PEDS · EP 04 · NMD
Before You Listen
Episode Setup
- Topic in one line: Part 1 of pediatric neuromuscular disease, anchored at the muscle and the anterior horn cell. The dystrophinopathies are framed by the reading frame hypothesis (Monaco, 1988), with Duchenne (DMD) as the out-of-frame phenotype (absent dystrophin, creatine kinase 50 to 100 times normal, Gower sign by age 3 to 5, ambulation loss 9 to 13) and Becker (BMD) as the in-frame phenotype (reduced or abnormal dystrophin, ambulation past 16, cardiomyopathy out of proportion to skeletal weakness). Care follows the Birnkrant 2018 framework. Succinylcholine is absolutely contraindicated. Spinal muscular atrophy (SMA) is autosomal recessive loss of SMN1 at 5q13 with SMN2 copy number setting severity. The three FDA-approved disease modifiers are nusinersen, onasemnogene abeparvovec, and risdiplam, and SMA was added to the United States Recommended Uniform Screening Panel (RUSP) in 2018.
- Prerequisites: the motor unit anatomy from EDX-01 (anterior horn cell, axon, neuromuscular junction, muscle fiber), the difference between myopathic and neurogenic electromyography patterns, and the basic transmission rules for X-linked recessive and autosomal recessive disease.
- Runtime: approximately 37 minutes (Part 1 of a 1 hour 14 minute episode).
Vignette. A 4-year-old boy is referred for delayed walking, frequent falls, and difficulty climbing stairs. He walked at 18 months. On examination he uses a Gower maneuver to rise from the floor, has bilateral calf pseudohypertrophy, demonstrates a waddling gait with hyperlordosis, and has 4-/5 hip flexor strength bilaterally. Deep tendon reflexes are diminished. Serum creatine kinase is 22,000 IU/L. There is no family history.
What is the most likely diagnosis, what is the underlying genetic mechanism that distinguishes the two main phenotypes of this disease, what disease-modifying therapy should be initiated now, and what anesthesia precaution must be communicated to every clinician who sees this child?
(Answer at the end of this chapter)
Section 1: Duchenne Muscular Dystrophy — Genetics, Clinical Presentation, and Diagnosis
Bottom line: Duchenne muscular dystrophy (DMD) is X-linked recessive at Xp21.2, the largest known human gene at roughly 2.4 megabases, and the severe phenotype is produced by out-of-frame mutations that yield absent dystrophin. Boys present between ages 2 and 5 with Gower sign, calf pseudohypertrophy, hyperlordotic Trendelenburg gait, and proximal lower extremity weakness; creatine kinase is 10,000 to 50,000 IU/L (50 to 100 times normal) from birth. Approximately 30 percent of cases are de novo, so absent family history is not reassuring. First-line diagnosis is multiplex ligation-dependent probe amplification (MLPA), with next-generation sequencing for MLPA-negative cases.
Genetics. DMD is X-linked recessive, caused by mutations in the dystrophin gene at Xp21.2. Dystrophin is a 427-kDa cytoskeletal protein that anchors the actin cytoskeleton to the extracellular matrix through the dystrophin-associated glycoprotein complex. Loss of dystrophin destabilizes the sarcolemma, so each muscle contraction tears the membrane and triggers repeated necrosis-regeneration cycles. The mutation distribution is characteristic: deletions account for 60 to 70 percent of cases and cluster in hotspots at exons 44 to 55 and 2 to 20; duplications make up 5 to 15 percent; point mutations account for 25 to 30 percent.
The reading frame hypothesis (Monaco, 1988). The single rule that explains the two phenotypes. Out-of-frame mutations in DMD disrupt the translational reading frame and produce a truncated, nonfunctional dystrophin that is rapidly degraded; the result is absent dystrophin and the severe DMD phenotype. In-frame mutations preserve the reading frame and allow production of a shortened but partially functional dystrophin; the result is the milder Becker phenotype. The rule holds in roughly 90 to 95 percent of cases and is the conceptual scaffold for exon-skipping therapy.
Out of frame equals profound structural failure. In frame equals partial structural integrity.
— PEDS-04-a podcast, ~01:52
Epidemiology and carrier status. DMD affects approximately 1 in 3,500 to 5,000 live male births. About 30 percent of cases arise from de novo mutations, so the mother is not always a carrier and family history may be completely silent. BMD is 3 to 6 times less common. Female carriers are usually asymptomatic, but 2.5 to 10 percent develop clinical symptoms (manifesting carriers) because of skewed X-inactivation. All female carriers require periodic cardiac surveillance regardless of symptoms, because dilated cardiomyopathy can emerge independently of skeletal muscle involvement.
Clinical presentation. Boys typically present between ages 2 and 5. The early signs are delayed walking (commonly 15 to 18 months), frequent falls, difficulty with stairs, and toe walking. The Gower sign, the compensatory maneuver of climbing the hands up the thighs to rise from the floor, is evident by age 3 to 5 and reflects proximal hip and knee extensor weakness. Calf pseudohypertrophy is the second classic sign and represents replacement of muscle by fat and fibrosis, not true hypertrophy. Gait shows compensatory hyperlordosis (offsetting hip extensor weakness), a wide-based waddling Trendelenburg pattern, and progressive equinus. Weakness follows a strict proximal-to-distal gradient, hitting the pelvic girdle before the shoulder girdle and the lower extremities before the upper. Cognitive involvement affects roughly one-third of boys (mean IQ approximately 85, with about 30 percent meeting intellectual disability criteria) because the brain-expressed Dp71 dystrophin isoform is also absent.
Figure 4.1 — Gower Sign Sequence
Five-panel sequence showing the compensatory maneuver: (1) supine to prone roll, (2) push to hands and knees, (3) walk hands back along the floor toward feet, (4) walk hands up shins to thighs, (5) achieve upright stance. Caption emphasizes that the maneuver reflects proximal hip and knee extensor weakness and is typically evident by age 3 to 5 in DMD. Search Wikimedia Commons and Servier Medical Art for an open-licensed illustration; license must be CC BY, CC BY-SA, CC0, or Public Domain.
Source: Wikimedia Commons, “Pseudoathletic appearance of calf muscle hypertrophy” (CC BY 4.0).
Creatine kinase (CK). CK is the most sensitive screening test in DMD: 10,000 to 50,000 IU/L, 50 to 100 times the upper limit of normal, present from birth and detectable in cord blood. CK peaks in early childhood and then declines as muscle mass is lost. BMD CK is 2,000 to 20,000 IU/L. Aldolase and the aminotransferases (AST, ALT) are also elevated; an unexplained AST/ALT elevation in a young boy should prompt a CK rather than a hepatology consult.
Diagnosis. Genetic-first is the modern strategy. Multiplex ligation-dependent probe amplification (MLPA) is first-line and detects the 70 to 80 percent of cases caused by deletions and duplications. If MLPA is negative, next-generation sequencing identifies point mutations and small insertion/deletions. Muscle biopsy is reserved for inconclusive genetic testing and shows the dystrophic triad (fiber size variation with central nucleation, necrotic and regenerating fibers, and endomysial fibrosis with fatty infiltration) plus absent dystrophin on immunohistochemistry.
High Yield — DMD genetics and presentation
- DMD = X-linked recessive, Xp21.2, out-of-frame dystrophin mutation, absent dystrophin protein.
- Reading frame hypothesis (Monaco, 1988) explains the DMD versus BMD divide and 90 to 95 percent of cases.
- 30 percent of DMD cases are de novo; absent family history is not reassuring.
- CK 10,000 to 50,000 IU/L (50 to 100 times normal) in DMD; 2,000 to 20,000 in BMD.
- Gower sign plus calf pseudohypertrophy plus Trendelenburg/lordotic gait is the classic triad.
- Diagnosis: MLPA first, then next-generation sequencing for MLPA-negative cases.
- All female carriers need lifelong cardiac surveillance; 2.5 to 10 percent are manifesting carriers.