Muscular Dystrophies: Diagnosis and Management

Introduction

The muscular dystrophies are a group of inherited disorders causing progressive degeneration of muscle fibres, typically producing proximal, symmetric weakness without sensory loss or reflex change until late in the disease - a pattern that helps distinguish them from neuropathic causes of weakness.¹ They range enormously in severity, from the severe, early-onset Duchenne muscular dystrophy to milder adult-onset forms.

This article focuses on the three most commonly examined dystrophies - Duchenne, Becker and myotonic dystrophy - since together they illustrate the key genetic and clinical principles (X-linked recessive dystrophinopathies versus autosomal dominant repeat expansion) that the topic as a whole is built around.

Duchenne muscular dystrophy affects roughly 1 in 3,500-5,000 male births, making it the commonest severe childhood muscular dystrophy, while myotonic dystrophy affects around 1 in 8,000 and is the commonest inherited muscle disease of adults. Around a third of Duchenne cases arise from new mutations rather than inheritance, which is an important counselling point: the absence of any family history does not make the diagnosis less likely in a boy with a typical presentation.

Duchenne and Becker muscular dystrophy

Both result from mutations in the dystrophin gene on the X chromosome, inherited in an X-linked recessive pattern - so they almost exclusively affect boys, with female carriers usually asymptomatic (though a minority of carriers develop mild symptoms or cardiomyopathy). Dystrophin normally stabilises the muscle cell membrane during contraction; without it, repeated contraction causes progressive membrane damage and muscle fibre death, which is gradually replaced by fat and fibrous tissue.

Clinical features

• Delayed motor milestones - late walking, frequent falls, difficulty climbing stairs or running compared with peers
• Gower's sign - the child uses their hands to push up on their thighs and 'walk' their hands up their legs to stand from a squat or the floor, reflecting proximal (particularly hip and thigh extensor) weakness
• Calf pseudohypertrophy - enlarged, firm-feeling calves from fatty and fibrous infiltration replacing muscle, not true muscle bulk
• Proximal weakness - waddling gait, difficulty rising from the floor or a low chair, difficulty raising the arms above the head
• Progressive loss of ambulation, typically in the early teens in Duchenne, later or not at all in Becker
• Scoliosis, often developing as ambulation is lost and truncal muscle support declines
• Cardiomyopathy (dilated) - can develop even before significant skeletal weakness is apparent, and requires active surveillance
• Respiratory muscle weakness - progressive restrictive respiratory failure
• Mild cognitive impairment - present in a proportion of boys with Duchenne, related to dystrophin's role in the brain as well as muscle

Myotonic dystrophy

Myotonic dystrophy is the commonest adult-onset muscular dystrophy and is caused by a CTG trinucleotide repeat expansion in the DMPK gene (type 1, the commoner and more severe form) or a related repeat expansion in CNBP (type 2), inherited in an autosomal dominant pattern with anticipation - the repeat can expand further in successive generations, causing earlier and more severe disease, similar in principle to Huntington disease.

• Myotonia - delayed muscle relaxation after contraction, classically demonstrated as difficulty releasing a handshake or grip ('warm-up phenomenon' - myotonia improves with repeated contraction), and by percussion myotonia (sustained dimpling of the thenar eminence after a tap with a tendon hammer)
• Distal-predominant weakness - in contrast to the proximal pattern of dystrophinopathies, myotonic dystrophy characteristically affects distal muscles (forearm, hand, ankle dorsiflexors) early
• Facial weakness and ptosis - producing a characteristic 'myopathic facies' - long, thin, expressionless face with temporalis and masseter wasting
• Frontal balding in affected men
• Cataracts - early-onset, often posterior subcapsular, and can be the presenting feature
• Cardiac conduction defects - a major cause of morbidity and sudden death, often out of proportion to the degree of skeletal muscle weakness
• Endocrine involvement - testicular atrophy, insulin resistance/diabetes, thyroid dysfunction
• Congenital myotonic dystrophy - a severe, early-onset form in infants of affected mothers, with profound hypotonia and respiratory/feeding difficulty at birth, illustrating anticipation at its most extreme

Clinical examination

• Pattern of weakness - proximal (dystrophinopathies) versus distal and facial (myotonic dystrophy)
• Gower's sign and observation of rising from a chair/floor
• Calf bulk - pseudohypertrophy in Duchenne/Becker
• Grip release and percussion myotonia - specifically for myotonic dystrophy
• Facial appearance - myopathic facies, ptosis, frontal balding
• Cardiorespiratory assessment - heart rate/rhythm, signs of heart failure, respiratory effort
• Reflexes - typically reduced in proportion to muscle bulk/weakness, but sensation is normal throughout all dystrophies
• Cataracts on examination in suspected myotonic dystrophy

Differential diagnosis

• Spinal muscular atrophy - a lower motor neurone disorder from anterior horn cell loss, causing proximal weakness in infancy/childhood but with fasciculations and a different genetic basis (SMN1 gene)
• Congenital myopathies - typically present at birth or in early infancy with hypotonia, usually less rapidly progressive than Duchenne
• Inflammatory myopathies (dermatomyositis, polymyositis) - proximal weakness but typically acquired in adulthood, with an inflammatory/autoimmune rather than genetic basis, and a different creatine kinase and biopsy pattern
• Limb-girdle muscular dystrophies - a genetically heterogeneous group causing proximal weakness in various patterns, distinguished by genetic testing
• Facioscapulohumeral muscular dystrophy - facial, scapular and upper arm weakness, distinct genetic cause and inheritance pattern
• Endocrine myopathy - thyroid disease, Cushing's syndrome - usually acquired and reversible

Investigations

• Creatine kinase (CK) - markedly elevated in Duchenne (often 10-100x normal) and Becker, present but often less dramatically raised in myotonic dystrophy
• Genetic testing - confirms the diagnosis by identifying the specific dystrophin gene mutation (DMD/BMD) or the CTG repeat expansion (myotonic dystrophy type 1), and is the preferred confirmatory test, reducing the need for muscle biopsy
• Muscle biopsy - historically used to demonstrate dystrophin absence/reduction by immunohistochemistry, or characteristic dystrophic changes; used less often now that genetic testing is more accessible, but still valuable when genetic testing is inconclusive
• Electromyography - shows a myopathic pattern (small amplitude, short duration motor unit potentials) and, in myotonic dystrophy, the characteristic 'dive-bomber' myotonic discharges
• Echocardiography and ECG - baseline and serial surveillance for cardiomyopathy (Duchenne/Becker) and conduction defects (myotonic dystrophy)
• Pulmonary function tests - baseline and serial monitoring of respiratory muscle involvement
• Slit-lamp examination - for cataracts in suspected myotonic dystrophy
• Genetic counselling and family screening - given the inheritance patterns, particularly identifying carrier status in female relatives of boys with dystrophinopathies

Management

There is no cure for the muscular dystrophies covered here, and management is built around multidisciplinary surveillance and supportive care, alongside disease-specific pharmacological options where available.

A practical point that applies across the dystrophies is the risk of corticosteroid-related and immobility-related bone disease. Boys with Duchenne on long-term steroids who are losing ambulation are at high risk of vertebral and long bone fragility fractures, so bone health monitoring, vitamin D and calcium optimisation, and consideration of bisphosphonates form part of routine care rather than an afterthought.

Transition from paediatric to adult services is a second recurring challenge. Patients who once died in adolescence now commonly survive well into adulthood, and the transition needs planning over years rather than occurring abruptly at 16 or 18 - covering respiratory and cardiac surveillance, education and employment, independent living, and, where relevant, discussion about relationships and fertility.

Anaesthetic risk warrants specific mention across the group. Patients with dystrophinopathies are at risk of rhabdomyolysis, hyperkalaemia and cardiac arrest with suxamethonium and with volatile anaesthetic agents, and these should be avoided in favour of total intravenous anaesthesia. This applies to any procedure, including dental and minor surgery, so the diagnosis should be flagged prominently in the notes and on any alert card the patient carries.

Duchenne/Becker muscular dystrophy

• Corticosteroids (prednisolone or deflazacort) - the mainstay disease-modifying treatment in Duchenne, shown to prolong ambulation and delay scoliosis and respiratory decline², though long-term steroid side effects (weight gain, growth impairment, bone health) need active monitoring
• Exon-skipping and gene-targeted therapies (e.g. eteplirsen and related agents, applicable to specific dystrophin mutations) - an evolving area, available for genetically eligible patients in specialist centres
• Cardiac surveillance and treatment - ACE inhibitors and beta-blockers once cardiomyopathy develops, and regular echocardiography from an early age
• Respiratory surveillance - regular pulmonary function tests, with non-invasive ventilation introduced as respiratory muscle weakness progresses
• Physiotherapy - maintaining mobility and preventing contractures for as long as possible
• Orthopaedic input - scoliosis surveillance and, where indicated, surgical correction; ankle-foot orthoses and standing frames to prolong function
• Multidisciplinary paediatric/adult neuromuscular clinic coordinating all of the above as the child grows into adulthood

Myotonic dystrophy

• Mexiletine - can reduce troublesome myotonia in selected patients³
• Regular ECG and cardiology review, with pacemaker or implantable defibrillator consideration given the risk of sudden death from conduction disease
• Respiratory monitoring and support as needed
• Cataract surgery when visually significant
• Screening and management of associated endocrine disease - diabetes, thyroid dysfunction, hypogonadism
• Anaesthetic caution - myotonic dystrophy carries an increased risk of anaesthetic complications (respiratory depression, cardiac arrhythmia, and a myotonic response to certain agents), and anaesthetists must be informed of the diagnosis in advance of any procedure
• Genetic counselling, given autosomal dominant inheritance with anticipation and the risk of severe congenital disease in offspring of affected mothers

Complications

• Loss of ambulation and progressive disability
• Dilated cardiomyopathy and heart failure (Duchenne/Becker)
• Cardiac conduction defects and sudden death (myotonic dystrophy)
• Respiratory failure - a leading cause of death in Duchenne muscular dystrophy
• Scoliosis, contractures
• Anaesthetic complications, particularly in myotonic dystrophy
• Psychosocial impact of a progressive, life-limiting diagnosis on the child/adult and family

Red flags

Cardiac and respiratory complications, rather than limb weakness, determine survival in the muscular dystrophies, and both can progress silently. The situations below warrant action irrespective of how mobile the patient appears.

Prognosis

Duchenne muscular dystrophy is the most severe of the dystrophies covered here: historically, life expectancy was limited to the 20s, usually from respiratory or cardiac failure, though modern multidisciplinary cardiorespiratory care and corticosteroid treatment have meaningfully extended both ambulation and survival into the 30s and beyond for many patients. Becker muscular dystrophy is generally milder and more variable, with many patients retaining ambulation into adulthood and a near-normal lifespan in some cases. Myotonic dystrophy is highly variable depending on repeat length and age of onset, but cardiac conduction disease remains a persistent risk of sudden death throughout life regardless of the severity of muscle weakness, which is why lifelong cardiac surveillance is non-negotiable.

Genetic counselling is central to care in all of these conditions and extends well beyond the index patient. In the dystrophinopathies, the mothers and sisters of an affected boy may be carriers, with implications both for their own reproductive choices and for their cardiac health, since manifesting carriers can develop cardiomyopathy and warrant surveillance themselves. In myotonic dystrophy, the combination of autosomal dominant inheritance and anticipation means relatives may be more severely affected than the index case, and the possibility of severe congenital disease in the children of affected mothers makes pre-conception counselling particularly important.