Clinical Spectrum of Amyotrophic Lateral
Sclerosis (ALS)
Leslie I. Grad,
1
Guy A. Rouleau,
2
John Ravits,
3
and Neil R. Cashman
1
1
Djavad Mowafaghian Centre for Brain Health, Department of Medicine (Neurology),
University of British Columbia, Vancouver V6T 2B5, Canada
2
Montreal Neurological Institute and Hospital, McGill University, Montre
´
al H3A 2B4, Canada
3
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093
Correspondence: jravits@ucsd.edu; neil.cashman@vch.ca
Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor
neurons, although there is marked phenotypic heterogeneity between cases. Typical, or
“classical,” ALS is associated with simultaneous upper motor neuron (UMN) and lower
motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary
lateral sclerosis and progressive muscular atrophy, have early and predominant involvement
in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they
would seem to have differing biology. Because the same phenotypes can have multiple
causes, including different gene mutations, there may be multiple molecular mechanisms
causing ALS, implying that the disease is a syndrome. Conversely, multiple phenotypes can
be caused by a single gene mutation; thus, a single molecular mechanism could be com-
patible with clinical heterogeneity. The pathogenic mechanism(s) in ALS remain unknown,
but active propagation of the pathology neuroanatomically is likely a primary component.
A
myotrophic lateral sclerosis (ALS) is a pro-
gressive, fatal neuromuscular disease char-
acterized by degeneration of the upper and low-
er motor neurons resulting in dysfunction of
the somatic muscles of the body (Cleveland
and Rothstein 2001; Bradley 2009). The term
“amyotrophic lateral sclerosis” was coined by
the French neurologist Jean-Martin Charcot in
the 1800s: “amyotrophic” refers to muscular at-
rophy, and “lateral sclerosis” describes the scar-
ring or hardening of tissues in the lateral spinal
cord. The major neuropathological features of
ALS are (1) extensive loss of lower motor neu-
rons from the anterior horns of the spinal cord
and brainstem (Hughes 1982; Ghatak et al.
1986); (2) degeneration and loss of Betz cells
(large pyramidal cell neurons) in the primary
motor cortex and degeneration of the lateral
corticospinal tracts, which contain the axons
projecting from the primary motor cortex to
the motor neurons (Hammer et al. 1979; Udaka
et al. 1986; Maekawa et al. 2004); and (3) reac-
tive gliosis, which corresponds to hypertrophy
of glial cells in the motor cortex and spinal cord
in the areas of degeneration (Murayama et al.
1991; Kawamata et al. 1992; Schiffer et al. 1996).
ALS is the most common form of motor
neuron disease, with a mean incidence of 2.8/
Editor: Stanley B. Prusiner
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100,000 in Europe and 1.8/100,000 in North
America, and a mean prevalence of 5.40/
100,000 in Europe and 3.40/100,000 in North
America (Chio et al. 2013). Men are slightly
more frequently affected than women, with a
male:female incidence rate ratio of 1.4 (Logro-
scino et al. 2010). The median survival period
following onset is independent of sex and is
usually 2–4 yr (Logroscino et al. 2010). In most
cases, disease onset occurs during late adult-
hood, but juvenile (before 25 yr) and “young-
onset” ALS cases (before 45 yr), respectively,
represent 1% and 10% of all cases (Turner
et al. 2012). In a recent epidemiological analysis
of ALS combining 37 studies, the mean age for
typical ALS disease onset (adult onset) was es-
timated at 61.8 + 3.8 yr (range 54 –67 yr) and
the mean age for ALS diagnosis at 64.4 + 2.9 yr
(range 58–68 yr) (Chio et al. 2013).
ALS CLINICAL PHENOTYPES
In ALS, there is generally a striking dissimilarity
in the degree of involvement of the upper motor
neurons (UMNs) and the lower motor neurons
(LMNs), the body regions affected, the degrees
of involvement of other systems, especially cog-
nition and behavior, and the progression rates
among clinical phenotypes (Ravits and La
Spada 2009). Phenotypes can be so distinctive
that they would seem to have differing underly-
ing biology; however, the known neuropathol-
ogy is more consistent and does not clearly cor-
relate with the different phenotypic subtypes of
disease. The question is often posed as to wheth-
er ALS is one disease with a common funda-
mental pathogenic mechanism or multiple dis-
eases with different mechanisms. The answer
may lie somewhere in between.
Approximately 10% of ALS cases are genet-
ically transmitted mainly by way of dominant
gene mutations, which have now been identified
in 60%–70% of cases of the familial fraction
of the disease (Haverkamp et al. 1995). These
mutations are predominantly associated with
Mendelian-inherited and primarily autosomal
dominant mutations in genes encoding Cu/
Zn superoxide dismutase (SOD1), TAR-DNA
binding protein 43 (TDP-43), fused in sar-
coma/translocated in liposarcoma (FUS/
TLS), and C9ORF72, but have been associated
with mutations in other genes as well (reviewed
in the ALS Mutation Database 2007; Deng et al.
2011; Stewart et al. 2012; Wu et al. 2012; Renton
et al. 2014). The 10% of cases with known fam-
ily history of ALS are referred to as familial ALS
(fALS), and the remaining 90% of cases with
no known familial history are referred to as
sporadic ALS (sALS). In the sALS group, about
5% will still harbor gene mutations seen in
fALS, indicating that they have been misclassi-
fied based on the genetic history, and some will
harbor genetic variations that may be predis-
posing, such as the ataxin-2 intermediate repeat
expansions (Elden et al. 2010). Phenotypically,
fALS and sALS are indistinguishable. Heteroge-
neity occurs even in the same gene mutation
within a family. The fact that many different
gene mutations have identical or at least highly
similar clinical phenotypes suggests that there
are multiple mechanisms that cause ALS, and
that ALS is likely a syndrome. But the fact that
one single genotype can cause different pheno-
types indicates that single mechanisms can lead
to multiple phenotypes. The explanation for
this is unknown, but, traditionally, phenotypic
variation is thought to result from the complex
interplay between multiple genes and gene –
environment interactions.
Clinical phenotypes of ALS can be grossly
classified based on the level and anatomical area
of motor neuron involvement and pattern of
onset (Table 1). Typical, or “classical,” ALS in-
volves simultaneous UMN and LMN signs and
is usually fatal within 4 yr of onset. Muscle
weakness begins in a discrete body region and
advances steadily over time and space. It usually
begins in any of the three main body regions
(face, arm, and leg), although it rarely begins
in the muscles affecting the trunk and/or respi-
ration. Pathological burden is normally distrib-
uted between UMNs and LMNs with a possible
slight skew to LMN dominance (Ravits et al.
2007a). Atypical forms of the disease are cases
in which there is much longer survival, or pure
UMN or LMN involvement. These atypical
forms may contain instances of spastic para-
plegia, autoimmune diseases, or demyelinating
L.I. Grad et al.
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LMN disease, to name a few of the many pos-
sible causes, and are typically referred to by dis-
tinct clinical designations, highlighting the dis-
tinctiveness of phenotypes but also raising the
question of whether or not these are fundamen-
tally different biological conditions or the ex-
tremes of one continuum.
Primary lateral sclerosis (PLS) refers to a
syndrome predominantly involving UMN de-
generation; it remains unclear whether this
phenotype is a discrete disorder or a variant of
ALS (Rowland 1999; Swash et al. 1999; Le For-
estier et al. 2001; Zhai et al. 2003; Singer et al.
2005). In the majority of PLS patients, symp-
toms begin in the legs and ascend relatively
symmetrically to the arms and bulbar muscles.
There is contention about the involvement of
LMNs in PLS, especially when sensitive tools
such as electromyography (EMG) are used
(Gordon et al. 2006; Singer et al. 2007). Patients
with clinically distinct PLS and no EMG abnor-
malities 4 yr after symptom onset can often
survive for decades (Gordon et al. 2006; Tarta-
glia et al. 2007), whereas patients with minor
EMG changes or some LMN involvement may
have lower survival and poorer prognosis,
which is consistent with more typical ALS pa-
tients presenting with predominant UMN signs
(Gordon et al. 2009). Frontotemporal dementia
(FTD), cognitive impairment, and altered be-
havior occur in PLS comparable with ALS
(Grace et al. 2011).
Progressive muscular atrophy (PMA) refers
to a syndrome with predominant LMN in-
volvement. As opposed to typical ALS, PMA
onset can occur in any body region, has a higher
occurrence in males, and generally has a later
onset. Approximately 30% of PMA patients
develop UMN symptoms within 18 mo of dis-
ease onset (Visser et al. 2007; Kim et al. 2009).
Patients with PMA show the same frontotem-
poral pattern of cognitive involvement as is seen
in typical ALS, suggesting there is no correlation
between the degree of UMN involvement and
cognitive involvement (Raaphorst et al. 2011).
Neurophysiological studies of central motor
conduction using transcranial magnetic stimu-
lation show abnormalities in 50%–63% of pa-
tients with clinical PMA (Kaufmann et al. 2004;
Floyd et al. 2009).
The clinical phenotype designations PLS
and PMA are based on the level of the underly-
ing pathology. Other phenotypic designations
for ALS are based on the body region first
affected at disease onset (Table 1). Bulbar-onset
ALS (bulbar palsy) describes patients whose
onset is in the muscles of speech, chewing,
and swallowing and is traditionally signified
with predominant LMN involvement, whereas
the pseudobulbar variant is indicative of pre-
Table 1. ALS phenotypes based on anatomical region of neuropathology
Anatomical region of involvement
Neuronal region Somatic region
Phenotypic variant UMN LMN Bulbar muscles Limb muscles
Based on neuronal level of involvement
Typical ALS þþ þ þ
PLS þþ 2 þþ
PMA 2 þþ þ/2 þþ
Based on somatic region of involvement
Bulbar ALS 2 þþ þþ 2
Pseudobulbar ALS þþ 2 þþ 2
Limb ALS þþ 2 þþ
Limb variants þ/2 þþ 2 þþ
Mill’s variant þþ 22 þþ
Adapted from data in Ravits et al. 2013.
ALS, amyotrophic lateral sclerosis; UMN, upper motor neuron; LMN, lower motor neuron; þ/2, possible but not typical;
þ, typical and to variable degree; þþ, primary feature.
Clinical Spectrum of ALS
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dominantly UMN involvement. Both bulbar
and pseudobulbar forms of the disease have
similar progression. Bulbar onset has a higher
predominance in females and is highly asso-
ciated with cognitive involvement, altered and
exaggerated emotional expression (Turner et al.
2010), and often directly correlates with depres-
sion. Sequential functional MRI studies during
the course of bulbar- and limb-onset ALS pro-
vide direct observations of the interrelationship
between brainstem and spinal-cord-derived
neural networks (Kollewe et al. 2011). The ini-
tial onset of ALS in the limbs, which occurs
in more than two-thirds of patients, is often
referred to as “limb-onset” and is considered
the primary typical form of ALS. Limb-onset
ALS itself consists of some variants that are pre-
dominantly LMN syndromes that tend to be
slowly progressive. The upper extremity region-
al variant consists of weakness exclusively con-
fined initially to the upper extremities and can
often be described under different names such
as hanging arm syndrome, brachial amyotro-
phic diplegia, and Vulpian –Bernhart syndrome
(Gamez et al. 1999). Patients often have bilateral
upper extremity weakness and atrophy that af-
fects the proximal arms and shoulders (Katz
et al. 1999; Wijesekera et al. 2009). There is no
difference in age of onset between this variant
and typical ALS, although the former is more
common in males. The lower extremity regional
variant is confined to the legs and can be alter-
natively identified as the pseudopolyneuritic
variant of ALS, flail leg syndrome, and leg
amyotrophic diplegia (Wijesekera et al. 2009).
It is relatively rare, consisting of 3%–3.5%
of all motor neuron disease cases, and occurs
predominantly in men and largely in the LMN,
with slow progression and a mean survival
ranging from 76 –96 mo. Finally, Mill’s variant
(hemiplegic ALS) is a rare ALS variant pheno-
type characterized by a progressive hemiplegic
pattern of motor deficit that ascends from the
leg or descends from the arm, resembling a type
of PLS (Rajabally et al. 2005; Baumer et al.
2014). Scarce literature on Mill’s variant exists,
although one positron emission tomography
(PET) study on a patient showed a distinct lat-
eralization of microglial activation in the hemi-
sphere contralateral to the hemiplegia (Turner
et al. 2005).
Clinical phenotypes of ALS can also involve
nonmotor regions. The overlap between fronto-
temporal dementia (FTD) and ALS is well doc-
umented and discussed below (Kiernan and
Hudson 1994; Abe et al. 1997; Strong et al.
1999; Lomen-Hoerth et al. 2002, 2003), with
up to 15% of FTD patients and 30% of ALS
patients experiencing overlapping symptoms.
At this time, it is uncertain whether behaviorally
or cognitively impaired ALS has distinctly dif-
ferent pathobiological mechanisms from typi-
cal ALS, or is simply an extension of a singular
disease spectrum (Strong et al. 2009). A survival
difference of more than 1 yr exists between
comorbid FTD/ALS patients compared with
those with ALS alone (Olney et al. 2005). In
addition to dementia, other systems can be in-
volved in what otherwise seems to be typical
ALS, including extrapyramidal motor systems
(Knirsch et al. 2000; Pradat et al. 2002; Gamez
et al. 2008; Kovacs et al. 2009), supranuclear
gaze systems (Averbuch-Heller et al. 1998; Do-
naghy et al. 2011), and the autonomic nervous
system (Grosskreutz et al. 2006; van der Graaff
et al. 2009). Defects in energy metabolism in-
cluding weight loss, hypermetabolism, and hy-
perlipidemia have been associated with ALS,
suggesting that other regions of the central ner-
vous system (CNS), such as the hypothalamus,
may be implicated or that these symptoms are
all part of one systemic disease (Dupuis et al.
2011). There is sufficient clinical, neuropatho-
logical, and neuroimaging evidence in the liter-
ature suggesting that these atypical symptoms
should be considered part of the neuropatho-
logical spectrum of ALS/motor neuron disease
(MND) (McCluskey et al. 2009).
NEUROPATHOLOGICAL
HETEROGENEITY OF ALS
ALS is neuropathologically defined as the loss of
UMNs (Betz cells in layer V of area 4 of Brod-
mann) and LMNs (alpha motor neurons in the
motor nuclei of the brainstem and Rexed Lam-
ina IX of the anterior horns in the spinal col-
umns). Wallerian/axonal degeneration in the
L.I. Grad et al.
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projecting pathways from the UMNs is typically
observed in the corpus callosum, centrum semi-
ovale, internal capsule, cerebral peduncle, basis
pontis, medullary pyramids, and lateral col-
umns in typical ALS. Similar degeneration is
seen in the anterior roots and peripheral nerves
of LMNs, leading to muscle denervation. In ad-
dition, there are astrogliosis, spongiosis, and
microglial activation, indications of a more pri-
mary role for non-neuronal cells in the disease
(Boillee et al. 2006; Haidet-Phillips et al. 2011;
Lasiene and Yamanaka 2011). Similar neuro-
pathology is reported for other ALS clinical
phenotypes such as PMA and PLS, differing
mostly in their anatomical distribution of pa-
thology rather than the nature and composition
of the pathology itself (Pringle et al. 1992; Ince
et al. 2003). Distinct pathological change is also
identified in the motor and extramotor areas of
the brain and spinal cord of patients whose dis-
ease was clinically limited to the LMNs (Geser
et al. 2011). PLS neuropathology also shows
changes in the LMNs, which display the same
molecular pattern as seen in typical disease (Ko-
bayashi et al. 2010).
Although traditional neuropathology typi-
cally features loss of motor neurons in the
brainstem and ventral horn of the spinal cord,
accompanied with signs of inflammation such
as astrocyte activation and proliferation of mi-
croglia (Philips and Robberecht 2011), molec-
ular neuropathology is redefining postmortem
changes. Often appearing either skein-like or
dense and round, ubiquitinated inclusions in
the cytoplasm of motor neurons of patients
are a classical neuropathological indicator of
ALS (Leigh et al. 1988; Lowe et al. 1988). In
fALS cases in which a SOD1 mutation is iden-
tified, the primary component of these pro-
tein inclusions is SOD1 itself (Kato et al.
2000). Normally, SOD1 is a soluble, ubiqui-
tously expressed, free-radical scavenging en-
zyme that exists as a functional homodimer.
There is also increasing evidence supporting
the presence of misfolded SOD1 in sporadic
cases with no SOD1 mutations (Bosco et al.
2010; Forsberg et al. 2010; Pokrishevsky et al.
2012; Grad et al. 2014), suggesting a more ex-
panded role for SOD1 in ALS pathology. fALS
cases in which mutations in the gene encoding
FUS, an RNA-binding transcriptional activator,
have been identified and also result in patholog-
ical inclusions in the cytosol of neural cells
(Huang et al. 2010; Sun et al. 2011). The pres-
ence of ubiquitinated protein deposits primar-
ily composed of TDP-43, a nuclear protein in-
volved in DNA and RNA processing that has
been translocated to the cytoplasm, hyperphos-
phorylated, and cleaved, have also been identi-
fied in 50% of brains from FTD patients (Arai
et al. 2006; Neumann et al. 2006). In addition,
essentially all sALS and nearly all fALS cases,
except those associated with mutations in the
genes encoding SOD1 and FUS regardless of
clinical phenotype (including PLS and PMA),
seem to have the hallmark neuropathological
deposition of ubiquitinated TDP-43 in the cy-
toplasm of CNS cells, suggesting that ALS may
be a TDP-43 proteinopathy. Heat maps of the
distribution of TDP-43 pathology show that ab-
normalities are widely present in the brain, not
just in motor regions (Geser et al. 2008). Despite
their structural, functional, and pathological
similarities, FUS and TDP-43 do not colocalize
within pathological inclusions in the cytoplasm
(Huang et al. 2010; Sun et al. 2011), suggesting
that the two proteins are involved in the pathol-
ogy via distinct, albeit related, mechanisms.
Finally, the discovery of GGGGCC hexanucleo-
tide repeat expansions within the C9ORF72
gene in ALS patients has now been identified
as the most common mutation in families
with ALS or FTD (Mackenzie et al. 2013). Hex-
anucleotide expansion in C9ORF72 is found in
nearly 40% of all fALS cases and up to 7% of
sALS (Maniecka and Polymenidou 2015). In
normal individuals, the hexanucleotide repeat
length is typically no longer than 25–30 units,
but in ALS patients possessing a C9ORF72 mu-
tation, repeat length can exceed 700 (DeJesus-
Hernandez et al. 2011; van Blitterswijk et al.
2013). C9ORF72-associated ALS cases typically
present with TDP-43 aggregation and p62-
positive/TDP-43-negative ubiquitinated inclu-
sions in the cerebellar and hippocampal regions
(Al-Sarraj et al. 2011; Troakes et al. 2012). Mu-
tations within C9ORF72 result in the subse-
quent production of aggregating dipeptide-re-
Clinical Spectrum of ALS
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