial, but stems primarily from the relatively low frequency of disease, the heterogeneity of causative factors, and the fact that every human genome contains a considerable number of potentially disease-related genetic variants. These issues can also complicate the interpretation of mutations observed at well-established disease genes, where factors such as gene size can mean the probability of observing entirely incidental patient variants is not negligible. Another issue concerning multiple ALS genes is that of pleiotropy, which refers to the association of one gene with multiple phenotypes. In the case of ALS, reported genes have also been associated with frontotemporal dementia (FTD), motor neuropathy, spastic paraplegia, progressive bulbar palsy, glaucoma, spinal muscular atrophy, spinocerebellar ataxia, oculomotor apraxia, and schizophrenia. In certain cases, even individual mutations can associate with multiple seemingly distinct clinical presentations. A prime example of this is a point mutation within the gene valosin - containing protein ( VCP) which, even within a single family, associates with variable combinations of ALS, FTD, Paget’s disease of bone, and inclusion body myopathy. Contrary to this, certain ALS mutations associate with very specific clinical profiles, such as the P525L mutation of fused in sarcoma (FUS) that is consistently observed in the context of aggressive early onset disease, and much of the clinical heterogeneity seen in the disease may reflect variation in causative as well as modifying factors.

The importance of individual ALS genes varies considerably according the ancestral background. Cumulatively, mutations within genes of major effect are identifiable in ~11% of patients of European ancestry (38–67% of FALS; 5–15% of SALS). Several common variants associated with ALS susceptibility have also been identified; however, interpretation of these variants is complicated by factors such as linkage disequilibrium ^‡

‡ Refers to the nonrandom association of two or more distinct genetic variants.

and the net contributions of identified common variant associations is not entirely clear.