Amyotrophic Lateral Sclerosis 1

A number sign (#) is used with this entry because 15 to 20% of cases of familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1, are associated with mutations in the superoxide dismutase-1 gene (SOD1; 147450) on chromosome 21q22. Although most cases of SOD1-related familial ALS follow autosomal dominant inheritance, rare cases of autosomal recessive inheritance have been reported.

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; 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; 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; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11; 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; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13; ALS21 (606070) is caused by mutation in the MATR3 gene (164015) on chromosome 5q31; ALS22 (616208) is caused by mutation in the TUBA4A gene (191110) on chromosome 2q35; and ALS23 (617839) is caused by mutation in the ANXA11 gene (602572) on chromosome 10q23. See also FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on chromosome 9p21.

Loci associated with ALS have been 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 ALS24 (617892) is conferred by mutation in the NEK1 gene (604588) on chromosome 4q33, and susceptibility to ALS25 (617921) is conferred by mutation in the KIF5A gene (602821) on chromosome 12q13. 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; ALS5 (602099), caused by mutation in the SPG11 gene (610844) on 15q21; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13.

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.

Familial ALS caused by mutations in the SOD1 gene usually causes autosomal dominant disease, but can also cause autosomal recessive ALS.

In Germany, Haberlandt (1963) concluded that ALS is an 'irregular' autosomal dominant disorder in many instances. Gardner and Feldmahn (1966) described adult-onset ALS in a family in which 15 members spanning 7 generations were affected.

Husquinet and Franck (1980) reported a family with ALS suggesting autosomal dominant inheritance with incomplete penetrance. Twelve men and 6 women were affected; 4 unaffected members of the family transmitted the disease. The first signs of the disease, which ran its course in 5 to 6 years, were in either the arms or the legs. As in most cases of ALS, death was caused by bulbar paralysis. Mean age at death was about 57 years.

In a review of a familial ALS, de Belleroche et al. (1995) found autosomal dominant inheritance with incomplete penetrance; by age 85 years, about 80% of carriers had manifested the disorder, and it was not uncommon to see obligate carriers in a family who died without manifesting the disease. Phenotypic heterogeneity was also common within families: for example, age of onset varying over 30 years within a family and duration of illness varying from 6 months to 5 years. Signs at onset were variable, but the disease usually began with focal and asymmetric wasting of hand muscles. Lower motor neuron involvement was usually conspicuous, whereas involvement of upper motor neurons was less marked.

Bradley et al. (2005) found no evidence for preferential maternal or paternal transmission among 185 families in which at least 2 individuals were diagnosed with ALS. Initial evidence suggesting anticipation was rejected following further analysis.

By analysis of a Swedish multigeneration registry spanning from 1961 to 2005, Fang et al. (2009) identified 6,671 probands with ALS. There was a 17-fold increased risk for development of ALS among sibs, and a 9-fold increased risk among children of probands. Sibs and children had a greater risk if the proband was diagnosed at a younger age, and the risk decreased with increasing age at diagnosis of the proband. Two cases were identified among the cotwins of ALS probands, yielding a relative risk of 32 for monozygotic twins. Spouses of probands had no significantly increased risk compared to controls. The findings indicated that there is a major genetic role in the development of ALS.

Possible X-linked Inheritance

In a family with ALS reported by Wilkins et al. (1977), X-linked dominant inheritance was suggested by the late onset in females and the lack of male-to-male transmission.

Siddique et al. (1987) did linkage studies in a family with 13 affected persons in 4 generations. There was no instance of male-to-male transmission. Kunst (2004) referenced an X-linked dominant, late-onset form linked to Xp11-q12 but reported only in abstract (Siddique et al., 1998).

Siddique et al. (1989) presented preliminary data from genetic linkage analysis in 150 families with familial ALS. Two regions of possible linkage were identified on chromosomes 11 and 21. The highest lod score observed was 1.46, obtained with D21S13 at theta = 0.20. The next highest lod score was observed with marker D11S21 (lod score = 1.05 at maximum theta of 0.001).

Siddique et al. (1991) presented evidence for linkage of familial ALS, termed ALS1, to markers on chromosome 21q22.1-q22.2 (maximum lod score of 5.03 10 cM telomeric to marker D21S58). Tests for heterogeneity in these families yielded a probability of less than 0.0001 that of genetic-locus heterogeneity, i.e., a low probability of homogeneity.

Genetic Heterogeneity

King et al. (1993) failed to find linkage to loci on chromosome 21 in 8 U.K. families with ALS, indicating genetic heterogeneity.

Associations Pending Confirmation

In a genomewide association study (GWAS) of 1,014 deceased patients with sporadic ALS and 2,258 controls from the U.S. and Europe, Landers et al. (2009) found a significant association between rs1541160 in intron 8 of the KIFAP3 gene (601836) on chromosome 1q24 and survival (p = 1.84 x 10(-8), p = 0.021 after Bonferroni correction). Homozygosity for the favorable allele, CC, conferred a 14-month survival advantage compared to TT. There was linkage disequilibrium between rs1541160 and rs522444 within the KIFAP3 promoter, and the favorable alleles of both SNPs correlated with decreased KIFAP3 expression in brain. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. The findings suggested that genetic factors may modify phenotypes in ALS.

Van Es et al. (2009) conducted a genomewide association study among 2,323 individuals with sporadic ALS and 9,013 control subjects and evaluated all SNPs with P less than 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genomewide data revealed genomewide significance for 1 SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort, and a combined analysis over the 2 stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A (609894), which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses.

Exclusion Studies

Wills et al. (2009) conducted a metaanalysis of 10 published studies, including 4 GWAS, and 1 unpublished study that had reported findings on association of sporadic ALS and paraoxonase (see PON1; 168820) SNPs on chromosome 7q21.3. The metaanalysis found no association between sporadic ALS and the PON locus and encompassed 4,037 ALS patients and 4,609 controls, including GWAS data from 2,018 ALS cases and 2,425 controls. The authors stated that this was the largest metaanalysis of a candidate gene in ALS to date and the first ALS metaanalysis to include data from GWAS.

Bradley and Krasin (1982) suggested that a defect in DNA repair may underlie ALS.

Rothstein et al. (1992) found in in vitro studies that synaptosomes in neural tissue obtained from 13 ALS patients showed a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in spinal cord, motor cortex, and somatosensory cortex compared to controls. The decrease in glutamate uptake was not observed in tissue from visual cortex, striatum, or hippocampus. Neural tissue from patients with other neurodegenerative disorders did not show this defect. In ALS tissue, there was no defect in affinity of the transporter for glutamate and no decrease in the transport of other molecules (gamma-aminobutyric acid and phenylalanine). Rothstein et al. (1992) suggested that defects in a high-affinity glutamate transporter (see, e.g., SLC1A1, 133550) could lead to neurotoxic levels of extracellular glutamate, contributing to neurodegeneration in ALS.

Liu et al. (1998) demonstrated increased free radical production in the spinal cord but not the brain of transgenic mice expressing mutant human SOD1 (G93A; 147450.0008), which preceded the degeneration of motor neurons. They hypothesized that in situ production of free radicals initiates oxidative injury and that antioxidants that penetrate into the central nervous system may be of therapeutic benefit.

Li et al. (2000) demonstrated an 81.5% elevation of caspase-1 (CASP1; 147678) activity in the spinal cord of humans with ALS when compared with normal controls, and, using an animal model, suggested that caspases play an instrumental role in the neurodegenerative processing of ALS. Caspase inhibition using zVAD-fmk delayed disease onset and mortality in the mouse model of ALS. Moreover, zVAD-fmk was found to inhibit caspase-1 activity as well as caspase-1 and caspase-3 (600636) mRNA upregulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. The findings also showed that zVAD-fmk decreased IL1-beta (147720), an indication that caspase-1 activity was inhibited.

Okado-Matsumoto and Fridovich (2002) proposed a mechanism by which missense mutations in SOD1 lead to ALS. They suggested that the binding of mutant SOD1 to heat-shock proteins leads to formation of sedimentable aggregates, making the heat shock proteins unavailable for their antiapoptotic functions and leading ultimately to motor neuron death.

Kawahara et al. (2004) extracted RNA from single motor neurons isolated with a laser microdissector from 5 individuals with sporadic ALS and 5 normal control subjects. GluR2 (GRIA2; 138247) RNA editing was 100% efficient in the control samples, but the editing efficiency varied between 0 and 100% in the motor neurons from each individual with ALS and was incomplete in 44 (56%) of them. Mice transgenic for GluR2 made artificially permeable to calcium ions developed motor neuron disease late in life (Feldmeyer et al., 1999), indicating that motor neurons may be specifically vulnerable to defective RNA editing. Kawahara et al. (2004) suggested that defective GluR2 RNA editing at the Q/R site may be relevant to ALS etiology.

Shibata et al. (1994) found SOD1-like immunoreactivity within Lewy body-like inclusions in the spinal cords of 10 of 20 patients with sporadic ALS. Skein-like inclusions and Bunina bodies, which were found in all 20 ALS cases, showed no SOD1-like immunoreactivity.

He and Hays (2004) identified Lewy body-like ubiquitinated (see UBB; 191339) inclusions in motor neurons from 9 of 40 ALS patients; all of the inclusions expressed peripherin. Similar inclusions were not identified in 39 controls.

Neumann et al. (2006) identified TDP43 (605078) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration (see 607485) and ALS. Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected CNS regions, including hippocampus, neocortex, and spinal cord. Neumann et al. (2006) concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders.

In mice, Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage within muscles was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression.

Pradat et al. (2007) found muscle NOGOA (604475) expression in 17 of 33 patients with spinal lower motor neuron syndrome observed for 12 months. NOGOA expression correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was detected as early as 3 months after symptom onset in patients who later developed typical ALS. Pradat et al. (2007) suggested that muscle NOGOA may be a prognostic marker for ALS in lower motor neuron syndromes. Tagerud et al. (2007) and Askanas et al. (2007) both commented that studies have demonstrated that NOGOA expression is increased in denervated muscles in mouse models and in other human neuropathies and myopathies. Both groups suggested that it may be premature to consider NOGOA muscle expression as a specific biomarker for ALS, as suggested by Pradat et al. (2007).

Using a specific antibody to monomer or misfolded forms of SOD1 (Rakhit et al., 2007), Liu et al. (2009) detected monomer/misfolded SOD1 in spinal cord sections of all 5 patients with familial ALS due to mutations in the SOD1 gene. The antibody localized primarily to hyaline conglomerate inclusions in motor neuron perikarya and occasionally to neuritic processes. In contrast, no immunostaining was observed in spinal cord tissue from ALS patients without SOD1 mutations, including 13 with sporadic disease and 1 with non-SOD1 familial ALS. The findings indicated a distinct difference between familial ALS1 and sporadic ALS, and supported the idea that monomer or misfolded SOD1 is not a common disease mechanism.

Rabin et al. (2010) studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. Whole-genome exon splicing was profiled from RNA pools collected from motor neurons and from the surrounding anterior horns. In the motor neuron-enriched mRNA pool, there were 2 distinct cohorts of mRNA signals, most of which were upregulated: 148 differentially expressed genes and 411 aberrantly spliced genes. The aberrantly spliced genes were highly enriched in cell adhesion, especially cell-matrix as opposed to cell-cell adhesion. Most of the enriching genes encoded transmembrane or secreted as opposed to nuclear or cytoplasmic proteins. The differentially expressed genes were not biologically enriched. In the anterior horn enriched mRNA pool, there were no clearly identified mRNA signals or biologic enrichment. Rabin et al. (2010) suggested possible mechanisms in cell adhesion for the contiguously progressive nature of motor neuron degeneration.

Using unbiased transcript profiling in the SOD1G93A mouse model of ALS, Lincecum et al. (2010) identified a role for the costimulatory pathway, a key regulator of immune responses. Furthermore, Lincecum et al. (2010) observed that this pathway is upregulated in the blood of 56% of human patients with ALS.

Kudo et al. (2010) used laser capture microdissection coupled with microarrays to identify early transcriptome changes occurring in spinal cord motor neurons or surrounding glial cells in models of ALS. Two transgenic mouse models of familial motor neuron disease, Sod1G93A and TAUP301L (157140.0001), were used at the presymptomatic stage. Identified gene expression changes were predominantly model-specific. However, several genes were regulated in both models. The relevance of identified genes as clinical biomarkers was tested in the peripheral blood transcriptome of presymptomatic Sod1G93A animals using custom-designed ALS microarray. To confirm the relevance of identified genes in human sporadic ALS (SALS), selected corresponding protein products were examined by high-throughput immunoassays using tissue microarrays constructed from human postmortem spinal cord tissues. Genes that were identified by these experiments and were located within a linkage region associated with familial ALS/frontotemporal dementia were sequenced in several families. This large-scale gene and protein expression study pointing to distinct molecular mechanisms of TAU- and SOD1-induced motor neuron degeneration identified several novel SALS-relevant proteins, including CNGA3 (600053), CRB1 (604210), OTUB2 (608338), MMP14 (600754), SLK (FYN; 137025), DDX58 (609631), RSPO2 (610575) and the putative blood biomarker Mgll (609699).

Pedrini et al. (2010) showed that the toxicity of mutant SOD1 (147450) relies on its spinal cord mitochondria-specific interaction with BCL2 (151430). Mutant SOD1 induced morphologic changes and compromised mitochondrial membrane integrity leading to the release of cytochrome c only in the presence of BCL2. In cells and in mouse and human spinal cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a conformational change in BCL2 that resulted in the exposure of its BH3 domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain failed to support mutant SOD1-mediated mitochondrial toxicity.

Ferri et al. (2010) exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and IMS, where Grx1 (GLRX; 600443) is localized, or in the mitochondrial matrix, where Grx2 (GLRX2; 606820) is localized, as a tool for restoring a correct redox environment and preventing aggregation of mutant SOD1 (G93A; 147450.0008). Overexpression of Grx1 increased the solubility of mutant SOD1 in the cytosol but did not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells or in immortalized motoneurons. Conversely, the overexpression of Grx2 increased the solubility of mutant SOD1 in mitochondria, interfered with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserved mitochondrial function and strongly protected neuronal cells from apoptosis. The authors concluded that the toxicity of mutant SOD1 primarily arises from mitochondrial dysfunction, and that rescue of mitochondrial damage may represent a therapeutic strategy.

Meissner et al. (2010) found that G93A mutant SOD1 activated caspase-1 (CASP1; 147678) and CASP1-mediated secretion of mature IL1-beta (147720) in a dose-dependent manner in microglia and macrophages. In cells in which CASP1 was activated, there was rapid endocytosis of mutant SOD1 into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm dampened the proinflammatory response. Mutant SOD1 induced caspase activation through a gain of amyloid conformation, not through its enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the life span of mutant Sod1 mice and was associated with decreased microgliosis and astrogliosis; however, age at disease onset was not affected. Treatment of mutant mice with an IL1 receptor inhibitor also extended survival and improved motor performance. The findings suggested that IL1-beta contributes to neuroinflammation and disease progression in ALS.

To determine whether increased SOD1 protects the heart from ischemia Armakola et al. (2012) reported results from 2 genomewide loss-of-function TDP43 (605078) toxicity suppressor screens in yeast. The strongest suppressor of TDP43 toxicity was deletion of DBR1 (607024), which encodes an RNA lariat debranching enzyme. Armakola et al. (2012) showed that, in the absence of DBR1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal cell line or in primary rat neurons was also sufficient to rescue TDP43 toxicity. Armakola et al. (2012) concluded that their findings provided insight into TDP43-mediated cytotoxicity and suggested that decreasing DBR1 activity could be a potential therapeutic approach for ALS.

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 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 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 (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.

For discussion of a possible association between variation in the SS18L1 gene and ALS, see 606472.0001-606472.0003.

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.

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.

Amyotrophic lateral sclerosis is a disorder that has prominently been mentioned as justification for assisted suicide. Ganzini et al. (1998) found that in the states of Oregon and Washington most patients with ALS whom they surveyed would consider assisted suicide. Many would request a prescription for a lethal dose of medication well before they intended to use it. Rowland (1998) reviewed the question of what it is about ALS that raised the question of suicide. The progressive paralysis leads to increase of loss of function, culminating in complete dependence on the help of others for all activities of daily living and, if life is sustained by assisted ventilation, loss of the ability to communicate or swallow. Ten percent of patients are under the age of 40 years. Some patients, wanting to live as long as possible, opted for tracheostomy and assisted ventilation at home. In a study of 92 patients receiving long-term assisted ventilation with tracheostomy, 20 lived for 8 to 17 years with the tracheostomy, and 9 became 'locked in' (they were conscious but severely paralyzed and unable to communicate except by eye movements). In the Oregon series, however, only 2 patients opted for tracheostomy with long-term mechanical ventilation, and among patients at the ALS Center at Columbia Presbyterian Medical Center, only 2.9% chose it (Rowland, 1998). The last year in the life of an ALS victim, Professor Morris Schwartz, was chronicled in a bestselling book written by Albom (1997).

In a prospective randomized control trial of 44 ALS patients, Fornai et al. (2008) reported that treatment of 16 patients with lithium plus riluzole resulted in slower disease progression compared to 28 patients treated with riluzole alone. All 16 patients treated with lithium survived for 15 months; 29% of the patients receiving riluzole alone did not survive by this endpoint. Studies in transgenic ALS mice showed a similar delay in disease progression and longer survival. Mice treated with lithium showed delayed cell death in spinal cord motor neurons, increased numbers of normal mitochondria in motor neurons, decreased SOD1 aggregation, and decreased reactive astrogliosis. Studies of cultured mutant murine motor neurons suggested that lithium treatment increased endosomal autophagy of aggregated proteins or abnormal mitochondria, which may have contributed to the observed neuroprotective effects.

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.

See also ANIMAL MODEL in 147450.

The murine Mnd (motor neuron degeneration) mutation causes a late-onset, progressive degeneration of upper and lower motor neurons. Using endogenous retroviruses as markers, Messer et al. (1992) mapped the Mnd gene in the mouse to proximal chromosome 8. Messer et al. (1992) suggested that examination of human chromosome 8, which shows homology of synteny, in human kindreds with ALS as well as related hereditary neurologic diseases might be fruitful. They presented evidence suggesting that a combination of genetic and environmental