Overview And Classification

Muscular dystrophies are a heterogeneous group of genetically determined disorders characterised by progressive degeneration of skeletal muscle. While Duchenne and Becker muscular dystrophies are the most common X-linked dystrophinopathies, several other primary muscular dystrophies present in pediatric practice with distinct clinical phenotypes, inheritance patterns, and genetic loci.

Genetic And Inheritance Profile

Limb Girdle Muscular Dystrophy

Definition And Overview

• Limb girdle muscular dystrophies are a group of clinically heterogeneous syndromes.
• They primarily affect the muscles of the hip and shoulder girdles.
• The disease is generally classified into two main clinical types.
• These include the pelvifemoral (Leyden-Möbius) type and the scapulohumeral (Erb's juvenile) type.

Genetics And Inheritance

• The condition exhibits genetic heterogeneity.
• The inheritance pattern can be autosomal dominant or autosomal recessive.
• There is also a high sporadic incidence associated with this disorder.

Clinical Features

Onset And Progression

• The age of onset is highly variable.
• Symptoms typically present from childhood to early adulthood, often in the second or third decade.
• It can easily be confused clinically with Becker muscular dystrophy.
• Confinement to a wheelchair usually becomes obligatory at around thirty years of age.

Musculoskeletal And Systemic Involvement

• Most childhood-onset cases present with predominant lower extremity weakness.
• The pelvic girdle is usually involved first and to a greater extent.
• Shoulder girdle involvement is often asymmetric.
• Hypertrophy of the calves and ankle contractures can develop in some forms.
• Cardiac or other systemic involvement remains variable depending on the specific genetic subtype.

Diagnosis

Laboratory And Histological Findings

• Serum creatine kinase (CK) levels are generally modestly elevated.
• However, CK levels can be significantly high in sarcoglycanopathies, dysferlinopathy, and caveolinopathy.
• Muscle biopsy demonstrates characteristic dystrophic muscle changes.
• Dystrophin protein levels remain normal, distinguishing it from dystrophinopathies.

Management And Prognosis

• Treatment is primarily symptomatic and supportive.
• Medical management includes promoting ambulation and regular physiotherapy.
• The disease is generally mildly progressive.
• Life expectancy typically extends into mid to late adulthood.

Congenital Muscular Dystrophies (CMD)

Definition And Overview

• Congenital muscular dystrophies are a group of hereditary disorders characterized by an early onset in the prenatal, neonatal, or early childhood period.
• They demonstrate histologic features that are suggestive of a dystrophic process.
• A distinguishing feature of congenital dystrophies is a remarkably high association with structural brain malformations, such as lissencephaly or polymicrogyria.
• The majority of these disorders are inherited in an autosomal recessive manner, with the exception of specific mutations like LMNA and COL6.

Clinical Features

• Affected infants typically present at birth or in the first year of life.
• They demonstrate severe generalized hypotonia, diffuse weakness, and a thin muscle mass.
• Distal arthrogryposis or multiple joint contractures are frequently present at birth.
• Ironically, the weakness is often static or only slowly progressive, following a more benign clinical course than the early onset would suggest.
• Tendon stretch reflexes are generally hypoactive or entirely absent.
• Ptosis, ophthalmoplegia, and severe bulbar weakness are typically rare in CMDs.
• Patients with associated cerebral dysgenesis often suffer from severe epilepsy and intellectual disability.

Classification

Diagnosis

• Serum creatine kinase (CK) levels are usually moderately elevated, ranging from several hundred to many thousands.
• A brain MRI is crucial to identify and evaluate any associated cerebral malformations.
• A muscle biopsy helps support the diagnosis by showing dystrophic myopathic features and extensive proliferation of endomysial collagen.
• Advanced molecular genetic testing can now confidently confirm the specific mutation.
• A confirmed genetic mutation combined with a typical phenotype often eliminates the need for an invasive muscle biopsy.

Myotonic Dystrophies

Definition And Genetics

• Myotonic dystrophies are multisystem disorders inherited in an autosomal dominant pattern.
• They are characterised by myotonia, progressive muscle weakness, and variable systemic involvement.
• Genetic anticipation is a prominent feature, meaning successive generations experience earlier and more severe disease.

Clinical Features

Classical Presentation

• Myotonia is the hallmark clinical sign.
• It is characterised by abnormally slow relaxation of muscle after a voluntary contraction or percussion.
• Muscle weakness typically follows a distal distribution.
• This distal wasting is a notable exception to the general rule of myopathies having proximal weakness.
• Patients develop a characteristic myopathic "hatchet facies".
• This includes an inverted V-shaped upper lip, scalloped temporalis muscles, and a high arched palate.

Systemic Manifestations

• Cardiac manifestations include severe conduction defects, heart block, and risk of sudden death.
• Endocrine disturbances are common and include testicular atrophy, insulin resistance, and hypothyroidism.
• Ocular involvement frequently presents as premature Christmas tree-like or iridescent spoke-like posterior capsular cataracts.
• Gastrointestinal smooth muscle dysfunction leads to poor peristalsis, delayed gastric emptying, and constipation.

Congenital Myotonic Dystrophy

• This severe variant presents exclusively in infants born to affected mothers.
• Antenatal history often reveals polyhydramnios and decreased fetal movements.
• Neonates present with severe hypotonia, facial diplegia, club feet, and potentially fatal respiratory failure.
• Clinical myotonia is characteristically absent in the neonatal period and early infancy.

Diagnosis And Management

• DNA analysis to detect trinucleotide or tetranucleotide repeat expansions is the definitive diagnostic test.
• Electromyography (EMG) is highly characteristic, revealing myotonic discharges that produce a classic 'revving engine' sound.
• Serum creatine kinase levels generally remain normal or are only mildly elevated.
• Management is primarily supportive.
• Disabling myotonia can be managed with membrane-stabilising agents such as mexiletine, phenytoin, or carbamazepine.

Facioscapulohumeral Muscular Dystrophy (FSHD)

Definition And Overview

• Facioscapulohumeral muscular dystrophy is the third most common muscular dystrophy.
• It is primarily inherited as an autosomal dominant trait.
• The condition demonstrates genetic anticipation, where successive generations experience earlier and more severe disease.
• Patients generally have a normal life span.

Genetics And Pathophysiology

The disease shares a common final pathway resulting in the abnormal expression of the DUX4 gene, which is normally dormant.

Clinical Features

Facial And Bulbar Weakness

• Facial and shoulder girdle muscle weakness are the earliest symptoms.
• Facial weakness is typically asymmetrical.
• Diminished facial movements manifest as an inability to smile or whistle.
• The mouth appears rounded and puckered due to protruding lips.
• Patients commonly exhibit an inability to completely close their eyes during sleep.

Musculoskeletal Manifestations

• Scapular winging is a prominent and asymmetrical feature.
• Biceps and triceps muscles are characteristically wasted and weak.
• Deltoid and forearm muscles are selectively spared, creating a classic "Popeye" arm appearance.
• Lower abdominal muscles weaken more than upper abdominal muscles.
• This abdominal weakness results in a positive Beevor sign.

Systemic And Extramuscular Manifestations

• High-frequency sensorineural hearing loss is frequently associated.
• Retinal vasculopathy resembling Coats disease can occur, particularly in early-onset cases.

Diagnosis

• Serum creatine kinase (CK) levels vary widely, ranging from normal to elevations of several thousands.
• Electromyography (EMG) reveals nonspecific myopathic potentials.
• Muscle biopsy shows extreme fiber size variation and extensive connective tissue proliferation.
• Definitive confirmation requires specific molecular genetic testing to detect D4Z4 repeat contractions.

Management

• Currently, no effective pharmacologic or genetic cure exists.
• Management involves light aerobic exercise and stretching to prevent disuse atrophy.
• Scapular fixation surgery can be performed to improve shoulder stability and arm abduction.
• Cosmetic reconstructive facial surgery utilizing fascia lata grafts can improve facial expressions.
• Routine audiograms and eye examinations for Coats disease are mandatory during follow-up.