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of Pages 6

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Available online at

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www.sciencedirect.com

Motor neuron diseases

Motor neuropathies and lower motor neuron

syndromes

A. Verschueren
Reference Centre for Neuromuscular Diseases and ALS, University Hospital La Timone, 264 rue Saint Pierre, 13385
Marseille cedex 05, France

info article abstract

Article history: Motor or motor-predominant neuropathies may arise from disease processes affecting the
Received 16 February 2017 motor axon and/or its surrounding myelin. Lower motor neuron syndrome (LMNS) arises
Received in revised form from a disease process affecting the spinal motor neuron itself. The term LMNS is more
16 March 2017 generally used, rather than motor neuronopathy, although both entities are clinically
Accepted 29 March 2017 similar. Common features are muscle weakness (distal or proximal) with atrophy and
Available online xxx hyporeflexia, but no sensory involvement. They can be acquired or hereditary. Immune-
mediated neuropathies (multifocal motor neuropathy, motor-predominant chronic inflam-
Keywords: matory demyelinating polyneuropathy) are important to identify, as effective treatments
Motor neuropathy are available. Other acquired neuropathies, such as infectious, paraneoplastic and radia-
Lower motor neuron syndrome tion-induced neuropathies are also well known. Focal LMNS is an amyotrophic lateral
Motor neuronopathy sclerosis (ALS)-mimicking syndrome especially affecting young adults. The main hereditary
ALS LMNSs in adulthood are Kennedy’s disease, late-onset spinal muscular atrophy and distal
Spinal muscular atrophy hereditary motor neuropathies. Motor neuropathies and LMNS are all clinical entities that
Benign monomelic amyotrophy should be better known, despite being rare diseases. They can sometimes be difficult to
differentially diagnose from other diseases, particularly from the more frequent ALS in its
pure LMN form. Nevertheless, correct identification of these syndromes is important
because their treatment and prognoses are definitely different.
# 2017 Elsevier Masson SAS. All rights reserved.

However, the term ‘lower motor neuron syndrome’ (LMNS),

1. Introduction
The motor or motor-predominant neuropathies may arise
from disease processes affecting the motor axon and/or its
surrounding myelin. Common features are muscle weakness
with atrophy that is often distal, and hyporeflexia with no
sensory involvement. The disease process also affects the
anterior horn cell, namely motor neuronopathy, which is
clinically similar but with possible proximal involvement.
rather than ‘motor neuronopathy’, is more generally used.
These are rare diseases, but their identification is impor-
tant when making a differential diagnosis from the more
frequent amyotrophic lateral sclerosis (ALS) in its pure LMN
form.
Thus, clinical evaluation is an important step for diagnosis.
Assessment of disease onset, asymmetrical weakness at
onset, distal vs proximal weakness, weakness in the distribu-
tion of individual peripheral nerves, subacute or progressive

E-mail address: annie.verschueren@ap-hm.fr.

http://dx.doi.org/10.1016/j.neurol.2017.03.018
0035-3787/# 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Verschueren A. Motor neuropathies and lower motor neuron syndromes. Revue neurologique (2017), http://
dx.doi.org/10.1016/j.neurol.2017.03.018
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2 revue neurologique xxx (2017) xxx–xxx

Disease onset Acute:

motor variant of GBS, AMAN,

Subacute:

Chronic

Hereditary Acquired

Topography usually asymmetrical

usually symmetrical

Distal HMN Focal LMNS or benign monomelic atrophy

Distal

UL focal LMNS LL focal LMNS

Hirayama disease
UL predominance LL predominance
dHMN yype 5 dHMN type 1 or 2
Distal PMA (flail leg)

Proximal SMA type III et IV Proximal

Proximal PMA (flail arm)
Bulbo-spinal SMA (Kennedy)

SMA Scapuloperoneal phenotype CIDP motor predominant

Mixed,
Jokela type SMA
Proximal and/or PMA (or pure LMN form of ALS)
distal
Hereditary PMA

Fig. 1 – Diagnostic algorithm for adult patients with pure motor weakness of peripheral origin, suspected based on signs
such as muscular atrophy, hyporeflexia/areflexia, fasciculations and cramps.

onset and stepwise progression should be documented (Fig. 1).
The examination should determine the precise pattern of the
motor deficit, presence of muscular atrophy or not, twitching,
cramps, myokymia and presence or absence of reflexes, all of
which are factors that can distinguish the different diseases.
Tremor may be present, providing an argument for hereditary
disease such as spinal muscular atrophy or spinal–bulbar
muscular atrophy.
The patient’s medical history (radiotherapy, infections,
poliomyelitis and so on) and general examination should be
carefully evaluated. The familial history should be done
systematically, as it can provide valuable information. For
example, distal hereditary motor neuropathy is often auto-
somal-dominant whereas Kennedy’s disease is X-linked.
Nerve conduction studies (NCS) and electromyography
(EMG) are essential for refining the clinical diagnosis. NCS

Please cite this article in press as: Verschueren A. Motor neuropathies and lower motor neuron syndromes. Revue neurologique (2017), http://
dx.doi.org/10.1016/j.neurol.2017.03.018
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Table 1 – Main underlying disease mechanisms of motor neuropathies and lower motor neuron syndrome (LMNS) in
adults.
Acquired
Immune
Acute onset: Guillain–Barré syndrome, acute motor axonal neuropathy
Progressive or stepwise: multifocal motor neuropathy or motor predominant CIDP
Subacute: paraneoplastic LMNS
Degenerative
PMA or pure LMN form of ALS: including variants: flail-leg/flail-arm syndromes
Focal LMNS or benign monomelic amyotrophy: including Hirayama disease, upper-limb focal LMNS with snake-eyes appearances on
cervical MRI (origin: microtrauma? microcirculatory disturbance?)
Radiation-induced
Mainly lumbosacral plexopathy
Infectious
HIV, Lyme disease, polioviruses, enteroviruses, flaviviruses, varicella-zoster virus (VZV), postpolio syndrome
Other
Lead, porphyria, amyloidosis toxicities
Hereditary
Distal hereditary motor neuropathy
Hereditary PMA (or pure LMN form of ALS)
Kennedy’s disease
Late-onset proximal spinal muscular atrophy (SMA) types III/IV
Late-onset spinal motor neuronopathy (or Jokela-type SMA)
CIDP: chronic inflammatory demyelinating polyneuropathy; PMA: progressive muscular atrophy; ALS: amyotrophic lateral sclerosis; MRI:
magnetic resonance imaging; HIV: human immunodeficiency virus.

may allow confirmation of pure motor involvement or reveal
subclinical sensory impairment, and determine the pattern of
involvement, symmetrical or not, and length dependence. An
axonal process is more often the case. On the other hand, a
demyelinating process, with or without conduction blocks,
should steer the diagnosis toward immune-mediated neuro-
pathies, such as chronic inflammatory demyelinating poly-
neuropathy and multifocal motor neuropathy. EMG can
confirm the neurogenic syndrome and its extension, and
determine the presence of spontaneous activities, fascicula-
tion potentials and/or whether the denervation is acute or
chronic. At this stage, electrophysiological studies can exclude
some differential diagnoses, such as muscle diseases (inclu-
sion-body myositis, distal myopathy) and disorders of the
neuromuscular junction.
In terms of this primary clinical electrophysiological
diagnosis, other examinations are also useful. Spine magnetic
resonance imaging (MRI), cerebrospinal fluid (CSF) and
biological examinations, specific antibody tests, other electro-
physiological studies [transcranial magnetic stimulation
(TMS) using the triple stimulation technique (TST)] and
molecular genetic testing may be done according to the
direction of the diagnosis. The present review outlines the
various motor neuropathies and LMNSs of adulthood (Table 1).
2. Immune-mediated motor neuropathies
Several of these neuropathies may be pure motor or motor-
predominant. They are important to differentiate because
they may respond to immunotherapy. An acute onset is
characteristic of Guillain–Barré syndrome, while a number of
variants have been described, including a pure motor disorder
such as acute motor axonal neuropathy (AMAN).
Chronic forms include multifocal motor neuropathy (MMN)
and motor-predominant chronic inflammatory demyelinating
polyneuropathy (CIDP). MMN typically presents with asym-
metrical distal weakness, with an initial involvement more
frequently in the upper limbs [1]. Motor weakness in the
distribution of individual nerves is characteristic, median or
ulnar nerve involvement is frequent, and either the radial or
fibular nerve may be involved. Progression is slow or stepwise,
and there is no sensory impairment. Another feature of MMN
is motor weakness without atrophy. Amyotrophy is late and,
sometimes, muscle hypertrophy may be present. Positive
features, such as fasciculations and cramps, are also common
in MMN, as are hyporeflexia and areflexia, while brisk reflexes
are possible.
Evidence of conduction blocks (CBs) is considered one of
the most relevant criteria for a diagnosis of MMN. CBs may be
present in nerves with no clinical involvement and, thus,
require careful consideration of NCS [2]. In patients with MMN,
CBs located between the nerve root and Erb’s point cannot be
detected by the classic NCS. However, TMS using TST can
reveal proximal focal CBs [3,4]. CSF protein levels are normal
or slightly elevated, while anti-GM1 antibodies are present in
40–50% of MMN patients. Plexus MRI may reveal nerve
enlargement and signal-intensity abnormalities. Intravenous
immunoglobulin (IV Ig) treatment improves the majority of
MMN patients and the functional prognosis is generally good.
Trials of IV Ig may be warranted in selected cases of
asymmetrical adult-onset LMNS with no demonstrable CBs,
particularly those with distal-onset upper-limb weakness
[1,2].
CIDP may present with a pure motor or motor-predomi-
nant form and subclinical involvement. Although NCS are very
sensitive for diagnosing CIDP and can show signs of
demyelination, if the motor axonal loss is severe, the specific
electrophysiological criteria of CIDP may not be met. In such
cases, other laboratory tests, such as elevated CSF proteins,
antiganglioside antibodies and plexus MRI are helpful. A nerve
biopsy could also be done in these atypical cases of CIDP, and

Please cite this article in press as: Verschueren A. Motor neuropathies and lower motor neuron syndromes. Revue neurologique (2017), http://
dx.doi.org/10.1016/j.neurol.2017.03.018
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may show signs of demyelination to confirm the primary
demyelinating process [5].
3. Other acquired motor neuropathies
These include numerous neuropathies, but they represent
less of a diagnostic problem because the medical history is
suggestive. Radiation-induced plexopathy, particularly lum-
bosacral plexopathy, may present with pure motor or motor-
predominant forms. The onset latency may be months to
years after high-dose radiation. These also present with
asymmetrical leg weakness (distal and/or proximal) with
areflexia, and progression is slow. Fasciculations are present
and myokymia suggestive [6]. Hypoglossal or glossopharyn-
geal neuropathy can appear after radiation therapy for oral
cancer. A medical history of radiotherapy can support these
complications if the neurological involvement corresponds to
the irradiation field.
Although rare, paraneoplastic pure motor neuropathy and
LMNS have been described with solid cancers [7] and with
lymphoproliferative disorders, particularly non-Hodgkin’s
lymphoma [8]. Paraneoplastic LMNS should be considered in
cases of subacute onset with rapid progression, within 6
months. In such cases, antineuronal antibodies (for example,
anti-Hu, anti-CV2/CRMP5), elevated CSF protein levels and the
presence of oligoclonal bands in CSF can help identify the
autoimmune nature of the disease. Any underlying cancer,
however, must be carefully researched. Treatment of mali-
gnancy along with immunomodulatory therapy may result in
a favorable long-term outcome [7].
Infections can cause LMNS in adults. ALS-like syndrome
has been described with human immunodeficiency virus (HIV)
infection and Lyme disease [9,10]. Poliomyelitis is a rare
complication of poliovirus infection and has been eradicated
in Western countries, but remains endemic in Nigeria,
Pakistan and Afghanistan. Other enteroviruses and flaviviru-
ses, such as West Nile virus, can also cause acute flaccid
paralysis due to anterior horn cell disease [11]. Postpolio
syndrome is easy to diagnose in a patient with a medical
history of acute poliomyelitis, although this may not always be
the case [12,13]. The syndrome develops after a period of stability
in a proportion of patients who have recovered from acute
poliomyelitis. Symptoms can include the development of new
weakness and muscle atrophy, fatigue and pain. EMG shows a
chronic process of denervation–reinnervation, with enlarged
reinnervated motor units in territories initially involved, as well
as in clinically unharmed or recently involved territories.
Lead and porphyric neuropathies are commonly motor-
predominant neuropathies, but are typically associated with
suggestive involvement of other organ systems; additional
features can include gastrointestinal symptoms, cognitive
disturbances and hematological changes. These are treatable
causes of motor neuropathy. Lead toxicity can lead to subacute
motor neuropathy, classically affecting the wrist and finger
extensors before spreading to other muscles. Porphyria may
present with an acute or subacute, predominantly motor
neuropathy and also with focal weakness at onset, such as
wrist drop or foot drop. Amyloid neuropathy may present with
a motor-predominant neuropathy at onset [14].
Please cite this article in press as: Verschueren A. Motor neuropathies and lower motor neuron syndromes. Revue neurologique (2017), http://
dx.doi.org/10.1016/j.neurol.2017.03.018
3.1. Degenerative LMNS
The most common acquired LMNS has a degenerative cause.
A combination of both upper motor neuron (UMN) and LMN
signs is the pathognomonic hallmark of ALS. Pure LMN forms,
such as progressive muscular atrophy (PMA), have been
described and represent one end of the motor neuron disease
(MND) clinical spectrum. Nevertheless, whether PMA is a
distinct nosological entity separate from ALS has been debated
since it was first described [15,16]. It represents almost 5% of
MND cases and is characterized by slower progression than
other forms of MND. Progressive LMN signs with no clinical
evidence of UMN involvement are characteristic, although a
substantial number of patients presenting with LMNS even-
tually develop UMN signs during the disease course. Neuro-
physiological techniques, such as TMS using TST, may
demonstrate evidence of subclinical corticospinal dysfunction
[17]. Brain MRI using diffusion tensor imaging may show
structural involvement of the corticospinal tract (CST) in
patients with ALS [18]. New techniques of brain MRI, spinal
cord MRI and positron emission tomography (PET) are now
being discussed as biomarkers, but their diagnostic value at
the individual level remains limited at this time [19]. Distinct
variants have been described, with flail-leg syndrome (the
pseudopolyneuritic variant or Marie–Patrikios form) charac-
terized by a progressive asymmetrical, predominantly LMN,
pattern of weakness with distal-onset weakness and wasting
of the lower limbs. Flail-arm syndrome (brachial amyotrophic
diplegia or ‘man-in-the-barrel’ syndrome) is a distinct variant
of MND typified by a progressive, predominantly LMN, pattern
of weakness in the upper limbs, typically beginning in
proximal muscle groups with progression to distal involve-
ment. Slower progression is common, whereas bulbar
dysfunction is rare and late. A variety of genetic mutations
found in familial ALS may be associated with PMA but, as with
classic ALS, sporadic PMA is the most frequent form [20].
3.2. Focal LMNS
Focal or segmental LMNS is a rare condition in which
neurogenic amyotrophy is restricted to either the upper or
lower limbs. This benign form of monomelic amyotrophy is
usually sporadic, and has an insidious onset with slow
progression over 4–5 years, followed by stabilization [20].
EMG features are suggestive of LMN dysfunction not only in
the affected limb but also, in some cases, in the clinically
uninvolved limb. Cervical or lumbar MRI is usually normal but,
in some upper-limb forms, the ‘snake-eyes’ appearance
(bilateral hyperintensities) in the anterior horns of the cervical
cord on axial T2-weighted MRI may be seen. This form of LMNS
is more common in young men with a history of strenuous
physical activity or a medical history of trauma, and has a
relatively benign prognosis [21].
Hirayama disease is a particular entity that presents with
insidious-onset focal wasting and weakness, most commonly
affecting the hand and forearm while sparing the brachiora-
dialis muscle, thus resulting in ‘oblique amyotrophy’, a clinical
sign first described in cases by Hirayama et al. [22].
Involvement of the contralateral upper limb may also be
present. Symptoms typically progress over a period of 1–5
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years and then stabilize. Bulbar, sensory and pyramidal signs
are absent. The condition has a striking male predominance,
an age of onset in the late teens or early 20s and is more
commonly seen in Asian countries. The first autopsy case
showed anteroposterior flattening and ischemic necrotic
changes in the anterior horns of the cervical cord at C5–T1,
which was most severe at C7–C8. These findings suggested
circulatory insufficiency of the lower cervical cord, yet the
intra- and extramedullary vessels were normal. MRI findings
in Hirayama disease may reveal lower cervical cord atrophy
(C5–C7), asymmetrical cord flattening and/or intramedullary
hyperintensities, with anterior displacement of the dorsal
dura on neck flexion. Radiological studies suggest that
sustained or repeated neck flexion might cause an anterior
shift of the cervical dural sac, while the compressed cervical
cord at the involved segments then induces increased
intramedullary pressure, resulting in microcirculatory dis-
turbances in the anterior horn, the structure most vulnerable
to ischemia in the spinal cord [23].
4. Distal hereditary motor neuropathy
These distal neuropathies (dHMNs) represent a genetically
heterogeneous group overlapping with axonal forms of
Charcot–Marie–Tooth disease, adding further complexity to
the diagnostic approach. They share features such as a slowly
progressive, length-dependent, distal-predominant pattern of
motor neuropathy. Significant sensory involvement is absent.
Most are inherited in an autosomal-dominant (AD) pattern,
but autosomal-recessive (AR) and X-linked inheritance pat-
terns have also been described [24,25]. Clinical phenotypes are
important for genetically classifying these diseases: upper-
limb predominance is dHMN type 5; vocal cord paralysis is
dHMN type 7; respiratory distress is dHMN type 6; and
pyramidal signs [26]. Yet, despite significant advances in
molecular genetics, the disease-causing mutation is identified
in only about 15% of patients with a typical presentation of
dHMN [27]. Mutations in the HSPB1, HSPB8 and BSCL2 genes are
the most frequent causes of AD dHMNs, with mutations in the
former two genes associated with a classic length-dependent
motor neuropathy beginning in the lower limbs (dHMN type 1
or type 2). Phenotypes associated with mutations in the BSCL2
gene include dHMNs with length-dependent motor neuropa-
thy, dHMN presenting with predominantly upper-limb distal
neuropathy (type 5) and dHMN with pyramidal signs. The
upper-limb onset phenotype (dHMN 5) may also result from
mutations in the GARS gene. Bulbar involvement is rare in
dHMNs, although vocal paralysis secondary to recurrent
laryngeal nerve involvement is a feature of dHMN type 7,
which may result from mutations in the dynactin (DCTN1) and
TRPV4 genes. Scapuloperoneal involvement has also been
described with mutations in the TRPV4 gene.
4.1. Hereditary LMNS
The most common adult-onset hereditary LMNS is spinal–
bulbar muscular atrophy (SBMA), or Kennedy’s disease. The
second most common is proximal spinal muscular atrophy
(SMA), but rarely in its late-onset form.
Please cite this article in press as: Verschueren A. Motor neuropathies and lower motor neuron syndromes. Revue neurologique (2017), http://
dx.doi.org/10.1016/j.neurol.2017.03.018
5
Kennedy’s disease is caused by a cytosine–adenine–
guanine (CAG) trinucleotide repeat expansion in the androgen
receptor gene on the X chromosome [28]. Degeneration of
motor neurons in the spinal cord and brain stem leads to a
slowly progressive disorder characterized by weakness and
atrophy of facial, bulbar and limb muscles, with no UMN signs.
Onset is typically at age 30–50 years, but there is marked
variability in age of presentation. Cramps, leg weakness,
tremor and fasciculations with bulbar symptoms are the most
common presenting symptoms. The weakness is typically first
noted in the lower limbs, affecting proximal muscles with
reduced or absent reflexes, and myalgias are frequent.
Associated androgen resistance may result in gynecomastia,
testicular atrophy and oligospermia. Axonal sensory neuropa-
thy is commonly associated, although it is usually subclinical
and revealed by NCS. The diagnosis is confirmed by molecular
genetic testing. The progression is slow, with loss of ambula-
tion at around 20–30 years after onset. Life expectancy may be
reduced, most commonly due to pneumonia as a result of
bulbar dysfunction. The syndrome is X-linked and usually
affects men, although women who are carriers may have mild
symptoms.
Proximal SMA is classified into four groups, on the basis of
age of onset and clinical course, as type I to type IV. SMA type
III has a milder phenotype with signs of weakness after 1 year
of age, although patients are able to walk unaided. It is
associated with wide variability in age of onset, disease
progression and ambulatory period, with some patients only
developing walking difficulties in adulthood. Weakness
affects the proximal muscles with atrophy and reduced or
absent reflexes, while tremor is suggestive. In contrast,
proximal SMA type IV presents in the third or fourth decade
of life with a slowly progressive and relatively benign course.
These are AR diseases, and patients are homozygous for
deletion of exon 7 in the SMN1 gene, located on chromosome
5q13 in >90% of cases. A small percentage of patients are
compound heterozygous for mutations of the SMN1 gene [20].
A third form of hereditary LMNS has recently been
described in Finnish families with an AD late-onset spinal
motor neuronopathy [LOSMoN, or Jokela-type SMA (SMAJ)]
[29]. A G66V mutation in the CHCHD10 gene is the cause of this
LOSMoN/SMAJ form of LMNS [30]. The first symptoms are
muscle cramps and fasciculations after age 25–30 years,
followed by a slowly progressive proximal and distal weakness
with no overt atrophy during the first decades of symptoms,
but with areflexia. Other features, such as tremor, myalgia and
mild bulbar findings, may arise. Nerve conduction velocities
are within the normal range and EMG shows widespread
neurogenic alterations. The disease is relatively benign in
terms of life expectancy and rate of disability progression;
however, it is noteworthy that some patients were initially
misdiagnosed as ALS.
5. Conclusion
Motor neuropathies and LMNS are clinical entities that need to
become better known. They are rare, but they represent
sometimes difficult differential diagnoses from other, more
frequent diseases, such as ALS in its pure LMN form.
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6 revue neurologique xxx (2017) xxx–xxx
Nevertheless, the correct identification of these syndromes is
important because their treatment and prognosis are defini-
tely different.
Disclosure of interest
The author declares that he has no competing interest.
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