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Introduction
The earliest descriptions of amyotrophic lateral sclerosis
(ALS) come from the 1800s. In 1848, Aran reported 11
cases of weakness, including a 43-year-old man who presented with cramps, focal wasting and paresis of the upper
limbs. The disease became generalized and the patient
died within 2years. One of the patients three sisters and
two of his maternal uncles had died from a similar dis
ease, suggesting that it was inherited.1 In 1873, however,
Charcot reported that ALS was never hereditary, and he
used this principle to delineate ALS from spinal muscular
atrophy.2 The view that ALS is rarely familial has persisted,
but since 1993 the discovery of several genes associated
with both familial ALS (FALS) and sporadic ALS (SALS)
has radically changed our view.
In this Review, we outline the genetic landscape in this
rapidly changing field. We describe what is known about
the genetics of heritable and apparently sporadic ALS,
highlight genotypephenotype correlations, and provide
suggestions for genetic counseling approaches. We point
out the lack of clear distinction between heritable and
apparently sporadic ALS and use this to explore different
models of inheritance.
Institute of
Pharmacology and
Clinical Neuroscience,
Section for Neurology,
Ume University,
SE901 85 Ume,
Sweden and
Department of
Neurology, University of
Ulm, Oberer Eselsberg
45, 89091 Ulm,
Germany
(P.M.Andersen). Kings
College London, MRC
Centre for
Neurodegeneration
Research, Institute of
Psychiatry, 16 De
Crespigny Park, London
SE5 8AF, UK
(A. Al-Chalabi).
Correspondence to:
P.M. Andersen
peter.andersen@
neuro.umu.se
REVIEWS
Key points
Familial amyotrophic lateral sclerosis (ALS) is frequently underdiagnosed,
and apparently sporadic ALS may, in many cases, be familial ALS with reduced
disease penetrance
A few genes are associated with a substantial proportion of ALS cases,
and many others probably contribute to only a few cases
Mutations in 12 genes have been found to cause familial ALS, the most
common being SOD1, followed by FUS and TARDBP
All genes mutated in familial ALS have also been found mutated in patients
diagnosed with sporadic ALS and, besides a lower mean age of onset, no
clinical difference exists between the two groups
No ALS gene has exclusively been associated with an ALS-only motor
phenotype, suggesting that ALS is a multisystem neurodegenerative syndrome
with a propensity for targeting the motor system
Most ALS cases are probably attributable to oligogenic inheritance, perhaps
in combination with environmental factors, but monogenic inheritance with a
mutation private to each individual is also possible
Superoxide dismutase 1
SOD1 is expressed in all cellsmainly in the cytosoland
its only known function is to catalyze the reduction of the
superoxide anion to O2 and H2O2. In the SOD1 gene, five
exons code for 153 evolutionarily conserved amino acids,
which, together with a catalytic Cu+ ion and a stabilizing
Zn2+ ion, form a subunit. Through noncovalent binding,
pairs of these subunits form SOD1 homodimers.
Following linkage analysis, in 1993 an international
consortium reported the identification of 11 missense
mutations in the SOD1 gene in 13 of 18 pedigrees with
high-penetrance dominantly inherited FALS.31 Since then,
166 SOD1 mutations have been reported to be associated
with ALS, and eight silent mutations and nine intronic
variants, presumed to be nonpathogenic, have been found.
Of the 166 disease-associated mutations, 147 are of the
missense type. The remaining 19 mutations are nonsense
and deletion mutations that result in a change in length
of the SOD1 polypeptide.3235 Of particular interest is
the discovery, reported in 2009, of an activated pseudoexon deep inside intron 4 that results in the addition of
seven novel amino acids after exon 4, followed by a stop
codon.33 This cryptic exon cosegregates with disease in a
large FALS pedigree and is presumed to be pathogenic.
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A M YOT R O P H I C L AT E R A L S C L E R O S I S
Table 1 | Established ALS-associated genes as of June 2011
Locus
(chromosome)
Gene
Protein length
(amino acids)
Number of
mutations
Analysis
type (initial)
Modes of
inheritance
Phenotypic
MND variants
Other features*
References
ALS1 (21q22.1)
SOD1
1532
166
Linkage
Dominantcp
Dominanticp
Recessive
Denovo mutation
ALS
PMA
PBP (rare)
BFA (rare)
Cognitive
impairment (rare)
Cerebellar ataxia
Autonomic
dysfunction (rare)
FTD (rare)
Rosen etal.
(1993)31
ALS2 (2q33.2)
ALS2
1,657
19
Linkage
Recessive
Juvenile PLS,
juvenile ALS or
infantile HSP
Unknown
Hadano etal.
(2001)42
ALS3 (18q21)
Not
identified
Unknown
None
Linkage
Dominant
ALS
NA
Hand etal.
(2002)122
ALS4 (9q34)
SETX
2,677
Linkage
Dominant
ALS
AOA2, cerebellar
ataxia, motor
neuropathy
Chen etal.
(2004)43
ALS5 (15q21.1)
SPG11
2,443
12
Linkage
Recessive
Juvenile ALS
NA
Orlacchio
etal.
(2010)123
ALS6 (16q11.2)
FUS
526
42
Linkage
Candidate
Dominantcp
Dominanticp
Denovo
mutations
Recessive
ALS
ALSFTD
Parkinsonism
FTD
Vance etal.
(2009)60
Kwiatkowski
etal.
(2009)61
ALS7 (20p13)
Not
identified
Unknown
None
Linkage
Dominant
ALS
NA
Sapp etal.
(2003)124
ALS8 (20q13.3)
VAPB
99
Linkage
Dominant
ALS, PBP
or PMA
Unknown
Nishimura
etal.
(2004)66
ALS9 (14q11.2)
ANG
147
17
Candidate
Dominantcp
Dominanticp?
ALS
PBP or
ALSFTD
Parkinsonism
Chen etal.
(2010)69
ALS10 (1p36.2)
TARDBP
414
44
Candidate
Linkage
Dominantcp
Dominanticp
Recessive (rare)
ALS
ALSFTD
PSP, PD
FTD
Chorea
Gitcho etal.
(2008)47
Sreedharan
etal.
(2008)48
Kabashi etal.
(2008)49
ALS11 (6q21)
FIG4
907
10
Candidate
gene
Dominant
ALS
PLS
CMT4J
Cognitive
impairment
Chow etal.
(2009)110
ALS12
(10p15p14)
OPTN
577
Homozygosity
mapping
Dominantcp
Recessive
ALS
POAG
van Es etal.
(2009)71
ALS13 (12q24)
ATXN2
1,313
6 (intermediate
length)
Candidate
gene
Dominant
ALS
NA
Elden etal.
(2010)75
*Other features reported in some but not all ALS patients with a particular mutation. Clinical features reported in non-ALS patients with mutations not associated with ALS. Abbreviations:
ALS, amyotrophic lateral sclerosis; AOA2, oculomotor apraxia type2; BFA, benign focal amyotrophy; cp, documented complete penetrance; CMT4J, CharcotMarieTooth disease type 4J;
icp, documented incomplete penetrance; FTD, frontotemporal dementia; HSP, hereditary spastic paraparesis; MND, motor neuron disease; NA, information not available; PBP, progressive
bulbar palsy; PD, Parkinson disease; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; PSP, progressive supranuclear palsy.
REVIEWS
Box 2 | Gene-hunting tools
HapMap
Genetic variation in humans seems to be inherited in blocks that tend to be
transmitted through the generations together. As a result, the genotype at
neighboring single nucleotide polymorphisms (SNPs) tends to correlate. The map
of this genetic correlation is available online and is known as the HapMap. 125
Tag SNP
Owing to the correlations in genotypes of related SNPs, it is only necessary to
know the genotype of one SNP to be able to make a good guess as to the genotype
at the correlating SNPs. The selection of one SNPknown as the tag SNPto
represent a group of SNPs is known as SNP tagging. The existence of tag SNPs
means that genotyping of about 300,000 SNPs provides information on 95% of the
common genetic variants in a person, making genome-wide association studies
(GWAS) possible.
GWAS
Technological advances have enabled hundreds of thousands of SNPs to be
assayed on a microchip. By selecting tag SNPs that between them capture
information on most of the genome, an association study can be performed that
examines the whole genome on a single microchip. Such GWAS have provided
many insights into complex disease, but have failed to explain as much disease
heritability as was hoped. One problem is that testing of thousands of SNPs
means that the level of statistical noise generating false-positive results is high.
Large sample sizes are required to guard against such eventualities.
Linkage
By tracking the inheritance of genetic variants through a family, investigators
can use statistical methods to test the likelihood that these variants match the
inheritance of the disease or trait. The genetic position of the variant then becomes
a marker for the position of the disease gene.
Alsin
Recessive mutations in the 34-exon ALS2 gene, which
encodes the GTPase regulator alsin, cause a slowly progressive, juvenile-onset, upper motor neuron phenotype,
and infantile hereditary spastic paraparesis.41,42 Alsin mutations have not been reported in patients with adult-onset
typical ALS.
Senataxin
Dominantly inherited missense mutations in the senataxin (SETX) gene are rare, but are found in a few FALS
pedigrees and some cases of SALS. 43 The hallmark
in individuals with such mutations is young onset of
a very slowly evolving form of ALS, in some cases with a
normal lifespan, and sometimes with atypical features
like ataxia.44,45 Interestingly, recessive SETX mutations can
result in the syndrome of ataxia and oculomotor apraxia
type2, axonal sensorimotor neuropathy, or a hereditary
motor neuropathy.46 Senataxin is presumed to be involved
in RNA processing.
TAR DNA-binding protein
The discovery that neuronal cytoplasmic inclusions in
patients with ALS or frontotemporal dementia (FTD)
contain TDP43, which is involved in RNA processing,
prompted analysis of TARDBP, the gene that encodes this
606 | NOVEMBER 2011 | VOLUME 7
Fused in sarcoma
The discovery of mutations in TARDBP prompted
screening of similar genes, including a candidate in a
known linkage region on 16q11.2, FUS. The FUS protein
resembles TDP43, and has been implicated in alternative splicing, genomic maintenance, and transcription
factor regulation. Several missense mutations, predominantly in exons 14 and 15, which encode the Cterminus,
were revealed, the commonest being Arg521Cys.60,61 42
mutations, in exons 3, 5, 6, 14 and 15, have now been
reported. The associated phenotype is typical ALS, but
some individuals also have cognitive impairment, FTD or
parkinsonism, or pure FTD without ALS.28,6265 The first
epidemiological studies found FUS mutations in 4.06.0%
of FALS and 0.71.8% of SALS cases,28,53,63 including two
SALS cases with denovo mutations.20,21
VAMP-associated protein type B
Linkage analysis of eight Brazilian familiesseven
of Portuguese and one of African descentrevealed
a locus at 20q13 harboring a missense mutation,
Pro56Ser, in the highly conserved VAMP-associated
protein typeB (VAPB) gene.66 Founder studies showed
a common founder for all eight families, consistent with
a Portuguese origin. VAPB is involved in intracellular
membrane transportation and is primarily located in the
endoplasmic reticulum. The Pro56Ser mutation induces
the formation of insoluble cytoplasmic aggregates containing the mutant protein. ALS patients with the same
Pro56Ser mutation have been found in Germany, Japan
and the USA, but surprisingly not in Portugal.28,67,68 Only
two other mutations (Thr46Ile and Ser160del) have been
reported in VAPB,67,69 and Ser160del is equally frequent
in control and patient populations (0.4%), suggesting
that it is nonpathogenic.67
Angiogenin
Angiogenin (ANG) on chromosome 14q11.2 was originally screened as a candidate gene in Irish and Scottish
families with ALS because it shares a metabolic pathway
with vascular endothelial growth factor, which is implicated in ALS.70 Furthermore, ANG is in linkage disequili
brium with the apurinic endonuclease gene, APEX1,
which was associated with ALS in earlier studies. Since
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A M YOT R O P H I C L AT E R A L S C L E R O S I S
2005, 17 ANG missense mutations have been reported
as rare causes of ALS, but only the Lys17Ile mutation has
been shown to cosegregate with the disease.71 This mutation cosegregated with ALS in all five affected members
of a Dutch pedigree. Interestingly, four of the patients
showed typical ALS while one presented with ALS
parkinsonism and later developed FTD.71 The Lys17Ile
mutation has also been reported in patients in France,
Ireland, Russia, Scotland and Sweden, and is the most
common ANG mutation reported.28,70
Optineurin
Through use of homozygosity mapping in cons an
guineous families with FALS and SALS, mutations in
optineurin (OPTN), a gene already known to be mutated
in primary open angle glaucoma and ataxia (POAG), were
found to cause ALS.72 One missense dominant mutation
(Glu478Gly, found in four patients from two FALS pedigrees), and two recessive mutationsa deletion of exon 5
(in two siblings) and a Gln398del nonsense mutation (one
patient each from two FALS families)were originally
reported.72 The mechanisms through which dominant
and recessive mutations cause ALS are likely to differ, as
are the mechanisms through which different mutations
result in ALS or POAG phenotypes. Effects on localization of the optineurin protein and nuclear factorB signaling probably account for differences in phenotypic
expression. Recently, a further 10 heterozygous mutations
in OPTN have been found in a few SALS or FALS cases
of European descent, but cosegregation with disease was
not reported in the FALS cases.73,74
Ataxin2
CAG-trinucleotide repeat expansion in the ataxin2
(ATXN2) gene to 34 or more repeats is associated with
spinocerebellar ataxia type2 (SCA2). Motor neuron
involvement is recognized as part of SCA2, and case
reports show that it can be the predominant phenotype.
Intermediate-length polyQ expansion (2733 repeats)
on one allele in ATXN2 is a significant genetic risk factor
for ALS in North American patients,75 a result that has
recently been confirmed in four large populations of SALS
and FALS cases.7679 The findings raise the possibility
that SCA2 and ALS represent opposite ends of a clinical
spectrum, with intermediate-length repeat expansions
presenting with more-prominent motor neuron degenera
tion, indicative of ALS, and longer expansions resulting in cerebellar ataxia. This idea is further supported
by the finding of ataxia in some patients with SOD1 or
SETXmutations.27,44,45
Ubiquilin 2
A five-generation family showing Xlinked dominant
transmission of ALS has shown linkage and cosegregation of a mutation in the ubiquilin 2 (UBQLN2) gene,
which encodes a ubiquitin-like protein.80 Some affected
individuals also had FTD. After analyzing other families
with ALS or ALSFTD in which there was no male-tomale transmission (and which were, therefore, consistent
with Xlinked inheritance), four other mutations were
identified in four unrelated families, all in a prolinerepeat domain. The age of ALS onset was significantly
younger in males than females, presumably because the
males are hemizygous and the females heterozygous for
the mutation. Ubiquilin 2 pathology was found in every
one of 47 ALS cases examined, including SALS, FALS and
ALSFTD, suggesting a potential common final pathway
for all ALS.
REVIEWS
Box 3 | Patterns of inheritance and their cause
Frequency
aa
85
90
Aa
95
100
AA
105
110
115
Threshold
Disease
A M YOT R O P H I C L AT E R A L S C L E R O S I S
gold standard to show causation is cosegregation of the
mutated gene defect in all affected members of a family
and absence of the mutation in old unaffected individuals,
preferably from the same family. This approach depends
on the availability of DNA and robust clinical information from many affected as well as unaffected members,
preferably over a number of generations. This scenario is
rare, and many studies, therefore, have been based on the
combined analysis of multiple smaller pedigrees, sometimes with samples available from only a few affected
individuals. In our opinion, the most convincing data for
causation in classic adult-onset ALS are for mutations in
SOD1, FUS, TARDBP and ATXN2, and, to a lesser degree,
ANG, SIGMAR1 ( non-opioid intracellular receptor 1), FIG4 (polyphosphoinositide phosphatase) and
VAPB. Convincing data also exist for a wider phenotypic
expression being the norm for OPTN and VCP (transitional endoplasmic reticulum ATPase, also known as
valosin-containing protein), and for younger and slower
onset phenotypes for SETX and ALS2. The newly identified UBQLN2 mutations occur in a gene that is a good
candidate, and are supported by functional evidence.
We should emphasize that robust evidence for pathogenicity is lacking for many mutations reported in the
above-mentioned genes. This applies in particular to
the mutations found in SALS cases that also exist in equal
frequencies in the control population. Unfortunately, many
of the control populations used for comparison with ALS
study populations are small and have insufficient statistical power, have not been randomly collected, or do not
have the same ethnic background or other demographic
characteristics as the patient cohort. Also, in many studies,
patients with ALS were compared with a control group
that included patients with other neurodegenerative diseases. The emerging picture that mutations in some ALSassociated genes (FUS, C9ORF72, TARDBP and VCP in
particular) may occasionally give rise to other neuro
degenerative phenotypes, including cerebellar ataxia,
dementia and/or parkinsonism (see below), raises questions about the composition of control populations. The
ideal control population for an association study consists
of newborn babies from the same population as the studied
ALS population. However, this kind of control DNA
is rarely available and, in our search of the ALS genetic
literature, we have only found one study in which such
statistically excellent control material was used.100
A number of genes and loci have been claimed to be
associated with ALS on the basis of GWAS that used thousands of patients and controls (Table2). Reading these
impressive reports, one must bear in mind that a statistical
association does not prove biological causation. Many of
the reported loci contain several genes and, in the absence
of further biological evidence including functional validation, caution should be exercised when interpreting these
studies. Furthermore, the GWAS methodology can seldom
detect multiple rare variants at a single locus, or even a
single rare variant. Lessons from studying SOD1 mutations since 1993 teach us that many mutations have only
been found in a single member of a single FALS family,
and the question of whether such a mutation reflects a
Genotypephenotype correlations
Unfortunately, except for variants of SOD1, few clinical
data have been published for most established ALS genes.
SOD1 mutations are dispersed all over the molecule and
can give rise to almost any described clinical ALS pheno
type, including progressive muscular atrophy, bulbar
palsy, and the VulpianBernhardt variant with a flailarm syndrome.5,6,2428,32,3436 No obvious correlation exists
between the mutated codon and the phenotype.
The clinical hallmark of ALS in patients with SOD1
mutations is asymmetric onset, most frequently in a lower
extremity, with paresis and wasting with predominantly
lower motor neuron features. Upper motor neuron signs
have been detected for all SOD1 mutations where robust
data from many patients are available. Intrafamily and
interfamily variations are common, and not all affected
members show the upper motor neuron signs strictly
required for a definite ALS diagnosis. A few cases of nonprogressing benign focal amyotrophy have also been
reported to have SOD1 mutations,101 but no case with predominantly upper motor neuron features or primary lateral
sclerosis has been reported. Extra-motor features such as
mild cerebellar ataxia (Asp90Ala, Glu100Lys),27,45 bladder
disturbance (Gly41Ser, Asp90Ala, Val118Leu),27,102 heat
sensations (Asp90Ala),27 sensory neuropathy (Ala89Val,
Asp90Ala)27,102 or a severe neuralgic pain syndrome, particularly early in the disease course (Ala4Val, Gly12Arg,
Gly37Arg, Asp90Ala, Glu100Gly, Gly127Arg)27,32 may
occur in some patients, while other affected members
of the same family do not show these atypical features.
Cognitive impairment is rare, but frontal lobe dementia
has been reported in cases with Gly41Ser and Leu144Phe
SOD1 mutations.102,103 A flumazenil PET study revealed
extensive changes in nonmotor areas in the frontal lobes
of 11 Asp90Ala-homozygous SOD1 patients, as well as in
two Asp90Ala-homozygous relatives without motor signs
or symptoms.104 This result needs to be confirmed, since it
REVIEWS
Table 2 | Selected genes and loci putatively associated with ALS
Gene
or locus
Nature
of variation
Geography
Evidence against
Discovery
method
Initial reports
UNC13A
SNP
Multiple
populations
Independent replication in
European populations
GWAS
C9ORF72
GGGGCCrepeat
expansion
Multiple populations
GWAS
DCTN1
SNP
Danish, German,
Swedish
Not replicated
Candidate gene
DPP6
SNP
Multiple
populations
Independent replication
Negative replications*
GWAS
TAF15
SNP
US, Swedish
Functional studies
Candidate gene
VEGF
SNP
haplotype
Multiple
populations
Animal model
Negative replications*
Candidate gene
Lambrechts etal.
(2003)130
NEFH
Tail domain
indel
Swedish, UK, US
Independent replications
Negative replications,
although SALS and tail
domain not tested
Candidate gene
SMN
Copy number
variation
French, Dutch
Replication
None
Candidate gene
SIGMAR1
SNP
Australia, Poland
Functional studies
Single study
Candidate gene
VCP
SNP
Italy, US
Independent replications
Single study
Candidate gene
ELP3
Microsatellite
None
Microsatellite
GWAS
PON1
SNP
Multiple
populations
Independent replications
Negative studies
Candidate gene
HFE
SNP
Independent replications
None
Candidate gene
KIFAP3
SNP
Functional studies
GWAS
APOE||
Haplotype
US, Swedish,
Russian
Independent replication
Negative or contradictory
studies (other allele)
Candidate gene
The strongest evidence is for UNC13A, HFE, VEGF, NEFH and the chromosome 9p21.2 locus, which can be considered an established association in European populations. *May be a sexspecific effect. Insertion/deletion. Association with survival, not susceptibility. ||Association with age of onset, not susceptibility. Abbreviations: ALS, amyotrophic lateral sclerosis; FALS,
familial ASL; FTD, frontotemporal dementia; GWAS, genome-wide association study; SALS, sporadic ALS; SNP, single nucleotide polymorphism.
A M YOT R O P H I C L AT E R A L S C L E R O S I S
(220years).5,25,26 An emerging picture is that SOD1 mutations resulting in a wild-type-like stable SOD1 dimer
tend to be associated with long survival, and onset in the
lower limbs. Mutations that result in an unstable SOD1
polypeptide are more frequently associated with variable
phenotypes even within families, and shorter survival
time.38 The observation that many SOD1 mutants result in
the same mean age of onset but very different disease progression rates, sites of onset or disease penetrance implies
that onset of symptomatic disease and progression may be
two different biological processes.6,25
Limited clinical data are available from patients with
mutations in the TARDBP, FUS, OPTN and ANG genes.
A predominantly adult-onset, lower motor neuron pheno
type and a survival time of 25years is the norm. In the
high-penetrance families, the age of onset for FUS mutation carriers seems to be slightly younger, and for TARDBP
mutation carriers seems to be older, compared with
the 4647years mean age of onset for carriers of highpenetrance SOD1 mutations.28,52,53 Bulbar onset seems to
be significantly more frequent in FUS and TARDBP cases
than in SOD1 cases, where the leg is the most frequent site
of onset. In general, cases with FUS mutations have shorter
survival than SOD1 and TARDBP cases, although wide
variability exists.28,47,5154
The neurodegenerative process in established genetic
ALS is not confined to the motor systems: cognitive impairment and, in some cases, fulminant FTD
(Lys17Ile in ANG; Ala4Ser, Gly41Ser, Ile113Thr and
Leu144Phe in SOD1; Pro56Ser in VAPB; Ala382Thr in
TARDBP; Gly156Glu, Gly174Gly175del, Gly206Ser and
Arg521Cys in FUS), occasionally combined with parkinsonism or cerebellar ataxia or both (Asp90Ala, Glu100Lys
in SOD1; Ile2547Thr in SETX; Arg524Ser in FUS) have
been reported, implying that ALS is a systemic syndrome
(Figure3).5,6,28,32,44,45,63,64,70,86,87,102,103 In some patients, these
nonmotor features emerge months or even years before
the motor symptoms. In fact, on the basis of published
clinical data, no established ALS gene is associated with
a strict motor-only phenotype in all reported cases.
Conversely, genes that are commonly associated with
other syndromes have, in rare cases, also been found to
be mutated in patients with ALS. These genes include
chromatin modifying protein 2B (CHMP2B),108 granulin (GRN),109 FIG4,110 SIGMAR1,111 VCP,112 and even
huntingtin (HTT)113 and NOTCH3.114
FTD
MAPT
GRN
CHMP2B
SOD1
DCTN1
Parkinsonism
Psychosis
Cerebellar
ataxia
SIGMAR1
UBQLN2
ANG
TARDBP VCP
FUS
ATXN2
C9ORF72
ALS
FIG4
SETX
AOA2
ALS2
SPG4
HSP/PLS
OPTN
SMN
VAPB
Motor
neuropathies
POAG
SMA/PMA
Figure 3 | Pleiotropy of genes associated with ALS. Hereditary ALS is not a many
genes, one degenerative syndrome situation. No ALS gene has exclusively been
associated with an ALS-only motor phenotype. The figure illustrates the reported
relationships between mutations in different genes and selected clinical
syndromes. The arrows point to the dominant clinical feature relevant to ALS.
Abbreviations: ALS, amyotrophic lateral sclerosis; AOA2, oculomotor apraxia
type2; FTD, frontotemporal dementia; HSP, hereditary spastic paraparesis; PLS,
primary lateral sclerosis; PMA, progressive muscular atrophy, POAG, primary open
angle glaucoma; SMA, spinal muscular atrophy.
REVIEWS
FALS families found in Italy and Sweden, suggesting independent denovo events. The widespread occurrence of
Ala4Val in North America is proposed to be explained
by its existence in the original native American populations, and its introduction into the white population after
1630.116,117 Although the Ala4Val families are on different
ethnic backgrounds, they all show the same highly aggressive phenotype, suggesting that the disease characteristics
are determined by the protein change.
The third most common SOD1 mutation seems to be
Ile113Thr, which in Scotland has been found in many
FALS pedigrees with high or low disease penetrance, and
also in SALS with a common founder.24 Similar findings of
Ile113Thr FALS pedigrees with low penetrance have been
observed in England and countries in the Commonwealth.5
In the Balkans, the most prevalent mutation is Leu144Phe,
which has also been found in adjacent countries.102,118 By
contrast, Europes largest country, Germany, seems to have
its own unique SOD1 variants, the most common being
Arg115Gly.118,119 Several cases homozygous or hetero
zygous for the Asp90Ala SOD1 allele have also been found
in Germany, making it the second most common mutation
there. Screening studies have revealed that the only SOD1
polymorphism worldwide is Asp90Ala, and that 1223%
of diagnosed FALS cases and 17% of SALS cases carry
a SOD1 mutation, making a total of 2.56.0% of all ALS
cases (Supplementary Table2 online). In most populations
studied, TARDBP and FUS mutations are found in about
one-third as many cases as SOD1 mutations, and the other
ALS genes seem to account for 1% of cases at most.28,53
Added together, the identified genes can explain, at most,
2535% of FALS and 510% of apparent SALS.
Clinical implications
Clinical genetic testing
Testing for mutations in the established monogenic ALS
genes has now become part of the clinical investigation
of ALS, although one should remember that only a small
group of patients carry such a mutation. As a general rule,
we recommend testing only patients with a diagnosis of
FALS, but as we learn more about the genetics of SALS
this situation may change. Robust clinical data of use in
clinical practice is meager for most mutations in most
ALS genes, and at present we can only recommend clinical
DNA testing for mutations in SOD1, TARDBP and FUS.
If resources permit, a wider screen could be performed,
including testing for OPTN, UBQLN2 and VCP and, in
juvenile cases, also SETX and ALS2. Clinical genetic testing
in ALS should be focused on these genes because results
from other genes may prove difficult to interpret. Screening
for other genes or risk single nucleotide polymorphisms,
as offered by commercial or research laboratories, has no
place in diagnosis or risk assessment.
A positive test for a mutation can expedite the diagnostic process, raising the possibility of putting the patient on
neuroprotective drugs like riluzole at an early stage. The
revised diagnostic ALS criteria now couple the finding of
progressive lower motor neuron lesions with a pathogenic
mutation as sufficient grounds to establish a diagnosis of
ALS. In addition, some ALS patients with a mutation may
612 | NOVEMBER 2011 | VOLUME 7
Genetic therapy
The discovery of ALS-causing mutations is now creating the possibility of developing tailored therapy for
patients with mutations in established ALS genes. The
first human clinical trials targeting SOD1 have recently
been initiated.121
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A M YOT R O P H I C L AT E R A L S C L E R O S I S
Conclusions and future perspectives
The genes associated with ALS show no common biological denominator, but can be divided into five main categories: axonal transport (DCTN1 and NEFH), mRNA
processing (FUS, TARDBP, ANG, SETX, TAF15, ELP3
and C9ORF72), endosomal vesicle trafficking (FIG4 and
VAPB), ubiquitination (UBQLN2 and UNC13A), and other
functions (SOD1). In addition to the genes now claimed
to be associated with ALS are a variety of hereditary lower
motor neuron-only syndromes, upper motor neuron syndromes, hereditary dementia syndromes associated with
genes such as MAPT, SIGMAR1, GRN and CHMP2B, and
cerebellar ataxia syndromes associated with 28 genes,
including ATXN2. Mutations in these genes may occasionally give rise to an ALS phenotype or a mixed phenotype.
The rare finding of patients with an ALS-like syndrome
carrying mutations in more remote genes usually associated with diseases like Paget disease, LundHuntington
disease or CADASIL are either coincidental findings or,
more likely, a manifestation of the sensitivity of the large
and complex motor system to a wide variety of insults.110114
Mutations in ALS genes will predominantly cause ALS
with high penetrance and a lower mean age of onset than
SALS (and will be easily recognized as FALS), but may,
in some rare individuals, give rise to other phenotypes,
sometimes in combination with ALS (Figure3).
The pleiotropic nature of ALS genes may be one reason
why the involved genes have been so difficult to identify.
When performing linkage or association studies, we have
considered individuals with parkinsonism or dementia
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