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Neuromuscular Disorders 31 (2021) 988–997

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Review
Intellectual disability in paediatric patients with genetic muscle diseases
Sabine Specht, Volker Straub∗
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle, UK
Received 17 July 2021; received in revised form 26 August 2021; accepted 27 August 2021

Abstract
The differential diagnosis of genetic muscle disease has become increasingly difficult due to the rapid progress in genetic medicine in
recent years. Where classifications based on the clinical picture were attributed to one gene only a few years ago, today we know that a
variety of clinical presentations can result from the same mutation and, conversely, various genes are associated with a similar phenotype. A
significant consideration in assessing a patient with muscle weakness is the presence or absence of intellectual disability, thus narrowing the
differential diagnostic approach in any child with an as yet undiagnosed muscle disease. Intellectual disability in neuromuscular diseases is
often associated with behavioural disorders and may be correlated with abnormal brain imaging. Conversely, brain involvement can sometimes
be seen without intellectual disability, but may be associated with an epilepsy risk and is helpful for the differential diagnosis. This review
focuses on the three most common causes of paediatric muscle diseases with intellectual disability, dystrophinopathies, myotonic dystrophy
type 1 and dystroglycanopathies. It also summarises differential diagnostic considerations when assessing a child with a genetic muscle
disease and intellectual disability. The recent scientific literature on this topic is reviewed, the frequency of intellectual disability assessed,
and specific clinical features are described. Where available, data on disease onset, progression and serum creatine kinase levels are presented
and the pattern of muscle involvement described in an algorithm. Central nervous involvement and brain imaging analysis was reviewed and
included.
© 2021 Elsevier B.V. All rights reserved.

Keywords: Intellectual disability; Dystrophinopathy; Dystroglycanopathy; Congenital myotonic dystrophy; Brain imaging; Behavioural disorders.

1. Introduction It is characterized by deficits of general mental abilities that

By definition, neuromuscular diseases (NMD) involve
the peripheral, but not the central nervous system (CNS).
However, there are relevant exceptions in children that are
important to note: dystrophinopathies, myotonic dystrophy
type one (DM1) and the dystroglycanopathies. Diseases
in these three groups form the most common cause for
CNS symptoms and signs in patients with primary muscle
diseases. The differential diagnosis for patients presenting
with weakness and intellectual disability (ID) is long and
complex (Fig. 1) and we will focus only on the most common
causes for this combination of clinical features.
The term ID has been suggested to replace the former term
mental retardation and reflects deficits in cognitive capacity
that start in the developmental period (DSM-V and ICD-11).
∗ as the serial reaction time task and the Bayley Scales of
Corresponding author.
E-mail address: volker.straub@newcastle.ac.uk (V. Straub).
have an impact on adaptive functioning in the conceptual,
social, and practical domains. A diagnosis of specific learning
disorders describes more specifically persistent difficulties in
reading, writing, arithmetic or mathematical reasoning skills
during formal years of schooling, whereas the term mild
neurocognitive disorder describes a cognitive decline with
ageing. It is for this reason that in the following we will
refer to ID. Co-occurrence of various manifestations of ID
is frequent; for example, individuals with autism spectrum
disorder (ASD) or with attention deficit hyperactivity disorder
(ADHD) can present with ID.
With regard to the assessment of children with ID, the
DSM-V proposes the use of both clinical assessments and
standardized testing. In the reviewed literature, the Wechsler
intelligence scales were most commonly applied for older
children and adults [1,2], whereas various other tests such
Infant and Toddler Development were applied for young

https://doi.org/10.1016/j.nmd.2021.08.012
0960-8966/© 2021 Elsevier B.V. All rights reserved.
S. Specht and V. Straub Neuromuscular Disorders 31 (2021) 988–997

Fig. 1. Diagnostic approach for a child with suspicion of a genetic neuromuscular disease and intellectual disability. The approach includes the assessment
of developmental milestones, a physical examination, serum creatin kinase activity, and a family history. The pattern of muscle involvement is relevant for
the differential diagnostic considerations. A brain MRI can be a valuable diagnostic tool for several of the conditions listed. Abbreviations: αDG-CMD,
α-dystroglycan associated congenital muscular dystrophy; BMD, Becker muscular dystrophy; CK, creatine kinase; CMS, congenital myasthenic syndrome;
CMT, Charcot-Marie-Tooth disease; DM1, myotonic dystrophy type 1; DMD, Duchenne muscular dystrophy; FH, family history; ID, intellectual disability;
LAMA2-CMD, laminin α2 associated congenital muscular dystrophy; PCH1, pontocerebellar hypoplasia with spinal muscular atrophy; PWS, Prader-Willi
Syndrome; SMALED, spinal muscular atrophy with lower extremity dominance.

children. In infants, although ID per se is difficult to assess,
certain red flags such as poor response to visual and auditory
stimuli, lack of eye contact or social smile might be a clue.
Formal ophthalmological and audiology assessments should
always precede IQ tests. In our review we have predominantly
focussed on children beyond the age of infancy.
When assessing a child with muscle weakness and ID,
a detailed clinical history, including the family history, may
help to shed light on the pattern of inheritance. A newly
diagnosed baby with congenital DM1, an autosomal dominant
disorder, will frequently lead to the diagnosis of DM1 in
one of its parents, typically the mother, and can also help
to identify other family members at risk.
Neuroimaging in a number of NMD has increasingly
been performed over the past 30 years, revealing a variety
of brain pathologies. These are now well established for
DMD and DM1, but less extensively explored in the rarer
conditions [3]. The introduction of functional brain imaging
techniques has contributed to a better understanding of
dysfunctional neuronal networks, where ID is not linked to
a morphological change detected by computed tomography
(CT) or by magnetic resonance imaging (MRI). As an
example, diffusion tensor imaging (DTI) allows the analysis
of white matter microstructure. Functional brain imaging
analysis can further reveal either abnormalities in cerebral
blood flow (single photon emission computed tomography)
or glucose metabolism (Positron emission tomography). On
the other hand, transcranial B mode sonography remains
an inexpensive, easily accessible and non-invasive tool that
facilitates the diagnostic approach particularly in young
children [3].
Regardless of the disease, it has been postulated that
fatigue originating in the CNS plays a considerable role
beyond sole muscle fatigability [4,5]. It has an impact on
executive functions such as working memory, processing
speed, verbal learning and cognitive inhibition response
time. Thus, there seems to be a negative feedback from
the pathological muscle activity to the central nervous
system through a downregulation of physical activities, which
may help protect the muscles from further damage. This
phenomenon has been investigated for Pompe disease, DM1,
facioscapulohumeral muscular dystrophy (FSHD), myasthenia
gravis and Charcot-Marie-Tooth disease type 1 (CMT1) [4,5].
In our literature review we focus on the most common
genetic muscle diseases in childhood that are associated with
ID.
2. Dystrophinopathies
2.1. Duchenne muscular dystrophy
Cognitive and behavioural abnormalities have been
extensively studied in patients with Duchenne muscular
dystrophy (DMD). It has been shown that ID, ASD,
ADHD and obsessive compulsive disorder (OCD) are well
characterized features of the X-linked recessive disease

989
S. Specht and V. Straub
[6] caused by mutations in the DMD gene. In a study of 222
patients with DMD an increased prevalence of epilepsy, 6.3%
compared to 0.5–1% for the general paediatric population,
was also reported as a CNS manifestation [7], suggesting an
increased neuronal excitability of the DMD brain.
The fact that not all patients with DMD show CNS
involvement and that CNS manifestations are heterogeneous,
is a result of the complex expression patterns of dystrophin
isoforms and how they are affected by mutations in the
DMD gene. The DMD gene has at least 7 promotors and 2
poly(A) addition sites that are able to produce several protein
isoforms. These isoforms are named after their length and
splicing pattern. Each transcript results in a more or less tissue
specific product and across human development is expressed
at different levels [8].
Patients devoid of all isoforms due to mutations in the
distal parts of the DMD gene have been described as having
the most severe ID, whereas those only missing the full-length
isoforms Dp427 are less affected [9]. The deletion hotspot
around exons 45–55 is predicted to affect the expression
of Dp140, which has been attributed to pronounced ID.
Doorenweerd and colleagues [8] explored the spatial and
temporal expression of different DMD isoforms. The study
revealed the highest expression of Dp140 in early stages of
brain development prior to birth and persisting low levels into
adulthood in both cortex and cerebellum. Dp71 and DP40
isoforms were expressed at intermediate levels ubiquitously at
all stages of development. Dp71 is expressed in astrocytes and
glial cells throughout development [9]. The lack of shorter
isoforms of DMD is associated with impairment of emotion
regulation (amygdala), poor memory skills (hippocampus)
and impaired higher-order cognitive functioning (cortex) [8].
The highest expression of brain isoforms was found in the
hippocampus and amygdala and to some degree in the cortex;
the lowest expression was seen in the cerebellum and the pons
of the human brain [8].
Brains of patients with DMD in general have a global
reduced total volume due to reduced grey matter volume
regardless of the underlying mutation. This is thought to
be the result of altered maturation rather than atrophy. In
addition, white matter alterations are evident in DMD on
microstructural level. The changes are consistently seen in
patients with and without glucocorticoid therapy [10].
A review in 2007 collected data from 32 studies starting
in 1980 and analysed 1234 individuals with DMD (2–
27 years). The average Full-Scale Intelligence Quotient
(FIQ) was 80.2 - one standard deviation below the normal
population with a mean IQ of 100. In this meta-analysis,
34% (426 patients) showed mild to severe ID (IQ <70).
No significant differences were described between the mean
Verbal IQ and Performance IQ (PIQ), having applied various
versions of the Wechsler intelligence scales and other test
batteries but not explicitly scrutinizing the working memory.
It was reported that the progressive loss of motor function
was only rarely considered when assessing the PIQ. The
existence of subgroups of cognitive deficits was postulated
[11]. Eighty percent of patients showed an impairment of
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Neuromuscular Disorders 31 (2021) 988–997
working memory and planning, even where the IQ was above
average. Moreover, executive functions and phonological and
semantic fluency were affected, suggesting impaired problem-
solving and planning. These findings were not related to the
site of the mutation [11].
In another study, 41 boys with DMD were compared to an
unaffected sibling assessing their intellectual abilities, which
included verbal, visuospatial, attention, memory and abstract
thinking [12]. The profile of intellectual abilities for patients
with DMD reflected poor verbal working memory. Compared
with their unaffected siblings, boys with DMD had difficulties
in remembering stories, repeating back digits, or following
extended verbal statements. Hence, it was proposed that the
phonological store and rehearsal ability are limited in DMD.
It was suggested that these difficulties have a major impact
on additional academic skills such as reading, maths and
dictation, as they require good verbal working memory [12].
A recent study examined implicit learning in patients
with DMD without ID involvement [13]. Implicit learning
is defined as a type of long-term human memory that
encompasses the subconscious knowledge or experience
necessary to carry out a particular task (e.g. phonological
processing, literacy skills or driving a car). All patients were
affected by implicit learning difficulties compared to healthy
controls regardless of the site of mutation (up- or downstream
of exon 45) and it was postulated that this was linked to
affection of lateral parts of the cerebellum [13].
A recent Italian study further assessed the profiles of
cognitive function and a possible impairment of executive
functions in 40 boys with DMD (6–12 years) without
intellectual and behavioural impairment [14]. Thus, 40% of
the primary cohort were excluded due to ID (IQ<70) and
19% due to neurobehavioral issues. The result of the study
confirmed low average working memory and planning with
a low score in the digit span subtest despite a normal IQ.
Furthermore, phonological and semantic fluency appeared to
be reduced [14].
2.2. Becker muscular dystrophy
Generally, diagnosing a boy with DMD does not pose a
challenge if proximal muscle weakness, calf hypertrophy, and
highly elevated creatine kinase (CK) levels are part of the
clinical picture, but a diagnosis can be delayed when the
clinical presentation is dominated by CNS symptoms, e.g.
severe autism, and a serum CK analysis was not considered.
This can be an even bigger challenge in patients with Becker
muscular dystrophy (BMD), the milder allelic variant of
DMD caused by in-frame mutations in the DMD gene. In
a prospective study, patients with BMD demonstrated a less
homogeneous cognitive phenotype than that seen in DMD and
their Wechsler Full Scale IQ was reported to be normally
distributed with a mean of 95.6 (SD 23.3). The frequency
of learning difficulties for reading was 21%, for spelling
32%, and for arithmetic 26%, significantly higher than the
frequency in the general population. No correlation was found
with the site of the deletion. The frequency of behavioural
S. Specht and V. Straub
problems in the clinical range was 67%, and more specifically
the frequency of autism was 8.3% [1].
Other studies have reported slightly different numbers,
depending on the assessment methods and the definitions of
CNS manifestations used. In a recent Japanese study, around
12–36% of patients with BMD were affected by cognitive
developmental delay [2], but more than 50% of patients
were reported to show behavioural problems. Considering that
>50% of patients with BMD have deletions affecting the
expression of DP140, with deletions of exons 45–47 (37.5%)
and exons 45–48 (18.7%) being the two most common ones,
it is not surprising that CNS symptoms are a frequent feature
of BMD. Given the genetic and therapeutic implications for
an accurate diagnosis of mutations in the DMD gene and
the fact that dystrophinopathy patients may primarily present
with CNS symptoms, screening of boys with non-syndromic
ID by comparative genomic hybridization (CGH) can identify
patients with dystrophinopathies.
2.3. Manifesting female carriers for DMD/BMD
This might even be more relevant for manifesting female
carriers of DMD or BMD. Heterozygous mutations in the
DMD gene in females most often remain asymptomatic. Up
to 17% of female carriers, however, present with muscle
weakness and approximately 30% with ID. Skewed X-
inactivation (XCI) is the most common reason for clinical
symptoms in female carriers, although it has been shown that
the pattern of XCI as ascertained from lymphocyte DNA does
not reflect the XCI pattern in other tissues in all patients [15].
Most manifesting carriers develop mild to severe muscle
weakness between early childhood and late adulthood but
predominantly during puberty [15,16]. Other typical features
are calf hypertrophy, exercise intolerance, scoliosis and
later in life a significant risk for cardiomyopathy. CK
levels are typically raised. Similarly to male patients,
several studies have confirmed a high incidence of ID
(30–55%) and behavioural problems in manifesting carriers
[17]. To our knowledge, a systematic approach to assess
the specific pattern of learning difficulties has not been
performed. However, small numbers of affected girls
underwent a Wechsler intelligence scales for children (WISC)
III evaluation. Similarly to DMD, a correlation was proposed
between ID and the type of mutation [17], but these
findings were not consistent. Manifesting female carriers for
DMD/BMD are more common than females affected by
some of the rare dystroglycanopathies, which form another
differential diagnosis for patients with genetic muscle diseases
and ID.
3. Congenital muscular dystrophy syndromes
The overall prevalence of congenital muscular dystrophies
(CMD) is estimated to be between 0.6–1 per 105 [18,19].
The most common subtype of this heterogeneous group of
diseases is caused by mutations in the LAMA2 gene, encoding
for the laminin alpha2 chain, and accounts for approximately
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Neuromuscular Disorders 31 (2021) 988–997
37% of CMD. It is now classified as LAMA2-CMD and
was formerly known as MDC1A or merosin-deficient CMD.
The second most frequent group of CMD is caused by
mutations in genes responsible for the correct expression
and processing of α-dystroglycan (αDG), a key extracellular
matrix receptor, expressed in both skeletal muscle and the
CNS. The congenital forms of these α-dystroglycanopathies
are referred to as αDG-CMD and account for about 27%
[20] of all CMD.
3.1. Alpha-dystroglycanopathies
Amongst αDG-CMDs, the most frequent phenotype is
muscle-eye-brain disease (MEB) and in Japan Fukuyama
congenital muscular dystrophy (FCMD) [20,21]. There are
currently 18 genes known to be responsible for αDG-
CMD, including the DAG1 gene, encoding dystroglycan itself.
Mutations in DAG1 lead to primary dystroglycanopathy,
whereas mutations in genes encoding for glycosyltransferases
involved in the correct glycosylation of αDG are referred to
as secondary or tertiary dystroglycanopathies [21].
The clinical presentation of α-dystroglycanopathies
is broad, ranging from congenital muscle hypotonia
and weakness (αDG-CMD) to adult-onset limb girdle
muscular dystrophy (LGMD). There is variable cardiac,
ophthalmological as well as brain involvement and muscle
biopsies typically show a dystrophic pattern [21]. CNS
symptoms can sometimes predominate the clinical picture,
hence should be considered in a child with elevated CK levels
and muscle hypotonia or genuine weakness. In the brain,
structural abnormalities range from lissencephaly type II,
consisting of a cobblestone cortex, enlarged ventricles, small
brainstem, hypoplastic vermis, and cerebellar polymicrogyria,
as seen in Walker-Warburg Syndrome (WWS), FCMD and
MEB, to white matter lesions and subcortical cerebellar cysts
[22]. A few patients with αDG-CMDs show both pachygyria
and polymicrogyria, abnormally thick and thin convolutions
of the cerebral cortex, particularly in the frontal and parietal
lobes.
WWS, first described in 1978, is the most severe
manifestation of αDG-CMD, presenting with severe muscle
hypotonia at birth and ID, failure to thrive, lissencephaly
type II, contractures and ocular abnormalities of the anterior
and posterior chambers including microphthalmia, retinal
detachment, hypoplasia of the optic nerve, coloboma, cataract
and iris malformation. Facial dysmorphism (prominent and
low set ears) and cleft lip or palate may be present
[23]. Muscle biopsy reveals severe degeneration of muscle
fibres, discontinuity of the basal lamina in muscle fibres
with detachment from the plasmalemma with interfascicular
fibrosis and lipomatosis. The CK is almost always elevated.
Most children do not survive the first year of life.
MEB was first described by Santavuori in the Finnish
population in 1989 and has a slightly milder phenotype
than WWS. Frequent clinical abnormalities comprise ID,
congenital hypotonia and weakness, severe eye involvement
including myopia, glaucoma, retinal hypoplasia and optic
S. Specht and V. Straub
nerve atrophy, and brain abnormalities similar to those
described for WWS, but milder. The CK activity is commonly
elevated (150 IU/l – 4300IU/L) [21]. The most common
genes associated with WWS and MEB are POMT1, POMT2,
POMGnT1, FKRP, FKTN, ISPD, TMEM5.
FCMD is caused by mutations in the FKTN gene and
predominantly found in the Japanese population due to a
founder mutation, a retrotransposal insertion of tandemly
repeated sequences within the 3 untranslated region of
the FKTN gene [24]. The phenotype is characterized
by progressive muscle weakness, ID and speech delay
and associated with white matter abnormalities, ventricular
dilatation and cortical malformations including cerebellar
abnormalities, gyration defects and cobblestone appearance
of the occipital cortex [21].
Mutations in the INPP5K gene lead to a CMD
phenotype with early onset cataracts (bilateral lens opacities),
often together with mild ID. Other features have been
described such as microcephaly, seizures, intention tremor and
contractures including a rigid spine. Patients usually show
delayed motor development but learn to walk independently
with proximal muscle weakness [25].
The most common genes responsible for αDG-CMD in
the UK are FKRP, POMGnT1 and POMT1 or POMT2 [20].
Importantly, patients with αDG-CMD can present with ID
in the absence of brain abnormalities [21,22] ranging from
borderline to severe. Unsurprisingly, a positive correlation was
established between profound ID and severe brain changes.
Epilepsy is estimated to be present in 30% of patients with
αDG-CMD in the presence of brain malformations.
3.2. Laminin α2 chain related congenital muscular
dystrophies
Epilepsy can also be a feature in patients with LAMA2-
CMD, a disease closely related to αDG-CMD. The
heterotrimer laminin 211 (Lm-211), consisting of the laminin-
α2, -β1 and -γ 1 chains, is an important basement membrane
ligand for αDG [20,21]. LAMA2-CMD is caused by biallelic
mutations in the LAMA2 gene. Most patients show a complete
loss of laminin α2 expression in skeletal muscle. Where a
partial deficiency of laminin α2 is found, the phenotype is
milder and the onset typically later. Typical clinical features
of LAMA2-CMD are congenital hypotonia, weakness and
joint contractures. Thirty percent of patients with complete
or partial laminin-α2 chain deficiency develop epilepsy, but
very rarely present with ID [20]. Literature describing ID in
LAMA2-CMD is scarce and describes moderate impairment
in some children with epilepsy. There is inconsistency
regarding the correlation between white matter changes or
additional structural brain changes and ID. One study from
1998 analysed a small cohort of patients with merosin-
deficiency, assessing ID and MRI changes and concluded that
in the presence of cerebellar hypoplasia, children frequently
presented with lower IQs on performance [26]. It is striking
that in several publications the genetic diagnosis remained
unconfirmed by either a missing second mutation in LAMA2
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Neuromuscular Disorders 31 (2021) 988–997
or inconsistencies between laminin α2 expression and white
matter changes [27]. Seizures are not primarily attributed to
the white matter hypointensity found in LAMA2-CMD, but
may be associated with additional cortical malformations or
ventricular dilation [27].
4. Myotonic dystrophy type 1
Another very important differential diagnosis in children
with ID and primary muscle weakness is DM1, the most
common genetic muscle disorder in the overall population. An
estimated 28% of all patients with a genetic muscle disease
suffer from DM1 and a point prevalence of 10.4 per 105
has been calculated for Northern England [18]. In children,
the incidence of the congenital manifestation of DM1 was
estimated to be 2.1 per 105 in the Canadian population [28].
Due to founder mutations in some parts (e.g. Quebec), the
incidence of DM1 varies widely worldwide between 1 and
10.4 per 105 .
This multisystemic, autosomal dominant inherited
disorder may entail myotonia, progressive muscle weakness,
predominantly affecting facial and distal muscles; moreover,
it is associated with cardiac arrhythmias [29] and typically
involves the digestive, ocular, endocrine and neurological
system. DM1 can be considered as a continuum, with
congenital DM1 being the most severe form. Disease severity
correlates with the number of expansions of a CTG repeat in
the 3 -untranslated region of the DMPK gene on chromosome
19. Whereas in healthy individuals the gene contains 5–37
CTG repeats, in patients with DM1 this exceeds 50 repeats
and may reach 4000 in patients with congenital DM1. The
expansion typically increases from one generation to the
next, resulting in progression in severity and increasingly
early age of onset, also known as anticipation. However,
there is no correlation between the size of repeat expansions
captured in blood at the time of diagnosis and the severity
of symptoms or clinical course. The reason for this is the
increase of repeat expansions over time and across different
tissues, causing somatic mosaicism in post-mitotic tissues,
predominantly in skeletal muscle, brain and the myocardium,
resulting in the progression of symptoms throughout life
[29].
The expansion of the untranslated region is toxic at an
RNA level through RNA foci accumulation and RNA mis-
splicing. Proteins of the muscle blind family (MBNL) that
bind to CUG repeats with high affinity and normally work
as splicing regulators, RNA transport and its decay, are
trapped and sequestered in nuclear clusters of CUG repeats.
As a result, many incorrect splice products and protein
isoforms are expressed in different tissues. Other effects of
mutant DMPK RNA on activation of signalling pathways
have been thoroughly studied in animal models and patients.
Offspring of affected mothers are at high risk to suffer from
congenital DM1. Interestingly, the instability of expanded
repeat sequences in germline transmission follows a pattern
by which enlargement of the expansion is usually significant
but not extensive in male transmissions whereas the greatest
S. Specht and V. Straub
instability happens in maternal transmission. Congenital DM1
therefore almost exclusively occurs to those born to affected
mothers [28,29].
Congenital DM1 varies greatly in its phenotypic expression
with an overall mortality rate of 16–41%, often due to
early respiratory failure or central apnoea [28,29]. Newborns
present with severe muscle hypotonia, often associated with
clubfeet and feeding difficulties. Interestingly, the weakness
improves over the first months and some motor development
is achieved. Invariably, executive functions and cognitive
abilities are typically moderately to severely compromised
[30]. With a positive family history, a baby with congenital
DM1 is easy to diagnose. However, the diagnosis can be
challenging if an affected baby is born to an undiagnosed
mother and can be even more difficult in childhood onset
DM1. DM1 with onset in childhood is defined as symptoms
presenting between 1 and 10 years after an uneventful pre-
or neonatal history and first year of life. The phenotypical
picture encompasses failure to thrive, abdominal symptoms, a
variable degree of muscle hypotonia, ID of variable severity
and normally no symptoms of myotonia before school age
[29,30].
CNS symptoms in children with DM1 are heterogeneous
and encompass developmental delay, ID and learning
disorders in various domains, personality and behavioural
disturbances, affective symptoms, and sleep disturbance. Most
studies on CNS involvement in DM1 have been conducted
in adults, but are highly relevant for paediatric patients.
A positive correlation between the cortical thickness of
parts of the brain and social cognition in adult patients
with DM1 has been reported [31]. All patients showed
pathological scores both in the Social Situation Test and
Emotion Attribution Tests that correlated with the CTG repeat
expansion size. A review by Angeard et al. [30] examined
the neuropsychological and psychiatric profiles of DM1
in childhood and explicitly addressed the question of
comorbidities between DM1 and ASD in the context of
brain-MRI findings. A recent study described a high-order
dysfunction, defined by impaired social cognition and referred
to as Theory of Mind [32] in 80% of adult DM1 patients
without primary ID. It was proposed that social dysfunction in
DM1 correlates with abnormal brain functional connectivity,
describing connectivity restricted to more central nodes in the
inferior temporal gyrus and the dorsolateral prefrontal cortex
as compared to healthy controls. This correlated with the
impaired mentalizing abilities of patients with DM1. Other
studies in adults showed a cognitive decline over time by loss
of attention and memory function and described that adult
patients with DM1 are prone to develop progressive focal
frontotemporal dementia affecting linguistic and executive
functions.
Neuroimaging reveals widespread white matter lesions
throughout the brain of patients with DM1, involving the
association fibres, commissural fibres and projection fibres,
and most typically affecting the anterior temporal lobes [33].
White matter changes are also associated with the loss of
myelin and axons, gliosis and the dilatation of perivascular
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Neuromuscular Disorders 31 (2021) 988–997
spaces [34]. On a functional level they have been correlated
with a reduced working memory in children and adolescents
with DM1 [34]. Cortical grey matter changes are found
in the frontal, parietal and occipital gyri of the brain;
subcortically the thalamus and basal ganglia are affected [33].
Defects in these grey matter structures have been shown to
correlate with changes of personality, apathy, anxiety, ADHD,
memory, visuospatial function and cognitive dysfunction. Tau
is one important intraneuronal protein affected that, when
aberrantly spliced, results in neurofibrillary degeneration. This
progressive process in the brain has been associated with
cognitive decline and dementia. Most recently, Weijs et al.
conducted a systematic review about human brain pathology
in DM1, discussing the coexistence of developmental (e.g.
heterotopic neurons) and neurodegenerative changes. Despite
comprehensive literature on neuroimaging in DM1 there is a
lack of studies that correlate in vivo neuroimaging with post-
mortem histopathological findings [35].
Knowledge about the underlying pathomechanisms leading
to ID in DM1 and the quantification of brain pathology by
imaging is important for the development of new treatment
approaches and the monitoring of their safety profiles and
efficacy, but for the diagnostic confirmation of DM1 genetic
testing remains the gold standard.
5. Discussion
In this review, we focussed on the most common
neuromuscular disorders that can present with ID, DMD,
BMD, αDG-CMD, LAMA2-CMD and congenital and
childhood DM1. Table 1 provides a comprehensive list
of these. Onset and progression of muscle weakness is
mentioned, which may be of relevance when ID or
behavioural problems precede muscle weakness, as can be
seen in cases with BMD. High CK levels are easy to interpret
in conditions such as dystrophinopathies, however, normal
levels, as described for some patients with LAMA2-CMD or
αDG-CMD, can be difficult to interpret or even misleading.
Table 1 also describes brain imaging findings. Additional CNS
symptoms consist of behavioural abnormalities, which have
been most comprehensively studied in DMD, BMD and DM1.
Epilepsy is a common feature in LAMA2-CMD and αDG-
CMD but has also been described in dystrophinopathies [7].
The diagnostic approach for a newborn and infant with
global developmental delay is broad and beyond the scope of
this review. We have focussed on a scenario in which muscle
weakness is present in a child beyond infancy with ID and
provided an algorithm that may help guide the diagnostic
approach (Fig. 1). Treatable and acquired conditions such
as hypothyroidism ought to be considered first. In infants
with profound muscle hypotonia, Prader-Willi syndrome also
needs to be excluded. When seeing a child with primary
muscle weakness and ID, one should always perform a
comprehensive neurological examination, review the family
history and determine serum CK levels. Pitfalls in this
context can be manifesting carriers of BMD/DMD that can
easily be missed when there is a negative family history. In
S. Specht and V. Straub Neuromuscular Disorders 31 (2021) 988–997

Table 1
For each of the mentioned neuromuscular diseases there is evidence of intellectual disability in childhood. ADHD, attention deficit hyperactivity disorder;
ASD, autism spectrum disorder (ASD); BMD, Becker muscular dystrophy; CK, creatine kinase; DMD, Duchenne muscular dystrophy; DM1, Myotonic
dystrophy type 1;ID, intellectual disability.

Disease Onset/ CK Intellectual Neuroimaging additional CNS Gene

progression Disability symptoms
Duchenne early childhood, > 10x n genotype- reduced total brain ASD (3–15%) DMD (out of
Muscular progressive, no phenotype and grey matter ADHD (11 frame mutations)
Dystrophy cognitive decline, association: volume, −32%),
(DMD) sometimes higher incidence white matter Obsessive
memory loss late in absence of alterations on compulsive
in life shorter isoforms microstructural level disorder (5–60%)
30–40% <70 [8,10] Anxiety (27%)
FIQ; on average 1 Epilepsy (6%)
SD < population [6,7]
FIQ [11]
Becker Muscular ID +/- >5–10x n Average mean IQ Brain atrophy [2] 67% total DMD (in frame
Dystrophy behavioural 21 −36% specific 24% mutations)
(BMD) disorders may learning developmental
precede muscle difficulties [1] (ASD, ADHD)
weakness and 21%
psychiatric
disorders
(depression,
schizophrenia,
OCD, bipolar,
anxiety)
8% epilepsy [1,2]
Manifesting ID +/- - >10x n, 30% behavioural DMD
female carrier behavioural typically 400 – problems and (X-inactivation,
DMD/BMD disorders may be 13,000 U/l delayed speech chromosomal
only symptom or abnormalities)
precede
heart/muscle
Myotonic infantile (1–10ys), 1–5 x n 50% mild – Possible white and ADHD, anxiety, DMPK gene with
dystrophy 1 classical moderate ID (FIQ grey matter internalizing CTG repeats >50
(> 10 ys) 50–70) involvement of disorders,
cortical and 80% central
subcortical regions fatigue
at all ages
Congenital DM1 prenatal Moderate to white and grey High comorbidity DMPK gene with
severe ID matter involvement with ASD and CTG repeats
of cortical and ADHD >750
subcortical regions
αDG-CMD CMD phenotype 5->10x n CMD: Profound in 70% cobblestone Seizures DAG1, POMT1,
(WWS, MEB, rarely n! to mild complex, pachygyric, Severe CNS POMT2,
FCMD, with LGMD: Moderate lissencephalic cortex, symptoms POMGnT1,
cerebellar to normal white matter changes, associated with LARGE, FKRP,
involvement, +/- prominent MRI findings FKTN, ISPD,
ID): prenatal/at infratentorial GTDC2,
birth involvement, B3GNT1,
LGMD phenotype cerebellar atrophy B3GALNT2,
+/- ID later onset and cysts, hypoplastic GMPPB,
[21] pons, small TMEM5,
brainstem, enlarged SGK196, DPM1,
ventricles, DPM2, DPM3
hydrocephalus,
microcephaly
[21,22]
LAMA2-CMD Congenital - 1- > 5x n Possible mild - persistent white 30% Epilepsy LAMA2
during childhood moderate matter changes
>5% structural
changes (occipital
cortical dysplasia,
subcortical
heterotopia,
cerebellar hypoplasia)

994
S. Specht and V. Straub
females with muscle weakness and ID of unknown origin,
CK screening, a karyotype analysis or an array CGH and
sequencing of the dystrophin gene should be considered for
the diagnosis of a manifesting carrier for DMD/BMD.
It is helpful to distinguish between three groups with
regard to CK elevation. Elevations > 10-fold of normal levels
are most often associated with dystrophic muscle disorders.
As such, the most common NMD, dystrophinopathies, ought
to be considered first in male and equally in female patients.
Manifesting carriers of DMD or BMD most commonly
show high CK levels, however, they may vary between
normal values and elevations > 10-fold of normal. The
other disease group to consider in the context of highly
elevated CK levels is that of CMD. Whereas CK elevations
5- >10-fold of normal are regularly seen in LAMA2-CMD,
this is equally common, however, not always the case, in
αDG-CMD. In patients with αDG-CMD the diagnosis can
be challenging because of the broad clinical spectrum and
if muscle immunoanalysis is not available or findings are
difficult to interpret. The typical brain malformations can then
be the most suggestive diagnostic findings [28]. Where CMD
is suspected in a child, founder mutations may help predict
a particular subtype, as is the case for FCMD in patients of
Japanese origin, WWS in Ashkenazi Jewish and a cluster of
a specific POMT1 gene mutation in the Turkish population
[36]. Brain imaging can be very helpful when a diagnosis
of LAMA2-CMD is suspected, since white matter changes
are the hallmark of both partial and complete laminin α2
deficiency. Normal or mildly elevated CK levels (1–5x normal
value) are seen in DM1.
The pattern of muscle weakness will help with
the differential diagnostic approach (Fig. 1). In
dystrophinopathies, weakness is predominantly proximal,
commonly starting in the lower limbs with the typical
Trendelenburg gait. Childhood DM1 on the other hand
presents with facial and distal weakness. In conditions with
neonatal onset such as congenital DM1, LAMA2-CMD and
αDG-CMD, muscle involvement is more generalised, and
patients present as floppy infants.
Other differential diagnoses that should be considered (Fig.
1) encompass mutations in the PMP22 gene, encoding for
the peripheral myelin protein 22. Whereas a deletion in
PMP22 leads to hereditary neuropathy with potential pressure
palsies (HNPP), duplications in the gene entail with 44% of
all cases the most common form of CMT, CMT1A. Point
mutations lead to variable phenotypes. It was reported that
70% of the patients with PMP22 mutations show decreased
white matter volume with predominance in the temporal and
parietal lobes. Likewise, 70% of patients showed impaired
cognitive functions, predominantly in executive functions,
working memory and verbal episodic memory [37].
Mitochondrial disease should always be considered when
at least two organ systems (muscle and brain) are involved.
It is beyond the scope of this review to comprehensively
discuss the broad spectrum of mitochondrial disease. Features
suggestive of a mitochondrial disease are mild CK elevations,
unless measured in the context of rhabdomyolysis, abnormal
995
Neuromuscular Disorders 31 (2021) 988–997
neuroimaging findings and characteristic histopathology in
muscle biopsies. Neuroimaging may reveal unspecific signs
such as delayed myelination or specific, symmetrical deep
grey matter signal abnormalities. Muscle biopsies can show
ragged red fibres, COX-negative fibres and subsarcolemmal
mitochondrial changes. Genetic testing includes both the
sequencing of mitochondrial DNA and of nuclear genes and
should be performed in patients with early disease onset and
progressive CNS symptoms in combination with hepatopathy,
cardiomyopathy and weakness and wasting of skeletal
muscles or arthrogryposis [38]. One condition that can show
overlap with muscular dystrophies is caused by mutations
in the CHKB gene, which encodes for choline kinase β,
an enzyme that catalyses the most abundant mitochondrial
membrane phospholipid that is formed through a pathway
within the mitochondria-associated endoplasmic reticulum
membrane (MAM). Recessive loss of function mutations of
CHKB can cause CMD and LGMD with raised serum CK
levels, severe ID and characteristic histopathological features
[38].
Congenital myasthenic syndromes (CMS) are a
heterogeneous group of rare inherited disorders due to
defective transmission at the neuromuscular junction. To
date, more than 30 genes have been identified that cause this
condition. The characteristic clinical features of CMS are
fatigable muscle weakness, mainly of the ocular, bulbar and
limb muscles. However, defective transmission may in some
cases also involve the CNS and lead to a more complex
clinical phenotype. Several genes have been identified that
cause CMS and ID, namely GMPPB and DPAGT1 [39] both
of which are involved in protein glycosylation, as well as
SLC18A3, SLC5A7, SNAP25B, COL13A1 and PREPL.
Another very rare differential diagnosis in patients with
muscle weakness and ID is pontocerebellar hypoplasia
with spinal muscular atrophy (PCH1). Patients typically
show spinocerebellar malformation, brainstem hypoplasia and
generalised cortical atrophy. Electrophysiological findings
include sensory and motor axonal neuropathy and denervation
on EMG. The clinical picture is heterogeneous and
at least five genes have been shown to be involved
in this disorder (EXOSC3, EXOSC8, VRK1, SLC25A46,
MORC2) [40]. Spinal muscular atrophy with lower extremity
predominance (SMALED) is characterised by congenital or
early onset, proximal more than distal lower limb muscle
weakness and atrophy with normal sensation. In the subtype
SMALED 1, caused by mutations in DYNC1H1, the broad
and heterogeneous phenotype includes spasticity and ID,
associated with cortical malformations of the frontal and
perisylvian regions on neuroimaging [41].
In general, ID has been sparsely studied in the context
of neuromuscular disorders in children. Terminology has
not been consistent throughout the literature and several
terms were used to describe ID in the context of
neuromuscular disorders, such as cognitive impairment,
cognitive deficits, learning disabilities, mental retardation and
cognitive developmental delay. The assessment of patients
has also been inconsistent and a variety of questionnaires
S. Specht and V. Straub
and test batteries have been described. We opted to use the
term ID, which captures aspects of CNS symptoms starting in
the developmental period and used the terminology suggested
by the most recent DSM-V. A better understanding of the
underlying pathomechanisms of ID in patients with genetic
neuromuscular diseases and a more standardised assessment
approach is a prerequisite for the implementation of optimized
care standards and the development of effective therapeutic
approaches.
Declaration of Competing Interest
The authors declare no conflict of interests.
Acknowledgement
We would like to acknowledge support of the Newcastle
NIHR Biomedical Research Centre for the work of our team.
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