Muscular dystrophies

Muscular dystrophies (MDs) are inherited diseases resulting in progressive degeneration of muscles resulting in muscle weakness. It is usually due to defective or absent glycoproteins within muscle membranes. This leads to abnormalities within the protein membrane structure and function, leading to degeneration, impaired regeneration, weakness and atrophy.

🔢 Classification

• X-linked muscular dystrophies:
• Duchenne muscular dystrophy (DMD) - caused by mutations in the dystrophin gene. Presents at 2 - 6 years old.
• Becker muscular dystrophy (BMD) - also caused by mutations in the dystrophin gene. Presents from adolescence - early adulthood.
• Emery-Dreifuss muscular dystrophy - this occurs due to mutations in the emerin and lamin proteins (proteins in the nuclear envelope) which causes muscle contractures, weakness and cardiac conduction abnormalities. Its onset is in childhood - early teens.
• Limb-girdle muscular dystrophies (LGMD) - a group of MDs that affect the shoulder and hips predominantly.
• Facioscapulohumeral muscular dystrophy - primarily affects the face, scapula, and upper arms due to deletions in the D4Z4 region on chromosome 4. May present in childhood - early adulthood.
• Myotonic dystrophy - characterised by myotonia (prolonged contractions of muscles). Presents at the age of 20-40 years old.
• Congenital muscular dystrophies - such as Duchenne-like CMD, Ullrich CMD, Walker-Warburg syndrome, Fukuyama CMD, Muscle-eye-brain disease (MEB). It has an onset at birth.
• Oculopharyngeal muscular dystrophy

🏘️ Epidemiology

As these are X-linked conditions, females with DMD or BMD are very rare. Female carriers may display mild symptoms of MD.

1. DMD is the most common muscular dystrophy, affecting approximately 1 in 5,000 live male births. Patients with DMD typically survive into their early 20's.
2. BMD is less common, with a prevalence of around 1 in 18,000-30,000 live male births. , while those with BMD can live into their 30's.

Pathophysiology

Duchenne Muscular dystrophy (DMD) and Becker Muscular Dystrophy (BMD)

Dystrophin is a glycoprotein that connects the muscle fibre’s cytoskeleton to the cell membrane and extracellular matrix via the Dystrophin-Associated Glycoprotien Complex (DGC). Normally, these protect the fibers from damage during contractions. The absence of dystrophin results in muscle instability and collapse of muscle. The instability allows for permeability of intracellular enzymes, such as creatine kinase (CK), to flow out of the cell. It also allows for entrance of calcium ions which disrupts homeostasis and leads to fibre death and fibrosis.

The protein is coded for by the DMD gene found on the X-chromosome. It is one of the largest genes in the body and has an increased chance of mutations during meiosis. The difference between DMD and BMD is the level of absence of the dystrophin protein:

• DMD - the mutations are usually due to deletion and depletion of exons (segments needed for coding of specific parts of a protein) as well as point mutations (addition, deletion or duplication of base pairs). This leads to complete loss of the dystrophin protein.
• BMD - the mutations occurring in BMD lead to impaired production which causes partially functional or reduced amounts of dystrophin as opposed to its complete loss. As a result it has milder symptoms (and a later onset).

The impaired function, reduction or absence of dystrophin leads to degeneration of muscle fibres faster than there is regeneration. This leads to necrosis of muscle fibres. The muscle fibres are replaced by adipose tissue and connective tissue. This loss of muscle fibres leads to muscle weakness.

DMD not only affects skeletal muscle but also brain cells and smooth muscle which has the following manifestations:

1. Brain cells - prolongs information-processing times, lowers IQ, causes learning difficulties and may result in autism spectrum disorders.
2. Smooth muscle cells - results in cardiomyopathy, prolonged intestinal transit times, respiratory failure.

Let’s look at the inheritance pattern of these X-linked MDs:

As they are X-linked recessive, it more commonly affects males (XY). It is passed on from a carrier mother to the children. A father may pass on the mutation to his daughter but she will not exhibit symptoms due to the presence of another X chromosome.

50% of male children born to a carrier mom and healthy dad will have DMD.

50% of female children born to a carrier mom and healthy dad will carry DMD.

1/3rd of the mutations are spontaneous while 2/3rds are maternally inherited.

😷 Presentation

DMD presents in early childhood (2 - 6 years) while BMD presents from adolescence to early adulthood.

Features of DMD and BMD are similar but DMD presents earlier and results in loss of ambulation in teenage years while BMD has a later onset with milder symptoms which allows for ambulation to be maintained for longer.

Let’s look at the features of both BMD and DMD:

• Duchenne muscular dystrophy (DMD)
• Muscle wasting and weakness - beginning in early childhood.
• Wheelchair-bound before puberty
• Respiratory failure - this occurs by the early 20's of those affected (this is the main cause of death).
• Pseudohypertrophic calves - due to fat and fibrosis replacing atrophied muscle
• Gower's manoeuvre/sign - the child's use of their hands to assist them standing up due to weakness of leg and hip muscles.
• Difficulty in lifting the child due to proximal muscle weakness
• Becker muscular dystrophy (BMD)
• Muscle wasting and weakness - beginning in adolescence.
• Wheelchair-bound in teens or adolescence

Let’s take a quick look at some of the features of the other MDs:

Emery-Dreifuss MD

• Contractures - most commonly in the elbows and ankles. Contractures are shortening of muscles and tendons that restrict the range of movement in limbs.
• Progressive weakness and wasting of muscles - starting with the upper arms and lower legs.

Myotonic dystrophy

• ⭐️ Prolonged muscle contractions - this is the key feature. Often presents with individuals unable to let go of someone’s hand after a handshake, or inability to release the grip on a doorknob after opening a door.
• Progressive muscle weakness
• Cataracts
• Cardiac arrhythmias

Facioscapulohumeral MD

It also presents in childhood - early adulthood.

• Sleeping with their eyes slightly open and weakness in pursing their lips - classic initial symptoms
• Weakness around the face, progressing to the shoulders and arms
• Inability to blow their cheeks out without air leaking from their mouth.

Oculopharyngeal MD

Presents in late adulthood.

• Weakness of the ocular muscles (around the eyes) and pharynx (around the throat) it typically presents with: 
• Bilateral ptosis, restricted eye movement and swallowing problems.
• Muscles around the limb girdles are also affected to varying degrees.

Limb-girdle MDs

• Progressive weakness around the limb girdles (hips and shoulders)

🔍 Investigations

• 🥇 Creatine kinase (CK) - as levels are significantly elevated in muscular dystrophy
• 🏆 Genetic testing - the main component of diagnosing DMD, SMA, and other MD's
• Muscle biopsies - can be used to confirm the disease, but are now replaced by genetic testing

🧰 Management