Genetics of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) was first described by Charcot in 1869 as what we would now call a sporadic disease—a disease believed to occur without a strong genetic influence. Only within the past 10 years has it been possible to fully explore genetic influence on disorders that seem to occur sporadically but likely result from the convergence of multiple genetic and environmental factors. This article reviews the genetics of familial ALS and summarizes current investigations of genetic influence in sporadic ALS. Genetic study clearly offers the potential for identification of molecular targets that would allow development of rational therapies for various forms of ALS, but much work remains.

Amyotrophic lateral sclerosis (ALS) was first described by Charcot in 1869 as what we would now call a sporadic disease—a disease believed to occur without a strong genetic influence. By 1880 Sir William Osler recognized that the Farr family of Vermont had a dominantly inherited progressive muscular atrophy, one phenotypic variation of ALS . It took another 100 years to develop the tools of molecular biology that allowed examination of the clearly inherited forms of the disease. Only within the past 10 years has it been possible to fully explore genetic influence on disorders that seem to occur sporadically but are in fact quite complex—those that likely result from the convergence of multiple genetic and environmental factors. The roughly 90% of ALS that occurs in individuals who have no family history of ALS is called sporadic ALS (SALS), whereas the remaining 10% of ALS that occurs in at least two people in the same family is considered familial ALS (FALS) .

This article reviews the genetics of FALS and summarizes current investigations of genetic influence in SALS.

Familial amyotrophic lateral sclerosis

FALS can be transmitted as a dominant or a recessive trait, but is most commonly an adult-onset disorder of autosomal dominant transmission. Autosomal recessive inheritance is rare and seems to be limited to people who have juvenile-onset ALS or people who have a double dose of particular mutations in the SOD1 gene. We have reported a single family with X-linked dominantly inherited ALS, a rarely observed phenomenon in neurogenetics .

In 1991 positional cloning identified linkage of familial ALS to the SOD1 locus on chromosome 21q22 and demonstrated genetic locus heterogeneity in FALS . Two years later mutations in SOD1 were linked to FALS, establishing SOD1 as the first causative gene for ALS (genetic nomenclature, ALS1) . Subsequently, homozygosity mapping of highly consanguineous families identified the gene ALSIN causing autosomal recessive ALS2 and the locus for ALS5 . Since then five additional genetic loci for FALS and seven for related motor neuron degenerations have been identified ( Tables 1 and 2 ) , establishing a multi-etiologic basis for FALS .

Table 1

Amyotrophic lateral sclerosis genes and loci

Frequency of cases	Genetic nomenclature	Inheritance pattern	Disease name	Gene	Locus	Protein product
20%	ALS1	AD	SOD-FALS	SOD1	21q22.1	Cu-Zn superoxide dismutase
Rare	ALS2	AR	Juvenile ALS type 3	ALS2	2q33	Alsin
Single family	ALS3	AD	FALS		18q21	Unknown
Rare	ALS5	AR	Juvenile ALS type 1		15q15.1–q21.1	Unknown
Three families	ALS6	AD	FALS		16q12	Unknown
Single family	ALS7	AD	FALS		20ptel	Unknown
Rare		AD	FALS and FALS/FTD	TDP-43	1p36	TAR DNA-binding protein
Single family	XALS	X- dominant	FALS		X	Unknown

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; FTD, frontotemporal dementia; SMA, spinal muscular atrophy.

Data from Siddique T, Dellefave L. Amyotrophic lateral sclerosis. In: David Lynch, Jennifer Farmer, editors. Neurogenetics: scientific and clinical advances. New York and London: Taylor and Francis; 2006. p. 693–720.

Table 2

Amyotrophic lateral sclerosis–related motor neuron disorders with upper and lower motor neuron involvement

Frequency of cases	Genetic nomenclature	Inheritance pattern	Disease name	Gene	Locus	Protein product
Rare	ALS4 ^a	AD	Distal hereditary motor neuronopathy with pyramidal features	SETX	9q34	Senataxin
Rare	ALS8 ^b	AD	SMA IV, Finkel type SMA	VAPB	20q13	VAPB
Rare	ALS/FTD1	AD	ALS with FTD	Unknown	9q21–q22	Unknown
More common	ALS/FTD2	AD	ALS with FTD	Unknown	9p21	Unknown
Rare	FTDP17	AD	Disinhibition-dementia-parkinsonism-amyotrophy complex	Unknown	17q	Unknown
Uncommon	SPG17	AD	Silver syndrome	Unknown	11q12–q14	Unknown
Old order Amish	SPG20	AR	Troyer syndrome	SPG20	13q12.3	Spartin
Rare		AD	Inclusion body myopathy associated with Paget disease of bone and FTD	VCP	9p21.1–p12	Valosin-containing protein

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; FTD, frontotemporal dementia.

a No bulbar involvement. Long, slow progression, distal wasting with pyramidal signs and sensory loss, previously called axonal Charcot Marie Tooth with pyramidal signs.

b This disorder seems to be proximal SMA IV (Finkel type) with some UMN findings.

SOD-ALS (ALS1)

The SOD1 gene is around 11 kilobases with five exons, four introns, and several alternatively spliced forms. More than 100 mutations, predominantly missense, have been reported in 68 of the 153 codons, spread over all five exons ( http://alsod.iop.kcl.as.uk/index.aspx ). The SOD1 protein is a 32 kd homodimeric protein consisting of 153 highly conserved amino acids. Each monomer has a Greek key β-barrel fold that binds to one copper and one zinc ion . The dimer interface is stabilized by hydrophobic interactions, with dimerization doubling the dismutase activity of SOD1. An electrostatic guidance channel shepherds superoxide ions to the active Cu ²⁺-containing site . In human SOD1 two cysteine residues are oxidized as a sulfhydryl bridge (C ₅₇, C ₁₄₆), which provides stability and increases melting temperature with the aid of the zinc ion. The dismutase reaction is likely limited only by substrate availability . The size- and charge-selective access to the active site specifically allows in the negatively charged superoxide ion, while excluding larger and positively charged ions .

There are three superoxide dismutases (SOD1, 2, and 3), all three of which are isoenzymes that play major roles in reducing free radical–induced cellular damage. They scavenge superoxide free radicals that are byproducts of oxidative respiration and the cytochrome P450 system. SOD1, the only one of the three implicated in FALS, is primarily a cytosolic enzyme, but small amounts are also present in mitochondria and other organelles .

Human SOD-ALS (ALS1)

A typical presentation of FALS, particularly ALS1, is one of early monomelic weakness without significant loss of muscle bulk, which may persist for many months before significant weakness or muscle wasting is noted at the site or elsewhere. In 2000, the Escorial Criteria were revised in recognition of this phenomenon. “Clinically definite familial ALS—laboratory supported” can be diagnosed if a pathogenic mutation has been identified in the presence of progressive upper or lower motor neuron signs in at least a single region in the absence of another cause for the abnormal neurologic signs . In practice, however, lower motor neuron features predominate in ALS1 with the first sign frequently being mild weakness in calf muscles accompanied by loss of the S ₁glutamate-mediated monosynaptic Achilles reflex, calling in question the role of glutamate toxicity. (T. Siddique, unpublished observation, 1998).

Age of onset does not correlate with mutation, ranging from 15 to 81 years, with mean onset at age 47 ± 13 years. Extremity onset, particularly in the legs, is much more common than bulbar onset and both genders are equally affected. Disease duration or rate of disease progression does correlate with some mutations, however, with particularly the A4V mutation that causes about 50% of ALS1 in North American families being consistently associated with a rapid course of 1.0 ± 0.4 years from symptom onset until death . A few other mutations confer a disease duration of 10 years or more, whereas some others exhibit extensive variability . Penetrance of SOD1 mutations is variable and mutation specific, with the I113T and D90A mutations markedly reduced compared with the generally high A4V mutation .

The dosage of certain SOD1 mutations, particularly D90A, seems to affect age of disease onset also. Generally individuals of Scandinavian origin who are D90A heterozygotes do not develop ALS. More than 80 cases that had homozygous D90A mutations from 40 independent pedigrees originating in Northern Scandinavia developed ALS, however. A slowly progressive form, often presenting as SALS, has been identified in homozygotes of other populations. Dominant pedigrees have also been reported . SOD1 enzyme activity is not associated with disease severity, with mutations that provide even marginally reduced activity producing disease .

Animal, biochemical, and cellular studies in SOD-ALS

The first mouse model overexpressing SOD1 was constructed in 1994 using the G93A mutation . The model has since been replicated with other SOD1 mutations in both mouse and rat and extensively studied . Transgenic mice or rats overexpressing mutant SOD1 develop an ALS-like phenotype, whereas those overexpressing wild-type SOD1 remain unaffected. SOD1 knockout mice show axonal damage; although their muscles show fiber-type grouping characteristic of denervation/reinnervation, they do not develop motor neuron degeneration or obvious clinical weakness. Despite the varied pathology described in animals that have ALS overexpressing mutant SOD1, the central lesson is that onset of disease correlates with levels of protein expression, which in turn is related to copy number of the transgene . This correlation suggests that mutant SOD1 must reach a critical threshold in its expression, above which it causes disease by gain of a toxic property that triggers degeneration of motor neurons . Two major hypotheses have been proposed. One is that although normal SOD1 activity serves as an antioxidant defense, the peroxidase, superoxide reductase, and superoxide generating properties of mutant SOD1 lead to the formation of toxic species, including peroxynitrite, superoxide, and decomposition products of hydrogen peroxide . Removal of copper essential for these reactions with copper chaperone of SOD or copper chelators, however, did not ameliorate disease in mutant SOD1 transgenic mice , which makes it unlikely the basis for disease.

We propose that formation of aggregates of SOD1 identified in brain and spinal cord of both SOD1 transgenic mice and ALS1 patients, like the mutant prion aggregates of Creutzfeldt-Jakob disease, are the toxic mechanism in SOD-ALS. Investigations with double transgenic mice in our laboratory established that wild-type SOD1 is recruited in the presence of mutant SOD1, not only hastening disease onset in G93A and L126Z mutant mice but also converting the otherwise unaffected A4V mice into diseased mice. Analyses of spinal cord tissue of these double transgenic mice revealed this phenomenon is accompanied by conversion of both mutant and wild-type SOD1 from a soluble form to an aggregated and detergent-insoluble form. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are cross-linked through intermolecular disulfide bonds. The dimers act as seeds in forming toxic intermediate species with possible membrane-disrupting properties. SOD1, normally an important protein in cellular defense against free radicals, is converted to an aggregated and apparently toxic species by redox processes, demonstrating direct links between oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS . We have observed SOD1 protein levels are highest in spinal cord of G93A mutants, with lesser amounts in brain and liver and least in kidneys, and increased accumulation occurs with age (N. Cole and T. Siddique, unpublished observation, 1997). These studies, taken together, suggest that the spinal cord and brainstem are unable to effectively deal with the mutant protein load, leading to the region-specific pathology and dysfunction noted in ALS mice, and probably in humans. This finding is important because rational therapy based on these observations can now be developed and tested.

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