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Genetics of MND

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 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)

Disease Onset Inheritance Locus Gene Reference
Combined UMN and LMN involvement
ALS1 Adult AD/AR 21q22.1 SOD1 (Rosen et al., 1993
ALS2 Juvenile AR 2q33.2 ALS2/Alsin (Hadano et al., 2001
ALS3 Adult AD 18q21 - (Hand et al., 2002
ALS4 Juvenile AD 9q34 SETX (Blair et al., 2000
ALS5 Juvenile AR 15q15-22 - (Hentati et al., 1998
ALS6 Adult AD 16q12 - (Ruddy et al., 2003
ALS7 Adult AD 20ptel - (Sapp et al., 2003
ALS8 Adult AD 20q13.33 VAPB (Nishimura et al., 2004
ALS X Adult X-linked Xp11-q12 - (Siddique et al., 1998
Pure LMN involvement
SMA Adult AD 2p13 DCTN1 (Puls et al., 2003 Puls et al., 2005
SMA Juvenile AR 5q13 SMN1 (Lefebvre et al., 1995 Rodrigues et al., 1995
SBMA/ Kennedy’s Disease Adult X-linked Xq11-q12 Androgen Receptor (La Spada et al., 1991 Biancalana et al., 1992
Pure UMN involvement
jPLS Juvenile AR 2q33.2 ALS2 (Yang et al., 2001
HSP See below
Mixed sensory and motor involvement
ALS- FTD/Parkinsonism Adult AD 17q21 MAPT (Siddique and Hentati, 1995
ALS- FTD/Parkinsonism Adult AD 17q - (Wilhelmsen et al., 2004
ALS- FTD Adult AD 9q21-22 - (Hosler et al., 2000
AbbreviationsALS= amyotrophic lateral sclerosis; AD= autosomal dominant; AR= autosomal recessive; SOD1= Cu/Zn superoxide dismutase 1; SETX= Senataxin; VAPB= vesicle associated membrane protein (VAMP)/ synaptobrevin-associated membrane protein B; SMA= spinal muscular atrophy; SBMA= spinobulbar muscular atrophy; jPLS= juvenile primary lateral sclerosis; HSP= hereditary spastic paraplegia; FTD= frontotemporal dementia; MAPT= microtubule associated protein tau; DCTN1= dynactin 1; SMN1= survival motor neuron 1

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

Gene Locuc Disease Inheritiance Reference
SPG4/ Spastin 2p22 Pure HSP AD (De Jonghe et al., 1996 Hazan et al., 1999
SPG13/ Hsp60 2q24-34 Pure HSP AD (Hansen et al., 2002
SPG10/ KIF5A 12q13 Pure or Complicated HSP AD (Reid et al., 1999a
SPG3A/ Atlastin 14q11- 21 Pure HSP AD (Dalpozzo et al., 2003 Zhao et al., 2001
SPG6/ NIPA1 15q11.1 Pure HSP AD (Rainier et al., 2003
SPG7/ Paraplegin 16q24.3 Pure or Complicated HSP AR (Casari et al., 1998 Wilkinson et al., 2004
SPG20/ Spartin 13q12.3 Troyer syndrome AR (Patel et al., 2002
SPG1/ L1CAM Xq28 Complicated HSP X-linkedR (Jouet et al., 1994
SPG2/ PLP Xq21 Complicated HSP X-linkedR (Bonneau et al., 1993
ALS2/alsin 2q33.2 IAHSP AR (Eymard-Pierre et al., 2002 Gros-Louis et al., 2003
SPG17/ BSCL2 11q12- 14 Silver Syndrome AD (Patel et al., 2001 Windpassinger et al., 2004
SPG8 8q23- 24 Pure HSP AD (Reid et al., 1999b
SPG21/Maspardin 15q22.31 Mast Syndrome AR (Simpson et al., 2003
SPG9 10q23.3-24.2 Complicated HSP AD (Lo Nigro et al., 2000
SPG12 19q13 Pure HSP AD (Ashley-Koch et al., 2001 Reid et al., 2000
SPG19 9q33- 34 Pure HSP AD (Valente et al., 2002
SPG14 3q27- 28 Complicated HSP AR (Vazza et al., 2000
SPG5 8q12-13 Pure HSP AR (Muglia et al., 2004
SPG11 15q13-15 ARHSP AR (Martinez Murillo et al., 1999 Shibasaki et al., 2000
SPG15 14q22-24 Complicated HSP AR (Hughes et al., 2001
SPG16 Xq11.2 Pure or Complicated HSP X- linkedR (Steinmuller et al., 1997
SPG26 12p11.1–12q14 Complicated HSP AR (Wilkinson et al., 2005
AbbreviationsSPG= Spastic Gait gene locus; AD= Autosomal dominant; AR= Autosomal recessive; HSP60= heat shock protein 60 (mitochondrial Chaperonin); KIF5A= kinesin heavy chain; NIPA1= non imprinted in Prader-Willi/Angelman syndrome 1; L1CAM= L1 cell adhesion molecule; PLP= proteolipid protein; IAHSP= infantile-onset ascending HSP; BSCL2= Berardinelli-Seip congenital lipodystrophy; ARHSP= autosomal recessive HSP.

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