# 24.19.2 Muscular dystrophy 6310 Kate Bushby and Ch

# 24.19.2 Muscular dystrophy 6310 Kate Bushby and Chiara Marini- Bettolo

section 24  Neurological disorders
6310
FURTHER READING
Hughes BW, Kusner LL, Kaminski HJ (2006). Molecular architecture 
of the neuromuscular junction. Muscle Nerve, 33, 445–​61.
Huxley HE, Hanson J (1972). The molecular basis of contraction. 
In: Bourne GH (ed). The structure and function of muscle, Vol 1, 
2nd edition. Academic Press, New York, NY.
Larsson L, et al. (1991). MHC composition and enzyme-​histochemical 
and physiological properties of a novel fast-​twitch motor unit type. 
Am J Physiol, 261, 93–​101.
Smerdu V, Karsch-​Mizrachi I, Campione M (1994). Type IIx myosin 
heavy chain transcripts are expressed in type IIb fibers of human 
skeletal muscle. Am J Physiol, 267, C1723–​8.
Walton JN, Mastaglia FL (1980). The molecular basis of muscle dis-
ease. In: Thompson RHS, Davison AN (eds) The molecular basis of 
neuropathology. Edward Arnold, London.
Wattjes MP, Kley RA, Fischer D (2010). Neuromuscular imaging in 
inherited muscle diseases. Eur Radiol, 20, 2447–​60.
24.19.2  Muscular dystrophy
Kate Bushby and Chiara Marini-Bettolo
ESSENTIALS
Muscular dystrophies are primary, genetically determined disorders 
of muscle. All cause muscle weakness, which is usually progressive. 
They are challenging to classify, but clinical characteristics can be 
combined with genetic and molecular information to obtain a useful 
operational nomenclature for prognosis and family counselling. In 
general, diagnosis is guided by the age at which clinical manifest-
ations appear, the distribution of weakness, and the rate at which 
muscle function is lost, but unusual features such as muscle pain and 
rhabdomyolysis may also contribute to the identification of a par-
ticular hereditary muscle disorder.
Congenital muscular dystrophies
Congenital muscular dystrophies are defined by their very early 
childhood onset and dystrophic features on the muscle biopsy. 
Clinically patients present with early onset of muscle weakness and 
hypotonia, and contractures are common. Respiratory and car-
diac involvement is common and can be severe. In some cases, 
the congenital muscular dystrophies can have overlapping genetic 
and clinical features with the congenital myopathies. Molecularly 
based subclassification allows the recognition of various subgroups 
including those associated with mutations in/​causing: (1) laminin 
A2 (LAMA2), (2)  α-​dystroglycan and glycosyltransferase enzymes 
(FKRP, FKTN, POMT1, POMT2, POMGnT1, LARGE, ISPD, GTDC2, 
DAG1, TMEME5, B3GALNT2, B3GNT1, GMPPB, SGK196, DPM1, 
DPM2, DPM3, DOLK) (3) collagen VI (COL6A1, COL6A2, COL6A3)—​, 
(4) lamin A/​C (LMNA), (5) selenoprotein 1 (SEPN1), (6) ryanodine 
receptor 1 (RYR1), (7) integrin A7 and A9 (ITGA7, ITGA9) (8) nesprin 
1 (SYNE1) (9) choline kinase beta (CHKB), and (10) other congenital 
muscular dystrophies with no genetic diagnosis but compatible 
clinical and histological features. Table 24.19.2.1 gives an overview 
on the congenital muscular dystrophy classification including no-
menclature, gene, phenotype, relative frequency in the UK popula-
tion and diagnostic test.
Dystrophin deficiency
Mutations (mostly deletions) in the dystrophin gene result in defi-
ciency of dystrophin protein and cause variable phenotypes ran-
ging from the more severe form, Duchenne muscular dystrophy to 
the milder form, Becker muscular dystrophy. Despite these being 
X-​linked diseases female carriers can also manifest the disorders. 
Cardiomyopathy can occur in conjunction with the skeletal muscle 
weakness, but also in the absence of overt weakness as X-​linked di-
lated cardiomyopathy.
Clinical features—​(1) Duchenne muscular dystrophy—​all affected 
boys are symptomatic within the first 3 years of life, although diag-
nosis is frequently delayed beyond this; motor milestones and 
speech are frequently delayed; there is a pronounced waddling 
gait on attempting to run. Hypertrophy of the calf muscles is al-
most universal. (2) Becker muscular dystrophy—​mean age at onset 
is 11 years; typically manifests with difficulty with high steps and 
climbing hills; may suffer muscle pain after exercise; frequently have 
hypertrophy involving the same muscle groups as seen in Duchenne 
muscular dystrophy. (3) About 10% of female carriers can also pre-
sent with variable skeletal and/​or cardiac muscle involvement. 
Exercise induced muscle pain is common as well as calf hyper-
trophy. (4) X-​linked dilated cardiomyopathy (XL-​dCMP)—​a distinct 
dystrophinopathy phenotype characterized by dilated cardiomyop-
athy and absence of overt skeletal muscle weakness. Treatment is 
similar to dilated cardiomyopathy and surgery may be necessary for 
refractory heart failure.
Investigation, diagnosis, and prevention—​serum creatine kinase 
is always massively elevated, but the level does not distinguish the 
severity of the disease. Molecular confirmation of the diagnosis is 
essential to assist in defining prognosis and allow provision of appro-
priate genetic counselling.
Prognosis and complications—​the prognosis of ‘dystrophinopathies’ 
is highly variable, especially among Becker MD and manifesting car-
riers. Untreated patients with Duchenne muscular dystrophy lose 
the ability to walk by the age of 12, but corticosteroids delay deteri-
oration. Scoliosis, respiratory failure, and cardiomyopathy develop 
during the teenage years. With appropriate multidisciplinary sup-
portive care, survival into or beyond the late twenties and thirties is 
becoming more common. Novel therapeutics directed to the muta-
tions in the dystrophin gene or the downstream effects of dystrophin 
deficiency are a prospect for treatments in the future and are cur-
rently being tested in trials, with likely availability of these new drugs 
on the market in the coming years. At the time of writing, conditional 
marketing approval in Europe only has been granted for ataluren, 
though access remains restricted.
Other muscular dystrophies
Facioscapulohumeral muscular dystrophy is an autosomal dom-
inant disease sometimes arising as the result of a new dominant 
mutation. Affected individuals manifest early symptoms, typically 
including facial weakness, shoulder girdle weakness, and foot-​
drop, often by their teens or twenties. Serum creatine kinase may 
be normal or mildly elevated. Diagnosis can be confirmed in 95% 


24.19.2  Muscular dystrophy
6311
of cases by demonstration of a deletion close to the telomere of 
chromosome 4q: more complex analysis is required for the other 
cases. The condition is usually slowly progressive; complications 
rarely include scoliosis and respiratory failure.
Emery–​Dreifuss muscular dystrophy—​caused by mutation of any 
one of several genes encoding components of the nuclear envelope 
(e.g. emerin, lamin A/​C). This may present at any age, with contrac-
tures of the ankles and elbows and rigidity of the spine often pre-
dating any clear weakness. Prognosis is determined by ability to 
manage life-​threatening cardiac arrhythmias and varies depending 
on the exact gene involved.
Limb-​girdle muscular dystrophies—​these comprise a range of dis-
orders that cause weakness of the proximal musculature. Important 
considerations in any case are (1) could it be a dominant disease? 
(e.g. limb-​girdle muscular dystrophy 1B; allelic with autosomal dom-
inant Emery–​Dreifuss muscular dystrophy), Bethlem myopathy; 
(2) age of presentation and of rate of progression—​these give im-
portant clues to likely diagnosis; (3) investigations—​creatine kinase is 
greatly elevated in all forms of autosomal recessive limb-​girdle mus-
cular dystrophy; electromyography confirms a primary myopathic 
process; muscle biopsy shows dystrophic changes on standard 
analysis, with more specialized testing for diagnosis of, for example, 
sarcoglycanopathies, calpainopathy, or dysferlinopathy.
Oculopharyngeal muscular dystrophy —​typically presents in the sixth 
decade with ptosis, dysphagia to solids, and dysphonia. Associated 
with an expanded triplet repeat in the gene for poly(A) binding 
protein 2.
Introduction
Muscular dystrophy is not a single disease. Many different types 
of muscular dystrophy can be recognized: all are primary, genet-
ically determined disorders of muscle and all cause muscle weak-
ness and wasting, which is usually progressive. The various types 
of muscular dystrophy share several characteristic findings on 
muscle biopsy, most notably a variation of fibre size, evidence of 
muscle fibre necrosis, and usually replacement of muscle tissue 
by fat and fibrous tissue. These pathological findings are often, 
but not always, accompanied by elevation of the serum creatine 
kinase. Although the key clinical sign in muscular dystrophy is 
muscle weakness, the distribution of that weakness and the asso-
ciation with other features such as wasting, hypertrophy, and joint 
contractures are the most helpful defining features in making a 
clinical diagnosis, together with age at presentation and rate of 
progression. Unusual presenting manifestations of muscular dys-
trophy are muscle pain, rhabdomyolysis, myoglobinuria, and 
cardiomyopathy.
Complications may include cardiac and respiratory failure or an-
aesthetic problems. These complications may be relatively specific 
to particular types of muscular dystrophy. Taken together with the 
clinical findings in any patient, precise diagnostic tests (through ei-
ther DNA analysis or protein analysis of a muscle biopsy sample) are 
available for most of these disorders, as knowledge of the underlying 
mechanism of disease for each of these entities has increased. 
Confirmation of the type of muscular dystrophy in any individual 
patient is critical to the provision of appropriate management, 
prognostic advice, and genetic counselling. No form of muscular 
dystrophy is currently curable, although various experimental 
therapeutic procedures are under investigation.
Classification of the muscular dystrophies
Various classifications of the muscular dystrophies have been pro-
posed, reflecting historical advances in the understanding of this 
group of diseases (Box 24.19.2.1). The current basis for classifi-
cation combines an appreciation of the clinical features with the 
ability to determine the molecular basis for the disease. Therefore, 
the eponymous names (e.g. Duchenne muscular dystrophy) still 
in common usage reflect the detailed clinical descriptions pro-
vided by early clinicians; other disease names reflect the recog-
nized pattern of muscle involvement in a particular condition (e.g. 
fascioscapulohumeral muscular dystrophy). Disease designations 
based on the genetic or protein defect in a particular disorder (e.g. 
dystrophinopathy) are becoming more widely used, reflecting the 
fact that some disorders previously believed to be clinically dis-
tinct actually represent different manifestations of lesions at the 
same locus. Genetic analysis has also revealed an unsuspected level 
of heterogeneity with different genetic causes for disorders that 
show superficial clinical similarities. This can be seen most strik-
ingly within the ‘limb-​girdle’ and congenital groups of muscular 
dystrophies.
The pathophysiology of the muscular dystrophies
Biochemical and physiological experiments failed to shed any light 
on the mechanisms by which muscular dystrophy could arise, and 
it has only been since the identification of the dystrophin gene 
(DMD) in 1987 that progress has been made. It is now quite clear 
that proteins involved in several different functions within the 
muscle cell can, when altered or absent, cause muscle damage and 
account for the pathological and clinical features of a muscular dys-
trophy. Some of these proteins are components of the membrane of 
the muscle fibre that may have a structural or signalling role, others 
are components of the nuclear envelope or muscle-​specific enzymes 
(Fig. 24.19.2.1).
General points on the diagnosis of muscular dystrophy
Box 24.19.2.2 summarizes some of the major considerations for 
arriving at the correct diagnosis of a muscular dystrophy. History 
taking at the time of presentation (Box 24.19.2.3) may be par-
ticularly informative. The clinical history may be pathognomonic. 
Detailed diagnostic information is given in the following text re-
lating to specific diseases. The main tools for specific diagnosis in 
muscular dystrophy are the use of antibodies for immunolabelling 
of muscle biopsy sections and/​or the application of specific DNA-​
based genetic analysis. Muscle MRI can also be helpful in achieving 
a diagnosis as it can show selective patterns of muscle involvement 
Box 24.19.2.1  Basis of the classification of muscular 
dystrophies
• Clinical description
• Genetics (autosomal dominant/​recessive/​X-​linked)
• Underlying gene/​protein defect
• Localization or function of the protein involved


section 24  Neurological disorders
6312
specific to various forms of muscular dystrophy and these specific 
patterns are increasingly well defined.
General points on the management of  
the muscular dystrophies
Despite the fact that no cures for muscular dystrophy have been es-
tablished, there are many management issues that may be important 
or specific to the various types. However, as yet there is little system-
atic or comprehensive clinical research into management and ran-
domized trials of management regimens are few and far between. It 
is nevertheless appropriate, where possible, that patients with a diag-
nosis or a suspected diagnosis of muscular dystrophy should be re-
ferred to a specialist clinic with access to the full range of specialists, 
who need to be involved in the coordinated care of these patients 
depending on their diagnosis and stage of disease. The multidiscip-
linary approach of these clinics ensures that patients have access to 
the full range of diagnostic facilities, are able to obtain specialized 
multidisciplinary care (including physiotherapy advice), and can 
obtain accurate genetic counselling where this is required. Access to 
patient support organizations and their staff is also of paramount im-
portance. Patients should also be informed and offered the option to 
sign on to disease specific patient registries, as these are a powerful 
tool to collect information to gather better understanding of these 
rare conditions and help develop standards of care, identify partici-
pants for clinical trials, and update patients with relevant information 
to their condition. The diagnosis of any kind of muscular dystrophy, 
in that it inevitably implies a progressive and incurable disease, pos-
sibly with implications for children or other relatives, is a consider-
able burden and one that needs to be recognized and supported.
The congenital muscular dystrophies
The congenital muscular dystrophies (CMDs) are defined by their 
very early childhood onset. They comprise several disorders with 
different molecular pathological bases for the diseases. For their 
presentation, see Box 24.19.2.4.
Extracellular matrix:
Plasma membrane
Cytoplasm
Nuclear envelope
Extracellular matrix
Cytoplasm:
Nuclear envelope:
Plasma membrane:
Collagen
Laminin
Fukutin
FKRP
POMGnt
LARGE
Myotilin
Emerin
Dystrophin
Integrins
Caveolin
Dysferlin
Sarcoglycans
Nesprins
Lamin A/C
Actin
Telethonin
TRIM32
Titin
Calpain 3
Ab-crystallin
Desmin
Fig. 24.19.2.1  Schematic diagram to show localization within the muscle fibre (where known) of some of the 
proteins involved in producing a dystrophic phenotype.
Box 24.19.2.2  Diagnosis of muscular dystrophy
• History (especially motor milestones, age at onset, physical prowess as 
a child).
• Age of patient (congenital/​childhood/​teenage/​adult presentation).
• Pattern of muscle involvement on examination (predominantly prox-
imal/​distal, upper limb/​lower limb, symmetrical/​asymmetrical).
• Pattern of associated features on examination (contractures, muscle 
wasting, hypertrophy).
• Level of serum creatine kinase in active disease (massive elevation in 
dystrophinopathy, sarcoglycanopathy, dysferlinopathy, calpainopathy, 
congenital muscular dystrophy (some); moderate elevation in 
facioscapulohumeral muscular dystrophy, Emery–​Dreifuss muscular 
dystrophy, congenital muscular dystrophy (some); normal to mild 
elevation in autosomal dominant limb-​girdle muscular dystrophy, 
facioscapulohumeral muscular dystrophy (some)).
• Electromyography (to exclude neurogenic causes of weakness and 
congenital myasthenias, especially if serum creatine kinase is not 
markedly elevated).
• Muscle imaging (ultrasound scans can confirm muscle involvement, 
but to confirm pattern of muscle involvement need MRI/​CT).
• Muscle biopsy, histology, and storage of frozen biopsy material for fur-
ther analysis.
• Specialized analysis of muscle biopsy (immunocytochemistry, 
immunoblotting, electron microscopy).
• DNA analysis is now the gold standard for diagnosis.
Box 24.19.2.3  History taking in muscle disease
• Question in detail about early motor development.
• Elicit what actually were the first symptoms experienced by a patient; 
this may be difficult but is important in highlighting the initial pattern 
of muscle involvement—​lower limb vs. upper limb/​ proximal vs. distal 
musculature.
• Ask ‘When were you at your fastest?’; this may be informative in 
determining age of peak motor performance.
• Ask about performance at school sports.
• Particularly useful indicators in that respect are the ability to climb 
ropes (upper girdle weakness), muscle pain on running, a tendency to 
spend all the time in goal at football(!).
• Do not assume that difficulty climbing stairs always indicates proximal 
muscle weakness—​it may reflect an inability to push up on the toes.
• Ask specifically about the ability to stand on tiptoe/​stand on heels. The 
need to wear heels on shoes at all times may indicate Achilles tendon 
contractures.
• Patients who had early Achilles tendon contractures may have had 
them operated on before being referred for diagnosis. Ask about this.


24.19.2  Muscular dystrophy
6313
Differential diagnosis
In the neonatal and early childhood presentation the main clinical 
diagnostic confusion (after excluding central causes of hypotonia) 
may be with spinal muscular atrophy (check SMN gene for char-
acteristic deletions), congenital myotonic dystrophy (facial weak-
ness is usually more pronounced and diagnosis can be excluded on 
genetic testing), and congenital myopathy (may be distinguished on 
muscle biopsy). In all of these conditions, serum creatine kinase is 
either normal or much lower than seen in many congenital muscular 
dystrophies.
With later childhood presentation the differential diagnosis is as 
already mentioned, plus Duchenne muscular dystrophy (though calf 
hypertrophy is usually more pronounced and serum creatine kinase 
is typically higher—​biopsy will exclude the diagnosis) or childhood 
presentation of a limb-​girdle type of muscular dystrophy.
Classification
There are several recognized forms of congenital muscular dys-
trophy and, as there is considerable heterogeneity in the group that 
remains, additional entities are ultimately likely to be distinguished 
at the genetic level. The diagnostic classification of this group of 
diseases was previously very clinically based, but is moving in-
creasingly into a molecularly based. This allows the recognition of 
various subgroups of CMD: laminin α2 (LAMA2) associated CMD 
(MDC1A), the types of CMD involving abnormal glycosylation of 
α-​dystroglycan (where there is frequent eye and/​or brain involve-
ment as well as muscle weakness), CMD associated with collagen VI 
mutations (Ullrich congenital muscular dystrophy or UCMD), and 
rigid spine muscular dystrophy-​1 (RSMD1) due to mutations in the 
selenoprotein-​1 gene (Table 24.19.2.1). Cases of CMD due to mu-
tations in genes also causing other types of muscular dystrophy are 
also increasingly recognized, for example with mutations in lamin 
A/​C. Rare cases of CMD, mental retardation, and abnormal mito-
chondria (CMDmt) have been described associated with mutations 
in choline kinase beta (CHKB).
Establishing the diagnosis
Serum creatine kinase may, in some forms of congenital muscular 
dystrophy, be normal, but is typically elevated at least twofold, 
and up to twentyfold or more in the laminin A2-​deficient group 
and the α-​dystroglycanopathies. Muscle biopsy shows dystrophic 
changes and allows examination for LAMA2, α-​dystroglycans, and 
collagen VI in muscle; skin is also used to distinguish cases with 
normal and abnormal or absent protein. MRI of the brain is a useful 
adjunct to diagnosis because it will confirm the presence of white 
matter changes, which are always present after age 6 months in pri-
mary LAMA2 deficiency, and the characteristic brain malforma-
tions in the types of CMD associated with α-​dystroglycanopathy 
(see Table 24.19.2.1).
Prognosis and management
The overall prognosis depends on the type of CMD and individual 
severity in the patient because there can be major variability even 
within the different subgroups. Children with the most severe forms 
are at risk of dying in early childhood. If they survive this period, 
with appropriate management of feeding problems, and respiratory 
and (in a minority) cardiac complications, survival into adult life is 
the norm. The muscle weakness in congenital muscular dystrophy 
may be relatively static, but the complications of that weakness can 
be severe, and vary according to the precise diagnosis. The degree of 
muscle weakness is quite variable. In primary laminin A2-​deficient 
CMD, the severity of the disease correlates roughly with the abun-
dance of laminin A2 in the muscle, with children completely lacking 
laminin A2 rarely achieving independent ambulation. Others may 
Box 24.19.2.4  Presentation of congenital muscular dystrophies
Neonatal presentation
• Hypotonia, which may be prenatal
• Feeding problems (usually mild)
• Joint contractures, especially knees, hips, and ankles (Fig. 24.19.2.2)
• Joint laxity that may coexist with contractures at other joints
Early childhood presentation
• Delayed motor milestones
• Failure to thrive
• Repeated respiratory infections
Later childhood presentation (rare)
• Mainly proximal muscle symptoms
• History of delayed motor milestones
• Rigid spine, contractures of ankles, hips, and knees
(a)
(c)
(b)
Fig. 24.19.2.2  (a) Typical clinical picture of a baby presenting with 
MDC1A (muscular dystrophy, congenital, type 1a). Note the hypotonic 
posture, and mild contractures of the hips, knees, and ankles. (b, c) 
Immunofluorescence picture of skin biopsy labelled with an antibody 
to laminin A2 (merosin), showing normal (b) and absent labelling 
(c) patterns. This investigation can be carried out on a variety of tissues 
including skin, muscle, and placenta.


section 24  Neurological disorders
6314
Table 24.19.2.1  The congenital muscular dystrophies
Disease and 
nomenclature
Gene
Relative 
frequency in the 
UK population 
(expressed as % 
of CMD clinic 
population)
Diagnostic tests
Phenotype
Collagen VI related 
dystrophies (COL6-​RD)
COL6A1, COL6A2, 
COL6A3
21%
Frequent absence 
or abnormality 
of collagen VI 
immunolabelling in 
muscle or cultured 
fibroblasts. Mutation 
testing
Characteristic pattern of joint hyperlaxity distally with 
proximal contractures. May be abnormal skin, including 
keloid scarring and hyperkeratosis
Can present as:
•  Ullrich congenital muscular dystrophy (UCMD)–​ severe 
non​ambulant and transient ambulant. UCMD is typically 
autosomal recessive, de novo dominant mutations are 
increasingly recognized
•  Intermediate phenotype
•  Bethlem myopathy (BM, milder allelic form)
CMD with abnormal 
glycosylation of 
α-​dystroglycan
(a dystroglycan-​
related dystrophy, 
α-dystroglycanopathy, 
a DGpathy)
fukutin, FKRP, LARGE, 
POMT1, POMT2 
POMGnT1, DAG1, 
DPM2/​DPM3, 
GMPPB, ISPD, GTDC2, 
B3GNT1, SGK196, 
TMEM5, and others
15%
Abnormal labelling 
of α-dystroglycans 
in muscle, mutation 
testing
Very variable brain phenotype ranging from normal to severe 
lissencephaly. Eye phenotype is also variable from normal to 
micro-​opthalmia
•  Walker–​Warburg syndrome
•  Muscle–​eye–​brain disease; Fukuyama CMD; 
Fukuyama-​like CMD
•  CMD with cerebellar involvement; cerebellar abnormalities 
may include cysts, hypoplasia, and dysplasia
•  CMD with mental retardation and a structurally normal 
brain on imaging; (includes patients with isolated 
microcephaly or minor white matter changes on MRI)
•  CMD with no evidence of abnormal cognitive 
development
Can present also as:
•  Limb-​girdle muscular dystrophy (LGMD) with mental 
retardation
•  LGMD without mental retardation
MDC1A (muscular 
dystrophy congenital 
type1A, Laminin A2 
deficiency LAMA2-​ 
related dystrophy, 
LAMA2-​CMD, merosin-​
deficient CMD)
LAMA2
10%
Absence of laminin 
A2 labelling in 
muscle and skin, 
mutation testing
White matter radiolucency on MRI, approx 30% have 
epilepsy. May have restricted eye movements. Progressive 
development of severe contractures, scoliosis, feeding and 
respiratory problems require close follow-​up
Congenital 
laminopathy (LMNA 
related dystrophy, 
LMNA-​CMD, LCMD, 
and Emery–​Dreifuss)
LMNA
3%
Mutation testing in 
LMNA
Very heterogeneous phenotype
Early onset axial weakness with absent or early loss of 
ambulation, dropped head syndrome, feeding difficulties, and 
respiratory involvement
Milder phenotypes
Cardiac phenotype: arrhythmogenic cardiomyopathy with 
conduction block and also ventricular tachyarrhythmias 
requiring use of an AICD
Selenoprotein 1 related 
myopathy presenting 
as CMD (SEPN1 
related myopathy, 
RSMD1)
SEPN1
1%
Immunolabelling in 
muscle is typically 
normal. Diagnosis 
established on 
mutation in SEPN1
Typical rigid and side sliding spine develops in first decade. 
Early respiratory failure while ambulation maintained.
Selenoprotein 1 gene mutations are also responsible for 
multiminicore disease
RYR1 related 
myopathy presenting 
as CMD (RYR1-​CMD)
RYR1
n/​a
Muscle biopsy 
shows central core, 
multiminicore,
centronuclear 
and non​specific 
pathologies. which 
can assume CMD 
like characteristics
Early scoliosis and absent or limited ambulation
Others
Various other causes 
of CMD have been 
described including 
mutations in integrin 
α-7 and α-9, nesprin 1, 
and CHKB
ITGA7, ITGA9, SYNE1 
CHKB
n/​a
Depends on 
causative gene 
which will need 
to be detected 
by protein and 
mutation testing
Depends on causative gene:
ITGA7 related CMD: delayed motor milestones, respiratory 
impairment, scoliosis
ITGA9 related CMD: similar to UCMD but no protruding 
calcanei, no respiratory failure, and acquired ability to walk
SYNE1-​related CMD: adducted thumbs, mental retardation, 
ophthalmoplegia
CHKB-​related CMD: large appearing mitochondria, cognitive 
impairment (with normal brain MRI), acanthosis nigricans like 
lesions and intense pruritus


24.19.2  Muscular dystrophy
6315
learn to walk independently but this is usually much later than usual, 
and these children may later lose this ability.
For all types of CMD, joint contractures and scoliosis are major 
complications of the disease and cause much additional disability, 
requiring careful management by physiotherapy, standing regimens, 
orthoses, and surgery where appropriate. Feeding problems may be 
intractable and lead to chronic malnutrition unless treated by naso-
gastric or gastrostomy feeding. Malnutrition may contribute to sus-
ceptibility to chest infections, which is also heightened by weakness 
of the respiratory muscles. These children are at risk of respiratory 
failure and their follow-​up should include monitoring for this com-
plication, which can be effectively managed by the provision of 
noninvasive home nocturnal ventilation. Cardiac failure is a rela-
tively rare complication in CMD but has been reported in MDC1A 
and the α-​dystroglycanopathies.
Fukuyama congenital muscular dystrophy, muscle–​eye–​brain 
disease, Walker–​Warburg syndrome, and other diseases within the 
α-​dystroglycanopathy spectrum may be dominated by intellectual 
and visual impairment. In MDC1A, brain changes on MRI are typ-
ically asymptomatic. In UCMD intellectual development is normal 
but respiratory failure is a major risk in the first decade. RSMD1 
overall carries a generally much milder prognosis with respect to 
mobility, but this may mask a serious risk of respiratory failure and 
scoliosis, both generally necessitating intervention by the end of the 
first decade, often while still ambulant.
Genetic counselling
CMD are generally inherited in an autosomal recessive fashion, 
however dominant inheritance is possible and needs careful rec-
ognition to provide correct genetic counselling. Indeed, collagen 
VI and lamin A/​C related disorders can be inherited in a recessive 
as well as a dominant pattern and these tend to be de novo mu-
tations. It is, therefore, important to recognize dominant acting 
mutations—​segregation studies are needed to determine whether 
the mutation is de novo, but the possibility of somatic or germline 
mosaicism in de novo mutations should always be considered to 
provide correct counselling. As the molecular basis for these dis-
orders has recently become much better established, specific diag-
nosis should be attempted in all cases in order to allow proper 
direction of management, as well as prenatal and carrier testing 
where requested.
Dystrophin deficiency
This group, including two of the most common forms of muscular 
dystrophy—​Duchenne and Becker muscular dystrophy—​involve 
the same gene and protein. These are X-​linked diseases, caused 
by mutations, most of which are deletions, in the dystrophin 
gene (DMD).
Presentation
Duchenne muscular dystrophy (OMIM 300377)
• All patients are symptomatic within the first 3 years of life, al-
though the mean age at diagnosis is 51.7 months (4.3 years) with a 
range of 10–​91 months.
• Motor milestones are often delayed (half the cases are not walking 
by 18 months).
• Speech is also frequently delayed.
• Patient is unable to run: there is a pronounced waddling gait on 
attempting to rush.
• Patient is unable to jump with both feet together or to hop: there is 
no spring in the step.
• ‘Climbs up legs’ on rising from the floor: Gower’s manoeuvre.
• Can present with anaesthetic complications. Anaesthesia guide-
lines can be found on http://​community.parentprojectmd.org/​
profiles/​blogs/​revised-​duchenne-​anesthesia-​recommendations- 
​2015
Becker muscular dystrophy (OMIM 300376)
• The mean age at onset of Becker muscular dystrophy is 11 years, 
although the range of age at presentation is extremely wide and the 
diagnosis may be made at any age, particularly if there is a family 
history.
• A proportion will have had delayed motor milestones (this may 
correlate as much with reduction in IQ as with major motor prob-
lems at that age).
• Many describe being unable to keep up with peers at school.
• There is difficulty with high steps and climbing hills.
• Muscle pains after exercise are a common complaint, especially in 
teenagers (rarely myoglobinuria).
Manifesting carriers of Duchenne muscular dystrophy/​Becker 
muscular dystrophy
A highly variable group, which may occasionally be as severely af-
fected as those with Duchenne muscular dystrophy or more or less 
mildly than those with Becker muscular dystrophy. Up to 10% may 
be at risk of cardiac complications of their carrier status.
Dystrophin-​associated cardiomyopathy OMIM 302045
There are symptoms and signs of hypertrophy progressing to dilated 
cardiomyopathy in the absence of major muscle symptoms. Some 
patients have an elevated serum creatine kinase.
Establishing the diagnosis
The clinical presentation of Duchenne muscular dystrophy (DMD) 
is very characteristic. Hypertrophy of the calf muscles is almost 
universal (Fig.  24.19.2.3a), sometimes accompanied by muscle 
hypertrophy elsewhere, most frequently involving deltoid, parts of 
the quadriceps, the tongue, and masseters. Wasting of the pectoral 
and scapular muscles leads to hypotonia around the shoulders, de-
tected as the child ‘slipping through the hands’ on being lifted. In 
the lower limbs, quadriceps power is weaker than that of the ham-
strings. Formal examination of a small child may be difficult, and 
the main clinical tool is observation of walking, attempting to run, 
jump, and climb stairs, and to rise from the floor. It is imperative 
to give the child space to attempt to run, as this will bring out the 
lack of spring in the step and the lack of fluidity of the attempted 
running.
Becker muscular dystrophy (BMD) has been described as a 
‘slow motion version of Duchenne muscular dystrophy’, in that the 
pattern of muscle involvement in these two allelic disorders is essen-
tially identical (Fig. 24.19.2.3c), but progresses at a much slower 
rate in BMD. Patients with BMD may be quite strong on formal 
muscle examination, but tend to show subtle signs of proximal 
muscle weakness on climbing stairs or running. They frequently 


section 24  Neurological disorders
6316
have hypertrophy involving the same muscle groups as seen in DMD. 
Some patients have pes cavus.
Serum creatine kinase is always massively elevated, even to more 
than 200 times normal, but levels of serum creatine kinase do not 
distinguish the severity of the disease. Muscle biopsy and electro-
myography are non​specifically but generally severely dystrophic. The 
muscle biopsy in BMD may also show some grouped fibre atrophy 
reminiscent of a ‘neurogenic’ pathology. Molecular confirmation of 
the diagnosis is essential to assist in defining prognosis and to pro-
vide appropriate genetic counselling. In addition, current standards 
of diagnosis include detailed characterization of the mutation as it 
is essential in view of mutation-​specific drugs that are now available 
or being developed for use, so far, in clinical trials. Multiple ligation 
probe amplification is a technique that can detect copy number of 
every exon and confirm the diagnosis in the 60–​80% of patients in 
whom a deletion or duplication of the dystrophin gene is present, 
regardless whether the patient is a male or female—​this was not 
the case with previously used techniques like multiplex polymerase 
chain reaction. For patients in whom deletion and duplication ana-
lysis are negative, testing for point mutations via direct sequencing 
techniques (Sanger sequencing or next-​generation sequencing) of 
the entire coding region is mandatory. In dubious cases of unknown 
pathogenicity of the variant identified or in patients with no detect-
able mutation, it is useful to consider a muscle biopsy by which, in all 
patients, the diagnosis can be established by not finding or finding 
reduced dystrophin in the muscle biopsy (Fig. 24.19.2.3d). This ana-
lysis also allows the distinction of dystrophinopathy from the much 
rarer (in most populations) limb-​girdle types of muscular dystrophy. 
Precision of the exact mutation is important for offering carrier 
testing to the mother and other family members (important to es-
tablish the risk of any cardiac problems as well as to allow genetic 
advice for future pregnancies) and also to allow future access to the 
mutation-​specific treatments that are currently under development, 
such as antisense oligonucleotide-​mediated exon skipping and stop 
codon suppression.
Prognosis
Within the ‘dystrophinopathy’ group the prognosis is highly vari-
able. By definition, untreated patients with DMD lose the ability 
to walk by the age of 12, though this definition is now difficult 
to apply as the widespread use of corticosteroids has delayed the 
loss of ambulation in many patients well into their teenage years. 
The development of scoliosis, respiratory failure and cardiomy-
opathy (Box 24.19.2.5) are also delayed with the use of steroids, 
and improved overall management means that survival into or 
beyond the late 20s and 30s is becoming more common. Patients 
with BMD are ambulant beyond 16 years of age, and may remain 
able to walk independently into their fifth decade or later. These 
patients are susceptible to cardiac failure at any age from the 
teens onward and should be monitored for this complication on 
a regular basis (Box 24.19.2.5). Respiratory failure is a late com-
plication in BMD and correlates with very late-​stage disease. The 
lifespan in BMD may be normal, or reduced in more severe dis-
ease. An ‘intermediate’ group is also recognized, patients losing 
ambulation between age 12 and 16: their overall prognosis is also 
intermediate between DMD and BMD. Around 8% of carriers of 
(b)
(a)
(c)
(d)
Fig. 24.19.2.3  (a) Child with Duchenne muscular dystrophy at 
presentation, showing the marked calf and quadriceps hypertrophy and 
tendency to rise onto the toes. (b) Teenage boy in the later stages of the 
disease, showing the complications of marked immobility, scoliosis, and 
muscle wasting. This young man has now been maintained on home 
nocturnal ventilation successfully for more than 7 years. (c) Clinical 
pattern at presentation in a young man with Becker muscular dystrophy. 
Note hypertrophic muscles in calves and quadriceps and mild wasting 
around the shoulder girdle. (d) Immunocytochemical analysis of 
dystrophin in normal muscle, Becker muscular dystrophy muscle, and 
Duchenne muscular dystrophy muscle. In normal muscle, dystrophin 
labels evenly around the periphery of the muscle fibres. This labelling 
is typically patchy and reduced in Becker muscular dystrophy, and is 
either completely or almost completely absent in Duchenne muscular 
dystrophy.
Box 24.19.2.5  Practice point: cardiac involvement 
in dystrophinopathy
• All patients with dystrophinopathy are at risk of developing cardio-
myopathy which progresses with age. It is frequently asymptomatic, 
and needs to be sought through full cardiac assessment including 
echocardiography, as treatment with antifailure medication may im-
prove function and prognosis.
• Cardiac transplantation has been used successfully in patients 
with Becker muscular dystrophy and manifesting carriers of 
dystrophinopathy. It may be more utilized in DMD as other manage-
ment modalities improve.
• Cardiac compromise is the major determinant of operative risk in 
boys with Duchenne muscular dystrophy, and all should have a full 
cardiac assessment in advance of any surgery at any age.


24.19.2  Muscular dystrophy
6317
DMD or BMD may develop some signs of the disease: rarely this 
is in a full-​blown form comparable to the disease in boys. In prac-
tice, there is a continuum of severity with the highest incidence 
in the DMD group (birth incidence 1 in 3500 male live births), 
while the estimated incidence in the BMD group is at 1 in 18 518 
male births. As the lifespan is so much longer in the BMD group, 
however, the prevalence of the two conditions is roughly similar 
(about 24 per million population in north-​east England).
Over the whole group, there is a correlation between dystrophin 
abundance (as measured in a muscle biopsy sample) and se-
verity: children with completely absent dystrophin tend to be con-
fined to a wheelchair slightly earlier than children whose biopsies 
contain low levels of dystrophin. Patients with BMD have much 
higher levels of dystrophin (see Fig. 24.19.2.3). These dystrophin 
levels also correlate in most cases with the type of mutation found in 
the dystrophin gene—​in DMD most deletions are out of frame, not 
supporting the production of dystrophin, whereas BMD patients 
typically have in-​frame deletions, allowing the production of a re-
duced amount of dystrophin of a slightly smaller size.
Although these correlations are useful in a general sense, they are 
not absolutely predictive of outcome in an individual case, and must 
always be taken in the context of the clinical features of the patient. 
Indeed, the move towards genetic testing as the primary step in diag-
nostics means that most patients now will not have a muscle biopsy 
routinely. They can be useful, however, in giving the best possible 
guide to prognosis, especially in those patients who present early 
with no clinical clues as to the severity of the disease, or who are 
identified by neonatal screening or the incidental finding of a high 
serum creatine kinase level.
Management
DMD is essentially a predictable disease with complications that 
need to be proactively sought and managed in different systems. 
Although, in the past, a nihilistic attitude to management in DMD 
was widespread, evidence of the benefits of proactive management 
is now available and all patients should have access to the highest 
possible care. The key to proper management is a team specializing 
in neuromuscular management, who can oversee the coordination 
of input from physiotherapy, orthopaedic, cardiac, respiratory and 
psychology specialists. Input from other specialties, including occu-
pational therapy, educational psychology, gastrointestinal medicine, 
and palliative care, may also be required. Indeed, corticosteroids to-
gether with multidisciplinary management of DMD boys have led 
to changes of the natural history of this condition, improvement of 
quality of life and prolonged survival with the possibility of life ex-
pectancy into the late thirties.
Duchenne muscular dystrophy: the early stages
Proper management of a child with DMD starts with awareness of 
the possibility of the diagnosis in any boy who is not walking by the 
age of 18 months or whose mobility is poor compared with that of 
his peers. The current mean age at diagnosis has improved over the 
last decade dropping from almost 5 years to 4.3 years with a range of 
10–​91 months, highlighting still unacceptable delays. The principal 
impetus to early diagnosis is currently the ability to offer parents 
the option of prenatal diagnosis in subsequent pregnancies. Early 
diagnosis is essential, as prompt management and interventions 
according to standards of care results in better outcomes. When 
specific treatments become available, there is likely also to be a need 
to implement such treatments before the disease is too advanced.
Once the diagnosis has been considered, measurement of the 
serum creatine kinase will confirm the suspicion and ideally a re-
ferral to a specialist unit should be made at this stage. The spe-
cialist unit should have rapid-​track access to DNA diagnostic and, if 
needed, muscle biopsy facilities to confirm the diagnosis as quickly 
as possible. DMD is a devastating diagnosis, and should be given to 
the family following guidelines for the best practice for disclosure of 
bad news: the parents should be seen together wherever possible in 
complete privacy, they should have time to sit and ask questions, and 
have access to experienced staff for support and further information. 
Access to support groups and the relevant national charity is appro-
priate. Supporting information should also be passed immediately 
to the GP, health visitor, and school who may never have looked after 
a child with this type of condition before.
As DMD is an X-​linked condition, early access to genetic counsel-
ling is also vital shortly after diagnosis (Box 24.19.2.6) and needs to 
be reinforced as the affected person and his siblings reach adulthood.
Untreated, DMD has a rapidly progressive course with loss of am-
bulation in the first decade of life and death before the age of 20. 
Thanks to the introduction of corticosteroids and multidisciplinary 
management in boys with DMD the life expectancy and disease 
course have changed substantially. As part of the multidisciplinary 
management, the introduction of nocturnal non​invasive ventilation 
and scoliosis surgery has been shown to have a positive impact on 
survival, in particular if combined. In addition, early cardiac treat-
ment with angiotensin converting enzyme (ACE) inhibitors and β-​
blockers can delay the progression of dilated cardiomyopathy. From 
Box 24.19.2.6  Genetic counselling in dystrophinopathy
Genetic counselling in dystrophinopathy is an essential part of the man-
agement of any family where a diagnosis of dystrophinopathy has been 
made because the potential implications go far beyond the index case.
• These are X-​linked diseases.
• The new mutation rate in the dystrophin gene is high.
• Most cases of Duchenne muscular dystrophy are born now in families 
with no prior history of the disease.
• None the less, even in these families, other female relatives (through 
the maternal line) are at risk of being carriers.
• The essential piece of information is the delineation of the dystrophin 
mutation in the affected child (easy to find in the 60% in whom the 
mutation is a deletion, but point mutation testing my sequencing re-
quired in the remainder).
• In the presence of a known mutation, female relatives can be offered 
testing directly to see if they are carriers or not.
• They may choose to have prenatal diagnosis on the basis of that 
testing.
• Even if mothers of boys with Duchenne muscular dystrophy can be 
shown not to be somatic carriers of the mutation in their son, they still 
may have a proportion of egg cells containing the mutation (a situation 
known as ‘germline mosaicism’). They therefore remain at a 10–​20% 
risk of having another affected child in a future pregnancy.
• Boys with Duchenne muscular dystrophy are increasingly surviving to 
adulthood with some having the opportunity to have children, and 
men with Becker muscular dystrophy often do (overall fitness reduced 
to around 2/​3). All of their daughters are obligate carriers of Becker 
muscular dystrophy, but none of their sons are at risk. Genetic coun-
selling is an important part of transition planning.


section 24  Neurological disorders
6318
early stages physiotherapy management of ankle and hip contrac-
tures with regular stretching exercises is fundamental for mainten-
ance ambulation. Boys frequently develop a toe-​walking gait which 
partially compensates for their proximal muscle weakness—​walking 
splints or ankle–​foot orthoses are, therefore, not appropriate at this 
stage and any early Achilles tendon contractures are better man-
aged through passive stretching and night-​time below-​knee splints. 
During the late ambulatory phase, at the point at which walking be-
comes impossible independently, knee–​ankle–​foot orthoses can be 
introduced to prolong ambulation, but are not essential.
Corticosteroids are at present the sole available treatment that has 
been proven to slow down the decline in muscle strength and prolong 
ambulation. It is recommended that corticosteroids (prednisolone 
or deflazacort) are started between the age of 2 and 5 years (when 
strength is plateauing or declining) for the preservation of strength. 
An increasing consensus has developed that use of daily corticoster-
oids (prednisolone at a dose of 0.75 mg/​kg per day or deflazacort at a 
dose of 0.9 mg/​kg per day) is preferred to alternative regimes; how-
ever, intermittent regimens are currently being tested in a double-​
blind randomized trial which may potentially lead to changes in 
these recommendations. Controlled trials show a clear benefit for 
strength and respiratory function for up to 18 months, and uncon-
trolled long-​term cohort studies report a significant delay in loss of 
ambulation, a reduction in the development of scoliosis, and a pro-
tective effect on respiratory and also cardiac function. Close moni-
toring for the side effects of corticosteroids is, of course, indicated, 
and crucial to minimize the potentially harmful effects of the treat-
ment. In DMD the most commonly reported side effects are weight 
gain (which can be addressed with careful attention to diet), reduc-
tion in height, delayed puberty, and behavioural side effects, which 
may respond to a change in timing of dosage to evening instead of 
morning, as well as to standard psychological means to improve be-
haviour management. A further concern is the development of sig-
nificant osteoporosis, which is a risk in any case in boys with DMD, 
but which may be exacerbated, particularly in the lumbar spine, by 
steroid usage. The prophylactic use of bisphosphonates in this pa-
tient group remains controversial, but intravenous bisphosphonate 
treatment is certainly indicated if there is a problem with symptom-
atic fracture, and this need not be an indication for discontinuation 
of steroid treatment. Prophylactic cardiac treatment with ACE in-
hibitors and β-​blockers is currently being investigated in a double-​
blind, randomized, multicentre, placebo-​controlled trial to assess 
whether this can prevent the development or delay the age of onset 
of cardiomyopathy in boys with normal left ventricular function on 
transthoracic echocardiography.
Duchenne muscular dystrophy: after mobility is lost
Despite optimal multidisciplinary management loss of ambulation 
inevitably occurs and interventions and adaptation should follow 
according to disease progression (early and late non​ambulatory 
phase). The prompt provision of a powered wheelchair with indoor 
and outdoor access is critical to the best possible maintenance of 
independence and access to wheelchair sports. In the early non-​
ambulatory phase provision of a manual wheelchair may also be ne-
cessary, predominantly for indoor use and as a backup. With disease 
progression upper limb strength will inevitably decline and alterna-
tive control devices need to be considered to maintain independ-
ence. Regular assessment of the wheelchair, with particular attention 
to correct seating, promoting upright and symmetrical spine pos-
ture, is fundamental to reduce scoliosis, as well as lower limb neutral 
posture to limit foot deformities. Scoliosis is seen in around 90% of 
patients with DMD who have not been treated with steroids, though 
corticosteroid use reduces this risk dramatically. For patients with 
progressive scoliosis, spinal surgery in an experienced setting is a 
good way to restore posture and comfort, and has an additive effect 
on survival. Physiotherapy priorities for all boys shift towards pos-
tural support, the prevention and containment of contractures, and 
respiratory maintenance. Alongside progressive loss of ambulation, 
respiratory muscle strength declines, and respiratory management 
and prompt intervention become fundamental. Regular measuring 
of respiratory muscle function (forced vital capacity) in order to 
monitor the progression of the disease and identification of early 
signs of respiratory failure is required in order for timely interven-
tion and to improve the quality of life and longevity in these patients, 
since respiratory failure is still among the main causes of death in 
patients affected by DMD.
As forced vital capacity falls further, boys are at serious risk 
of chest infections and ultimately nocturnal respiratory failure. 
Respiratory care should begin early with prompt access to anti-
biotics at the first sign of any infection, access to immunizations, 
support for and augmentation of coughing, and non​invasive venti-
lation. Patients are at risk of hypercapnia, and oxygen should not be 
administered without proper monitoring of blood gases and a low 
threshold for initiating respiratory support. Symptoms of respira-
tory failure may be extremely insidious and totally missed unless 
explicitly sought (Box 24.19.2.7). Routine overnight pulse oxim-
etry (which can readily be carried out at home provided that the 
equipment is available) can show a trend of deteriorating overnight 
Box 24.19.2.7  Respiratory failure in neuromuscular disease
Respiratory failure in neuromuscular disease is a complication which 
needs to be specifically sought.
• It may be the result of intercostal muscle or diaphragmatic weakness 
or a combination of the two. The presence of a scoliosis or other spinal 
deformity may be an additional factor.
• Nocturnal problems tend to dominate.
• Frank symptoms of morning CO2 retention may be seen (poor colour, 
morning sickness, headaches, confusion) but these are late symptoms 
and the problem should be detected by investigation or careful history 
taking before this stage.
• Increasing frequency of chest infections may indicate incipient respira-
tory failure.
• Subtle signs include loss of appetite and weight loss, loss of energy and 
enthusiasm.
• Poor sleep, increasing wakefulness at night, inability to lie flat may also 
be seen together with a tendency to fall asleep during the day.
• Difficulties swallowing and difficulty completing sentences may also 
be seen.
• In many muscle diseases, the main risk of respiratory failure is when the 
patient is no longer able to walk independently and weakness is pro-
nounced (for example Duchenne muscular dystrophy, Becker mus-
cular dystrophy, congenital muscular dystrophy, facioscapulohumeral 
muscular dystrophy, limb-​girdle muscular dystrophy, and so on).
• In other muscle diseases, respiratory failure may be an earlier feature 
and present while the patient is still ambulant (for example multicore 
and other congenital myopathies, some forms of congenital muscular 
dystrophy).


24.19.2  Muscular dystrophy
6319
oxygenation and, together with the monitoring of symptoms, high-
light the time at which elective nocturnal respiratory support, 
ideally at least through non​invasive ventilation initially, should be 
provided. Such respiratory support abolishes symptoms, reduces 
the tendency to chest infections and undoubtedly improves life-
span, in particular if combined with spinal surgery, with a good 
quality of life.
In the late stages of DMD, nutrition may be of concern. Loss of 
weight occurs in most boys as a result of dysphagia, slow eating due 
to chewing difficulties and low mood as the disease progresses, and 
issues of diet and the possibility of supplemental nutrition (possibly 
by gastrostomy) need to be addressed. Patients may need referral to 
Speech and Language therapy to assess their swallowing function as 
dysphagia can lead to aspiration pneumonia.
Constipation is also frequently reported in DMD and can be se-
vere; it may also contribute to reduced appetite. Constipation is usu-
ally managed with laxatives or a combination of laxatives and rectal 
enemas; however, these should be used carefully as they can lead to 
a vasovagal reaction.
DMD patients have an increased anaesthetic risk and pre-​an-
aesthetic cardiac and respiratory assessment is important. When 
exposed to inhalational anaesthetics or muscle relaxants like 
succinylcholine, patients can develop rhabdomyolysis. Non-​de-
polarizing neuromuscular blockers can be used safely instead of 
succinylcholine. Inhalational anaesthetics should be avoided if 
possible and intravenous anaesthetics should be used instead.
DMD patients are exposed to increased fracture risk due to ster-
oids. Early mobilization and rehabilitation is essential. Internal 
fixation should be taken into consideration to shorten immobiliza-
tion. There is also a high risk of vertebral fractures, and these can 
sometimes be asymptomatic.
Fat embolism syndrome is extremely rare, though a life-​threatening 
event, that usually presents following a fracture of long bones, but 
can present also after minor trauma. Signs and symptoms suspicious 
of fat embolism syndrome are shortness of breath and/​or neuro-
logical symptoms following a fall or fractures. Respiratory function 
should be supported. A chest CT scan may be helpful to confirm the 
diagnosis.
Thanks to improvements in care management life expectancy for 
patients with DMD has increased, and patients are now reaching 
adulthood with a relatively good quality of life. While this was not the 
case a few years ago, a young DMD man can now aim to reach higher 
education levels and also achieve independent living. Transition 
of care to adulthood needs timely planning, to allow care hand-
over ideally to a multidisciplinary team, to monitor and promptly 
address care needs arising in an adult men with DMD in order to 
maximize health. While at present only few adult men with DMD 
achieve independent living, this is likely to become more common 
in future and represents a challenge for the patient and family; the 
team around the family should be able to provide adequate support 
to achieve this and overcome barriers.
The actual cause and timing of death in DMD is hard to pre-
dict. Some patients will die of a particularly severe chest infection. 
In others cardiomyopathy may be difficult to control or a cardiac 
arrhythmia may arise. Any medical intervention at the later stages 
should be carefully managed by an experienced team. Early onset 
of cardiomyopathy is a poor prognostic sign. Talking about death 
to these patients and their parents, helping them to prepare and also 
address their fears and uncertainties, is another important but easily 
neglected aspect of management.
Education
On average, children with DMD have an IQ around 1 standard de-
viation below the normal mean; often a striking verbal performance 
deficit is observed and there is a deficit in number span. Learning 
problems are not progressive. Additional behavioural phenotypes 
may complicate the pattern of learning needs, including a tendency 
to behaviour in the autistic spectrum in some children. Schooling 
should offer the best possible environment for learning, taking into 
account the profile of needs of the individual child, and including 
full attention to information technology equipment, while sup-
porting the very real physical needs of the child. Families and areas 
vary as to whether this will be best provided through mainstream or 
special schooling. With a good education and medical support, boys 
with DMD and the appropriate intellectual potential can go on to 
higher education, and should be encouraged to do so.
Becker muscular dystrophy
Management issues in BMD tend to cover the same broad areas as 
DMD, but with the deterioration in muscle function over a much 
longer timescale. Certain complications, such as scoliosis, are very 
unusual. Other complications, such as cramping muscle pains after 
exercise, which can be a particular problem in the teenage years, 
are more common. Despite the fact that BMD is much milder than 
DMD, it can represent a considerable and insurmountable dis-
ability for the person who has it, and problems with adjustment, 
poor self-​esteem, and poor body image are all fairly common in 
this group. There are no hard data to define completely any intel-
lectual problems in BMD, but on average it is likely that this group 
has a general reduction in IQ, although probably not to the ex-
tent seen in DMD. Cardiac complications may occur at any age 
in BMD and require proactive surveillance and management (see 
Box 24.19.2.5): respiratory complications tend to be a feature of 
the late stages of the disease.
Fascioscapulohumeral muscular dystrophy
Fascioscapulohumeral muscular dystrophy (FSHD) is an example 
of a muscular dystrophy named for the most characteristic pattern 
of muscle involvement observed (that of involvement of the facial, 
scapular, and humeral muscles predominantly). However, other 
muscle groups usually become involved with time and may even be 
involved at onset.
Presentation
•	 Age at presentation is variable. Most affected individuals manifest 
some symptoms by their teens or twenties. Occasionally symp-
toms may be very minor, even late in adult life.
•	 Symptoms may, unusually for a muscular dystrophy, be very 
markedly asymmetrical.
Early symptoms typically include facial weakness (inability to bury 
eyelashes or puff cheeks; this often goes unnoticed), shoulder girdle 
weakness manifesting as problems in reaching high shelves, chan-
ging light bulbs, or climbing ropes, and foot-​drop.


section 24  Neurological disorders
6320
An infantile form of FSHD is recognized with early childhood 
onset, extremely marked facial weakness, and progressive weakness 
of both the shoulder and pelvic girdle musculature. Lumbar lordosis 
may be profound. Hearing loss and retinal telangiectasia may be 
seen in any patient with FSHD but are particularly associated with 
this most severe form of the disease.
Differential diagnosis
The clinical pattern of FSHD can be very distinctive, and the asym-
metry of muscle involvement is a major clue. However, facial weak-
ness may be very variable and, if it is absent or subtle, confusion can 
arise with forms of limb-​girdle muscular dystrophy.
Diagnostic investigations
Serum creatine kinase may be normal or mildly elevated. Muscle 
biopsy and electromyography (EMG) provide supportive evidence 
for a muscular dystrophy; some inflammatory features are some-
times also seen in the biopsy. Most cases (if not all) of FSHD are 
linked to altered expression of the DUX4 gene in the macrosatellite 
repeat D4Z4 region chromosome 4q35. A DNA-​based test is avail-
able that can confirm the diagnosis in 95% of cases. This test involves 
the demonstration of a DNA deletion that is consistently associated 
with the disease and shows a shortening of the D4Z4 allele, which 
causes altered expression of the DUX4 gene. This common form of 
FSHD is known as FSHD1. A smaller percentage of patients (about 
3–​5%) have epigenetic factors that alter the chromatin relaxation in 
the D4Z4 (DUX4 permissive allele) area, without a shortening of the 
D4Z4 allele; in this group of patients mutations have been identi-
fied in the chromatin modifier SMCHD1. This group of patients is 
known as FSHD2.
Prognosis and management
Infantile FSHD is a progressive disease that leads to early con-
finement to a wheelchair and the development of such complica-
tions as scoliosis and respiratory failure. This condition is most 
frequently seen as a result of a new dominant mutation in cases 
with no family history, and these children often have particularly 
large DNA deletions on chromosome 4. The development of a 
lumbar lordosis, seen also in later-​onset fascioscapulohumeral 
muscular dystrophy, together with secondary hip flexion con-
tractures, can be very disabling. Bracing may be partially suc-
cessful at controlling the lordosis, but at the expense of some loss 
of mobility.
More typically, FSHD is a slowly progressive disease. As the 
disease progresses it can involve the proximal as well as the 
distal lower limb muscles. Around 20% of patients with FSHD 
will become unable to walk independently, most when aged over 
40. Involvement of the proximal lower limbs before the age of 
20 years is a poor prognostic sign, indicating an increased like-
lihood of wheelchair use. Some patients describe progression as 
being stepwise in nature, with periods of faster deterioration al-
ternating with phases of plateauing of their symptoms. Foot-​drop 
is a common complaint, which can be helped by the provision of 
daytime ankle–​foot orthoses. A significant proportion of patients 
with FSHD complain of painful muscles, for which no cause can 
be found and for which pain relief may be difficult. Some pa-
tients find swimming or a small dose of antidepressants useful 
for this symptom. More severely affected patients with FSHD 
may develop respiratory failure or swallowing problems, and 
these complications should be sought. Cardiomyopathy is rarely 
reported.
Genetic counselling
FSHD1 is an autosomal dominant disease and as such an affected 
person has a 50% chance of transmission to his or her offspring, 
regardless of sex. Use of the new DNA diagnostic techniques has 
shown that up to 30% of cases of FSHD may represent de novo dom-
inant mutations. Germline mosaicism is also common. Genetic 
analysis has also shown a higher proportion of asymptomatic gene 
carriers than expected, with females overrepresented in this group. 
The availability of a relatively straightforward genetic test in this 
disorder has opened up the possibility of presymptomatic and pre-
natal testing, which were previously impossible. However, despite 
an overall correlation between the size of the deletion found and the 
severity of the symptoms, the DNA test is not useful in predicting 
the severity of the disease—​people in individual families with appar-
ently the same sized deletion may have a very variable experience of 
the disease (Fig. 24.19.2.4).
FSHD2 is inherited in a digenic manner, meaning that SMCHD1 
and DUX4-​permissive alleles segregate independently and each 
parent will carry either a SMCHD1 or a permissive DUX4 allele. 
Clinically, this means that heterozygous patients are asymptomatic. 
Putting this together, there is a risk to between 25 and 50% of the 
offsprings being affected, depending on the haplotypes in the wider 
Fig. 24.19.2.4  Mother and daughter with fascioscapulohumeral 
muscular dystrophy. The mother is extremely mildly affected and has 
minimal symptoms. By contrast the daughter was affected from early 
childhood and has been wheelchair dependent outside from her early 
teens. Note the daughter’s expressionless face and her posture—​she is 
leaning forward due to a combination of her marked lumbar lordosis, a 
major feature of the condition, and hip flexion contractures.


24.19.2  Muscular dystrophy
6321
family. As for FSHD1, there is variability in disease expression even 
within the same family.
Emery–​Dreifuss muscular dystrophy  
(OMIM 300384)
Classic Emery–​Dreifuss muscular dystrophy (EDMD) has a highly 
characteristic phenotype. X-​linked recessive, autosomal dominant, 
and (very rare) autosomal recessive forms are recognized, and the 
genes involved in these conditions encode proteins that are com-
ponents of the nuclear envelope (Fig. 24.19.2.5). The gene involved 
in X-​linked EDMD is emerin (EMD), and that involved in auto-
somal dominant and autosomal recessive EDMD2 and 3 is lamin 
A/​C (LMNA/​LMNC). Other genes have also been implicated in 
patients with an Emery–​Dreifuss phenotype, including nesprin 
1 and 2 (SYNE1 and SYNE2), EDMD 4 and 5, four-​and-​a-​half-​
LIM protein 1 (FHL1) EDMD6 and transmembrane protein 43 
(TMEM43) EDMD7.
Presentation
•	Patients may present at any age, most typically in the early 
teens, although symptoms may be present much earlier 
than that.
•	 Contractures of the ankles and elbows and rigidity of the spine 
often predate any clear weakness.
•	 Consequently, these patients have frequently had Achilles 
tendon release before the diagnosis is suspected.
•	Weakness and wasting are typically humeroperoneal in 
distribution.
A key part of these conditions, which may rarely be seen at pres-
entation, is cardiac involvement, most typically arrhythmias (see 
next). Several alternative phenotypes (a form of congenital mus-
cular dystrophy limb-​girdle muscular dystrophy 1B and a pure 
cardiac disease—​Box 24.19.2.8 and see Fig. 24.19.2.5) exist in com-
bination with mutations in the same gene as autosomal dominant 
EDMD (lamin A/​C). Lamin A/​C mutations are also described in 
several diseases where there is no predominant muscle phenotype, 
including partial lipodystrophy, some forms of progeria syndromes, 
mandibuloacral dysplasia, and a form of peripheral neuropathy. 
Some patients may show overlapping features of these different syn-
dromes. Laminopathy is much more phenotypically diverse than 
X-​linked EDMD and a high index of suspicion of this disorder is 
necessary, especially due to the almost inevitable life-​threatening 
cardiac complications.
Confirming the diagnosis
Serum creatine kinase is typically mildly elevated in EDMD. Muscle 
biopsy shows non​specific histological features: in X-​linked EDMD, 
emerin is absent in muscle and skin. Detection of mutation in the 
emerin gene is necessary to offer genetic counselling to female rela-
tives at risk of being carriers.
The involvement of lamin A/​C (the gene responsible for auto-
somal dominant EDMD) cannot be determined by antibody analysis 
in muscle, but requires the demonstration of a lamin A/​C mutation. 
Many lamin A/​C mutations arise anew, and germline mosaicism is 
common. Use of specific genetic testing has shown that, in fact, in 
(a)
(b)
Fig. 24.19.2.5  Muscular dystrophy phenotypes characterized by 
prominent contractures. (a) This patient has autosomal dominant 
Emery–​Dreifuss muscular dystrophy, with a proven mutation in his 
lamin A/​C gene. The elbow and Achilles tendon contractures seen 
here, combined with his markedly rigid spine, are very similar to the 
pattern of contractures and weakness seen in the X-​linked form of the 
disease. (b) Bethlem myopathy in a woman with marked contractures 
of the elbows, ankles, and spine. In addition she has finger flexion 
contractures, demonstrated here by attempting to straighten the 
fingers with the wrist extended.
Box 24.19.2.8  The skeletal muscle laminopathies
• Forms of congenital muscular dystrophy, Emery–​Dreifuss muscular 
dystrophy and limb-​girdle muscular dystrophy are all caused my 
mutations in lamin A/​C, a component of the nuclear envelope.
• The phenotype is variable, depending on age at onset and the 
presence or not of contractures as a major component of the 
phenotype.
• Where contractures are present, these typically involve the elbows, 
Achilles tendons, and spine. In these patients, there is often a 
humeroperoneal pattern of muscle weakness as in X-​linked Emery–​
Dreifuss muscular dystrophy.
• Where contractures are less of a feature, patients typically present with 
proximal muscle weakness.
• In all groups, cardiac involvement is the most important complica-
tion. Arrythmias may lead to sudden death and should be sought and 
treated appropriately.
• A  phenotype with exclusively cardiac involvement has also been 
described.
• New mutations and germline mosaicism is common in this group.


section 24  Neurological disorders
6322
contradistinction to what had been previously reported, autosomal 
dominant EDMD is more frequent than the classically described 
X-​linked form.
Differential diagnosis
In addition to previously mentioned other genes (SYNE1, SYNE2, 
FHL1, TMEM43) that can give rise to Emery–​Dreifuss phenotype, 
other muscular dystrophies may present with contractures as an im-
portant component (see Fig. 24.19.2.5). Some forms of CMD may 
be associated with contractures and a rigid spine. Bethlem myop-
athy may present congenitally (often with torticollis) or in early 
childhood: here finger flexion contractures, elicited especially on 
wrist extension, are more prominent and cardiac involvement is not 
associated. Bethlem myopathy is itself genetically heterogeneous, 
involving mutations in any of the genes for collagen VI-​α1, -​α2, and 
-​α3. The condition is allelic to the much more severe CMD, UCMD. 
Unlike in UCMD, where examination of skin and muscle frequently 
shows an abnormality of collagen VI expression, in Bethlem myop-
athy collagen VI labelling in muscle may be normal. Immunoanalysis 
of cultured fibroblasts may be a useful diagnostic tool before pro-
ceeding to mutation analysis, which is time-​consuming due to the 
large size of the three genes to be screened and the presence of many 
polymorphisms. Muscle MRI demonstrates a very characteristic 
pattern of muscle involvement that can be used to help diagnosis 
and guide mutation testing. Patients with Bethlem myopathy may 
show skin abnormalities such as follicular hyperkeratosis and ab-
normal scarring.
In some cases, calpainopathy (limb-​girdle muscular dystrophy 
2A) may be associated with contractures of the ankles, elbows, fin-
gers, and paraspinal muscles. However, the associated weakness 
here is predominantly proximal and of a characteristic distribution 
(see next). These patients typically have a higher creatine kinase, 
absent calpain 3 on biopsy and CAPN3 mutations.
Prognosis and management
The prognosis in EDMD relates almost directly to the ability to 
manage the life-​threatening arrhythmias to which every patient 
with either the X-​linked or dominant form is susceptible. Severe 
arrhythmias are inevitable by the third decade. All patients with this 
diagnosis should, therefore, be under regular cardiological review, 
and once a rhythm disturbance has been detected cardiac pacing 
may be life saving. However, in autosomal dominant EDMD evi-
dence suggests that the risk of ventricular arrhythmias necessitates 
the use of an implantable defibrillator. In this condition there is also 
a risk of cardiomyopathy, which may be less amenable to routine 
treatment.
Management of the contractures in EDMD is the other main 
issue, and will involve close liaison with a physiotherapist. 
Operative treatment of contractures, especially at the Achilles ten-
dons, is commonly performed, but, although such surgery does 
work in the short term, contractures often recur. With increasing 
age, however, contractures frequently stabilize. Muscle weak-
ness may worsen but progression is usually very slow. Rigidity 
of the spine may complicate weakness of the respiratory muscles 
and nocturnal respiratory support may be needed. Monitoring 
should include regular assessment of forced vital capacity when 
sitting and lying, and symptom enquiry for any symptoms of re-
spiratory impairment.
The limb-​girdle muscular dystrophies
The broad definition of the term ‘limb-​girdle muscular dystrophy’ 
comes from the classification of Walton and Nattrass in 1954, when 
the term was suggested to describe those patients with weakness of 
the proximal musculature who did not fulfil the criteria for either 
the X-​linked muscular dystrophies or fascioscapulohumeral mus-
cular dystrophy. The term has always encompassed a heterogeneous 
group of disorders: now that many of them can be distinguished at 
the gene or protein level it is no longer sufficient to use it without 
qualification as to the specific type of disease (Table 24.19.2.2). The 
type of limb-​girdle muscular dystrophy may be suggested by the 
precise pattern of muscle involvement, with confirmation from a 
combination of genetic and protein analysis. The ability to provide a 
precise diagnosis in limb-​girdle muscular dystrophy has greatly im-
proved the prognostic and genetic information that can be given to 
these patients. In recent years, thanks to the development and intro-
duction of next-​generation sequencing techniques for diagnostic 
purposes, this particular field of limb-​girdle muscular dystrophies 
(LGMDs) has grown rapidly, and new genes have been identified 
as causative of LGMD, or known genes causative of other forms of 
muscular disorders were identified as responsible for the limb-​girdle 
phenotype. Careful attention is needed when counselling about 
these newly identified conditions and prognostic implications.
The approach to diagnosis in limb-​girdle  
muscular dystrophy
Could it be dominant disease?
Autosomal dominant limb-​girdle muscular dystrophy (LGMD) 
represents only around 10% of the total LGMD population, 
and LGMD1A, -​1C, -​1D, and -​1E have been very rarely re-
ported. In families with a dominant history the most likely diag-
noses are fascioscapulohumeral muscular dystrophy (exclude 
fascioscapulohumeral muscular dystrophy on DNA analysis espe-
cially if there is any suspicion of facial weakness), LGMD1B (al-
lelic with autosomal dominant EDMD—​see Box 24.19.2.8), and 
Bethlem myopathy. New mutations are common, however, so, if the 
clinical features are suggestive of one of these disorders, the diag-
nosis should be pursued even in the absence of a family history.
Features that should raise the suspicion of dominant disease are 
less marked elevation of creatine kinase (typically normal to five 
times normal in dominant disease and much higher than this in 
active recessive disease), or the presence of early and prominent 
contractures. As knowledge of the disorders within the auto-
somal dominant LGMD classification has grown, together with 
a greater understanding of the other phenotypes that have been 
identified in association with mutations in the same genes, a key 
feature of these diseases has clearly emerged as variability. So, for 
example, LGMD1A is due to mutations in myotilin, which is also 
responsible for a form of myofibrillar myopathy. Patients in this 
group may have mutations in a range of different genes and the 
phenotypes may be very variable, including both proximal and 
distal muscle weakness, and cardiac and respiratory complica-
tions. LGMD1B or laminopathy has already been discussed in 
the section on EDMD—​a very high index of suspicion of this 
diagnosis is definitely required. Caveolin 3 mutations, respon-
sible for LGMD1C, are also now recognized in a form of rippling 


24.19.2  Muscular dystrophy
6323
Table 24.19.2.2  The more prevalent autosomal recessive types of limb-​girdle muscular dystrophy
Type of muscular dystrophy (gene symbol)
Calpainopathy
(LGMD 2A)
(CAPN3)
Dysferlinopathy
(LGMD 2B/​MM)
(DYSF)
Sarcoglycanopathies 
(LGMD 2C–​2F) 
(SGCA, SGCB, SGCC, SGCD)
Dystroglycanopathies
(LGMD 2I, 2K, 2M, 2N, 2O, 2P, 
2T, 2U) (FKRP, POMT1, fukutin, 
POMT2, POMGnT1, DAG1, 
GMPPB, ISPD)
LGMD2L
(ANO5)
Distribution
Worldwide, some isolates (e.g. 
Reunion, Amish, Basque)
Worldwide. Founder effect in Libyan 
Jewish population.?Others
Worldwide. Regional differences in different 
types
Worldwide. Founder mutation 
in Scandinavia for FKRP
Worldwide. UK 
founder mutation
Status of 
diagnosis
Protein, mutations
Protein, mutations
Protein, mutations (may not be readily found in 
all patients)
Abnormal glycosylation of  
α-​dystroglycan and laminin 
A2, mutations in FKRP, POMT1, 
fukutin, POMT2, POMGnT1, 
DAG1, GMPPB, ISPD
Mutation in AN05
Protein
Calpain 3 deficiency detectable by 
monoclonal antibody on blots
Dysferlin deficiency detectable on 
sections and blots
• Dystrophin may be mildly abnormal
• γ and α: may see selective reduction
• β and δ: mostly see depletion of all
Secondary reduction in α-​
dystroglycan and laminin A2 in 
some muscle biopsies
No protein test yet 
available: all antibody 
analysis normal
Mutations
Widely distributed, few recurrent. 
All types of mutation seen, large 
deletions rare. Changes may be non-​
pathogenic. Except in homozygotes, 
difficult to correlate mutation type 
with rate of progression
Widely distributed, few so far 
recurrent
• α R77C seen in 42% of chromosomes
• γ two predominant mutations, N. African 
and gypsy. Otherwise mutations very 
heterogeneous
• Missense mutations mainly in extracellular 
domain
Depending on causative gene 
involved.
FKRP common mutation 
(C826A) responsible for many 
cases
Founder mutation 
in UK and other 
N. European groups
Age at onset
Typically 8–​15, may be from early 
childhood or adulthood
Most present around 20 (± 5 years). 
Onset not in first decade
α most variable—​may be from childhood to 
adulthood. γ, β, δ tend to be more severe. 
Majority of all types will present in first decade
Congenital form may be very 
severe: ranges to very mild 
disease in LGMD group
Typically late 
adulthood; males 
usually younger than 
females
Mode of 
presentation 
and selective 
Muscle 
involvement
Highly selective pattern of muscle 
involvement wasting post. 
compartment of thighs, scapular 
winging. Sparing of hip abductors. 
Relative involvement of muscle 
groups important
Variable. May be:
• lower limbs first
• proximal alone, mixed proximal/​ 
distal alone
• distal presentation most commonly 
posterior, may be anterior
Weakness, toe walking, muscle pains/​cramps are 
typical presentations. Main muscles—​shoulder 
girdle involvement more prominent than DMD, 
scapular involvement, hamstrings more than 
quadriceps, lordosis, foot-​drop in some before 
loss of mobility
Proximal muscle weakness
Asymmetrical 
muscle atrophy, 
may be proximal or 
distal, clinically may 
resemble LGMD2B
Early 
development
Motor milestones normal; physical 
prowess in childhood may be less 
good than peers
Normal—​good athletic prowess
Motor milestones less delayed than DMD, even 
if later very severe
Usually normal, but can be 
delayed in some forms
Normal
Rate of 
progression
May not be linear—​can see rapid 
change with no gender effect. 
Otherwise gradual with time. Age at 
death probably typically in 60s
Usually slow—​some more rapidly 
progressive Cases have similar age 
at onset
Variability main feature:
• poor correlation between age at onset/​ 
progression
• rate of progression very variable
• may be great intrafamilial variation, even 
with sibs
Variable, usually mild
Usually mild; typically 
maintain ambulation 
until old age, 
women may remain 
asymptomatic
Age of 
confinement 
to wheelchair
20–​30+
Typically beyond 30s. Seems to be 
normal lifespan
Earliest 9 years. Variability in mild cases very 
marked. Occasional asymptomatic cases in 
adult life (esp. α). Typically even most severe 
cases live to 30s
In mild cases 40+, in severe 
forms <20
Late adulthood if at all
(continued)


section 24  Neurological disorders
6324
Atrophy
Posterior compartment of thighs, 
latissimus dorsi
Typically distal LL, biceps—​may be 
very selective. Atrophy of proximal 
deltoid, hypertrophy of distal
Anterior and posterior thighs, shoulder girdle
Proximal
Patchy and may be 
assymetrical
Hypertrophy
Occasionally see calf hypertrophy
Very rare—​a few cases have transient 
calf hypertrophy at presentation 
which may be painful
Common in calves, also elsewhere. May be 
macroglossia
Common in calf muscles
May be seen in some 
muscle groups
Contractures
AT contractures common. 
Occasionally more widespread
No
AT contractures, lordosis, hip flexion contractures 
(may be problem in rehab.). Scoliosis less 
common than DMD even when WCB
Not common in LGMD forms, 
reported in LGMDK, 2M, 2P
Not common
Facial 
involvement
Mild facial weakness unusual. Also 
macroglossia very occasionally seen
No facial weakness
No facial weakness, may see macroglossia. In 
later stages typical transverse smile
Mild facial weakness common
No
Cardiac status
Normal
Normal
α usually not present (one Dutch patient). β, γ, δ 
may be important
Cardiomyopathy significant 
complication
Cardiomyopathy not 
reported to date
Respiratory 
status
Respiratory impairment may be 
significant in some
Normal
Common, may be at later stage than DMD
Some cases require nocturnal 
ventilation
Well-​preserved 
respiratory status
Intellectual 
function
Normal
Normal
Normal
Normal or mildly impaired
Normal
Creatine kinase
10–​100 × normal
May be low or mildly raised in young 
presymptomatic cases, rising to huge 
elevation by early teens. Very high in 
active phase of disease, falling with age
10–​100 × normal
10–​100 × normal
10–​100 × normal
Biopsy
Dystrophic
Dystrophic plus inflammation, may be 
perivascular or more widespread
Dystrophic
Dystrophic
Dystrophic
Other
Muscle imaging confirms highly 
selective pattern of muscle 
involvement
Muscle imaging may reveal 
asymptomatic proximal changes 
in distal onset and vice versa. 
Phenotypes may vary with same 
mutation and between sibs
Genotype–​phenotype correlations: α-​null tend 
to be more severe; β truncating very severe, 
huge variation with missense. Majority in γ are 
truncating mutations. δ mutations so far are rare
Allelic with forms of congenital 
muscular dystrophy
Muscle imaging can 
be quite specific
Note
Finnish anterior tibial MD 
homozygotes may show reduction 
of calpain on blots
May have been misdiagnosed as 
polymyositis or distal myopathy
Main differential diagnosis is with 
dystrophinopathy. Occasional cases may 
resemble calpainopathy. No clinical guidelines 
to distinguish subgroups, though very mild 
disease most likely to be α
N/​K
Females may remain 
asymptomatic with 
hyperCKaemia
LGMD, limb-​girdle muscular dystrophy; DMD, Duchenne muscular dystrophy; WCB, wheelchair bound; N/​K, not known; LL, lower limbs; AT, Achilles tendon.
Table 24.19.2.2  Continued


24.19.2  Muscular dystrophy
6325
muscle disease, as well as in patients presenting with myalgia or 
hypercalcaemia. Therefore, a broad level of knowledge about the 
possible diagnostic features in these different disorders is neces-
sary when taking the family tree for these patients, as well as is 
in the individual clinical assessments required—​rippling, for ex-
ample, may be seen only if specifically elicited.
What is the age and nature of the presentation?
Variability in the age of presentation and the rate of progression 
is usual in the various autosomal recessive types of LGMD. 
However, some broad conclusions can be helpful (Fig. 24.19.2.6). 
Childhood presentation is most common in sarcoglycanopathy, 
which may superficially resemble dystrophinopathy, with 
frequent calf (and other muscle) hypertrophy. Adult-​onset 
cases are less frequent and are essentially ‘Becker-​like’ in 
presentation. However, whatever the age at presentation, in 
sarcoglycanopathy, quadriceps is almost always stronger than 
the hamstrings. This is the reverse of the pattern seen in dys-
trophin deficiency. Another important differential diagnosis in 
a ‘Becker-​like’ (including the presence of calf hypertrophy and 
cardiomyopathy) presentation is LGMD2I, which is the most 
common form of LGMD in northern Europe. Calpainopathy 
may present with early childhood symptoms, especially con-
tractures of the Achilles tendons, but onset is most commonly 
between 8 and 15 years of age. Dysferlinopathy typically pre-
sents in the late teens or early twenties, and early features may 
include proximal weakness or distal involvement (usually 
manifesting as difficulty standing on tiptoe). LGMD2L can re-
semble dysferlinopathy in many ways.
Which investigations should be performed?
Serum creatine kinase is greatly elevated in all forms of autosomal 
recessive LGMD, but may be only marginally elevated or within 
the normal range in autosomal dominant LGMD. EMG confirms 
a primary myopathic process. Standard analysis of the muscle bi-
opsy together with immunohistochemistry analysis has been so 
far necessary to confirm dystrophic changes (which, especially in 
dysferlinopathy, can be accompanied by evidence of inflamma-
tion) and attempt to determine the type of LGMD together with 
the clinical features (Fig. 24.19.2.7). Gene analysis is required to 
confirm the diagnosis. However, if so far the muscle biopsy analysis 
together with the clinical picture were directing the targeted genetic 
testing, with the advent of novel sequencing techniques, allowing 
a simultaneous testing of multiple known genes causative of mus-
cular dystrophy, genetic testing is going to replace some of the more 
invasive investigations (i.e. muscle biopsy). Nevertheless, muscle 
(a)
(b)
(c)
(d)
Fig. 24.19.2.6  Typical clinical pictures of patients with different 
types of autosomal recessive limb-​girdle muscular dystrophy (LGMD). 
(a) Calpainopathy or LGMD2A. Note the predominantly atrophic pattern 
of muscle involvement and Achilles tendon contractures. The stance 
is often wide based due to the imbalance of the hip abductors and 
adductors and tight Achilles tendon. (b) Dysferlin deficiency or LGMD2B. 
Note the wasting of the posterior calf muscles and flat-​footed stance. 
(c) Child with γ-​sarcoglycanopathy or LGMD2C. Note the lordotic 
posture and scapular winging, both of which may be more marked 
at presentation in sarcoglycanopathy than in dystrophin deficiency. 
(d) Adult with γ-​sarcoglycanopathy, to illustrate the variability in severity 
of sarcoglycan deficiencies and the muscular hypertrophy, which may be 
as marked or more marked than in dystrophin deficiency.
Fig. 24.19.2.7  Multiplex western blotting as an approach to diagnosis 
in limb-​girdle muscular dystrophy. Two strips of a western blot of control 
human skeletal muscle protein extracts immunostained with a mixture 
of antibodies to the proteins indicated. Absence or reduced intensity of 
a particular species, compared with the other proteins labelled in the 
same lane, can indicate which gene and protein are implicated in that 
patient’s disease.
Courtesy of Dr L V B Anderson, University of Newcastle upon Tyne.


section 24  Neurological disorders
6326
biopsy and immunohistochemistry analysis may be still necessary 
and fundamental to interpret genetic variants of unknown clinical 
significance.
Scheme for specialized investigations
Do the clinical features or family history suggest a specific disorder 
(Boxes 24.19.2.9–​24.19.2.11)? If so, look for that first.
The sarcoglycanopathies
Dystrophin staining may be mildly abnormal in these pa-
tients, reflecting the close and interdependent relationship 
between the proteins of the dystrophin-​associated complex; 
however, the predominant abnormality on immunolabelling or 
immunoblotting will be the absence or reduction of one or more 
of the sarcoglycans. The pattern of reduction of these proteins 
may give a clue as to the primary gene involvement. Detection of 
the mutation is necessary to offer prenatal diagnosis and specific 
genetic counselling.
Calpainopathy
Here the sarcoglycans are normal, as is dystrophin. Currently avail-
able antibodies to calpain 3 do not work on tissue sections but 
need to be used on immunoblotting. Detection of reduced or ab-
sent calpain on immunoblotting (see Fig. 24.19.2.7) indicates the 
need to search for calpain 3 mutations, which are highly variable, 
are generally non-​recurrent, and may involve any part of the large 
(24 exons) gene. Studies consistently report a level of around 20–​
25% of non​detection of the second mutation in calpain 3, suggesting 
the presence of a significant number of mutations missed by cur-
rent screening technologies. A secondary reduction in calpain 3 may 
be seen in some cases of dysferlin deficiency. The situation at the 
muscle biopsy level is also complicated by the fact that patients with 
mutations, especially in the autocatalytic domain of calpain 3, show 
normal protein expression on immunoblotting. A multidisciplinary 
approach to diagnosis in calpainopathy, including the recognition 
of often a very characteristic phenotype, together with protein and 
genetic testing, is still required. Interestingly and to add complexity 
to this field, recent reports suggest rare cases of dominant inherited 
calpain 3 mutations and further studies are in progress to better 
understand this new entity.
Dysferlinopathy
Here, all other proteins with the possible exception of calpain 3 are 
within the normal range, and deficiency of dysferlin can be demon-
strated on tissue sections or immunoblotting. Decreased or absent 
dysferlin in muscle is an indication to proceed to mutation detec-
tion. The dysferlin gene is very large (55 exons) and, as with the other 
forms of LGMD, mutations are highly variable.
LGMD2I and other forms of LGMD with abnormal glycosylation 
of a dystroglycan
It is increasingly recognized that mutations in the same genes, 
which can cause a congenital muscular dystrophy with abnormal 
glycosylation of α dystroglycan, can also cause a much milder lgmd 
phenotype. Indeed, mutations in the FKRP gene can give rise to a 
severe congenital muscular dystrophy (MDC1C) phenotype as well 
Box 24.19.2.9  Clinical features of sarcoglycanopathies
• These most frequently present in childhood, but may present at any 
age. Intrafamilial variability is common.
• These conditions are most closely related clinically to dystrophinopathy 
which will be the major differential diagnosis and have a similar spec-
trum of severity.
• Typically motor milestones are less delayed than in dystrophinopathy.
• Muscle hypertrophy is common.
• Intelligence is not affected.
• Cardiomyopathy is an important complication, though not universal, 
and should be sought through careful surveillance.
• Respiratory failure is an important late complication.
• Scoliosis is seen in the most severely affected individuals.
• Prognosis overall is typically better than dystrophinopathy presenting 
at a similar age.
Box 24.19.2.10  Clinical features of calpainopathy
• This is the most common form of limb-​girdle muscular dystrophy in 
most populations.
• May present at any age but typically 8–​15 years.
• Highly selective muscle involvement: posterior thigh weakness, and 
wasting; scapular winging common at onset.
• Muscle hypertrophy rare—​tends to be predominantly atrophic 
pattern.
• Preservation of hip abductor muscles even at late stages contributes to 
characteristic wide-​based stance.
• Most have Achilles tendon contractures:  a subgroup presents with 
much more prominent contractures in an Emery–​Dreifuss muscular 
dystrophy-​like pattern.
• Progression is variable but never as fast as Duchenne muscular 
dystrophy.
• Cardiac involvement is not common but respiratory impairment may 
be seen in late stages.
• Prognosis in all but the most severe and early onset cases is good.
Box 24.19.2.11  Dysferlinopathy: clinical features
• Presentation most commonly in late teens or early twenties.
• Patients often report good muscle prowess before onset of disease. 
Serum creatine kinase may not be massively elevated in presymptomatic 
cases.
• Occasional patients present with unilateral calf swelling which may be 
tender and lead to the clinical diagnosis of myositis.
• Primary muscle involvement is always in the lower limbs, with absence 
of upper girdle involvement at onset.
• Lower limb involvement may be of proximal muscles or distal 
muscles. The distal muscles involved first are typically posterior 
(leading to difficulty standing on tiptoe as an early feature) but may 
be anterior.
• Progression is typically slow and life expectancy is not reduced. This is 
the usually mildest type of limb-​girdle muscular dystrophy.
• Cardiomyopathy is not reported and respiratory involvement is usually 
mild and at a very late stage only.
• The main differential diagnosis, especially in patients presenting 
with distal weakness, may be an alternative form of distal myopathy. 
Typically here the creatine kinase is not so high. Patients with ANO5 
mutations (LGMD2L) can present in a very similar way, though pres-
entation typically may be later and the pattern of muscle involvement 
may be more asymmetrical.


24.19.2  Muscular dystrophy
6327
as a much milder and common lgmd phenotype (LGMD2I). The 
phenotypic spectrum of disease is highly variable, and disease onset 
can range from the first to the fourth decade of life. This milder 
phenotype is actually the more common presentation with mu-
tations in FKRP (LGMD2I), which is a relatively common cause 
of LGMD in northern Europe where there is a founder mutation. 
Respiratory failure and cardiomyopathy are common features, to-
gether with muscle hypertrophy and myalgia. Creatine kinase levels 
can range from moderately raised to very high levels depending 
on the subtype. The diagnostic clue in these cases is abnormal α 
dystroglycan on muscle immunolabelling, sometimes associ-
ated with a secondary reduction also in laminin A2 especially on 
immunoblotting.
Other forms of limb-​girdle muscular dystrophy
Additional rare forms of LGMD have also been described. 
LGMD2G is mainly seen in Brazil and is due to mutations in 
telethonin. LGMD2H is restricted mainly to the Hutterite popula-
tion of Canada and is due to mutations in TRIM32. Homozygous 
titin mutations in Finland (where a distal myopathy due to titin 
mutations is relatively common) cause LGMD2J. LGMD2L is due 
to mutations in AN05 and mutations in this gene also cause a form 
of Miyoshi myopathy. The LGMD group is rapidly expanding; at 
present the LGMD classification is complex and 23 genes have 
been identified so far in the autosomal recessive group (LGMD2A-​
LGMD2W). The existence of families with an LGMD phenotype 
but no detectable mutations to date suggests that novel muscular 
dystrophy genes remain to be identified and this process is likely 
to be accelerated by the application of the rapid sequencing tech-
nologies that are currently coming on line. With the introduction 
of next-​generation sequencing techniques, patients can now be 
screened using muscular dystrophy related gene panels, which al-
lows simultaneous testing of multiple known genes causative of 
muscular dystrophy. Where targeted Sanger sequencing or panel 
gene screening fail to identify a causative gene, whole exome 
sequencing (WES) has the potential to identify novel causative 
genes. WES analysis can be performed as a panel analysis in first 
instance, screening for known genes first, but offers also the op-
portunity to widen the screening in order to identify novel genes. 
These novel and powerful diagnostic techniques will likely reverse 
the diagnostic workout and approach from what was a phenotype-​
genotype correlation to a genotype–​phenotype correlation. And, 
if the muscle biopsy and other investigations were so far in most 
cases preceding the genetic test, this will likely be reversed and 
used as a tool to prove pathogenicity of variants identified by novel 
sequencing techniques. Limits of these sequencing methods have 
to be kept well in mind. Indeed, despite the genome coverage being 
wide; deletion and duplications, as well as repeat sequences are not 
always well spotted, and coverage of large genes can represent a 
challenge. In these cases, standard techniques offer a better diag-
nostic approach.
Management
Once the diagnosis is secure, management should include moni-
toring and treatment for the specific complications of the various 
subtypes. Attention needs to be given to the particular prevalence of 
cardiac or respiratory involvement and appropriate surveillance and 
treatment initiated. If a clear diagnosis is not possible (e.g. where 
appropriate samples are not available or where the diagnosis cannot 
be reached even after exhaustive investigation), the management 
should, as a minimum, include physiotherapy and regular cardiac 
and respiratory surveillance.
Oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy is unusual in that it has an ex-
ceptionally late presentation. It is another example, like FSHD, were 
the muscular dystrophy is named for the most characteristic pattern 
of muscle involvement observed.
Presentation
•	 Presentation is typically in the sixth decade.
•	 It commonly presents with ptosis, dysphagia to solids, and dys-
phonia, which may be as severe as in myotonic dystrophy.
•	 Other features include ophthalmoparesis, facial weakness, and 
proximal muscle weakness.
Diagnosis
The muscle biopsy in oculopharyngeal muscular dystrophy typically 
shows the presence of rimmed vacuoles and intranuclear inclusions. 
DNA analysis confirms the presence of an expanded guanine–​
cytosine–​guanine repeat in the poly(A)-​binding protein 2 gene 
(PABPN1 gene; MIM 602279) on chromosome 14q11.
Prognosis and management
Ptosis can be managed surgically, but frequently recurs. Dysphagia 
may respond, at least partially, to surgical intervention with 
myotomy of the cricopharyngeal muscle and other annular muscle 
fibres. Potentially life-​threatening complications may include aspir-
ation pneumonia and regurgitation. Progression of the limb muscle 
weakness is highly variable.
Genetic counselling
Oculopharyngeal muscular dystrophy is an autosomal dominant 
disorder. Genetic analysis offers the potential for presymptomatic 
testing if this is specifically sought.
Prospects for specific treatment in  
muscular dystrophy
Drug treatments have a limited place in the treatment of muscular 
dystrophy at present, apart from the use of corticosteroids in DMD 
and cardiac medications in conditions where cardiomyopathy is a 
specific risk. Proactive and anticipator treatment for patients and 
their families based on knowledge on the likely course of specific 
diseases remains the mainstay of treatment at present, and this is 
likely to be the case at least for the current generation of patients. 
This treatment is ideally provided through a specialized multidis-
ciplinary team, bringing together with the ‘myologist’ the skills 
of medical and associated colleagues from physiotherapy, occu-
pational therapy, genetics, cardiology, respiratory medicine, and 
orthopaedics. Treatments to modify the underlying disease are