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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

Clinical genetics of amyotrophic lateral


sclerosis: what do we really know?
Peter M. Andersen and Ammar Al-Chalabi
Abstract | Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized
by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the
nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most
common being SOD1, FUS and TARDBPmutations in the other genes are rare. The identified genes explain
2535% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem
to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can
be inherited in an autosomal dominant, autosomal recessive or Xlinked manner, and families with low disease
penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many
patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized
hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features
reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also
been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing
the specific gene defect and the disease penetrance in the particular family.
Andersen, P.M. & Al-Chalabi, A. Nat. Rev. Neurol. 7, 603615 (2011); published online 11 October 2011; doi:10.1038/nrneurol.2011.150

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.

Epidemiology of familial ALS


In retrospective studies, 0.813.5% of patients with ALS
report a family history (Supplementary Table1 online),
but many of these studies contain flaws, making them
unreliable (see Box1 for possible sources of error). In
Competing interests
The authors declare no competing interests.

some prospective studies in which genealogies have been


actively investigated, the prevalence of a family history
increases to 1723%,36 and even this is probably an
underestimate since many of the factors listed in Box1
are difficult to exclude. Thus, many cases labeled as sporadic may well have a family history. Furthermore, SALS
and FALS are clinically indistinguisable:68 all genes found
mutated in FALS cases have also been found mutated in
SALS (see below and Table1); first-degree relatives of
patients with SALS have an increased risk of ALS (see
below) and other neurodegenerative diseases;9 similar
superoxide dismutase 1 (SOD1)-positive and TAR DNAbinding protein 43 (TDP43)-positive inclusions have
been found in SALS and FALS;10,11 the neuroprotective
drug riluzole has an effect on both SALS and FALS;12 and
cerebrospinal fluid samples from SALS and FALS cases
have similar toxic effects on rat spinal cord neurons cultured invitro.13 The classification into SALS and FALS,
therefore, while convenient for genetic counseling, is not
particularly meaningful biologically.
The FALS label does not exclude the possibility that
environmental, endogenous or epigenetic factors con
tribute to the disease. The uncertainty around the definition of FALS has been explored previously.1417 We support
the proposal of classification into possible, probable and
definite FALS,17 recognizing that screening for mutations
in the ALS-associated genes identified to date (Table1)
can account for, at most, 2530% of all cases of FALS (see
below and Supplementary Table2 online). Also, since ALS
has a lifetime prevalence of about 1 in 300,18 the possibility arises that two family members can develop ALS

NATURE REVIEWS | NEUROLOGY

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

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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

Box 1 | Factors leading to underrepresentation of FALS


Inadequate recording of pertinent family history in the
patients charts
Manifestation as different subtypes of ALS in different
family members
Reluctance of the patient to report a hereditary disease
Loss of contact between different members of a family
Small family size with a resulting smaller number of
chances for others to be affected
Early death to other causes of individuals in the family
who transmit the gene defect
Development of ALS in a child before the parent who
transmitted the gene defect
Incomplete disease penetrance
Misdiagnosis of family members with ALS
Illegitimacy
Abbreviations: ALS, amyotrophic lateral sclerosis; FALS, familial ALS.

from different causes, including common or different


environmental influences (if such influences exist).15,17,18
SALS is more properly termed isolated ALS, since this
terminology allows for the possibility of environmental
and/or genetic causes, whereas sporadic disease is, by
definition, nongenetic.
Traditional Mendelian patterns of inheritance have been
recognized in adult-onset FALS. The most commonly
reported patterns are dominant inheritance with complete
penetrance, dominant inheritance with incomplete penetrance, and recessive inheritance.5,6,8 A FALS pedigree with
compound heterozygosity for two different SOD1 mutations (one allele encoding an Asp90Ala substitution and
the other encoding an Asp96Asn substitution),19 and even
SALS cases with proven denovo mutationsin SOD118
and fused in sarcoma (FUS)20,21have been reported. No
studies of the frequency of the different modes of inheritance exist but, in our experience, families with dominant
inheritance with apparently incomplete penetrance are frequent, and the patients are often diagnosed as SALS cases.
As an example, 42 of the 166 SOD1 mutations have been
604 | NOVEMBER 2011 | VOLUME 7

reported in patients diagnosed as having SALS, compared


with 23 in FALS pedigrees with recognized reduced pene
trance. With smaller families becoming the norm, even a
disease gene with a penetrance of 0.9 will seem sporadic
in one-third of cases, and a lower penetrance, say 0.5, will
seem sporadic in two-thirds of cases.22 The median age
of onset in FALS pedigrees with low-penetrance mutations in SOD1 is 5864years, which is comparable to that
reported for SALS in epidemiological studies, contrasting
with 4647years in families with high-penetrance SOD1
mutations.6,2326 This observation supports the idea that
many cases designated as SALS actually represent FALS
with reduced disease penetrance.

Genes with ALS-causing variants


Identification of the genetic causes of ALS has proven
difficult even with modern statistical techniques and
tools (Box2). The combination of age-dependent onset
in adults (the oldest patient with an SOD1 mutation was
94years old at onset 27), short disease duration, genetic
heterogeneity even within the same pedigree, phenotypic variability, incomplete disease penetrance, and frequent misdiagnosis means that DNA is rarely available
from sufficient numbers of family members from large
pedigrees with multiple affected individuals in multiple
generations.2328 Linkage studies in ALS have, therefore,
been restricted to the few large pedigrees with Mendelian
inheritance and high penetrance.
Genetic variations have also been associated with ALS
following candidate gene studies based on hypotheses of
ALS causation, genome-wide association studies (GWAS),
or exome capture sequencing studies. A complete list of
ALS-associated genes is available with analysis tools at
the ALS Online Database,29,30 and a selection is discussed
in the sections that follow.

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.

Although most SOD1 mutations are easily detected by


standard sequencing of the exons and flanking intronic
regions, mutations like this will not usually be found by
current DNA-screening methods. However, the finding
of reduced dismutation activity in erythrocytes provides
a hint that an intronic mutation causing an alteration in
the polypeptide sequence may be present.35
Mutational hot and cold spots were initially thought to
exist in SOD1 but, as more patients from different populations have been screened, no obvious pattern has emerged,
except for a cold spot between codons 23 and 36, where
only two mutations have been reported.32,34 Invitro studies

show that some mutant forms of the protein; for example,


Cys6Ser and Asp90Ala, are as stable as the native SOD1
molecule, while others such as Ala4Val and Gly127del are
highly unstable.6,3538 Most mutations have been found
to cause a reduction in dismutation,6 but some, such as
Gly37Arg, Ala89Val and Asp90Ala, have been found to
result in molecules with essentially normal or only slightly
reduced erythrocyte dismutase activity.36,37 The finding of
normal SOD1 activity for some mutants and absence of
correlation between disease severity and dismutation
activity,6,38 the creation of motor neuron diseases in transgenic rodents overexpressing human mutant SOD1,39

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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.

and the absence of motor degeneration in mice without


SOD1,40 have led to the conclusion that mutant SOD1
causes neurodegeneration by an acquired novel cytotoxic
function, which remains enigmatic.

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

protein, in FALS families. Since 2008, 44 heterozygous


mutations have been found, many showing segregation
with disease in FALS pedigrees.4749 The mutations nearly
all affect the Cterminus, and all but one are missense,3,23
the exception being Tyr374X.50 The mutations result in
redistribution of TDP43 from the nucleus to the cytoplasm in neurons and glia in the spinal cord. TARDBP
mutations have been reported in 46% of FALS cases
without SOD1 mutations, and 02% cases of diagnosed
SALS.30,5053 Most cases have typical ALS, but ALS with
cognitive impairment andsometimesfulminant FTD,
FTD without ALS, ALS with extrapyramidal signs, FTD
with parkinsonism without motor neuron disease and,
most recently, clinical definite Parkinson disease have also
been reported.3,28,5459

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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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.

The 9p21 locus


The existence of a common genetic etiology between
ALS and FTD was proposed in 1991 with the finding of
ALS and FTD (in some cases with hallucinations or
psychosis) in multiple generations in a large Swedish
family.81 Every affected patient had a parent with either
ALS or FTD, no individual had both conditions, and the
suggestion was made that a common genetic factor could
cause either condition. Linkage analysis in this pedigree,
and later in 13 similar pedigrees, pointed to a major locus
on 9p21.2 for FALS, FALSFTD, FALS with parkinsonism,
and also SALS in some populations.8287
The causative gene defect has recently been reported as
a massive hexanucleotide-repeat expansion, (GGGGCC)n,
in the intron between noncoding exons 1a and 1b of the
uncharacterized gene C9ORF72.88,89 Normal individuals
have, at most, 23 repeats, whereas individuals with ALS or
FTD can have up to 1,600 repeats. This expansion seems
to account for a significant proportion of familial and
apparently sporadic ALS and FTD cases. Speculatively,
the dynamics of such a hexanucleotide-repeat expansion
may explain the variability in phenotypes and disease
penetrance previously reported in these families, and
the association to the 9p21 locus of many cases with
apparently sporadic disease. Whether all 9p21-linked
families carry GGGGCC expansions in C9ORF72 is
presentlyunknown.

Non-Mendelian inheritance of ALS


A number of observations suggest a role for genetic
factors in SALS. A meta-analysis of three twin studies
gives an estimate of SALS heritability of 0.61 (95% CI
0.380.78).90 A marked male preponderance is observed
in SALS, in particular among patients under 50years of
age,91 and certain phenotypic subtypes show a sex preference: bulbar onset is more common among women than
men in older age groups,18,91 and flail-arm syndrome (also
known as VulpianBernhardt syndrome) is nine times
more frequent among men than women.92 Longitudinal
epidemiological analysis of ALS mortality in Norway,
Sweden and the USA found that ALS affects an inherently susceptible population subset.93 An epidemiological analysis in Ireland showed that neurodegenerative
diseases as a whole are more frequent among relatives
of those with SALS,9 and a clinic-based study in the UK
showed an eightfold increase in the background risk of
ALS in siblings of those with apparently sporadic ALS.94
Two possible models might explain the genetic contribution to SALS (Figure1, Box3). Mendelian disease
genes might be responsible even in the absence of a
family history if the mutation is new or low-penetrance;

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Box 3 | Patterns of inheritance and their cause

Frequency

aa

85

90

Aa

95

100

AA

105

110

115
Threshold

Burden of disease-causing factors


No disease

Disease

Figure 1 | Patterns of inheritance in ALS. The three main


patterns of inheritance are shown. In the top panel, one
gene with two variants, A and a, is shown with the
genotypes and frequencies assuming equal allele
frequencies. This is classic Mendelian inheritance. The
middle panel shows a polygenic model, with the result of
three or more genes combining to produce a phenotype (for
example, IQ). Each column represents a different genotypic
combination. The effect of environmental noise results in a
normal distribution for the trait, and the model is, therefore,
used to describe the genetics of quantitative traits.
The bottom panel shows the liability threshold model. The
polygenic model is modified with a threshold for phenotypic
expression. The result is complex inheritance with familial
clustering of a discrete phenotype. The top and bottom
panels model the genetics of ALS. Abbreviation: ALS,
amyotrophic lateral sclerosis.

if the family is small, thus reducing the likelihood of


other affected family members; or if the family history
is unknown or uninformative for other reasons. While
such FALS genes undoubtedly account for some cases of
SALS, a more widely accepted view is that multiple genetic
variants, each of small effect, combine with environmental triggers and risk factors to lead to motor neuron
degeneration. This polygenic, multifactorial contribution
to risk is described in genetic theory as the liability thres
hold model95 and has implications for relatives. Under
this model, everyone has an underlying burden of risk
factors for developing ALS, and this liability to disease is
normally distributed in the population (Figure2). Those
whose burden is above a particular threshold develop ALS.
One of the consequences of the liability threshold model is
that first-degree relatives would be expected to have a risk
roughly equivalent to the square root of the population
risk.96 For ALS, the lifetime prevalence of 1 in 300 equates
to a risk of 5.6% in first-degree relatives of a person with
SALS, and a relative risk of 17. In support of this model, a
population-based study that made no distinction between
FALS and SALS found that the relative risk was 17 (95%
CI 8.130.4) for siblings and 9 (95% CI 6.212.0) for offspring of those with ALS.97 The estimate of the risk to a
first-degree relative may seem high but should be put in
context. The lifetime risk of not developing ALS would
608 | NOVEMBER 2011 | VOLUME 7

Discrete phenotype transmitted from parent to child


with high probability
Mutation in a single gene results in a specific phenotype,
such as disease. This is the usual pattern of inheritance
for familial amyotrophic lateral sclerosis resulting from
superoxide dismutase 1 (SOD1) mutation. If inheritance
of the mutation does not always result in the phenotype,
penetrancethe probability that the genotype is
manifested in the phenotypeis said to be reduced.
Continuous phenotype showing familial tendency
Variation such as height is difficult to explain on the
basis of variation in a single gene. Variation in three or
more genes, all of which contribute to the phenotype, is
sufficient to generate a normal distribution of the trait in
the population, with the offspring trait value related to the
value in the parents.
Discrete phenotype showing familial clustering
This is the classical complex disease pattern. Although
relatives might show an increased risk of the disease
or trait, inheritance is not obviously Mendelian. The
accepted explanation is that multiple genes and
environment contribute to the burden of disease risk, but
unless the burden is sufficiently great, disease will not
manifest. This is known as the liability threshold model.
Continuous phenotype transmitted from parent to child
with high probability
This is the most unusual pattern, and is caused by many
different possible alleles of a gene, each of which would
result in a different effect. For example, age of onset
of LundHuntington disease is a continuous trait that
correlates strongly with the number of CAG repeats in the
huntingtin gene. The higher the number of repeats, the
younger the onset.

decrease from the population background of about 99.7%


to about 94.4%, which still means the overwhelming likelihood is that a first-degree relative with no other family
history will die of causes other than ALS.
Besides mutations in known FALS genes, few robustly
replicated genetic associations have been found in SALS
(Table2). A locus on chromosome 9p21.2 that shows
linkage to FALS has shown replicable association in
several populations in SALS.85,98,99 The population attribut
able risk of the chromosome 9p21.2 locus may be as high
as 10%, meaning that if those with the allele were prevented from developing ALS, 10% fewer cases would be
observed. Other credible replicated associations are shown
in Table2.
In the future, a polygenic fingerprint may allow a diagnostic test for SALS or risk assessment for relatives, but
at present the clinical contribution of our knowledge of
the complex disease genetics of ALS is targeted towards
understanding disease mechanisms, recognizing that a
genetic contribution exists in all ALS cases, and providing reassurance that relatives of patients with SALS have a
very low risk of developing this condition.

Which mutations are pathogenic?


Whether all the above-mentioned genes and mutations
are disease-causing in ALS is currently unknown. The
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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
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

Burden of disease-causing factors

Figure 2 | Why complex inheritance leads to familial


clustering. The figure shows two normal distributions
superimposed. The left-most distribution is the pattern of
disease liability in the normal population. Those affected
by a complex disease must carry sufficient liability to have
crossed the threshold and manifested disease. Their
relatives inherit disease liability variants selected from the
right-most end of the distribution, and the relatives risk is,
therefore, shifted to the right. The light shading indicates
the proportion of the normal population affected. The dark
shading indicates the additional proportion for relatives.

coincidental benign genetic variant, found only because


we searched for it, or whether it represents a private
mutation that is pathogenic only in this particular family,
remains unresolved.

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

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Table 2 | Selected genes and loci putatively associated with ALS
Gene
or locus

Nature
of variation

Geography

Initial supporting evidence

Evidence against

Discovery
method

Initial reports

UNC13A

SNP

Multiple
populations

Independent replication in
European populations

Not replicated in Japanese


or Chinese samples

GWAS

van Es etal. (2009)98


Shatunov etal. (2010)99

C9ORF72

GGGGCCrepeat
expansion

Multiple populations

Independent replication in FALS


and FALSFTD

Not replicated in Japanese


or Chinese SALS

GWAS

Morita etal. (2006)82


Vance etal. (2006)83
DeJesus-Hernandez etal.
(2011)88
Renton etal. (2011)89

DCTN1

SNP

Danish, German,
Swedish

Replication within study

Not replicated

Candidate gene

Mnch etal. (2004)126

DPP6

SNP

Multiple
populations

Independent replication

Negative replications*

GWAS

van Es etal. (2008)127


Cronin etal. (2008)128

TAF15

SNP

US, Swedish

Functional studies

Cosegregation not shown


in FALS

Candidate gene

Ticozzi etal. (2011)129

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

Figlewicz etal. (1994)131


Tomkins etal. (1998)132
Al-Chalabi etal. (1999)133
Vechio etal. (1996)134
Rooke etal. (1996)135

SMN

Copy number
variation

French, Dutch

Replication

None

Candidate gene

Corcia etal. (2002)136


Veldink etal. (2005)137

SIGMAR1

SNP

Australia, Poland

Functional studies

Single study

Candidate gene

Battistini etal. (2005)102

VCP

SNP

Italy, US

Independent replications

Single study

Candidate gene

Johnson etal. (2010)112

ELP3

Microsatellite

UK, US, Belgium

Animal model and independent


linkage in a fly model

None

Microsatellite
GWAS

Simpson etal. (2009)138

PON1

SNP

Multiple
populations

Independent replications

Negative studies

Candidate gene

Slowik etal. (2006)139

HFE

SNP

UK, Ireland, Italy,


Dutch, US, Chinese

Independent replications

None

Candidate gene

Wang etal. (2004)140


Yen etal. (2004)141

KIFAP3

SNP

UK, US, Dutch,


French, Ireland

Functional studies

One negative replication

GWAS

Landers etal. (2009)142

APOE||

Haplotype

US, Swedish,
Russian

Independent replication

Negative or contradictory
studies (other allele)

Candidate gene

Zetterberg etal. (2008)143


Li etal. (2004)144

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.

suggests that nonmotor areas may be involved even before


the motor areas.
Age of ALS onset in patients with SOD1 mutations
ranges from 6years (Ile104Phe) to 94years (Asp90Alahomozygous), with a mean of 4547years for mutations
with high penetrance.25,26 Three high-penetrance mutationsGly37Arg, Leu38Val and Gly114Alahave been
associated with a significantly reduced mean age of onset.25
A consistent finding in many populations is the occurrence
of dominant pedigrees with low penetrance, sometimes
obscuring the heredity of the disease. 23 SOD1 mutations have shown such a pattern.46,34,36,105 A particularly
notable case is the widespread Ile113Thr variant, which
can pass asymptomatically from a patient down through
to the grandchildren or even great-grandchildren before
manifesting.24 The mean age of ALS onset in these families
is 5865years, with many obligate gene carriers dying in
their 9th or 10th decade from non-neurological causes.5,6,24,25
No codon in SOD1 seems to be specifically associated with
incomplete penetrance. All SOD1 mutations are inherited
610 | NOVEMBER 2011 | VOLUME 7

as a dominant trait with the exception of the most common


mutation Asp90Ala, which in 14 populations is inherited as
a recessive trait.46,27,32,102 In five highly inbred FALS families, single individuals homozygous for dominant SOD1
mutations have been observed. In at least three of these
families, the homozygous patient showed a more aggressive
phenotype, suggesting a mutation-load dose effect.34,105107
Well-documented untreated survival times in ALS
patients with SOD1 mutations range from a few months
(Cys6Gly, Cys6Phe) to 44years (Leu144Phe). Some mutations (Ala4Val, Gly41Ser, Gly93Ala, Arg115Gly) are consistently associated with short survival independently of
site of onset, while others (Gly41Asp, His46Arg, homo
zygosity for Asp90Ala) are always associated with onset
in the lower limbs and very slowly ascending paresis, with
the patient surviving for a decade or more.25,27,32 In a third
group of mutations, some individuals have short survival
while others in the same family show long survival. This
phenomenon is best illustrated by Gly37Arg (survival
range 236years), Ile104Phe (338years) and Ile113Thr
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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
(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

Population studies of genetic ALS


With the caveat that less than 10% of the worlds ALS
population has been examined and almost all studies
have been performed in North America, Europe, China,
South Korea, Japan and Taiwan, a population genetic
picture is emerging: ALS caused by clearly pathogenic
gene mutations is unevenly distributed among even seemingly similar populations and nations. While ANG mutations seem to be relatively common in Scotland, Italy and
Ireland, they are very rare in England, the Netherlands,
France, Germany and Sweden,69 where they account for
1% or less of ALS patients. TARDBP and FUS mutations
are relatively common in Italy (a focus for TARDBP exists

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.

on Sardinia3), France, Germany, Taiwan and the USA, but


are rare in Japan and Sweden.28,53
SOD1 mutations are especially prevalent in Scandi
navia, where they account for 6% or more of cases in some
areas.6,27 The main reason for this prevalence is the wide
spread polymorphism of the Asp90Ala SOD1 allele. About
5% of the populations of northern Sweden, Finland and
probably also Norway are heterozygous (unaffected) carriers of the Asp90Ala SOD1 allele.27 In these populations,
the Asp90Ala allele gives rise to ALS mostly as a recessive
trait, but Asp90Ala heterozygous carriers may also have a
slightly increased risk, probably through a liability thres
hold effect.6 Asp90Ala SOD1 homozygous and hetero
zygous SALS and FALS patients have been reported from
all western European countries except Ireland and Iceland,
and this mutation is currently the commonest identified
cause of ALS worldwide.46,32,101,102,105 A haplotype study
found that all Asp90Ala SOD1 patients globally share a
common ancestor estimated to be over 18,000years old.115
All Asp90Ala-homozygous ALS patients reported to date
share the same characteristic homogenous, slowly evolving
motor phenotype, in some patients also including ataxia,
bladder disturbance, heat sensations and pain syndromes.27
By contrast, the rare Asp90Ala-heterozygous patients
always belonging to families where no homozygous
individuals have developed ALSpresent with variable
phenotypes, frequently of an aggressive nature.46,32,101
The Ala4Val SOD1 allele is the second most common
SOD1 mutation, and accounts for almost half the SOD1
families in the USA.25,26,32 The Ala4Val variant in North
America has a different haplotype from the three Ala4Val

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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

present with a preparetic phase and atypical features.5,27,102


Many of these patients undergo extensive and expensive
investigations before ALS diagnosis. Furthermore, some
mutations are associated with a specific phenotype, allowing some prognostic estimations and genetic counseling
for the family. However, we recommend that genetic
testing in a suspected new ALS case should only be performed with the full consent of the patient, and after
genetic counseling. Diagnostic screening for mutations
should not be conducted without the patients consent.
Another important consideration is that if DNA testing
is initiated in a patient, the whole family is, de facto, being
investigated indirectly, which may have emotional and
legal implications for the relatives.
Guidelines for presymptomatic genetic testing in ALS
have been published by the European Federation of
Neurological Societies (Supplementary Box1 online).120
Presymptomatic testing of at-risk relatives should only be
performed with the full knowledge of all involved indivi
duals. The test result should not reveal the genotype of a
living unaffected individual who has declined testing. For
example, the grandchild of an ALS patient with a known
SOD1 mutation should not be tested if the childs father or
mother has declined. Finding a mutation in the grandchild
would reveal the parent also to be a gene carrier. If the
parent is deceased from ALS or other causes, the grandchild can be tested. Relatives of patients with mutations
associated with reduced disease penetrance (Ile113Thr
SOD1 in particular) should receive particular attention.
The unpredictable disease penetrance and the variable
survival time in these families makes it difficult, in our
experience, for genetic counselors to provide accurate risk
assessments.5 Uncertainty about the future is usually the
main reason for wanting to receive presymptomatic testing.
A positive test result in someone from an ALS family with
high disease penetrance can understand the implications,
and better plan for the future than someone from a family
with reduced disease penetrance. In cases of reduced pene
trance, the uncertainty is not attenuated by the positive
result, and can cause much emotional discomfort. In our
opinion, presymptomatic genetic testing should only be
offered to members of FALS families with high-penetrance
mutations in SOD1, FUS or TARDBP. Too little is presently
known about the variability of clinical features and disease
penetrance in the other ALS genes to permit appropriate
counseling if an individual should test positive.
Presymptomatic genetic testing in a healthy relative in a
FALS family should not be confused with research genetic
analysis performed among relatives of ALS patients with
the purpose of finding genes involved in ALS patho
genesis. These analyses should only be performed with full
informed consent, and in accordance with the Declaration
of Helsinki.

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
1.

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as having a neurodegenerative condition with a different


cause. However, at least in some instances, the collective
evidence now strongly suggests that mutations in the genes
unequivocally linked to an ALS phenotype can also result
in other neurodegenerative syndromes. This pleiotropy
will have consequences for genetic counseling in clinical
practice, for the development and testing of new drugs,
including possible personalized stem cell therapies in the
future (which cells to transplant, and where and when
during the disease course?), and for future research to find
the remaining ALS genes. The number of mutated genes
that can cause an ALS-like phenotype may be high, even of
the order of hundreds. An important scientific challenge
will be to find all such genes, elucidate their degenerative
pathways, and devise specific diagnostic and treatment
tools for the mutation carriers.
Review criteria
Amyotrophic lateral sclerosis genetic studies were
identified from searches of the ALSoD database, from
publications in English listed in PubMed to June 2011.
Combinations of the following keywords were used: ALS,
amyotrophic lateral sclerosis, motor neuron disease,
MND, dementia, FTD, FTLD, semantic dementia,
non-fluent aphasia, SOD1, CuZn-SOD, TDP43,
TARDBP, FUS/TLS, fused in sarcoma, VAPB,
ANG, ELP3, KIFAP3, NFH, mutation, criteria,
epidemiology, gene, endophenotype, epigenetics
and phenotype. Publications were also identified through
the authors collections of scientific literature.

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Author contributions
Both authors researched data for the article, made
substantial contributions to discussions of the content,
wrote the article, and reviewed and/or edited the
manuscript before submission.
Supplementary information
Supplementary information is linked to the online
version of the paper at www.nature.com/nrneurol

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