Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. ... Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. Some forms of ALS occur with frontotemporal dementia (FTD). Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture. - Genetic Heterogeneity of Amyotrophic Lateral Sclerosis ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. ALS6 (608030) is caused by mutation in the FUS gene (137070) on chromosome 16p11.2; ALS8 (608627) is caused by mutation in the VAPB gene (605704) on chromosome 13; ALS9 (611895) is caused by mutation in the ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by mutation in the TARDBP gene (605078) on 1p36.2; ALS11 (612577) is caused by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435) is caused by mutation in the OPTN gene (602432) on chromosome 10p; ALS14 (613954) is caused by mutation in the VCP gene (601023) gene on chromosome 9p13-p12; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11.23-p11.1; ALS17 (614696) is caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; ALS18 (614808) is caused by mutation in the PFN1 gene (176610) on chromosome 17p13.3; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; and ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13. See also FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on chromosome 9p21. Loci associated with the disorder are found on chromosomes 18q21 (ALS3; 606640) and 20p13 (ALS7; 608031). Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (601517) contribute to susceptibility to ALS (ALS13; 183090). Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; 162230); deletions in the gene encoding peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1; 601143). Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100), caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433), caused by mutation in the senataxin gene (SETX; 608465) on 9q34; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13. A locus on chromosome 15q15-q21.1 (ALS5; 602099) is associated with a juvenile-onset form.
Horton et al. (1976) suggested that there are 3 phenotypic forms of familial ALS, each inherited as an autosomal dominant disorder. The first form they delineated is characterized by rapidly progressive loss of motor function with predominantly lower ... Horton et al. (1976) suggested that there are 3 phenotypic forms of familial ALS, each inherited as an autosomal dominant disorder. The first form they delineated is characterized by rapidly progressive loss of motor function with predominantly lower motor neuron manifestations and a course of less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second form is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke column, and spinocerebellar tracts. The third form is similar to the second except for a much longer survival, usually beyond 10 and often 20 years. Examples of type 1 include the families of Green (1960), Poser et al. (1965) and Thomson and Alvarez (1969). Examples of type 2 include the families of Kurland and Mulder (1955) and Engel et al. (1959). Engel et al. (1959) described 2 American families, 1 of which was of Pennsylvania Dutch stock with at least 11 members of 4 generations affected with what was locally and popularly termed 'Pecks disease.' Examples of type 3 include the families of Amick et al. (1971) and Alberca et al. (1981). In the Spanish kindred reported by Alberca et al. (1981), early onset and persistence of muscle cramps, unilateral proximal segmental myoclonus, and early abolition of ankle jerks were conspicuous clinical features. Brown (1951, 1960) described 2 New England families, Wetherbee and Farr by name, with autosomal dominant inheritance of a rapidly progressive neurodegenerative disorder with loss of anterior horn cells of the spinal cord and bulbar palsy. (See also Hammond, 1888 and Myrianthopoulos and Brown, 1954). Neuropathology showed a classic 'middle-root zone' pattern of posterior column demyelination in addition to involvement of the anteriolateral columns and ventral horn cells. Although the disorder was clinically indistinguishable from ALS, the pattern of posterior column demyelinations was unexpected. Osler (1880) had described the Farr family earlier (McKusick, 1976). Variability in disease severity in the Farr family was indicated by the case of a 78-year-old woman with relatively minor findings who had buried a son and whose mother had been affected (Siddique, 1993). Powers et al. (1974) reported the first autopsy in a member of the Wetherbee family from Vermont. The patient was a 35-year-old woman who began to experience weakness in the left leg 1 year before her terminal admission. She then gradually developed weakness and atrophy of the left hand, right lower limb, and right hand. One month before admission she developed dyspnea which steadily worsened, and she was admitted to hospital because of severe ventilatory insufficiency secondary to muscle weakness. She showed atrophy of all extremities, areflexia, and, except for slight movement of the left shoulder and right foot, quadriplegia. The patient died on the second hospital day. Autopsy showed severe demyelination type of atrophy of all muscles. Gray atrophy of the lumbar and cervical anterior roots was evident grossly. Microscopic neuronal changes included a moderate loss of neurons from the hypoglossal nuclei and dorsal motor vagal nuclei, severe neuronal loss from the anterior horns of the cervical and lumbar cord with reactive gliosis, eosinophilic intracytoplasmic inclusions in many of the remaining lumbar anterior horn cells, and a moderately symmetric loss of neurons from the Clarke column. A severe asymmetric loss of axons and myelin was demonstrated throughout the cervical dorsal spinocerebellar tracts and lumbar posterior columns, with moderate loss in the lumbar lateral corticospinal tracts. Powers et al. (1974) concluded that the disorder corresponded exactly to a subgroup of familial ALS described by Hirano et al. (1967). Engel (1976) concluded that the 'Wetherbee ail' and the Farr family disease were consistent with ALS (Engel et al., 1959). Alter and Schaumann (1976) reported 14 cases in 2 families and attempted a refinement of the classification of hereditary ALS. Hudson (1981) stated that posterior column disease is found in association with ALS in 80% of familial cases. In a kindred with an apparently 'new' microcephaly-cataract syndrome (212540), reported by Scott-Emuakpor et al. (1977), 10 persons had died of a seemingly unrelated genetic defect--amyotrophic lateral sclerosis. Veltema et al. (1990) described adult ALS in 18 individuals from 6 generations of a Dutch family. Onset occurred between ages 19 and 46; duration of disease averaged 1.7 years. The clinical symptoms were predominantly those of initial shoulder girdle and ultimate partial bulbar muscle involvement. Iwasaki et al. (1991) reported a Japanese family in which members in at least 3 generations had ALS. At least 2 individuals in the family also had Ribbing disease (601477), a skeletal dysplasia that was presumably unrelated to the ALS.
De Belleroche et al. (1995) noted that the SOD1 H46R mutation (147450.0013) was associated with a more benign form of ALS with average duration of 17 years and only slightly reduced levels of SOD1 enzyme activity. The authors ... De Belleroche et al. (1995) noted that the SOD1 H46R mutation (147450.0013) was associated with a more benign form of ALS with average duration of 17 years and only slightly reduced levels of SOD1 enzyme activity. The authors referred to a family with an I113T mutation (147450.0011) in which 1 affected member of the family died after a short progression and another member survived more than 20 years. Cudkowicz et al. (1997) registered 366 families in a study of dominantly inherited ALS. They screened 290 families for mutations in the SOD1 gene and detected mutations in 68 families; the most common SOD1 mutation, A4V (147450.0012), was present in 50% of the families. The presence of either of 2 SOD1 mutations, G37R (147450.0001) or L38V (147450.0002), predicted an earlier age at onset. Additionally, the presence of the A4V mutation correlated with shorter survival, whereas G37R, G41D (147450.0004), and G93C (147450.0007) mutations predicted longer survival. The clinical characteristics of patients with familial ALS arising from SOD1 mutations were similar to those without SOD1 defects. However, Cudkowicz et al. (1997) reported that mean age at onset was earlier in the SOD1 group than in the non-SOD1 group, and Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times. Sato et al. (2005) measured the ratio of mutant-to-normal SOD1 protein in 29 ALS patients with mutations in the SOD1 gene. Although there was no relation to age at onset, turnover of mutant SOD1 was correlated with a shorter disease survival time. Regal et al. (2006) reported the clinical features of 20 ALS patients from 4 families with the SOD1 G93C mutation (147450.0007). Mean age at onset was 45.9 years, and all patients had slowly progressive weakness and atrophy starting in the distal lower limbs. Although symptoms gradually spread proximally and to the upper extremities, bulbar function was preserved. None of the patients developed upper motor neuron signs. Postmortem findings of 1 patient showed severe loss of anterior horn cells and loss of myelinated fibers in the posterior column and spinocerebellar tracts, but only mild changes in the lateral corticospinal tracts. Lipofuscin and hyaline inclusions were observed in many neurons. Patients with the G93C mutation had significantly longer survival compared to patients with other SOD1 mutations.
In affected members of 13 unrelated families with ALS, Rosen et al. (1993) identified 11 different heterozygous mutations in exons 2 and 4 of the SOD1 gene (147450.0001-147450.0011). Deng et al. (1993) ... - Autosomal Dominant Mutations In affected members of 13 unrelated families with ALS, Rosen et al. (1993) identified 11 different heterozygous mutations in exons 2 and 4 of the SOD1 gene (147450.0001-147450.0011). Deng et al. (1993) identified 3 mutations in exons 1 and 5 of the SOD1 gene in affected members of ALS families. Eight families had the same mutation (A4V; 147450.0012). One of the families with the A4V mutation was the Farr family reported by Brown (1951, 1960). Pramatarova et al. (1995) estimated that approximately 10% of ALS cases are inherited as an autosomal dominant and that SOD1 mutations are responsible for at least 13% of familial ALS cases. Jones et al. (1993) demonstrated that mutation in the SOD1 gene can also be responsible for sporadic cases of ALS. They found the same mutation (I113T; 147450.0011) in 3 of 56 sporadic cases of ALS drawn from a population-based study in Scotland. Among 233 sporadic ALS patients, Broom et al. (2004) found no association between disease susceptibility or phenotype and a deletion and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing against a major role for wildtype SOD1 in sporadic ALS. In a review of familial ALS, de Belleroche et al. (1995) listed 30 missense mutations and a 2-bp deletion in the SOD1 gene. Siddique and Deng (1996) reviewed the genetics of ALS, including a tabulation of SOD1 mutations in familial ALS. Millecamps et al. (2010) identified 18 different SOD1 missense mutations in 20 (12.3%) of 162 French probands with familial ALS. Compared to those with ALS caused by mutations in other genes, those with SOD1 tended to have disease onset predominantly in the lower limbs. One-third of SOD1 patients survived for more than 7 years: these patients had an earlier disease onset compared to those presenting with a more rapid course. No patients with SOD1 mutations developed cognitive impairment. - Autosomal Recessive Mutations Andersen et al. (1995) found homozygosity for a mutation in the SOD1 gene (D90A; 147450.0015) in 14 ALS patients from 4 unrelated families and 4 apparently sporadic ALS patients from Sweden and Finland. Consanguinity was present in several of the families, consistent with autosomal recessive inheritance. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Age at onset ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1 to 4 years' disease duration in all patients, and none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype like that in the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Thus, familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms. Al-Chalabi et al. (1998) concluded that a 'tightly linked protective factor' in some families modifies the toxic effect of the mutant SOD1, resulting in recessive inheritance. - Susceptibility Genes and Association Studies Siddique et al. (1998) could demonstrate no relationship between APOE genotype (107741) and sporadic ALS. Previous studies had resulted in contradictory results. Siddique et al. (1998) found no significant difference in age at onset between patients with 1, 2, or no APOE*4 alleles. In 1 of 189 ALS patients, Gros-Louis et al. (2004) identified a 1-bp deletion in the peripherin gene (170710.0001), suggesting that the mutation conferred an increased susceptibility to development of the disease. Among 250 patients with a putative diagnosis of ALS, Munch et al. (2004) identified 3 mutations in the DCTN1 gene (601143.0002-601143.0004) in 3 families. One of the mutations showed incomplete penetrance. The authors suggested that mutations in the DCTN1 gene may be a susceptibility risk factor for ALS. Veldink et al. (2005) presented evidence suggesting that SMN genotypes producing less SMN protein increased susceptibility to and severity of ALS. Among 242 ALS patients, the presence of 1 SMN1 (600354) copy, which represents spinal muscular atrophy (SMA; 253300) carrier status, was significantly increased in patients (6.6%) compared to controls (1.7%). The presence of 1 copy of SMN2 (601627) was significantly increased in patients (58.7%) compared to controls (29.7%), whereas 2, 3, or 4 SMN2 copies were significantly decreased in patients compared to controls. In 167 ALS patients and 167 matched controls, Corcia et al. (2002) found that 14% of ALS patients had an abnormal copy number of the SMN1 gene, either 1 or 3 copies, compared to 4% of controls. Among 600 patients with sporadic ALS, Corcia et al. (2006) found an association between disease and 1 or 3 copies of the SMN1 gene (p less than 0.0001; odds ratio of 2.8). There was no disease association with SMN2 copy number. Dunckley et al. (2007) provided evidence suggestive of an association between the FLJ10986 gene (611370) on chromosome 1 and sporadic amyotrophic lateral sclerosis in 3 independent patient populations. The susceptibility allele of dbSNP rs6690993 conferred an odds ratio of 1.35 (p = 3.0 x 10(-4)). Simpson et al. (2009) performed a multistage association study using 1,884 microsatellite markers in 3 populations totaling 781 ALS patients and 702 control individuals. They identified a significant association (p = 1.96 x 10(-9)) with the 15-allele marker D8S1820 in intron 10 of the ELP3 gene (612722). Fine mapping with SNPs in and around the ELP3 gene identified a haplotype consisting of allele 6 of D8S1820 and dbSNP rs12682496 strongly associated with ALS (p = 1.05 x 10(-6)). Lambrechts et al. (2009) performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene (192240) and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype (dbSNP rs699947; 192240.0002), which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing. Sabatelli et al. (2009) identified nonsynonymous variants in the CHRNA3 (118503) and CHRNB4 (118509) genes on chromosome 15q25.1 and the CHRNA4 gene (118504) on chromosome 20q13.2-q13.3, encoding neuronal nicotinic acetylcholine receptor (nAChR) subunits, in 19 sporadic ALS patients and in 14 controls. NAChRs formed by mutant alpha-3 and alpha-4 and wildtype beta-4 subunits exhibited altered affinity for nicotine (Nic), reduced use-dependent rundown of Nic-activated currents, and reduced desensitization leading to sustained intracellular calcium concentration, in comparison with wildtype nAChR. Sabatelli et al. (2009) suggested that gain-of-function nAChR variants may contribute to disease susceptibility in a subset of ALS patients because calcium signals mediate the neuromodulatory effects of nAChRs, including regulation of glutamate release and control of cell survival. In a 3-generation kindred with familial ALS, Mitchell et al. (2010) found linkage to markers D12S1646 and D12S354 on chromosome 12q24 (2-point lod score of 2.7). Screening of candidate genes identified a heterozygous arg199-to-trp (R199W) mutation in exon 7 of the DAO gene (124050) in 3 affected members and in 1 obligate carrier, who died at age 73 years of cardiac failure and reportedly had right-sided weakness and dysarthria. The proband had onset at age 40, and the mean age at death in 7 cases was 44 years (range, 42 to 55 years). The mutation was also present in 3 at-risk individuals of 33, 44, and 48 years of age, respectively. The R199W mutation was not found in 780 Caucasian controls. Postmortem examination of the obligate carrier showed some loss of motor neurons in the spinal cord and degeneration of 1 of the lateral corticospinal tracts. There was markedly decreased DAO enzyme activity in the spinal cord compared to controls. Coexpression of mutant protein with wildtype protein in COS-7 cells indicated a dominant-negative effect for the mutant protein. Rat neuronal cell lines expressing the R199W-mutant protein showed decreased viability and increased ubiquitinated aggregates compared to wildtype. Mitchell et al. (2010) suggested a role for the DAO gene in ALS, but noted that a causal role for the R199W-mutant protein remained to be unequivocally established. In a study of 847 patients with ALS and 984 controls, Blauw et al. (2012) found that SMN1 duplications were associated with increased susceptibility to ALS (odds ratio (OR) of 2.07; p = 0.001). A metaanalysis with previous data including 3,469 individuals showed a similar effect, with an OR of 1.85 (p = 0.008). SMN1 deletions or point mutations and SMN2 copy number status were not associated with ALS, and SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. - Modifier Genes Giess et al. (2002) reported a 25-year-old man with ALS who died after a rapid disease course of only 11 months. Genetic analysis identified a heterozygous mutation in the SOD1 gene and a homozygous mutation in the ciliary neurotrophic factor gene (CNTF; 118945.0001). The patient's mother, who developed ALS at age 54, had the SOD1 mutation and was heterozygous for the CNTF mutation. His healthy 35-year-old sister had the SOD1 mutation, but did not have the CNTF mutation. Two maternal aunts had died from ALS at 56 and 43 years of age, and a maternal grandmother and a great-grandmother had died from progressive muscle weakness and atrophy at ages 62 and less than 50 years, respectively. Giess et al. (2002) found that transgenic SOD1 mutant mice who were Cntf-deficient had a significantly earlier age at disease onset compared to in transgenic mice that were wildtype for CNTF. Although linkage analysis in mice revealed that the SOD1 gene was solely responsible for the disease, disease onset as a quantitative trait was regulated by the CNTF locus. In addition, patients with sporadic ALS who had a homozygous CNTF gene defect showed significantly earlier disease onset, but did not show a significant difference in disease duration. Giess et al. (2002) concluded that CNTF acts as a modifier gene that leads to early onset of disease in patients with SOD1 mutations.
In 2 regions of northwestern Italy with a total population of approximately 4.5 million, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (2001) determined a mean annual incidence rate of 2.5 per 100,000 from 1995 to ... In 2 regions of northwestern Italy with a total population of approximately 4.5 million, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (2001) determined a mean annual incidence rate of 2.5 per 100,000 from 1995 to 1996. The data were comparable to similar studies in other Western countries, suggesting diffuse genetic or environmental factors in the pathogenesis of ALS. Chio et al. (2008) found that 5 of 325 patients with ALS in Turin province of the Piemonte region of Italy had mutations in the SOD1 gene. Mutations were identified in 3 (13.6%) of 22 patients with a family history of ALS, and 2 (0.7%) of 303 sporadic cases. Chio et al. (2008) noted that the frequency of FALS (5.7%) was lower in this population-based series compared to series reported from ALS referral centers.