About 5-10% of patients have a "familial", or genetically-determined, form of the disease which runs in families (FALS). In the vast majority of cases, inheritance is autosomal dominant. In other words, it is unlikely to skip a generation, and the children of a familial ALS patient have a 50/50 chance of inheriting the causative gene. The genes that cause ALS can have variable "penetrance", which means the liklihood that the disease will develop. For example, someone carrying a gene for ALS has around a 90% chance of developing the illness by the time they're 80. However, that leaves a 10% chance that they will never develop the disease, and there is always the possibility that they will die of some unrelated cause many years before they would have developed MND had they lived longer. In this way it can be difficult to trace MND through families; particularly for individuals whose paternal lineage may have died prematurely as a result of the two World Wars.
Currently only a handful of genes are known in MND (Genetics of MND). About 20% of patients with familial MND carry a mutation called SOD1 which stands for super-oxide dismutase one. Normally, SOD is a protein which "cleans up" rubbish or debris in the cells; when there is a faulty gene (and there are more than 100 different abnormal versions) this process does not work properly, and it is thought that this cellular debris may accumulate in the cells and have a toxic effect. The discovery of the SOD1 gene has allowed researchers to create a model of the disease in mice, by breeding animals that carry one of the human genetic mutations of SOD1. This allows for pre-clinical testing of potential drugs before clinical trials, and also allows scientists to carry out basic research on what is causing the breakdown of motor neurones.
Familial Amyotrophic Lateral Sclerosis (FALS) subgroups
Whereas approximately 90% of ALS cases are sporadic (SALS) with no known genetic linkage, 10% are inherited and known as familial ALS (FALS) (Strong et al., 1991 SALS and FALS share indistinguishable clinical and pathological features (Mulder et al., 1986 which suggests the possibility of common mechanisms underlying motor neurone degeneration in both sporadic and familial ALS. FALS inheritance is mainly autosomal dominant, but autosomal recessive and X-linked modes of inheritance have also been reported. SALS and the majority of FALS is adult-onset, although three loci have been described that lead to juvenile-onset disease (ALS2, ALS4 and ALS5). Approximately 20% of FALS cases are caused by point mutations in the [Cu/Zn SOD1] gene on chromosome 21 (Deng et al., 1993 Rosen et al., 1993 Over 100 SOD1 mutations have been described so far (for an updated list see http://www.alsod.org) resulting in highly variable phenotypes, even within families carrying the same mutation. Since the discovery of SOD1 mutations most studies on the pathogenesis of ALS have focused on mutant SOD1 mediated motor neuron death, utilising transgenic in vivo and in vitro models.
Loci identified in Motor Neurone Disease (MND)
Genetic risk factors for Sporadic Amyotrophic Lateral Sclerosis (SALS)
Several genetic risk factors, or susceptibility genes, have been implicated in sporadic ALS. These include neurofilament heavy chain (NF-H) (Al-Chalabi et al., 1999 Figlewicz et al., 1994 Skvortsova et al., 2004 Tomkins et al., 1998 vascular endothelial growth factor (VEGF) (Greenway et al., 2004 survival motor neuron 2 (SMN2) (Veldink et al., 2001 apolipoprotein E epsilon 4 (ApoEε4) (Drory et al., 2001 Moulard et al., 1996 the gene encoding the p150 subunit of dynactin (DCTN1) (Munch et al., 2004 the mitochondrial gene cytochrome c oxidase (Comi et al., 1998 the gene encoding DNA repair enzyme abasic endonuclease (APEX) (Hayward et al., 1999 angiogenin (ANG) (Greenway et al., 2004 and aberrant mRNA processing of excitatory amino acid transporter 2 (EAAT2) (Aoki et al., 1998 Lin et al., 1998 The absence of mutations in FALS suggests that the mutations found in SALS patients are susceptibility factors rather then a direct cause of the disease (Aoki et al., 1998 Vechio et al., 1996
Hereditary spastic paraplegia (HSP)
21 HSP genes have been mapped so far, 9 of which have been identified: cell adhesion molecule L1 (L1-CAM), the gene encoding proteolipid protein (PLP1), atlastin, spastin, the neuronal specific kinesin gene KIF5A, the mitochondrial chaperone heat shock protein gene HSP60 (mitochondrial chaperonin), paraplegin, non imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), spartin, Berardinelli-Seip congenital lipodystrophy (BSCL2), maspardin and the ALS2/alsin gene ALS2 .
Loci identified in HSP
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