Genetics of familial and sporadic amyotrophic lateral sclerosis

Biochimica et Biophysica Acta 1762 (2006) 956 – 972 www.elsevier.com/locate/bbadis

Review

Genetics of familial and sporadic amyotrophic lateral sclerosis Francois Gros-Louis, Claudia Gaspar, Guy A. Rouleau ⁎ Center for the Study of Brain Diseases, CHUM Research Center, Notre Dame Hospital, J.A. de Sève Pavillion, Room Y-3633, 1560, Sherbrooke Street East, Montreal, QC, Canada H2L 4M1 Received 21 November 2005; received in revised form 12 January 2006; accepted 17 January 2006 Available online 10 February 2006

Abstract Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) are a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade, identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of total cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. This review provides an overview of the genetics of both familial and sporadic forms of ALS. © 2006 Elsevier B.V. All rights reserved. Keywords: Amyotrophic lateral sclerosis; Genetic; FALS; SALS

1. Introduction Amyotrophic lateral sclerosis (ALS) is the most common adult onset neurodegenerative disorder characterized by the death of large motor neurons in the cerebral cortex and spinal cord [1]. Dysfunction and death of these cell populations lead to progressive muscle weakness, atrophy and, ultimately, paralysis and death within 3 to 5 years after disease onset [2]. The disease occurs in sporadic and familial forms, with an estimated incidence of between 0.4 and 1.8 per 100,000, which is quite uniform throughout the world, with the exception of several high incidence foci on the Pacific island of Guam and on the Kii peninsula of Japan. Thus, the life-long risk to develop ALS, considering a 70-year-old life expectancy, is approximately 1 in 2000. Though most cases of ALS are sporadic, 10% of cases have affected relatives, some with clear Mendelian inheritance and high penetrance [2]. Inheritance in familial ALS (FALS) is usually autosomal dominant, but some autosomal recessive pedigrees have been described [3–8]. To date, mutations in only one gene, called Cu/Zn superoxide dismutase (SOD1), lead to classical dominantly inherited ALS, accounting for about 10– ⁎ Corresponding author. Tel.: +1 514 890 8000x24699; fax: +1 514 412 7602. E-mail address: [email protected] (G.A. Rouleau). 0925-4439/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2006.01.004

15% of FALS cases [9]. Cognitive impairment and dementia also coexist with ALS in approximately 3–5% of the cases [10]. The mechanism whereby mutant SOD1 causes specific degeneration of motor neurons remains unclear. The identification of other genes responsible for the disease and the understanding of the molecular pathways involved will bring some new insights into the mechanisms of disease pathogenesis, and will elucidate the underlying mechanism for specific motor neuron degeneration observed in ALS. The focus of this review is on the genetic epidemiology of ALS with a brief discussion on common molecular pathways underlying different motor neuron disorders. 2. Familial ALS To date, eight FALS loci and six ALS related genes have been identified by genetic analysis, through linkage studies and positional cloning (Table 1). Both autosomal dominant and autosomal recessive forms occur. Unfortunately, only one of these genes, named SOD1, leads to a classical adult onset form of ALS. Despite intensive research efforts, the mapping and the identification of genes responsible for classical form of FALS has met with limited success. This difficulty arises in part because large families with sufficient statistical power for

F. Gros-Louis et al. / Biochimica et Biophysica Acta 1762 (2006) 956–972 Table 1 Reported FALS/MND loci FALS/MND loci (OMIM)

Gene (OMIM)

Adult onset dominant typical ALS ALS1a (105400) SOD1 (147450) ALS3 (606640) ALS6 (608030) ALS7 (608631) Adult onset dominant atypical ALS ALS with frontotemporal dementia (105550) ALS with dementia/ MAPT parkinsonism (157140) (600274) Progressive LMN DCTN1 disease (607641) (601143) ALS8 (608627) VAPB (605704) Juvenile onset dominant ALS ALS4 (602433) SETX (608465) Juvenile onset recessive ALS ALS2 (205100) ALS2 (606352) ALS5 (602099)

Chromosomal location

References

21q22,1

[11,12]

18q21 16q12 20ptel-p13

[54] [61–63] [63]

9q21–q22

[73]

17q21.1

[77]

2p13

[88]

20q13.3

[64,65]

9q34

[55,57]

2q33

[6,8,40]

15q15.1–q21.1

[7]

ALS: amyotrophic lateral sclerosis. LMN: lower motor neuron. MND: motor neuron disease. a Note that both dominant and recessive linked-SOD1 mutations have been reported.

linkage analysis are hard to come by due to the late onset and age-dependant penetrance of the disease, and the relative short survival time of affected ALS patients. While the study of SOD1 has led to great advances in understanding the molecular mechanisms and underlying pathogenesis of this disease, identifying mutations in other genes in ALS patients will be of significant impact in the field. Because familial and sporadic forms of ALS are clinically and pathologically similar, understanding the familial form will illuminate possible epidemiological and pathophysiological mechanisms in sporadic ALS. 2.1. ALS1 (OMIM: 105400) The mapping of ALS1 was first reported in 1991 with linkage to chromosome 21 [11]. In 1993, eleven different missense mutations in the SOD1 gene were identified, confirming it as the causative gene [12]. The SOD1 gene is located on chromosome 21q22.1, spans about 9.3-kilobases (kb) of genomic DNA, comprises five exons and encodes for a 153-amino acid long protein of 16 kiloDalton (kDa). Mutations in the SOD1 gene, now identified in all exons of the gene, are responsible for approximately 15 to 20% of FALS, representing only 1–2% of all patients with ALS [9,12]. The clinical features of SOD1-linked ALS appear to be indistinguishable from ALS

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without SOD1 mutations, although in the former the disease has a slight tendency to begin in the limbs rather than the bulbar region [13]. SOD1 had been intensively investigated prior to its association with FALS due to its biological importance as an antioxidant. It is highly conserved through evolution and is expressed in all cells in eukaryotes. SOD1 is an abundant protein constituting approximately 1% of total cytosolic protein. Three different superoxide dismutases are encoded in the human genome: Cu/Zn SOD (SOD1), Mn SOD (SOD2) and extracellular SOD (SOD3). Together, they are one of the several types of enzymes in a biochemical pathway that scavenges free radical oxygen (O2–) produced by mitochondrial respiration and other biological processes. All these metalloenzymes contain a redox-sensitive transition metal within their active site. They dismutate superoxide to hydrogen peroxide (H2O2), which is then converted to water by either catalase or glutathione peroxydase. In the presence of iron, hydrogen peroxide can S generate hydroxyl radical ( OH), a particularly devastating free radical species. 2.1.1. Brief overview of SOD1 mutations Different SOD1 mutations cause distinct phenotypes that differ with respect to penetrance, age of onset, disease progression, survival and clinical manifestations. All SOD1 mutations are dominant, except for the substitution of alanine for aspartate at position 90 (D90A), which can be either recessive or dominant [14]. An ALS family with affected individuals carrying a single copy of the SOD1 D90A recessive mutation and also a copy of a novel, D96N mutation have been also reported [15]. This is the first description of compound heterozygosity in ALS, and also suggests that D96N may be another recessive mutation. To date, over one hundred and twenty-two different SOD1 mutations have been reported, including one hundred and fifteen amino acid substitutions, three insertions and four deletions (http://www.alsod.org). Most of the individual mutations result in substitution of one single amino acid. Such substitutions have been identified in seventyfour different codons and represent almost half of the one hundred and fifty-three amino acid residues of the wild-type Cu/Zn SOD protein. An epidemiological study of the SOD1 mutations in FALS established a number of interesting facts [16]: (1) mutations in SOD1 are highly specific to FALS as such mutations were not detected in over two hundred normal individuals, nor in nearly one hundred patients with Parkinsonism or in patients with other neurological disorders; (2) mutations are detected in only 23% of ALS families, suggesting that additional gene defects may be responsible for ALS; (3) the A4V mutation is the most commonly detected of all SOD1 mutations in familial ALS, and give raise to the most aggressive form of ALS, with reduced survival time after onset (i.e., 1.2 years as compared to 2.5 years for all other familial ALS patients) [17]. In contrast, the H46R mutation located within the copper binding domain leads to an average life expectancy of 18 years after disease onset [18,19]. It is also interesting to note that the reported H48Q mutation, which is adjacent to the H46R mutation, leads to a severe form of ALS with rapid progression [20]. There are also considerable

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variations in disease phenotype among and within SOD1-linked families, including age of onset and rate of disease progression. Usually, the mean age of onset is slightly earlier in SOD1-linked FALS (46.9 years) compared to non-SOD1 patients (50.5 years), and the mean age of onset can also vary among different SOD1 mutations [16]. It is interesting to note that SOD1 mutations that are associated with earlier age of onset, such as G37R and L38V, are different from those associated with a more severe phenotype, such as A4V, suggesting that SOD1 enzyme properties that modulate the timing of disease onset differ from those involved in the rate of disease progression [16]. Therefore, it is apparent that the clinical phenotype must be modified by other genetic and/or environmental factors. Keeping this in mind, haplotype analysis has demonstrated that SOD1 D90A linked-FALS arose from a single founder and interestingly, a cis-acting element falling within the regulatory region of SOD1 and modifying the recessive haplotype has been suggested [21]. Recently, another study of A4V mutation carriers identified a small common haplotype surrounding the SOD1 locus, suggesting again a founder effect, which may partly explain the high prevalence of this mutation in North America [22]. This finding also leads to the hypothesis that a genetic variant within the haplotypic region might be responsible for the accelerated course of the disease progression seen in A4V cases. Unfortunately, DNA sequencing of four candidate genes within the reported region failed to identify any genetic modifiers [23]. 2.1.2. Mutant SOD1 animal models Overexpression of either G37R, G85R, G86R, G93A, H46R/ H48Q or H46R/H48Q/H63G/H120G mutant SOD1 protein in mice leads to a neurodegenerative disease that is quite similar to the human illness [24–29]. Transgenic rats overexpressing G93A or H46R mutant SOD1, also develop an ALS-like phenotype [30,31]. Each model of ALS is phenotypically consistent with a given specific mutation, and they vary in their age at onset, disease progression, and particular histopathological features, mimicking the diversity of phenotypes observed in human ALS. Furthermore, the variable penetrance and age at onset caused by SOD1 mutations can be also be mimicked in transgenic mouse models of ALS by varying the mouse strain on which a mutation is carried [32]. This background strain effect suggests an existence of strong modifying genetic factors in ALS. The initial description of SOD1 gene mutations in familial ALS led to the hypothesis that the disease was caused by altered free radical scavenging, resulting from compromised enzymatic activity due to the loss of Cu/Zn function [17]. This loss of function hypothesis was further disproved as SOD1 knock out mice, in which the murine Sod1 gene was disrupted, do not have motor neuron disease [33]. Moreover, as mentioned, overexpression of mutant SOD1 protein leads to an ALS-like phenotype in mice. A toxic gain of function rather than a loss of function of mutant SOD1 gene is also indicated by the finding that wild-type human SOD1 gene, expressed at similar protein levels, does not cause disease, and indeed is neuroprotective in a variety of assays of oxidative stress [34]. Proposed pathogenetic

mechanisms include oxidative stress, glutamate excitotoxicity, neurofilament disorganization, copper toxicity and apoptotic cell death [35]. However, the mechanism through which mutant SOD1 exerts toxicity and results in selective motor neuron death remains uncertain. The use of mouse models has been of particular importance in studying the pathogenesis of amyotrophic lateral sclerosis. All published mouse models have used the endogenous murine Sod1 promoter that results in high levels of expression of the mutant transgene in all tissues. Although these models implicate mutant SOD1 in the development of motor neuron degeneration, many questions regarding the mechanism of pathogenesis remain unanswered. One of the central mysteries in ALS research is why a ubiquitously expressed gene such as SOD1 causes selective devastation to motor neurons in the absence of pathology in other tissues. In an attempt to address this issue, a study conducted in our lab showed that neuron-specific expression does not cause motor neuron cell death, in contrast to observations in transgenic lines overexpressing FALS-associated SOD1 mutations in a constitutive manner [36]. One possible explanation is that expression of the mutant protein in motor neurons may not be sufficient to lead to the development of a neurodegenerative disease in mice, suggesting that mutant SOD1 expression in other cells may be necessary for the development of the disease. This finding was later confirmed by other groups, where specific expression of mutant SOD1 in either neurons [37] or in astrocytes [38] does not lead to motor neuron degeneration in mice. Furthermore, study of chimeric mice, created from mixtures of normal and mutant SOD1expressing cells, showed that motor neuron toxicity requires damage from mutant SOD1 acting within non-neuronal cells, and that motor neurons expressing only wild-type SOD1 develop some aspects of ALS pathology [39]. Most importantly, they have shown that motor neurons containing mutant SOD1 survived longer when surrounded by cells expressing wildtype SOD1, further suggesting that toxicity of SOD1 mutations is not cell autonomous. This alteration of mutant cells by surrounding wildtype cells bodes well for the future of stem cell therapy. Thus, the ALS-like pathology seen in the chimeras but not in the mice with mutant SOD1 overexpression in neurons or astrocytes alone suggests that expression of mutant SOD1 in both cell types is necessary to initiate the disease process. 2.2. ALS2 (OMIM: 205100) The initial description of the rare juvenile-onset recessive ALS2 locus on chromosome 2 was published in 1994 [40]. A positional cloning approach, primarily in families of Arabic origin with a rare juvenile-onset recessive form of the disease, led to the identification of the ALS2 gene 7 years later [6,8]. These families displayed a juvenile onset (age 3 to 23 years) of progressive spasticity of the limbs, facial and pharyngeal muscles. The mutation detected in this family was a single basepair deletion in a novel gene, predicted to result in a frameshift mutation leading to a premature stop codon and truncated protein. Mutations in ALS2 account for different but relatively

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similar neurodegenerative disorders of motor neurons. To date, there are ten reported mutations in the ALS2 gene leading to either ALS, where both upper/lower motor neurons are affected, or to primary lateral sclerosis (PLS), or infantile onset ascending hereditary spastic paraplegia (IAHSP) where only upper motor neurons are affected [3–6,8]. The ALS2 gene encodes for alsin, a protein with multiple motifs homologous to guanine–nucleotide exchange factors. The protein contains similarity to three domains: an amino-terminal region that shares homology to RCC1 (regulator of chromatin condensation), a Pleckstrin-DB1 centrally located domain and a carboxyl-terminal VPS9 domain. These domains harbor characteristics of various guanine exchange factors (GEFs). The protein also contains a motif called MORN (Membrane Occupation and Recognition Nexus) located between the Pleckstrin and VPS9 domains. MORN motifs are not fully characterized and they are found in a number of proteins of unknown function. Alsin has been shown to function as a GEF for Ran, Rho and Rab GTPases [41]. It has also been shown that alsin binds specifically to small GTPase Rab5 and functions as a GEF for Rab5 through the VPS9 domain, suggesting that alsin may be involved in the organization of the actin cytoskeleton and vesicle trafficking [42,43]. In addition, alsin can also interact specifically with Rac1, a small Rho GTPase [44,45]. Interestingly, alsin can also binds specifically to different mutant variants of the SOD1 protein through its RhoGEF–Pleckstrin domain [46]. Further investigation of this physical interaction between alsin and SOD1 may help understand the pathogenesis underlying ALS and other motor neuron diseases. ALS2 comprises thirty-three exons spanning 80 kb of genomic human DNA. This gene is predicted to encode a 184-

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kDa protein consisting of 1657 amino acids. ALS2 mRNA can be alternatively spliced to produce alsin and another shorter transcript of about 2.6 kb (396 amino acid long) [6,8]. This short variant is produced by alternate splicing at the 5′ donor site after exon 4, resulting in a premature termination of the transcript after twenty-five amino acid residues in intron 4. However, the existence of an endogenous functional short form of alsin has been questioned [47]. 2.2.1. ALS2 reported mutations Eight out of ten reported mutations in the ALS2 gene are deleterious mutation (Table 2) [4–6,8,48]. One nonsense mutation and one splice site mutation have also been reported [3,4]. All reported mutations lead to premature termination of the transcript and a truncated protein. All affected patients are homozygous and all parents and unaffected sibs are heterozygous for one of these reported mutations. The pattern of inheritance and the nature of the mutations identified in this gene suggest that motor neuron degeneration seen in ALS2 patients results from a loss of function. A common feature of all reported mutations is the loss of the carboxy-terminal VPS9 domain, suggesting that loss of VPS9-associated GEF function results in a deficit in intracellular cell trafficking. Many other variations have been found in ALS2, but each variant identified was also present in control subjects, suggesting that mutations in ALS2 are not a common cause of FALS and SALS [49–51]. As mentioned, mutations in this gene could also cause other motor neuron diseases such as ALS, PLS and IAHSP. It was first hypothesized that mutations affecting both transcripts could lead to ALS, the most severe form of the disease, while mutations affecting only the long isoform could cause milder phenotypes, such as PLS and IAHSP. However, this theory was

Table 2 Reported ALS2 mutations Variants a

Previous name

Exon Nb

Alsin isoforms

Disease (OMIM)

Origin

Variant type

Effect

Ref.

138delA

261delAT

Exon 3

Short/Long

Tunesian

1-bp deletion at codon 46

553delA

Exon 4

Short/Long

Turkish

1-bp deletion at codon 553

1007–1008delTA

1130delAT

Exon 4

Short/Long

Italian

2-bp deletion at codon 336

1425–1426delAG

1425delAG

Exon 5

Long

Kuwaiti

2-bp deletion at codon 475

1470 GNT

1470 GNT

Exon 6

Long

French

1867–1868delCT

1867delCT

Exon 9

Long

Saudi

2537–2538delAT

2660delAT

Exon 13

Long

Juvenile PLS (606353) IAHSP (607225)

CAG-acceptor splice site mutation 2-bp deletion at codon 623

Italian

2-bp deletion at codon 846

2292 CNT

3115 CNT

Exon 18

Long

IAHSP (607225)

Nonsense C to T mutation

3619delA

3742delA

Exon 23

Long

IAHSP (607225)

Buchari Jewish Algerian

1-bp deletion at codon 1207

4721delT

4844delT

Exon 32

Long

IAHSP (607225)

Pakistani

1-bp deletion at codon 1574

Premature stop at codon 50 Premature stop at codon 189 Premature stop at codon 341 Premature stop at codon 497 10-bp deletion in the transcript Premature stop at codon 646 Premature stop at codon 853 Premature stop at codon 998 Premature stop at codon 1208 Premature stop at codon 1618

[6,8]

553delA

Juvenile ALS (205100) Juvenile ALS (205100) IAHSP (607225) Juvenile PLS (606353) IAHSP (607225)

[48] [4] [6] [4] [8] [4] [3] [4] [5]

ALS: amyotrophic lateral sclerosis. PLS: primary lateral sclerosis. IAHSP: infantile ascending hereditary spastic paraplegia. a Variant were renamed according to the published guidelines (Antonarakis SE, 1998). The numbers refer to the position in the ALS2 messenger RNA sequence NM_020919.2 and nucleotide “A” from the ATG initiation codon is referred as 1.

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dismissed as no obvious genotype–phenotype correlation was found among all reported mutations. 2.2.2. Alsin knockout mouse Two different groups have reported the generation of an alsin knockout mouse [52,53]. However, no major motor deficits consistent with ALS or other motor neuron diseases were present in these models. Even though ALS2 knockout mice lack obvious developmental abnormalities, primary cultured neurons derived from these mice are more susceptible to oxidative stress when compared with wild-type controls [52]. These findings suggest that loss of ALS2 function is insufficient to cause major motor deficits in mouse, but predisposes neurons to oxidative stress. 2.3. ALS3 (OMIM: 606640) A genome-wide screen of a large pedigree with autosomal dominant adult-onset ALS yielded evidence for linkage to chromosome 18q21 with a maximum lod score of 4.5 [54]. This large European family with at least twenty affected members has no mutations in the SOD1 gene. This suggests that the ALS3 locus is thus a genetically distinct form of FALS and it is the first reported adult-onset dominant ALS locus since ALS1. Clinical presentation of affected family members is pretty uniform with typical ALS features with upper and lower motor neuron signs and with progressive weakness involving all four limbs. The mean age at onset is 45 years and the mean duration of the disease is 5 years. The reported 7.5-centiMorgan (cM), 8-Megabase (Mb) region is flanked by markers D18S846 and D18S1109. The candidate region contains around 30 genes including two very promising candidate genes in terms of biological function. Unfortunately, direct sequencing of these two candidate genes (TXNL and FECH) did not reveal any causing mutation (data not published). 2.4. ALS4 (OMIM: 602433) A study of an 11-generation pedigree with a chronic and slowly progressive rare autosomal dominant form of juvenile ALS established linkage to chromosome 9q34 with a maximum lod score of 18.8 [55]. The region lies between markers D9S1831 and D9S164 and defines an interval of 5-cM. The strong genetic evidence combined with the absence of SOD1 mutations suggested that this locus is genetically distinct from previously mapped familial ALS syndromes. Further analysis on this pedigree refined the position of the ALS4 locus to a 0.5Mb interval [56]. More recently, different missense mutations in the senataxin gene (SETX) were found in three unrelated families from the United States, Belgium and Austria with a subtype of dominant ALS [57]. The SETX gene comprises twenty-six exons spanning over 91-kb of genomic DNA. The predicted 302.8-kDa protein is 2,677-amino acids long and contains a C-terminal classical 7-motif domain found in the superfamily 1 of DNA/RNA helicases. This gene also shares strong homology to human RENT1 and IGHMBP2, two genes known to have roles in RNA processing. Interestingly,

mutations in IGHMBP2 are linked to spinal muscular atrophy, a motor neuron disease characterized by the degeneration of lower motor neurons [58]. 2.4.1. SETX mutations Different SETX mutations causing distinct phenotypes have been reported. It appears that heterozygous dominant mutations within SETX lead to the described form of ALS4, and loss of function recessive mutations cause an unrelated disorder called ataxia-oculomotor apraxia type 2 (AOA2: OMIM 606002). Ataxia-oculomotor apraxia (AOA) is a genetically heterogeneous group of autosomal recessive disorders characterized by cerebellar ataxia/atrophy, oculomotor apraxia, late peripheral neuropathy, immunodeficiency and slow progression leading to severe motor handicap. Three distinct heterozygous missense mutations in this gene, L389S, R2136H and T3I, have been linked to ALS [57], while homozygous deletions including missense, nonsense and deleterious mutations have been associated with AOA2 [59,60]. SETX mutations lead to two phenotypically different disorders which have distinct patterns of inheritance, suggesting that ALS4 is likely to be caused by a gain of function mechanism of the mutated senataxin protein. 2.5. ALS5 (OMIM: 602099) ALS5-linked families show typical ALS features and appear to be present in both North African and European populations. The onset of the disease is juvenile, ranging from 8 to 18 years, with slow progression [7]. In contrast with ALS2 patients, families linked to the ALS5 locus do not present with spasticity of limb, facial, and tongue muscles [7]. Genetic analysis of different kindreds with this type of rare and recessive ALS did not show linkage to markers on chromosome 2q33, suggesting genetic locus heterogeneity and making ALS5 a distinct genetic entity. A genome-wide search in different families from North Africa, Tunisia and Germany with the disorder established linkage on chromosome 15q15.1–q21.1 between D15S146 and D15S123 [7]. 2.6. ALS6 (OMIM: 606030) Three independent studies have reported linkage of unlinked dominant adult-onset typical ALS families to chromosome 6 [61–63]. One group has performed a genome-wide screen in sixteen pedigrees from the United States with familial ALS in which no mutations in the SOD1 gene were found. They identified a novel ALS locus, designated ALS6, in one family, with a candidate region spanning 51-cM (38-Mb) on chromosome 16p12.1–16q21 [63]. A second group performed a genome screen of ALS families from the United Kingdom lacking SOD1 mutations [61]. They identified the same ALS6 locus on chromosome 16q12.1–q12.2 and refined the candidate region to a 14.74-cM genetic interval, which corresponds to a physical distance of 6.6 Mb. Finally, a third group also reported linkage to the same region by performing a genome-wide linkage screen in two large European families with ALS without SOD1 mutations [62]. Their results led to further refinement of

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the candidate interval to a 10.1-cM (4.5-Mb) region. All the reported ALS6-linked families, seemingly from different origins, do not share the same disease haplotype, suggesting that more than one gene within the candidate region or different mutations in the same gene could underlie ALS6. 2.7. ALS7 (OMIM: 608631) A FALS locus on chromosome 20, named ALS7, has also been identified in the same genetic analysis performed in the sixteen U.S. non-SOD1 pedigrees with dominant familial ALS mentioned above [63]. They established linkage in one family and the candidate region spans 6.25 cM (1 Mb) on chromosome 20ptel-p13 with a two-point lod score over 3.0. Two contiguous markers (D20S103 and D20S117) led to a multipoint LOD score maximum value of 3.46 at D20S103. The genetic evidence that ALS7 stands on a distinct genetic entity is not very strong, as similar linkage in other families has not been replicated and this locus has been identified based on genotypes of only two affected individuals, both in the same generation. Identifying other ALS families linked to ALS7 or collecting additional family members of the described pedigree will help to confirm this locus. 2.8. ALS8 (OMIM: 608627) A genome-wide genetic screen of a large Caucasian Brazilian family with autosomal dominant late-onset atypical ALS yielded evidence for linkage to chromosome 20q13.33 with a maximum lod score 6.02 [64]. The reported 2.7-Mb region is flanked by markers D20S430 and D20S173. Further investigation led to the identification of a missense P56S mutation in the VAPB gene segregating within the same described Brazilian family [65]. This large family with twenty-six affected members distributed in three generations showed clinical and neurological signs that may be compatible with ALS. The phenotype is characterized by slow progression of the disease, a clinical onset occurring between 31 and 45 years, lower motor neuron symptoms in all patients, postural tremor, cramps and fasciculations. The presence of atypical signs, such as essential tremor and lower motor neuron degeneration with no upper motor neuron involvement, which is rarely seen in typical ALS, may also be compatible with spinal muscular atrophy. The vesicle-associated membrane protein B gene (VAPB) comprises six exons spanning over 57.7 kb of genomic DNA. It encodes a 33-kDa protein, named VAMP-B or VAP-33, containing two hundred and forty-three residues. The protein encoded by this gene is a membrane protein found in plasma and intracellular vesicle membranes, and can associate with microtubules [66]. VAMP-B protein is found as a homodimer, or as a heterodimer with VAMP-A, another vesicle-associated membrane protein. VAMP-B can also interact with synaptobrevin-1 (VAMP-1) and synaptobrevin-2 (VAMP-2), and may be involved in vesicle trafficking [66,67]. The VAMP-B protein contains three distinct structural domains including an aminoacid terminal MSP domain (Major Sperm Protein), a central region containing an amphipathic helical structure predicted to

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form a coiled/coil protein–protein interaction motif and a hydrophobic carboxy terminus trans-membrane domain [67,68]. 2.8.1. VAPB mutation The P56S missense mutation initially described in a Brazilian family was also found in seven additional kindreds with variable clinical manifestations including late-onset spinal muscular atrophy and late-onset atypical ALS with slow progression [65]. Intra- and inter-familial heterogeneity suggests the presence of modifying or environmental factors that could alter the clinical phenotype. The proline to serine change at codon 56 was generated by a C to T substitution at nucleotide 166 within exon 2 of the VAPB gene. This proline is highly conserved among several species and was not detected in unaffected siblings and in four hundred control chromosomes of normal individuals. To date, there are eight families including over two hundred affected individuals bearing the P56S mutation. Seven of these families are from Portuguese origin and one is from African origin. Haplotype analysis showed a common founder for all families regardless of origin [69]. It is unlikely that phenotypic variability between patients can be explain by a cis-acting element close to the VAPB gene, as the genetic background around the VAPB gene is common to all affected individuals with the P56S mutation [69]. One patient in one kindred also developed typical ALS, while other affected members had symptoms that are more related to late-onset spinal muscular atrophy. It is possible that this ALS patient could in fact be suffering from sporadic ALS. The ALS symptoms seen in this patient may mask another co-segregating neurological disorder leading to an alternative ALS diagnosis. Indeed, a characteristic muscular atrophy phenotype, called spinal muscular atrophy type Finkel (OMIM: 182980), was described in 1962 in a Portuguese-Brazilian family and an African-Brazilian family [70]. However, it is not excluded that the noticed genetic heterogeneity could be explained by modifier or environmental factors. It would be interesting to see if mutations in the VAPB gene can be associated with typical dominant ALS in other families from different origins. 2.8.2. VAPB animal models There are no mouse models for VAPB, even though the protein is highly conserved in the mouse. However, in drosophila, male mutants die in early larva stage and show severe motor deficits and a severely compromised synaptic microtubule assembly [71]. 2.9. ALS with frontotemporal dementia (OMIM: 105550) Coexistence of frontotemporal dementia (FTD) and ALS was first described in 1975 [72]. To study the genetics underlying this condition, a genome-wide screen was performed using two distinct data sets comprising over seven hundred nonSOD1 families with ALS (each with at least two individuals diagnosed as having ALS) [73]. A genetic locus was identified between markers D9S301 and D9S167 on 17-cM region on chromosome 9q21–q22, using families in which individuals develop both ALS and FTD or either ALS or FTD alone. The wide range of clinical features among families suggests that

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other genetic or environmental factors may modulate the phenotype. Families with ALS alone did not link to this locus. It is likely that this new locus represents a distinct genetic entity from the previously reported ALS locus on chromosome 9q34 as the two regions do no overlap with each other, the pattern of inheritance as well as age of onset is different, and the phenotype associated with each locus is clinically distinct. As similar conjoined ALS-FTD phenotype has also been described in a Swedish family without linkage to chromosome 9q21–q22, suggesting genetic heterogeneity for this particular subclass of neurodegenerative disease [74]. , 2.10. ALS with frontotemporal dementia and Parkinson s disease (FTDP) (OMIM: 600274) Motor neuron degeneration can also occasionally occur in patients with Parkinson's disease and frontotemporal dementia. This disease is also called Disinhibition–dementia–parkinsonism–amyotrophy complex (DDPAC) or FTDP17 [75]. The pathologic features distinguish this disease from the ALS– parkinsonism–dementia complex of Guam seen in the peninsula of Japan and from ALS–FTD linked to chromosome 9. Mutations in the microtubule-associated protein tau gene (MAPT) are associated with FTD and Parkinsonism [76,77]. The human MAPT gene is located on chromosome 17q21 and consists of a fourteen coding or partially coding exons [78]. This gene can undergo multiple splicing events and this has led to confusion about the number of MAPT exons. Interestingly, intron 13 is always retained in human MAPT mRNAs, although it is removed in some mouse transcripts by RNA splicing [79]. Rademakers and colleagues favored the definition of fifteen exons: with exon 13, intron 13, and exon 14 being a single exon. The last exon comprises the 3′-untranslated region. Tau is a member of the microtubule-associated protein family, which have the principal function stabilizing microtubules and promoting their assembly by binding to tubulin [80]. In addition, tau is likely to regulate motor proteinmediated transport of vesicles and organelles along the microtubules by modulating their stability [81,82]. 2.10.1. MAPT mutations Various mutations have been identified in the MAPT gene including intronic, splice site and missense mutations [76,77, 83]. Considerable variability in clinical and pathologic presentation of patients with MAPT mutations can be seen. However, not all patients showing ALS symptoms with FTD and Parkinson's disease have MAPT mutations, suggesting again here, as well as with other FALS loci and ALS–FTD, genetic heterogeneity. 2.10.2. MAPT animal model Different transgenic mice models overexpressing different human tau isoforms either ubiquitously or specifically in neurons have been generated [84–87]. These mice acquire age-dependent central nervous system pathology similar to FTDP17 including axonal degeneration in brain and spinal cord, progressive motor disturbance and behavioral impairment.

2.11. Progressive LMN disease, dynactin type (OMIM: 607641) Another linkage to chromosome 2 has been identified in a family with a slowly progressive and rare autosomal dominant form of motor neuron disease without sensory symptoms [88]. Age of onset is in early adulthood and patients develop breathing difficulties due to vocal fold paralysis, progressive facial weakness and muscle atrophy in the hands. Weakness and muscle atrophy in the distal lower extremities were also noted in affected individuals. Some, but not all, clinical features overlap with ALS. A genome-wide screen established linkage to chromosome 2p13 between markers D2S291 and D2S2114, with a maximum lod score of 4.05 [88]. Mutation analysis of a gene called dynactin1 (DCTN1), encoding the largest subunit of the axonal transport protein, showed a missense mutation resulting in an amino acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain. Dynactin is a heteromultimeric protein complex consisting of at least seven different polypeptides that binds to both microtubules and cytoplasmic dynein during vesicle transport [89]. 2.11.1. DCTN1 mutations The DCTN1 gene encodes the largest subunit of dynactin, a macromolecular complex consisting of ten to eleven subunits ranging in size from 22 to 150 kDa. It spans approximately 19.7-kb of genomic DNA and consists of at least thirty-two exons. A single-basepair change in the DCTN1 gene, resulting in an amino acid substitution of serine for glycine at position 59, was first identified in all affected individuals presenting with progressive LMN disease [88]. The G59S substitution occurred in the highly conserved CAP-Gly motif of the p150 subunit of dynactin, a domain that binds directly to microtubules. Three heterozygous missense mutations of the DCTN1 gene were also detected in two other families [90]. The authors distinguished the phenotype in their patients from the G59S-linked previously reported ones by the presence of upper motor neuron signs and suggested that mutations in the DCTN1 gene may be a susceptibility factor for ALS. 2.11.2. DCTN1 animal models Transgenic mice overexpressing the p150 subunit of dynactin in which disruption of the complex occurs have been found to develop a late onset, progressive motor neuron disease [91]. Dominant negative mutations in the Drosophila melanogaster homolog for DCTN1 produce an abnormal eye formation in heterozygous flies with severe disruption in the organization of the retina and in the retinal axonal projections [92]. An RNAi-based screen in flies targeted against different subunit of the dynactin complex including the p150 subunit showed that dynactin functions locally within the presynaptic arbor to promote synapse stability at the neuromuscular junction [93]. 3. Sporadic ALS The etiology and pathogenesis of amyotrophic lateral sclerosis remain largely unknown. A genetic component is also thought to contribute to the pathogenesis of sporadic ALS,

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which accounts for the majority of ALS cases. However, identification of gene defects in SALS cases has met with limited success so far. Several groups have reported on gene variants and association studies found in individuals with sporadic ALS. These studies linked SALS to particular genetic variants account for a small number of the total cases reflecting a complex pattern of inheritance with very low penetrance, a high degree of heterogeneity and/or the existence of environmental factors predisposing to ALS. With the exception of few familial ALS cases in which other neurodegenerative disorders can simultaneously occur, FALS and SALS are clinically indistinguishable. However, there are some minor interesting differences. The mean age of onset in familial cases (∼46 years), is earlier than those with sporadic ALS (∼56 years) [13]. A 1:1 male to female ratio is observed in FALS while in SALS an unexplained male preponderance of 1.5:1 is reported worldwide, although this ratio tends to decrease and approaches 1:1 after age 70 [94]. 3.1. Superoxide dismutase 1 (SOD1) SOD1 mutations have been shown to be associated with 10– 15% of FALS. Some reports have also identified SOD1 mutations in apparent SALS patients. The incidence of SOD1 mutations in SALS patients varies in different surveys and it ranges from 1 to 7% [95–99]. All described SOD1-linked SALS mutations do not have specific phenotypic characteristics that distinguish them from other non-linked SALS patients. The mean age at onset in mutant SOD1-linked SALS patients is 41.4 years, which is about 10 years below the mean age at onset described in patients with sporadic ALS without SOD1 mutations [95]. However, further studies are needed to support this finding. The most frequent SOD1 mutation detected in SALS cases worldwide is the I113T mutation. It is unclear whether or not the SOD1-linked SALS patients are truly sporadic, as incomplete disease penetrance has been associated with different described SOD1 mutations including the I113T [100]. Moreover, some of the reported mutations in SALS have also been associated with FALS which makes it difficult to distinguish sporadic cases from familial ones at the genetic level [101]. 3.2. Dynactin (DCTN1) As mentioned earlier, mutations in the p150 subunit of the DCTN1 gene lead to progressive lower motor neuron disease with atypical ALS features in some unrelated families [88,90]. A T1249I mutation in exon 13 of this gene has also been found to be associated with sporadic ALS [90]. However, such as in sporadic SOD1-linked SALS, an incomplete penetrance of this mutation in conjunction with other predisposing genetic factors has to be taken into consideration. So, the apparently sporadic patient bearing a mutation in this gene might have been misdiagnosed and could in fact be a familial case. 3.3. Neurofilaments Abnormal accumulation of neurofilaments is a pathological feature of several neurodegenerative diseases, including ALS,

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Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Neurofilaments, the major type of intermediate neurofilaments expressed in adult neurons, are formed by the coassembly of three type IV intermediate neurofilament proteins, the neurofilament light (NF-L), neurofilament medium (NF-M) and neurofilament heavy (NF-H) subunits. There is also growing evidence for potential peripherin involvement, a type III intermediate neurofilament, in human disease. Currently, it remains unclear to what extent intermediate neurofilamant abnormalities contribute to ALS pathogenesis. It has been postulated that defects in axonal transport may be an underlying common pathway that leads to the degeneration of motor neurons in ALS patients and transgenic SOD1 mouse models. Uniquely characterized by their length, motor neurons of the brain and spinal cord can reach a meter in length in an adult human. The significant length of these axons makes active axonal transport, both anterograde and retrograde, essential for normal cellular function. 3.3.1. Mutations in neurofilamant subunits (NEFH, NEFM and NEFL) Codon deletions or insertions in the KSP phosphorylation domain of NEFH have been detected in a small number of sporadic cases of ALS (approximately 1% of total cases) [102– 104]. However, even if the functional consequences of these NEFH phosphorylation variants are unknown, these variants are viewed as risk factors for the disease. Missense mutations and a 3-bp in-frame deletion in the NEFL gene subunit have also been also reported in patients with Charcot–Marie–Tooth type 2 neurodegeneration [105,106]. Genetic variations within NEFM have also been associated with Parkinson's disease. 3.3.2. Peripherin (PRPH) Peripherin is a type III intermediate neurofilamant protein expressed predominantly in the peripheral nervous system, with low levels detectable in spinal motor neurons [107,108]. Upregulation of peripherin mRNA has recently been observed in a familial ALS case [109]. Under certain conditions, including in transgenic mice expressing a mutant form of SOD1 linked to ALS, the murine Prph gene was found to produce different particular Prph splicing species, which are assembly-incompetent and toxic when expressed in cultured neuronal cells [109]. The recent identification of a frameshift mutation in the peripherin gene of a patient with SALS strongly argues in favor of neurofilament involvement in ALS [110]. Of particular interest is that the detected PRPH frameshift deletion mutant expression leads to the disruption of neurofilament assembly in cultured cells. 3.3.3. Neurofilament animal models Several transgenic mouse lines and knockout mice implicating different neurofilament subunits have been extensively studied over the past years (for review see, [111]). The study of the phenotype in the neurofilament overexpressor mouse models led to some interesting findings, including neurodegeneration, abnormal accumulation of intermediate neurofilament, which is reminiscent of what was found in ALS patients and

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SOD1 transgenic mice. Significant loss of motor axons has been detected in NEFL null mice and double NEFM/NEFH knockout [97,112]. Overexpression of peripherin in NEFL null background mice induces motor neuron disease [113], and provoke death when expressed in cultured motor neurons [114]. The precise mechanism by which accumulation of intermediate neurofilament leads to neurodegenerative disorders is not fully understood. It has been proposed that the severe loss of motor neurons seen in these transgenic mouse models might be caused by the disruption of axonal transport. 3.4. Vascular endothelial cell growth factor (VEGF) VEGF, first discovered as a tumor-secreted protein that promotes the formation of new blood vessels and vascular permeability, is an important angiogenesis factor [115]. The first implication of VEGF in ALS came with the description of a mouse model where deletion of the hypoxia-response element in the Vegf promoter leads to muscle weakness, atrophy, and death due to degeneration of lower motor neurons [116]. The precise mechanism through which reduced VEGF levels result in an ALS-like phenotype in these mice is not clear: both chronic neuronal ischemia and loss of a direct trophic effect of VEGF on motor neurons have been proposed [116,117]. Interestingly, intercross of the VEGF mutant mice with transgenic mice overexpressing mutant G93A-SOD1 led to a more severe phenotype with earlier age of onset [118]. This finding may indicate that VEGF is a modifier of motoneuron degeneration in SOD1-linked ALS mouse. In a meta-analysis of over one thousand and nine hundred individuals, three polymorphisms in the VEGF promoter/leader sequence have been associated with an overall 1.8-fold increase risk of developing ALS [118]. Further investigations of VEGF promoter elements have confirmed these results in one other population [119] but failed to be reproduced it in others [120,121]. 3.5. Survival motor neuron (SMN) The search for a link between spinal muscular atrophy (SMA) and ALS has been extensively pursued in many epidemiological studies. SMA is caused by homozygous mutations in the survival motor neuron 1 gene (SMN1) [122]. The SMN1 gene maps to chromosome 5q13.3 in a 0.5-Mb duplicated region. So, two copies of SMN exist, the telomeric copy called SMN1 and the centromeric copy called SMN2. These highly homologous genes contain nine exons and encode an identical two hundred and ninety-four amino acid long protein. A one nucleotide difference within the full-length cDNA sequence of exon 7 leads to alternative splicing events, and distinguishes SMN1 from SMN2 [123,124]. SMN2 gene deletions are not associated with SMA but may represent possible risk factors for lower motor neuron disease [125]. Several conflicting studies have been conducted to investigate whether alterations of SMN1 or SMN2 are possible genetic risk factors for ALS. An overrepresentation of SMN2 gene deletions were found in 16% of patients with sporadic ALS, compared to only 4% in normal non-affected individuals [126]. In contrast, another study reported no

differences in SMN2 copy number and surprisingly showed an abnormal SMN1 copy number in sporadic ALS patients [127]. A recent study showed a decrease in the copy numbers of both SMN1 and SMN2 associated with increase susceptibility to develop ALS [128]. These conflicting data may result from the use of moderate size populations and the use of inappropriate control populations (in which ethnic origin, age and gender matching would be critical to find significant statistical associations). Interestingly, genetic mapping of a modifying locus that could delay disease progression in SOD1 mutant mice showed strong genetic evidence for a locus on chromosome 13 comprising the Smn gene and the neuronal apoptosis inhibitory protein (Naip) gene [32]. Three different groups found, however, that NAIP gene mutations are specific for spinal muscular atrophy and do not predispose to sporadic ALS [129–131]. The SMA critical region contains several genes with duplications that could be important for motor neuron metabolism. Positional cloning and sequencing of this region could, therefore, reveal additional polymorphisms relevant to ALS. 3.5.1. SMN animal models The establishment of a mouse model for human SMA in which the Smn1 gene has been knocked-out leads to developmental arrest and death during peri-implantation stage [132]. However, transgenic mice expressing the human SMN2 gene in the Smn−/− background showed pathological characteristics and variable phenotypic changes mimicking those found in human SMA [132]. In addition, a strong correlation between SMN2 copy number and severity of the phenotype were noted [133]. The SMA-like mice also exhibited a massive accumulation of neurofilaments, which is reminiscent of mouse and human SOD1-linked FALS [134]. 3.6. Glutamate excitotoxicity Glutamate is the major excitatory neurotransmitter in the brain and is suspected to play a role in the etiology of ALS. Glutamate is released from presynaptic terminals, is Ca2+dependant and activates specific receptors (AMPA and/or GluRs) on postsynaptic neurons by diffusing across the synaptic cleft. Repetitive motor neuron firing can lead to excitotoxic death if glutamate release is not cleared properly at the postsynaptic dendrites of upper and lower motor neurons. Glutamate transporters are key components of the mechanism necessary to clear glutamate from the synaptic cleft and prevent neurotoxic effects and neuronal death. There is evidence for glutamate excitotoxicity involvement in ALS, namely changes in glutamate levels in the cerebrospinal fluid of ALS patients [135,136]. Furthermore, the level of EAAT2 (also called GLT-1), the main astroglial glutamate transporter, is found to be severely reduced both in the motor cortex and in the spinal cord from sporadic ALS patients [137]. Abnormal EAAT2 mRNA was subsequently detected in sporadic ALS patients, offering an explanation for the reduction in EAAT2 protein levels [138]. Aberrant EAAT2 mRNA splicing is seen in about 65% of sporadic ALS patients, and this defect might exert a dominant negative effect resulting in the glutamate-mediated motor

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neuron death seen in ALS [138]. However, the presence of aberrant mRNA transcripts of EAAT2 in ALS cases could not be explained by mutations in the EAAT2 gene [139–141]. An abnormal editing of the messenger RNA encoding the GluR2 subunit of glutamate AMPA receptors in the spinal motor neurons of individuals affected by ALS has also been reported and this defect may be a contributing factor to neuronal death in ALS patients [142]. Interestingly, treatment of ALS patients with riluzole, the only drug approved for ALS, blocks glutamate release from presynaptic neurons and has been shown to prolong survival in patients [143]. 3.7. Ciliary neurotrophic factor (CNTF) The protein encoded by the CNTF gene is a polypeptide hormone whose actions appear to be restricted to the nervous system, where it promotes neurotransmitter synthesis and neurite outgrowth in certain neuronal populations, and may also be required for survival of motor neurons in vivo [144]. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency but it is not causally related to neurological disease [145]. A study in a SOD1-linked family, bearing the SOD1 V148G mutation and showing intra-familial phenotypic variability, revealed a homozygous null mutation in the CNTF gene in one affected individual [146]. This 25-yearold patient bearing both mutations died of ALS eleven months after onset of the disease, while other affected members of the family bearing either the V148G mutation alone or with heterozygous CNTF mutations developed ALS between ages of 43 and 62 years. Crossbreeding between the described G93A-SOD1 transgenic mice and CNTF null mice leads to a characteristic ALS phenotype with earlier age of onset for G93A-SOD1/CNTF−/− mice, when compare to G93A-SOD1 transgenic mice alone [146]. No changes in the disease progression were noted in these double mutant mice and no differences in age of onset nor in disease progression were noticed between G93A-SOD1 mice and G93A-SOD1/CNTF+/− mice. These observations suggest that CNTF may be a modifying factor of SOD1-linked ALS. Of particular interest, about 2% of the general population may carry homozygous CNTF mutations, but several studies showed that these variants are not risk factors for neurological disease, including ALS [145,147–150]. A study using four hundred ALS patients did not find any differences in age of onset, clinical presentation, rate of progression, or disease duration for ALS patients bearing one or two copies of the null allele, excluding CNTF as a major disease modifier in ALS [147]. However, further studies are needed to assess the impact of CNTF as a candidate modifier gene for ALS.

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3.8.1. Apolipoprotein E (APOE) Investigation of the effect of Apolipoprotein E (APOE), a confirmed risk factor for different neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and multiple sclerosis, led to conflicting data regarding the implication of the APOEε4 genotype on the risk of developing ALS [151– 156]. Conflicting data regarding the association of SALS with this particular APOEε4 genotype and phenotypic variations regarding age at onset, site of onset, and duration of the disease have also been reported in many studies [151–156]. 3.8.2. DNA repair enzyme apurinic/apyrimidinic endonuclease (APEX) Defects in DNA repair enzymes have been proposed as underlying mechanisms predisposing to ALS. It was reported that levels of the DNA repair enzyme apurinic/apyrimidinic endonuclease called APEX were reduced in the frontal cortex of patients with sporadic ALS [157]. APEX gene mutations were reported by different groups, but they do not seem to account for a large proportion of ALS cases [158–161]. 3.8.3. Angiogenin (ANG) ANG is located 237-kb downstream of APEX and is a potent mediator of new blood vessel formation, similar to VEGF which has been found to increase the risk of developing ALS [118]. Starting from the hypothesis that VEGF pathway might be also involved in ALS and keeping in mind that the described association with polymorphisms within the APEX gene might not be linked to APEX itself but to a gene in close proximity, a group has identified another more robust allelic association with the ANG gene [158]. 3.8.3.1. Hemochromatosis gene (HFE). Increased oxidative stress is likely to play a role in mediating the different pathogenic mechanisms leading to motor neuron death in SOD1linked and unlinked ALS. Several studies have found evidence of elevated iron levels in ALS-affected tissue. The misregulation of iron, a detrimental catalyst in biological free radical oxidations, can amplify the formation of reactive oxygen species by driving the Fenton reaction or through other nonFenton mechanisms [162]. Therefore, processes that result in iron accumulation may confer susceptibility to neurodegenerative diseases such as ALS. Mutations in the HFE gene are associated with an iron overload disease known as hemochromatosis [163], and rare polymorphisms in this gene have also been reported to be associated with sporadic ALS [164–166]. Further studies are needed to confirm this association and to determine the relationship between variations within this gene and ALS.

3.8. Other candidate genes 3.9. Other chromosome rearrangements Several studies showed either positive or negative association with potential candidate genes in different cohorts of sporadic ALS patients. The use of an inappropriate sample size or inappropriate controls regarding ethnicity, age and gender may explain the lack of reproducibility in all these seemingly statistically underpowered studies.

In the general population, the prevalence of balanced chromosomal abnormalities is low, but an increased rate of constitutional chromosomal rearrangements in apparently sporadic ALS was reported in various studies [167,168]. Four constitutional translocations in sporadic ALS patients

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include: t(7;13)(p22;q21), t(4;19)(p22;p13.1), t(4;20)(p15.3; q11.2), and t(18;21)(q23;q22). Two pericentric inversions, inv (X)(p11.2q21.3) and inv(12)(p11q13) have also been identified. One of these translocations involves chromosomes 18 and 21, two chromosomes where FALS loci have been previously described. The chromosomal breakpoints on chromosome 21 localize to the 21q22 region, which harbors the ALS-associated SOD1 gene, but a physical involvement of the SOD1 gene has been excluded. This suggests the presence of another genetic susceptibility locus [169]. Considering the relatively small size of the different studied populations, further studies conducted in larger ALS populations are needed to confirm these results. It would be of great interest to know if those chromosomal rearrangements disrupt or define sets of functionally significant genes and how such genetic rearrangements could lead to ALS. 4. Environmental factors There is some evidence of gene-to-gene interaction or gene and/or environmental factors in ALS. For instance, Parkinsonism with progressive dementia complex (PDC) is recognized as a clinical variant of a form of ALS that occurs to a high incidence among the Chamorro people of the island of Guam. The illness has dramatically declined in the last two decades, but incident cases of ALS, Parkinsonism and dementia alone or together, with mixed manifestations, are still being diagnosed albeit at much lower incidence. The epidemiological evidence for a major environmental determinant in the causation of ALS/ PDC is very strong, although the possibility of the existence of significant genetic determinants of disease phenotypes within families has also been suggested and is under active investigation. The high prevalence of a specific polymorphism in the MAPT gene in the ALS Guam population implicates this gene as a potential modifying factor [170]. The major environmental hypotheses associated with the disease on the island of Guam are toxicity owing to ingestion of cycad-based foods, an unknown slow viral agent, or an imbalance in water mineral content causing a parathyroid disorder that affects calcium, magnesium and aluminium metabolism [171,172]. Interestingly, a specific gene-to-environment interaction between MAPT and cycad toxin has been reported to modulate the MAPT mRNA expression [173]. The theory that a related toxin called β-methylaminoalanine (BMAA), a potent excitotoxin of glutamate receptors found in the cycad fruit, was frequently brought into question due to a relatively low level detection of BMAA in the diet of the Chamorro people of Guam [174]. The cycad hypothesis has recently been revised by a report witch showed that biomagnification leads to an increased accumulation of bioactive neurotoxic BMAA in the Guam ecosystem [175,176]. It has been shown that BMAA can be biomagnified in flying foxes, which were often present in the diet of the Guam people. The biomagnification of BMAA through the Guam ecosystem may explain the higher incidence of ALS-PDC seen among the Chamorro people of Guam. Further investigations are needed to confirm these results and it would be interesting to investigate if flying foxes develop ALS.

Other environmental risk factors, including behavioral and occupational exposures, have been investigated in ALS patients, but no significant specific factor has been consistently related to ALS. Smoking has been proposed as a risk factor in ALS [177,178] but it remains in question [179]. The association of physical activity and ALS has stimulated great interest over the past years, but no consistent links with exercise or trauma have been observed to increase the risk of developing ALS [180,181]. Exposure to pesticides or solvents has also been studied in ALS. Chemicals used in agricultural work could play a possible role of developing ALS [182,183] but, this finding lacks replication by other groups. 5. Discussion Despite extensive research progress in ALS and other motor neuron diseases over the past decade, the mechanism of pathogenesis in ALS is still largely unknown and no effective therapy is yet available. Genetic analysis has identified a primary cause of FALS occurring in about 2% of the total cases. The number of different loci and reported mutations that have been identified in families with FALS make this form of the disease highly heterogeneous. Some mutations in several genes have also been associated with sporadic ALS, accounting for a small percentage of the total cases. An important issue in the study of Mendelian diseases is the phenomenon of genetic heterogeneity, whereby distinct mutations at the same locus or different loci can cause the same, indistinguishable phenotype. A more complex scenario has to be taken into consideration where many different genes, each with allelic variations, contribute to the total variability observed in the trait, with no particular gene having a single large effect. The identification of other genetic variations will have direct implications in ALS research in particular, and motor neuron diseases in general. It thus appears that inherited ALS will show a high degree of genetic heterogeneity, as well as clinical diversity. This has implications for genetic linkage analysis strategies, rendering the conventional approach of establishing linkage with multiple large families exceedingly difficult. However, linkage analysis, association and case control studies have allowed the identification of a number of genetic factors leading or predisposing to ALS. It remains to be determined whether the various ALSrelated genes identified so far define sets of functionally significant, interacting genes. If this is the case, an understanding of the functions of the associated proteins and pathways may provide further insight into the pathogenesis of this disease and ultimately lead to new approaches to treatment. Many conflicting data generated by different groups who have studied different populations around the world have been published. The use of an adequate size population with appropriate control individuals is needed in order to reach enough statistical power and to observe significant results. Homogeneity regarding ethnical origin, age, age of onset, disease duration, site of the first symptoms and gender among a particular population is essential to design a good and robust genetic study. The requirement for larger sample sizes and possibly more sensitive and efficient analytic tools that allow for

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consistent detection across study populations bodes well for the future as non cost-effective genotyping strategies become more and more available. 6. Conclusions It has been over 13 years since the first mutation description in the SOD1 gene in ALS patients. Identification of other major genes that could explain the majority of ALS cases is still a challenge. High genetic heterogeneity and complex interactions between genetic and environmental factors are the main obstacles in the process of finding new ALS genetic determinants. Therefore, ALS should be referred to as a multifactorial complex disease. A common pathway among all identified genes and genetic factors associated with ALS is becoming apparent and involves intracellular cell trafficking and axonal transport. To what extent these related pathways are implicated in ALS remain to be determined. It is interesting to note that genes such as ALS2, VAPB, MAPT, DCTN1, EAAT2, NEFH, PRPH and CNTF, in which mutations have been found in a subset of ALS patients, are all related to intracellular trafficking either via axonal transport, vesicle docking and transport, or microtubule and neurofilament stabilization. Furthermore, this common theme is also seen in other motor neuron diseases and neurodegenerative disorders such as hereditary spastic paraplegia, Parkinson's disease, spinal muscular atrophy and Charcot–Marie–Tooth disease. It is also noteworthy that alternative splicing abnormalities are also involved in different ALS related genes such as ALS2, MAPT, EAAT2, PRPH, GluR2, CNTF, SMN1 and SMN2. Such genetic defects, in combination with other genetic rearrangements and heterogeneity, suggest that an individual phenotype could result from the sum of several contributing gene defects and epigenetic influences which individually do not cause disease, and could explain the difficulties in identifying genes that cause ALS. The identification of other genes associated with motor neuron disease, as well as the determination of genetic and/or environmental factors that predispose to sporadic ALS are critical in the development of therapies for ALS. The generation of other ALS animal models in which the disease can be closely replicated would also be the utmost importance to reach a full understanding of the molecular mechanisms and environmental factors that cause ALS. Acknowledgments This work was supported by the Muscular Dystrophy Association (USA) and the ALS association (USA). G.A.R. and F.G.L. are supported by the Canadian Institutes for Health Research (CIHR). References [1] R. Tandan, W.G. Bradley, Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management, Ann. Neurol. 18 (1985) 271–280.

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