Distrofia muscolare di Becker

What is muscular dystrophy?

The muscular dystrophies (MDs) are a group of inherited disorders characterised by progressive muscle wasting and weakness. Becker's muscular dystrophy (BMD) is similar to the more common muscular dystrophy - Duchenne muscular dystrophy (DMD) - but the clinical course is milder. As with DMD, there is muscle wasting and weakness which is mainly proximal. Generally, walking difficulties begin after the age of 16.¹

Female carriers of BMD may be affected, either by some degree of muscle weakness and/or by cardiomyopathy.

Globally, the prevalence has been estimated at 1.6 per 100,000 people (about one third of DMD prevalence). BMD is caused by abnormalities of the dystrophin gene, which is responsible for the muscle protein dystrophin. In BMD, abnormal but only partly functional dystrophin is produced (cf DMD, where dystrophin is lacking).

• It is inherited in an X-linked recessive pattern. There are various gene defects which give rise to BMD, affecting different parts of the dystrophin gene. The clinical severity of BMD varies and this is probably due to:
  

  • Variation in the individual genetic defects and hence in the dystrophins thus produced.

  • Factors other than the dystrophin gene, which determine the severity of BMD in an individual. In one reported family, two brothers with an identical gene defect had very different clinical manifestations of BMD.¹

• BMD can occur as a new mutation. Therefore, not all mothers of BMD patients will be carriers of the gene. BMD can also occur through mosaicism (where only some cell lines are affected).

Sintomi

Onset is usually in childhood, frequently by 11 years. It can present in several ways such as waddling gait, or exercise related cramps, with or without myoglobinuria. Rarely, cardiomyopathy may be the presenting feature. Despite childhood onset, independent walking is never lost before the third decade. The clinical severity varies.

Early symptoms

• Delayed walking (sometimes).

• Muscle cramps on exercise.

• Most BMD children are not 'athletic' and may struggle with school sports.

Later symptoms

• Muscle weakness:
  

  • Affects the proximal muscles of the limbs mainly.

  • May begin in teenage years or 20s, causing difficulty in climbing stairs, fast walking and lifting heavy objects.

• BMD patients can walk independently until the age of 16 or later (cf DMD, where patients cannot walk beyond the age of 12). Walking ability is lost (usually at the age of 40-60) but sometimes earlier, around the age of 20-30.

Segni

• Wasting of the proximal muscles; hypertrophy of others, particularly the calf muscles.

Altre presentazioni

• Mioglobinuria.

• Anaesthetic complications - a dangerous, malignant hyperthermia-like reaction with some anaesthetic agents.

• Cardiomyopathy may be the first presentation, if muscle weakness is subclinical.

• There is a higher incidence of learning difficulties, behavioural problems and autistic spectrum disorders, compared with the general population.

Indagini

Indagini iniziali

• Serum creatine kinase (CK) - shows moderate-severe increase in BMD (5-50 x normal levels).⁴

• Raised CK levels in this scenario merit specialist referral for further investigation.

Ulteriori indagini

• Analisi genetica.

• Muscle biopsy - for dystrophin staining.

• Genetic tests and counselling for the family.

• Monitoring for cardiomyopathy (see 'Cardiac complications', below).

• Other muscular dystrophies: differentiation is by the clinical features such as age of onset and pattern of muscle weakness, by muscle biopsy features and by DNA analysis.

• Altre miopatie - ad esempio, tireotossicosi, sindrome di Cushing.

• Neurological causes of muscle weakness: spinal cord lesions, atrofia muscolare spinale, malattia del motoneurone, sclerosi multipla. These conditions may have additional features such as sensory loss, upper motor neurone signs or muscle fasciculation.

Management includes multidisciplinary care with physiotherapy to reduce joint contractures and prolong walking. Early treatment includes steroid treatment. Early treatment of cardiomyopathy with ACE inhibitors is recommended and referral for cardiac transplantation is appropriate in severe cases.

The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases.⁵

Supportive treatment includes:

• Exercise programmes and physiotherapy. Recent evidence suggests that exercise training is beneficial.⁶

• Muscle cramps may be helped by night splints, massage or compression treatment using air-filled boots.

• Optimise nutrition:
  

  • Vitamin D and calcium for bone health.

  • Avoid obesity.

• After walking ability is lost - wheelchairs and other aids.

• Psychological support and employment advice.

• Monitoring/treatment of complications.

Musculoskeletal complications

• Weakness can lead to joint contractures and scoliosis, which may require orthotic or orthopaedic treatment.

• Complications of immobility - eg, constipation and osteoporosis.

Cardiac complications⁷

La gravità della cardiomiopatia e dell'insufficienza cardiaca congestizia potrebbe non essere parallela alla gravità della malattia muscolare scheletrica. Le aritmie atriali e ventricolari possono essere pericolose per la vita. Il grado di ipoventilazione e disfunzione polmonare influisce anche sulla funzione cardiaca nella distrofia muscolare.⁸

• Cardiomiopatia dilatativa:
  

  • Occurs in most BMD patients.^{4 9} It is the main factor influencing survival.

  • May be the presenting feature, if muscle weakness is mild. The severity of cardiac involvement does not correlate with the severity of skeletal muscle weakness.¹⁰

  • Asymptomatic (subclinical) cardiomyopathy is common.¹¹

  • Symptoms may be nonspecific - eg, fatigue, poor sleep, weight loss, vomiting.

• Arrhythmias.

Monitoring and treatment

• Regular cardiac monitoring from diagnosis/from age 10 years, including:
  

  • Clinical evaluation.

  • Electrocardiogram (ECG) and echocardiogram - these may be difficult to interpret due to scoliosis.

  • Other possible tests - cardiac MRI, multigated acquisition study (MUGA) and tissue Doppler echocardiography may be more helpful than standard echocardiography.¹²

• Treatment is with standard regimens - eg, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and diuretics for cardiac failure.

• Consider anticoagulation, as thromboembolism risk is increased.

• Nutrition and respiratory function should be optimised.

• Some patients require cardiac transplantation.⁹

Anaesthetic complications⁷

• Life-threatening rhabdomyolysis (malignant hyperthermia-type reaction) to some anaesthetic agents.

• Hyperkalaemia in response to succinylcholine.

• Higher risk of complications due to cardiac disease.

• Careful assessment and monitoring are required with any anaesthetic procedure or surgery.

Altre complicazioni

• Respiratory muscle weakness:
  

  • Depending on the clinical severity of muscle weakness, this is a possible complication. Management would be similar to that for DMD respiratory complications. See the separate Duchenne Muscular Dystrophy articolo.

• Pain in the lower back, spine and legs.¹³

• Life expectancy is often reduced but there is a wide variation in severity and the prognosis can be excellent.

• Cardiomyopathy is the cause of death in about half of BMD patients.¹⁴

Rischio di cardiomiopatia

• Female carriers of the BMD gene may have an increased risk of cardiomyopathy.

• L'entità del rischio è discutibile; le prove sono contrastanti riguardo ai tassi di cardiomiopatia nei portatori e se l'aspettativa di vita sia influenzata.¹⁵

• An international workshop in 2002 recommended regular cardiac screening for BMD carriers.⁷ This recommendation has, however, been questioned.¹⁵

Portatori manifestanti⁴

Most carriers are asymptomatic but a small percentage (2-5%) may have skeletal muscle symptoms; they are known as manifesting carriers of BMD:

• The reason why the gene manifests in some women but not in others may be through the mechanism of 'X-inactivation', where the normal X chromosome is inactive and the X chromosome carrying the BMD mutation is the active one.

• As with BMD boys, there may be no family history of the disease.

• Some cases of BMD manifesting carriers were previously diagnosed as having another type of muscular dystrophy but, with new techniques such as dystrophin staining, have been identified as having BMD.

Caratteristiche cliniche

• C'è una grande variazione individuale nella gravità dei sintomi - da una lieve debolezza muscolare, dolori o ingrossamento del muscolo del polpaccio, a una malattia grave come quella nei ragazzi.

• L'insorgenza dei sintomi può avvenire in età adulta.

• Di solito c'è una progressione graduale dei sintomi nel tempo.

• Può verificarsi un coinvolgimento cardiaco.

Diagnosi

• La biopsia muscolare che esamina la distrofina è solitamente utile.

• Test genetici, inclusi i modelli di inattivazione del cromosoma X.

Management, follow-up and prognosis
Questo varia a seconda della gravità individuale dei sintomi.