Ductus muscular dystrophy
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"Duchenne muscular dystrophy"[MeSH Terms]
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Duchenne Muscular Dystrophy (DMD)
(I believe you meant "Duchenne" - "Ductus" appears to be a typographic error. Ductus refers to a tubular anatomical structure, not a muscle disease.)
Overview
Duchenne muscular dystrophy is the most common inherited muscle disease and the most common severe neuromuscular disease in humans, with an incidence of approximately 1 in 3,500-5,000 male births. It is an X-linked recessive disorder (gene locus: Xp21.2) caused by mutations in the DMD gene encoding the protein dystrophin.
- OMIM: #310200
- About one-third of cases arise from de novo mutations (no family history)
Pathophysiology
The DMD gene is the largest known human gene (~2.4 Mb, 79 exons). Most pathogenic mutations are frameshift mutations (deletions, duplications, or point mutations) that produce a non-functional or absent dystrophin protein.
Dystrophin's role:
- Acts as a mechanical link between the intracellular sarcomere (actin cytoskeleton) and the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the sarcolemma
- Absence of dystrophin disrupts this link, causing a calcium leak into muscle fibers
- This triggers chronic necrosis, inflammation, and degeneration of muscle fibers
- Repeated cycles of degeneration and regeneration eventually exhaust regenerative capacity, replaced by adipose and connective tissue
In Becker muscular dystrophy (BMD), in-frame mutations allow production of a partially functional, truncated dystrophin - causing a milder phenotype.
Clinical Features
Onset and Motor Manifestations
- Presents in boys aged 2-5 years (mean diagnosis age ~41 months)
- Delayed motor milestones, abnormal gait, difficulty running, frequent falls
- Calf pseudohypertrophy (replacement of muscle by fat and fibrosis)
- Gower's sign - child uses arms to push off thighs when rising from floor
- Progressive weakness initially in lower limbs (proximal > distal)
- Loss of ambulation by 10-15 years of age
Cardiac Involvement
- Dilated cardiomyopathy (DCM) from cardiac fibrosis is nearly universal
- Rhythm and conduction abnormalities
- Left ventricular dilation progressing to congestive heart failure
- Cardiorespiratory failure is the primary cause of death
Respiratory Involvement
- Scoliosis impairs respiratory mechanics
- Chronic respiratory insufficiency develops in all patients
- Progressive respiratory failure requiring noninvasive ventilation
Other Features
- Kyphoscoliosis and joint contractures (by age ~20)
- Lower IQ and nonprogressive cognitive impairment in many patients
- Associated learning disorders, autism spectrum features, and ADHD
- The degree of cognitive impairment may correlate with the mutation location in the DMD gene
Female Carriers
- Most carrier females are asymptomatic
- Up to 20% of female carriers may manifest symptoms (muscle weakness, elevated CK, DCM)
- Severe disease in females most often from skewed lyonization or X-autosome translocation
Diagnosis
| Test | Finding |
|---|---|
| Serum CK | 20-100x elevated (often >10x normal); can be detected on newborn dried blood spots |
| Genetic testing (DNA analysis) | Positive in ~90-95% of patients; first-line confirmatory test |
| Muscle biopsy | Indicated if genetic testing is negative (~5% of cases) |
| Immunohistochemistry (IHC) | Absent/markedly reduced dystrophin staining (carboxy-terminal epitopes) |
| Muscle biopsy histology | Variation in fiber size, necrosis, inflammation, fibrosis, fiber regeneration |
Newborn screening pilots (e.g., Ohio) using two-tiered CK + DNA analysis on dried blood spots have successfully identified affected patients, though NBS for DMD is not yet universally implemented in the US.
Treatment
Management requires a multidisciplinary team including neurology, cardiology, pulmonology, orthopedics, physical/occupational therapy, and psychosocial support.
Corticosteroids
- Prednisone 0.75 mg/kg/day - prolongs ambulation, improves muscle strength, may slow scoliosis progression and help respiratory function
- Deflazacort 0.9 mg/kg/day - comparable efficacy with less weight gain than prednisone; both are preferred over intermittent dosing
Exon-Skipping Therapies (FDA-conditionally approved)
These are phosphorodiamidate morpholino oligomers (PMOs) that restore the reading frame:
| Drug | Exon targeted | Dose | Approval status |
|---|---|---|---|
| Eteplirsen | Exon 51 | 30 mg/kg IV once weekly | FDA conditionally approved |
| Golodirsen | Exon 53 | 30 mg/kg IV once weekly | FDA conditionally approved |
| Viltolarsen | Exon 53 | 80 mg/kg IV once weekly | FDA conditionally approved |
| Casimersen | Exon 45 | 30 mg/kg IV once weekly | FDA conditionally approved |
These agents increase dystrophin protein expression and slow the rate of functional decline. Choice among them requires expert neurologic consultation based on which exon is affected in the individual patient.
Cardiac Management
- Beta-blockers and ACE inhibitors for cardiomyopathy
- ACE inhibitors can slow progression of myocardial fibrosis
- Myocardial fibrosis is associated with poorer prognosis
Respiratory Management
- Pulmonology follow-up with spirometry
- Noninvasive ventilation (NIV/BiPAP) when indicated
- Monitoring and management of scoliosis-related restrictive lung disease
Orthopedic Management
- Physical therapy to prevent/slow joint contractures
- Monitoring for scoliosis; spinal fusion if indicated
- Assistive devices and wheelchair provision
Endocrine/Nutritional
- Monitoring for steroid-related complications (obesity, bone health, adrenal insufficiency)
Genetics and Inheritance Summary
- Inheritance: X-linked recessive
- Gene: DMD, Xp21.2 (largest known human gene)
- Protein: Dystrophin (427 kDa)
- Common mutations: Large deletions (~65-70%), duplications (~10%), point mutations (~20%)
- Frameshift mutations → DMD (severe, absent dystrophin)
- In-frame mutations → BMD (mild, truncated but partially functional dystrophin)
Prognosis
Without modern management, death typically occurred in the second decade. With current multidisciplinary care, corticosteroids, cardiac management, and assisted ventilation, many patients now survive into their 30s-40s. The primary cause of death remains cardiorespiratory failure.
Sources: Goldman-Cecil Medicine (International Edition); Tietz Textbook of Laboratory Medicine, 7th Ed.
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