- Clinical science
Muscular dystrophies are a group of progressive diseases that affect the musculoskeletal system. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive diseases, whereas limb-girdle muscular dystrophy (LGMD) may be either autosomal dominant or recessive. Muscular dystrophies are commonly due to mutations involving muscular genes (e.g., dystrophin-protein coding gene). Patients typically present with muscular complaints affecting specific muscle groups, particularly the pelvic girdle musculature. DMD is the most severe form of muscular dystrophy, with disease onset typically occurring at two to three years of age. BMD usually does not become evident before the age of 15. DMD progresses rapidly and typically leads to ambulatory inability by age 12. Diagnosis of DMD and BMD is established based on blood tests that show increased creatinine kinase, whereas diagnosis of LGMD is mainly based on genetic analysis. Treatment of muscular dystrophies is usually supportive and includes physiotherapy, assistive devices (e.g., wheelchair), and psychological support. The life expectancy for patients with DMD is approx. 30 years, whereas patients with BMD and LGMD have a longer life expectancy.
- Inheritance pattern
Chromosomal defect affects the dystrophin gene (one of the biggest known genes in humans) on the short arm of the X chromosome (Xp21).
- → Frameshift deletion in DMD
- → In-frame deletion in BMD
- The dystrophin protein anchors the cytoskeleton of a muscular cell to the extracellular matrix by connecting cytoskeletal actin filaments to membrane-bound dystroglycan that is, in turn, connected to extracellular laminin.
- Largest known protein-coding gene in the human DNA. Therefore, there is an increased risk of spontaneous mutations.
- Mutations and subsequent alterations of the dystrophin protein → partial (BMD) or almost complete impairment (DMD) of the protein → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells and subsequent replacement with connective and fat tissue → muscle appears larger (“pseudohypertrophy”)
Duchenne is caused by Deleted Dystrophin.
- Onset before age 5 years old
- Paresis and atrophy starting in the proximal lower limbs (pelvic girdle), later spreading to the upper body and distal areas
- Weak reflexes
- Waddling gait (bilateral )
- Gower maneuver: To stand up, the patient supports himself on his thighs and uses the hands to essentially "walk" up the body until reaching a standing position. It is a classic sign in DMD but also occurs in e.g., Becker muscular dystrophy, dermatomyositis.
- Calf pseudohypertrophy (see “Pathophysiology”)
- Inability to walk by approx. 12 years of age
- Cardiac and respiratory muscle involvement
- Cognitive impairment
- Symptoms identical to those of DMD
- Slower progression (patients often remain ambulatory into adult life) and milder symptoms
- Heart involvement is more common compared to DMD.
- ↑↑ creatine kinase in serum of almost all affected individuals (also, in > 50% of female carriers)
- ↑ serum aldolase
- Genetic analysis (confirmatory test): detect dystrophin gene mutation
- Muscle biopsy
The differential diagnoses listed here are not exhaustive.
Currently there is no curative treatment for muscular dystrophies!
- Medical therapy
- Orthopedic assistive devices (wheelchair, walkers)
- Psychological support
- Ventilation support