Journal of Neurology (2018) 265:1717–1725

https://doi.org/10.1007/s00415-018-8856-1

NEUROLOGICAL UPDATE

Update on muscle disease

J. Witherick1 · S. Brady1

Received: 8 March 2018 / Accepted: 30 March 2018 / Published online: 18 April 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
In this article, we highlight some of the most important developments from the last few years in the field of muscle diseases,
including new additions to the congenital myasthenic syndromes (CMS) and limb-girdle muscular dystrophies (LGMD),
advances in our understanding of the pathophysiology of certain muscle disorders and progress in diagnostics and thera-
peutics. Unsurprisingly, the most prominent developments have come from the field of genetics, with significant advances
in diagnosis and gene therapy giving hope to those with hitherto untreatable conditions.

Keywords  Myopathy · Inclusion body myositis · Myasthenia gravis · Limb-girdle muscular dystrophy · Duchenne muscular
dystrophy · Spinal muscular atrophy

Aetiology published the findings of a large molecular genetic study of

Inclusion body myositis
Inclusion body myositis (IBM) is the commonest acquired
myopathy in those over 50 years of age. Previously, definite
diagnosis was based on the presence of certain pathological
changes identified on muscle biopsy, in particular an auto-
aggressive endomysial inflammatory infiltrate as evidenced
by invasion of intact muscle fibres, the presence of rimmed
vacuoles, and amyloid-positive inclusions or 15–18  nm
tubulofilaments identified using electron microscopy. More
recently, it was shown that mitochondrial changes and pro-
tein aggregates (particularly autophagy-associated protein—
p62) are, respectively, sensitive and specific pathological
features [8]. Increasing knowledge of the pathological fea-
tures of IBM and its characteristic pattern of weakness at
presentation (finger flexion and knee extension weakness)
led to the development of the most sensitive criteria to date,
the 2011 European Neuromuscular Centre (ENMC) diag-
nostic criteria [45]. While pathological findings such as pro-
tein aggregation and mitochondrial abnormalities suggest
that autophagy may play a role in IBM, the aetiology and
pathogenesis of the condition remain uncertain, limiting the
potential for therapeutic intervention. Gang et al. recently
* J. Witherick
Jonathan.Witherick@nbt.nhs.uk
1
Southmead Hospital, Bristol, UK
181 IBM patients [21]. They discovered the presence of rare
missense variants in the autophagy-related genes SQSTM1
(p62) and VCP (which encodes an ATPase associated with
various cellular activities) in some patients, suggesting a
possible genetic susceptibility to IBM. Reconciling the
inflammatory and degenerative doctrine of IBM, Benven-
iste et al. suggested that there may be an initial inflamma-
tory event which overloads protein degradation systems in
genetically susceptible individuals, leading to protein depo-
sition within the muscles and initiating a cyclical myopathic
process [4].
Although it is now clear that IBM bears little clinical sim-
ilarity to other inflammatory myopathies, it was originally
classified as an idiopathic inflammatory myopathy because
of the pathological features observed. The inflammatory ele-
ment of IBM was further informed by molecular profiling
[24] and microarray analysis [23] of muscle tissue, including
the identification of B-cell immunoglobulin transcripts in
muscle tissue indicating antigen-mediated B-cell activity.
In 2011, Greenberg et al. identified a 43 kDa muscle protein
targeted by circulating antibodies in 52% of patients with
IBM [46]. The target antigen was subsequently identified as
cytosolic 5′-nucleotidase 1A (cN1A) in contemporaneous
papers published in Annals of Neurology by Pluk et al. [42]
and Larman et al. [31].
Larman et al. utilised mass spectrometry of human mus-
cle lysate reactive with serum from a patient with IBM to
identify potential candidate autoantigens [31]. These were

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then cross-referenced with peptides that were enriched
in whole exome sequencing of patients with IBM. cN1A
was the only candidate protein within the human proteome
homologous to the isolated peptide. Furthermore, cN1A was
one of seven antigens isolated by mass spectrometry. West-
ern blotting confirmed reactivity of sera from patients with
IBM with recombinant cN1A.
In a parallel study, Pluk et al. identified a Mr 44,000
polypeptide (muscle protein 44—Mup44) by immunoblot-
ting sera from patients with IBM [42]. Analysis using liquid
chromatography–mass spectrometry indicated that the pep-
tide was analogous to cN1A. The findings were confirmed
with consequent immunoprecipitation of sera from patients
with IBM with recombinant cN1A.
The development of a reliable serological marker for IBM
would alter the current investigative strategies employed in
suspected cases of IBM. The most recent diagnostic crite-
ria put forward—the 2011 European Neuromuscular Centre
criteria [45]—are the most sensitive criteria to date, with
a specificity of close to 100%. Diagnostic performance
of cN1A antibody detection is limited by area under the
curve parameters in which increasing sensitivity is com-
promised by declining specificity. A specificity of 95% can
be achieved, but with a sensitivity of approximately 33%.
One study improved the sensitivity to 76% using multiple
immunoglobulin isotypes [22]. A further potentially limit-
ing factor is the identification of cN1A antibodies in other
conditions including Sjögren’s syndrome (36% of cases) and
systemic lupus erythematous (20% of cases) [27]. Further
research is required before antibody testing for IBM can be
incorporated into diagnostic criteria [28].
Tubular aggregate myopathy
Tubular aggregate myopathies (TAM) are a heterogene-
ous group of disorders characterised by tubular aggregates
(TA) on muscle biopsy. TAs are densely packed areas of
membranous tubules first identified in muscle biopsies from
dyskalaemic patients [17]. Immunohistochemical and ultra-
structural studies have revealed that TAs are derived from
the sarcoplasmic reticulum [47]. TAs display a character-
istic histochemical staining pattern, appearing bright red
on modified Gömöri trichrome, positive on nicotinamide
adenine dinucleotide tetrazolium reductase (NADH-TR)
and myoadenylate deaminase (ADD) stains, and negative
on cytochrome oxidase (COX) and succinate dehydrogenase
(SDH) stains. However, TAs are not specific for TAM and
can be seen in a number of conditions, for example normal
ageing [7], alcohol- and drug-induced myopathies, and, as
described below, CMS [12]. Recently, several causes of an
autosomal dominant TAM have been described in patients
with calcium channelopathies.
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Journal of Neurology (2018) 265:1717–1725
Using exome sequencing, Bohm et al. identified a het-
erozygous missense mutation in the gene encoding stromal
interaction molecule 1 (STIM1) in four families affected by
an autosomal dominant TAM [11]. STIM1 plays a key role
in the activation of ORAI1, the pore-forming unit of C ­ a2+
2+
release-activated ­Ca (CRAC) channels. Analysis of cyto-
plasmic ­Ca2+ in transfected myoblasts using flow cytometry
techniques demonstrated enhanced store-operated ­Ca2+ entry
(SOCE), indicative of a gain of function as predicted by the
missense mutation. Affected patients displayed predomi-
nantly proximal lower limb weakness, variable ophthalmo-
paresis without ptosis, and increased plasma creatine kinase
(CK) levels (4-27 × normal). It was later discovered that
gain-of-function mutations in STIM1 were also responsible
for the rare Stormorken and York platelet syndromes, in
which there was platelet dysfunction manifesting as throm-
bocytopenia and bleeding diathesis, miosis, ophthalmople-
gia without ptosis, and TAM [33, 37, 38]. Gain-of-function
mutations in ORAI1 have also been identified as a cause
of Stormorken-like syndrome with TAM and miosis, but
without haematological abnormalities [38]. Loss of function
mutations in both STIM1 and ORAI1 are associated with
reduced muscle strength and endurance, delayed motor mile-
stones, and severe combined immunodeficiency syndrome
[18, 41].
The effects of loss-of and gain-of function mutations in
STIM1 and ORAI1 provide insights into the key role of cal-
cium physiology and the central nature of CRAC channels
in cell function and diseases of muscle and of the immune
system. The identification of pupillary abnormalities in
patients with TAM is a useful clinical indicator to guide
genetic testing.
Congenital myasthenic syndromes
Congenital myasthenic syndromes (CMS) are a clinically
and genetically heterogeneous group of rare inherited dis-
orders resulting from dysfunction of proteins integral to the
function of the neuromuscular junction (NMJ). The dis-
covery of new genetic causes of CMS continues to inform
our understanding of the NMJ. Determining the underlying
genotype in CMS is clinically relevant as it influences treat-
ment decisions.
Over the last few years, mutations in genes involved in
protein glycosylation have been identified in limb-girdle
pattern CMS (LG-CMS) which demonstrates a favour-
able response to acetylcholinesterase inhibitors. The first
gene identified encoded glutamine-fructose-6-phosphate
transaminase 1 (GFPT1) on chromosome 2p13.3 [50].
GFPT1 catalyses the transfer of an amino group from
glutamine to fructose-6-phosphate, yielding glucosamine-
6-phosphate and glutamate. This is the first, and rate-
limiting, step of the hexosamine biosynthesis pathway,
Journal of Neurology (2018) 265:1717–1725 1719
the major end product of which is UDP-N-acetylglucosa-
mine, a key substrate for protein glycosylation. Whilst
the precise function of GFPT1 in relation to the NMJ is
unknown, the resulting hypoglycosylation of key NMJ
proteins, including muscle-specific kinase and acetylcho-
line receptor (AChR) subunits, is thought to be central to
the pathogenesis of the condition.
Following its initial identification, Guergueltcheva
et al. published a case series describing the clinicopatho-
logical features of 24 patients with CMS due to mutations
in GFPT1 (CMS-GFPT1) [25]. Most patients developed
symptoms in the first decade of life with fatigable limb-
girdle weakness and minimal muscle atrophy; however,
onset was as late as the fifth decade in some patients.
CMS-GFPT1 is classified as LG-CMS because of the
presence of prominent limb-girdle weakness with mini-
mal facial and ocular involvement. CMS due to mutations
in DOK7 is also a common cause of LG-CMS. Clini-
cal features that can help differentiate these two condi-
tions are the absence of ocular, facial, bulbar, and res-
piratory muscle weakness, and a sustained benefit from
acetylcholinesterase inhibition in CMS-GFPT1. Tubular
aggregates (TA) were identified in 13/18 muscle biop-
sies from patients with CMS-GFPT1 and were best seen
with nicotinamide adenine dinucleotide (NADH) stain-
ing. All patients treated with acetylcholinesterase inhibi-
tors (22/24) showed a good response to treatment with a
median dose of 217 mg/day, though the benefit was not
sustained in four patients from two pedigrees.
Guergueltcheva et al. found that not all patients with
LG-CMS and TAs on muscle biopsy have mutations in
GFPT1, suggesting additional genetic causes. Using
whole exome and high throughput sequencing, Belaya
et al. identified mutations in the gene encoding dolichyl-
phosphate (UDP-N-acetylglucosamine) N-acetylglucosa-
minephosphotransferase 1 (DPAGT1) in CMS patients
with TA on muscle biopsy who were GFPT1-negative
[3]. DPAGT1 plays an essential role in N-linked protein
glycosylation, including of AChR subunits, and in recep-
tor export with knockout resulting in reduced end plate
AChR expression.
The initial report of five patients with CMS due
to mutations in DPAGT1 demonstrated a similar age
of onset to CMS-GFPT1 with fatigable limb-girdle
weakness and an absence of facial, ocular, and bulbar
involvement. In addition to TAs, muscle biopsy revealed
reduced 125I-a-bungarotoxin binding sites and a fivefold
reduction in post-synaptic folding of the NMJ, a find-
ing also seen in CMS due to AChR deficiency. In keep-
ing with these observations, all patients responded to
treatment with anticholinesterase medication and two
patients derived additional benefit from treatment with
3,4-diaminopyridine.
Limb‑girdle muscular dystrophy
The last few years have seen further additions to the growing
list of limb-girdle muscular dystrophies (LGMD). The typi-
cal phenotype of LGMD is prominent wasting and weakness
of the pelvic and, less commonly, the shoulder girdle mus-
cles. Additional clinical features such as contractures, selec-
tive muscle hypertrophy and atrophy, asymmetry, pattern of
weakness and cardiorespiratory involvement, in addition to
serum CK, the histopathological features on muscle biopsy,
and immunoblotting of muscle, can help direct genetic test-
ing. Increasing use of genetic testing has revealed that clini-
cal phenotypes are shared by several different LGMD and,
conversely, mutations in a single gene such as LMNA or
CAV3 are associated with different phenotypes even within a
single family. LGMD can be inherited in either an autosomal
dominant or recessive fashion (LGMD type 1 and LGMD
type 2, respectively); the greater prevalence of autosomal
recessive LGMD was recognised not long after delineation
of the condition [14].
LGMD1H, first described in 2010, is the most recently
discovered of the eight autosomal dominant LGMD that
have so far been identified [5]. The cause of LGMD1G
was subsequently identified as being due to a defect in the
mRNA-processing protein HNRPDL [57], the same research
group having mapped the gene to 4p21 10 years previously
[52].
Autosomal recessive (AR) LGMD are approximately nine
times more commonly encountered than the dominantly
inherited LGMD. Seven new types of autosomal recessive
LGMD (types 2R-T and 2 W-Z) have been described in the
last 5 years. Most are extremely rare and described only
in single families. These include LGMD2Y, caused by a
truncating mutation in TOR1AIP1 and reported in a sister
and brother from a consanguineous Turkish family [17], and
LGMD2Z, identified in four siblings in a consanguineous
Spanish family with a homozygous missense mutation in
protein o-glucosyltransferase 1 (POGLUT1) [51].
The prevalence of LGMD varies in different populations
worldwide. The commonest autosomal recessive LGMD
include types 2A, 2I, and 2L. LGMD2A (calpainopathy),
the most common LGMD globally, is caused by mutation of
CAPN3 which encodes calpain-3, a calcium-dependent pro-
teolytic enzyme that binds to titin and has roles in cytoskel-
etal remodelling, membrane repair and muscle regeneration
[44]. Over 500 different mutations have been identified in
the CAPN3 gene. The disease subtype is characterised by
variability of clinical features and rate of progression (the
most rapid progression is seen in individuals with two null
mutations). The typical clinical presentation of LGMD2A
is pelvic girdle weakness affecting the posterior thigh and
adductor muscle accompanied by scapular winging and
contractures, and without cardiorespiratory involvement.
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Serum CK is moderately raised but may be normal, and mus-
cle biopsy may show lobulated fibres and an eosinophilic
inflammatory infiltrate.
LGMD2I, common in Denmark and parts of the UK, was
first described in 2001 by Brockington et al. [9]. It is caused
by a mutation in the fukutin-related protein (FKRP) gene
on chromosome 19q13.3. The mutation leads to abnormal
glycosylation and consequent dysfunction of α-dystroglycan,
a key component of the cellular architecture in skeletal mus-
cle (and other tissues). Clinical features which help in iden-
tifying LGMD2I include exercise-induced symptoms, calf
hypertrophy (which is seen in up to 77% of patients), quadri-
ceps femoris muscle wasting, a very high serum CK, the
presence of a concomitant cardiomyopathy, and inflamma-
tory changes on muscle biopsy with reduced α-dystroglycan
staining. As with many other LGMD, disease onset and pro-
gression are variable and the condition may be misdiagnosed
as Duchenne or Becker muscular dystrophy [49].
LGMD2L is caused by mutations in ANO5 and is thought
to represent 10–20% of all undiagnosed LGMD pedigrees
[40]. More than 20 mutations have so far been identified in
the ANO5 gene on chromosome 11 which encodes anoc-
tamin 5, an integral intracellular transmembrane glycopro-
tein with a central role in myogenesis. Patients can present
with prominent wasting and weakness of the quadriceps
femoris muscles, a pseudometabolic syndrome, asympto-
matic hyperCKaemia, or distal myopathy. Serum CK can
be significantly elevated and muscle biopsy may reveal
deposition of amyloid. Several studies have shown a male
predominance [48, 56].
Immune‑mediated necrotising myopathy associated
with HMGCR antibodies
The immune-mediated necrotising myopathies (IMNM)
are characterised histologically by prominent muscle fibre
necrosis but minimal inflammation on muscle biopsy.
IMNM is associated with malignancy, statins, and anti-
bodies to signal recognition protein (SRP) and 3-hydroxy-
3-methylglutaryl-coenzyme A reductase (HMGCR). The
identification of antibodies to HMGCR, the target of statin
medications, in patients with IMNM has been one of most
interesting developments in the last few years.
The presence of novel antibodies recognising a 100- and
200-kDa protein in patients with a necrotising myopathy was
first reported by Stine et al. [13]. It was noted that 63% of
the patients had been exposed to statins prior to the devel-
opment of clinical symptoms. The antibodies were subse-
quently established to be directed against HMGCR [32].
However, unlike self-limiting statin-associated muscle
problems which resolve on drug withdrawal, patients with
HMGCR antibody-positive INMN require immunotherapy.
Although initial reports suggested that the condition may
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Journal of Neurology (2018) 265:1717–1725
be statin induced, statin-naïve cases were also identified.
These cases were particularly noted in younger patients
[59]. Further case series have also reported clear variation
in the strength of association with statin exposure amongst
patients demonstrating HMGCR antibodies [1, 58]. Recently
it has been hypothesised that cases of IMNM with HMGCR
antibodies but without exposure to statin medication may
be due to dietary sources of statins such as soy proteins,
certain grains, and oyster mushrooms [2]. Unfortunately, the
rarity of the condition has precluded randomised controlled
trials and treatment guidance is instead based on anecdote
and case series. From these reports, it appears that younger,
statin-naïve patients may be more resistant to treatment.
Therapies employed to achieve clinical remission include
steroids, with the addition of one (if not two) steroid-sparing
agent, or immunomodulatory therapies such as intravenous
immunoglobulin, cyclophosphamide or rituximab [43, 59].
Despite the results of several case reports and case series, the
association between HMGCR-positive IMNM and malig-
nancy remains uncertain.
Diagnostics
Imaging
The use of muscle imaging, particularly MRI, in the diag-
nosis and monitoring of both acquired and inherited muscle
diseases continues to increase. Imaging studies allow visu-
alisation of pathological changes previously only identifiable
following histological analysis, including oedema—a surro-
gate marker of inflammation, replacement of muscle tissue
with fat or connective tissue, and muscle atrophy. The use of
conventional sequences, T1 and short-tau inversion recov-
ery (STIR), is well established. Novel sequences including
diffusion tensor imaging (DTI), tractography, and magnetic
resonance spectroscopy will enable more detailed analysis
of the structure and metabolism of muscle tissue, potentially
yielding information that may support or direct diagnosis.
MRI is also being used to guide muscle biopsy and has
consequently been shown to improve diagnostic accuracy
in various conditions, including inflammatory myopathies
[55]. The pattern of muscles affected within a limb and the
pattern of involvement within certain muscles can aid diag-
nosis particularly in distal myopathies, collagen VI disor-
ders, and muscular dystrophies with spinal rigidity (in which
MRI was shown to have a diagnostic sensitivity of 0.9 [36]).
There are, however, limitations and situations where MRI
may be misleading. For example, although muscle oedema
is suggestive of an inflammatory myopathy and muscle atro-
phy and fatty replacement of a muscular dystrophy, muscle
oedema may be seen in muscular dystrophy and muscle atro-
phy and fatty replacement can be observed in long-standing
Journal of Neurology (2018) 265:1717–1725 1721
steroid-responsive inflammatory myopathy. Correct inter-
pretation requires close correlation with clinical features and
results of parallel investigations.
The replacement of muscle tissue by fat is a common
feature of muscular dystrophy as well as other myopathies
and can be readily detected using MRI [60]. Changes in
the quantitative fat fraction calculated from gradient echo
sequences or MR spectroscopy has the potential to provide a
quantitative, objective, and sensitive end point in the assess-
ment of disease status or progression [10]. Given the vari-
ability in disease progression in many muscular dystrophies
(depending on the age of the patient) and the difficulties
inherent in assessing clinical metrics that require patient co-
operation and motivation, such a measure has clear advan-
tages. Furthermore, MRI has the ability to detect subclinical
changes enabling trials with smaller numbers of participants
over shorter time frames in these extremely rare diseases
[20].
Therapeutics
Myasthenia gravis
The place of thymectomy in the management of myasthe-
nia gravis (MG) has been a subject of debate ever since
the surgical removal of thymus tissue was first shown to
improve symptoms in MG by Ernst Sauerbruch in 1911.
Alfred Blalock was the first to demonstrate disease remission
following resection of a thymic tumour in a young woman
with myasthenic gravis [6]. Further operations on patients
without tumours supported Sauerbruch’s initial findings,
but ultimately failed to establish any curative credentials.
Subsequent practice has been based on clinical experience,
anecdote and case series, incorporating increasingly sophis-
ticated surgical techniques, but with no real guidance as to
the place surgery should take within disease management
protocols.
A significant step forward in establishing the role of
thymectomy in myasthenia gravis was the recent publication
by Wolfe et al. of the international, multicentre, randomised
control trial (the myasthenia gravis thymectomy study)
comparing the effects of thymectomy and alternate-day ster-
oids versus alternate-day steroids alone in the treatment of
myasthenia gravis [61]. The authors used a time-weighted
approach to the primary end points—the Quantitative
Myasthenia Gravis score (QMG) and the average pred-
nisone dose requirement—to address the inherent variabil-
ity of the condition. Results over the 3-year time frame of
the study demonstrated a clinically meaningful advantage
to thymectomy on both metrics, with patients undergoing
thymectomy showing a meaningfully lower QMG and lower
steroid requirement (32 versus 54 mg). Secondary end points
provided further evidence as to the benefits of surgery over
steroids alone, particularly the requirement for azathioprine
and reduced hospital admissions for disease exacerbation.
Whilst the study has provided further clarity, questions
remain. These include the long-term benefit of thymec-
tomy beyond 3 years, as prompted by the study data which
showed a reduction in the benefit of thymectomy over the
duration of the study period. Whilst comparison with the
wide range of medical immunotherapies currently employed
to treat myasthenia gravis would provide more meaningful
clinical guidance, the logistics of such a study may prove
insurmountable. The results of the study have increased the
upper age limit for those in whom thymectomy can be con-
sidered to 65 years of age. However, significant changes to
clinical guidelines for the management of myasthenia gravis
are not yet on the horizon. In the UK, the guideline’s cor-
responding author wrote in a later editorial that ‘the advice
that thymectomy should be considered (rather than making
any stronger recommendation) remains’ and that more work
needs to be done to identify which groups would benefit
most from thymectomy [53]. Finally, there remains a debate
as to whether video-assisted thymectomy is as efficacious
as open surgery. The former is associated with a lower
operative morbidity and is much more cosmetically accept-
able meaning that many more patients may be prepared to
undergo the procedure.
Gene therapies
Within the last few years, the first gene therapies for the
treatment of neuromuscular disorders have been tested and
licensed, heralding the onset of a potential paradigm shift in
the management of previously incurable and largely untreat-
able conditions.
Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a significantly
life-shortening, childhood-onset, X-linked condition result-
ing from mutations in the gene encoding dystrophin, a key
protein for muscle stability and contractility. Novel thera-
peutic strategies employed in DMD have aimed to partially
restore dystrophin protein expression by exon skipping using
antisense oligonucleotides and stop-codon suppression. An
alternative approach has been to upregulate the expression
of utrophin, a sarcolemmal protein which mirrors many of
the structural characteristics of dystrophin.
Eteplirsen is a phosphorodiamidate morpholino oligonu-
cleotide, a DNA analogue, that restores the mRNA reading
frame of dystrophin, producing a functional but truncated
protein in patients with exon 51-amenable deletions. Initial
open-label studies demonstrating restoration of dystrophin
expression in vivo provided proof of concept [15]. These
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1722
studies were followed in 2013 by publication of the first
randomised control trial (RCT) [35] which demonstrated a
23% increase in dystrophin-positive muscle fibres at the end
of the blinded treatment phase and a further increase of up to
52% at the study’s conclusion. Clinically, a 16 m benefit in
the 6-min timed walk (6MTW) was observed in those treated
at 24 weeks, rising to 63 m at 48 weeks despite the initiation
of the placebo cohort on treatment at 24 weeks. Criticisms of
the study include small sample size, phenotypic heterogene-
ity, and the chosen outcome measures.
The results of an open-label extension trial were pub-
lished 3 years later in 2016 [34]. The study utilised age-,
treatment-, and genetically matched historical control data
to draw comparisons with the natural history of the condi-
tion and demonstrated a statistically significant advantage
in the treated cohort of 151 m on 6MWT at 36 months and
a reduction in loss of ambulation. The rate of decline of
minimum and maximum inspiratory pressures, and forced
vital capacity were less than that seen in prior natural history
studies [26, 30] though this data was not available for the
matched historical controls. The results of this study and the
initial RCT have supported a successful, albeit controversial
in some quarters, application for the Food and Drug Admin-
istration (FDA) approval in the USA.
Spinal muscular atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive
condition caused by deletion or mutation in the survival
motor neuron 1 (SMN1) gene, resulting in insufficient pro-
duction of the SMN protein. Whilst the specific role of SMN
in muscle function is unknown, its deficiency results in pro-
found muscle weakness, failure to thrive, and early death.
SMA is the commonest hereditary cause of childhood mor-
tality. Nusinersen is an intrathecally administered uniformly
modified 2′-O-methoxyethyl phosphorothioate antisense oli-
gonucleotide that enhances production of SMN protein from
the SMN2 gene, effectively a backup to SMN1. A phase III
study was prematurely terminated following pre-specified
interim analysis [19]. The analysis demonstrated that 41%
(21/51) of infants in the treatment group recorded a motor
milestone response (according to the Hammersmith Infant
Neurological Examination-2 score) versus 0% (0/27) in the
placebo group. On the basis of these results, nusinersen has
been granted both FDA and European Medicines Agency
approval within the last 18 months, giving hope to the many
patients and families affected by SMA.
Myotonic dystrophy
A phase 2 study of the use of Tideglusib in myotonic dystro-
phy type 1 (DM1) is approaching completion of recruitment
in the UK. Tideglusib is an irreversible glycogen synthase
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Journal of Neurology (2018) 265:1717–1725
kinase 3 (GSK-3) inhibitor that has been shown to reduce
muscle weakness and myotonia in a mouse model of DM1
[29]. GSK-3 suppresses CUG-binding protein 1 activity, an
important skeletal muscle translational regulator, by inhibit-
ing activation by cyclin D3-dependent kinase 4. GSK-3 plays
an essential role in many biological processes beyond myo-
genesis and has been linked with several diseases including
diabetes, inflammation, cancers, neurodegeneration, and
psychiatric disorders. GSK-3 inhibitors are being studied as
a potential treatment in a number of diseases including Alz-
heimer’s disease [16], progressive supranuclear palsy [54]
and in the promotion of natural tooth repair [39].
Conclusion
There have been many advances in the field of muscle dis-
eases over the last few years. We have observed improve-
ments in the investigation and diagnosis of muscle disease
using MRI, and the widespread use of modern molecular
genetic techniques has helped to elucidate the genetic basis
of many more muscle diseases. However, further work needs
to be done on our understanding of the pathogenesis of many
of these disorders. Arguably, the greatest advances have
been the development of treatments for previously untreat-
able hereditary neuromuscular diseases. Future advances in
our understanding and management of these rare and devas-
tating diseases continues to depend on international collabo-
ration between scientists and clinicians in the neuromuscular
community.
Compliance with ethical standards 
Conflicts of interest  JW reports no disclosures. SB received a travel
bursary from Sanofi-Genzyme in 2016.
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