Duchenne Muscular Dystrophy (DMD)

Overview

Genetics & Molecular Pathology

• Gene: DMD (Xp21.2) - one of the largest human genes (~2.4 Mb)
• Mutation types: Frameshift deletions/duplications (~70%), point mutations (~30%)
• Result: Complete absence of dystrophin protein (vs. partial loss in the milder Becker MD)
• The reading frame rule: Out-of-frame mutations = DMD (severe); in-frame mutations = Becker MD (milder)
• Female carriers: Usually asymptomatic, but up to 20% can show muscle weakness or dilated cardiomyopathy (DCM) due to skewed X-inactivation (lyonization)

Clinical Features

Cardiac Involvement

• Dilated cardiomyopathy (DCM) is the hallmark - caused by progressive cardiac fibrosis and left ventricular dilation
• Rhythm/conduction abnormalities are common
• Cardiorespiratory failure is the primary cause of death
• Some patients develop isolated X-linked DCM (OMIM #302045) without severe skeletal muscle disease

Diagnosis

1. Serum CK: Elevated 20-100x above normal (markedly elevated even presymptomatically)
2. Genetic testing (DNA analysis): Positive in ~90-95% of patients - first-line confirmation
3. Muscle biopsy (if genetic testing negative, ~5% of cases):
   • Histology: Variation in fiber size, necrosis, inflammation, fibrosis, regeneration
   • Immunohistochemistry (IHC): Complete/near-complete absence of dystrophin (carboxy-terminal antigens)
   • "Revertant fibers" (small clusters retaining dystrophin) may be seen
4. Newborn screening: Elevated CK can be detected from blood spots; two-tiered CK + DNA programs have been piloted (e.g., Ohio) but are not yet standard in the US

Treatment

Corticosteroids (mainstay)

• Prednisone 0.75 mg/kg/day - prolongs ambulation, helps respiratory function, slows scoliosis progression
• Deflazacort 0.9 mg/kg/day - similar efficacy to prednisone with less weight gain; FDA-approved for DMD

Exon-Skipping Therapies (FDA-conditionally approved)

Cardiac Management

• ACE inhibitors - slow progression of myocardial fibrosis; started early even before symptomatic cardiomyopathy
• Beta-blockers and diuretics for established DCM

Respiratory Management

• Regular pulmonary function monitoring
• Noninvasive ventilation (BiPAP/NIV) as respiratory function declines

Orthopedic Management

• Physiotherapy to prevent contractures
• Monitoring for scoliosis; spinal fusion when indicated
• Timely provision of wheelchairs and assistive devices

Prognosis

Management of Status Asthmaticus

NAEPP ED/Hospital Management Algorithm

Step 1 - Initial Assessment

Note: In early severe asthma, PaCO2 is low (hyperventilation). A normal or rising PaCO2 signals respiratory muscle fatigue - prepare for intubation.

Step 2 - Immediate Treatment

1. Oxygen

• Target SpO2 ≥90% (≥95% in pregnancy, children)
• Controlled O2 via mask/nasal prongs; avoid high-flow that may delay recognition of deterioration

2. Short-Acting Beta-2 Agonists (SABA) - First-line, most important

• MDI + spacer is preferred when the patient can cooperate - equal or greater efficacy, fewer side effects, shorter hospital stay
• Levalbuterol has no proven advantage over racemic albuterol and costs significantly more

3. Ipratropium Bromide (Anticholinergic)

• Add to SABA for severe exacerbations
• Dose: 0.5 mg nebulized Q20 min x 3 doses (or 4-8 puffs MDI)
• Provides additive bronchodilation by blocking muscarinic-mediated bronchoconstriction
• Note: No proven additional benefit in the inpatient setting (use in ED/initial phase)

4. Systemic Corticosteroids - Start early

• No proven advantage for IV over oral when GI absorption is intact
• No proven benefit from higher doses in severe exacerbations
• Courses <7 days: no taper needed
• Inhaled corticosteroids can be started at any point during treatment

Step 3 - Adjunct Therapies (for Refractory Cases)

Magnesium Sulfate

• IV MgSO4: 1-2 g IV over 20-30 min (pediatric: 25-75 mg/kg max 2 g)
• Indicated for FEV1/PEFR <25% predicted or inadequate response to bronchodilators
• Mechanism: inhibits smooth muscle contraction (calcium antagonism)
• Nebulized MgSO4: 95-384 mg in sterile water; effective as adjunct after aggressive beta-agonist/steroid therapy
• Monitor: BP and deep tendon reflexes during infusion (hypotension and neuromuscular blockade are rare at these doses)

Epinephrine / Terbutaline (Parenteral)

• For severe exacerbations with minimal air entry where inhaled therapy is ineffective
• Epinephrine: 0.01 mg/kg IM (1:1000, max 0.5 mg) Q15-20 min x 3 doses
• Terbutaline SC: 0.01 mg/kg SC (max 0.25 mg) Q20 min x 3 doses; or IV continuous 0.2-5 mcg/kg/min
• Terbutaline IV may reduce the need for mechanical ventilation

Ketamine

• 1-2 mg/kg IV load + 1 mg/kg/hr infusion, titrated to effect
• Bronchodilatory properties via catecholamine release and direct smooth muscle relaxation
• Useful for preintuabtion sedation and for intubated patients not improving on MV
• Preferred induction agent for RSI in status asthmaticus

Heliox (Helium-Oxygen mixture, typically 70:30)

• Reduces turbulent airflow through narrowed airways; reduces work of breathing
• Useful as a bridge while other therapies take effect
• Most beneficial when helium concentration is maximized (limits FiO2 to 30% - avoid if hypoxic)

Aminophylline (controversial, less used now)

• 6 mg/kg IV load over 20 min, then 0.5-1.2 mg/kg/hr infusion
• Narrow therapeutic window, multiple drug interactions, cardiac toxicity risk
• Generally not first-line; used only when other therapies fail

Step 4 - Ventilatory Support

Non-Invasive Ventilation (BiPAP/NIV)

• Use for preoxygenation before intubation
• Reduces work of breathing, may temporarily stave off respiratory arrest
• Reassurance and coaching are key - anxious patients may resist mask

Mechanical Ventilation - Indications

• Impending or actual respiratory arrest
• Altered consciousness, exhaustion, cyanosis despite O2
• Rising PaCO2 with worsening acidosis

RSI Protocol for Status Asthmaticus

Post-Intubation Ventilator Strategy ("Controlled Hypoventilation")

• Low RR (8-12/min) with low tidal volume (6-8 mL/kg) - allow adequate exhalation time
• High inspiratory flow rate to maximize expiratory time (I:E ratio 1:3 to 1:5)
• Permissive hypercapnia acceptable - avoid auto-PEEP (breath stacking)
• Auto-PEEP causes barotrauma and hemodynamic compromise
• Long-term NMBA may be needed to reduce oxygen consumption and ventilator dysynchrony

Extracorporeal Life Support (ECMO)

• Last-resort option for refractory cases with life-threatening hypoxia or hemodynamic compromise

Step 5 - Agents of No Proven Benefit (avoid)

• Sodium bicarbonate (does not improve outcomes)
• Antibiotics (unless clear evidence of bacterial infection - most exacerbations are viral)
• IV beta-agonists (no advantage over inhaled; increased systemic side effects)
• Lidocaine for RSI (no high-quality evidence)

Discharge Criteria & Plan

• FEV1/PEFR ≥70% and sustained 60 min after last treatment
• SpO2 stable, no distress, normal exam
• Discharge medications: SABA PRN, oral corticosteroids (prednisone 40 mg x 5-7 days), initiate/continue ICS
• Follow-up: within 1-4 weeks with PCP or asthma specialist
• Provide written asthma action plan and peak flow diary

Recent evidence note: A 2024 systematic review (PMID 39402635, Crit Care) found that inhaled sevoflurane is an emerging option for adults with refractory status asthmaticus in the ICU, with bronchodilatory properties and favorable safety profile - though it remains outside standard practice guidelines.

The Floppy Child (Infantile Hypotonia)

Definition

Clinical Recognition

• "Frog-leg" posture in supine - legs abducted, externally rotated, hips and knees flexed with laxity
• Excessive head lag on traction (pull-to-sit) - head falls back completely
• Slip-through sign in vertical suspension - infant slides through examiner's hands
• Draping in horizontal (ventral) suspension - head and limbs hang limply
• Increased passive range of motion at ankles and hips
• Weak cry, poor suck, feeding difficulties

Step 1 - The Critical Branch Point: Central vs. Peripheral

Differential Diagnosis - Full Classification

A. CENTRAL CAUSES (~60-80%)

• Most common acquired cause
• History of perinatal distress, birth asphyxia
• Encephalopathy + seizures + multiorgan dysfunction

• Down syndrome (Trisomy 21) - most common chromosomal cause; characteristic facies, hypotonia, Brushfield spots
• Prader-Willi syndrome - severe neonatal hypotonia, poor feeding in infancy → insatiable appetite/obesity later; hypoplastic genitalia, intellectual impairment
• Angelman syndrome - hypotonia + seizures + absent speech + inappropriate laughter

• Lissencephaly, holoprosencephaly, polymicrogyria
• Cerebellar hypoplasia

• Present after a symptom-free interval once feeding begins (toxic intermediate accumulation)
• Amino acidopathies, organic acidurias, urea cycle defects
• Congenital lactic acidosis - mitochondrial disease, pyruvate metabolism defects
• Congenital disorders of glycosylation (CDG) - hypotonia + cerebellar hypoplasia + coagulopathy + inverted nipples + abnormal fat distribution
• Pompe disease (Glycogen storage type II) - cardiomegaly + hypotonia + macroglossia

• Perinatal - difficult breech delivery or hypoxic-ischemic injury
• Clues: absent pain response below level, sphincter dysfunction, priapism

B. PERIPHERAL CAUSES (~15-30%)

Anterior Horn Cell (Spinal Motor Neuron)

• Most important peripheral cause - autosomal recessive, SMN1 deletion (Xp21.2)
• SMA Type 0: weakness at birth, arthrogryposis, respiratory failure in early infancy
• SMA Type 1 (Werdnig-Hoffmann): onset <6 months, proximal > distal weakness, fasciculations of tongue, abdominal breathing (diaphragm relatively spared), absent reflexes
• CK may be mildly elevated (<1000 U/L)
• EMG: acute and chronic denervation
• Treatment is urgent: nusinersen (Spinraza - intrathecal antisense oligonucleotide), onasemnogene abeparvovec (Zolgensma - gene replacement), risdiplam (Evrysdi - oral); benefit decreases with delay

Peripheral Neuropathy

• Rare cause; includes congenital hypomyelinating neuropathy and Dejerine-Sottas disease
• Reflexes disproportionately absent relative to weakness (demyelinating pattern)
• NCS: markedly slowed conduction velocities

Neuromuscular Junction (NMJ)

• Transient - maternal antibodies (anti-AChR) cross placenta
• Mother has myasthenia gravis; resolves within weeks
• Fatigable weakness, ptosis, poor suck

• Genetic (not antibody-mediated); persistent
• Various mutations in NMJ proteins (AChR subunits, rapsyn, ColQ, etc.)

• Ingestion of Clostridium botulinum spores (honey, soil)
• Age: 1-6 months typically
• Descending paralysis: constipation → poor feeding → hypotonia → respiratory failure
• Dilated, poorly reactive pupils; absent gag; repetitive nerve stimulation shows incremental pattern
• Treatment: BabyBIG (human botulism immune globulin)

Muscle Disorders

• Generally normal or mildly elevated CK
• Diagnosis by muscle biopsy + genetic testing

• Elevated CK, early onset hypotonia and contractures
• Merosin-deficient CMD - absent laminin-α2 on biopsy, white matter changes on MRI
• Ullrich CMD - collagen VI deficiency; joint hypermobility distally + contractures proximally
• Syndromic CMD (cobblestone lissencephaly group): Fukuyama CMD, Walker-Warburg syndrome, Muscle-Eye-Brain disease - severe myopathy + CNS malformation + ocular defects

• Maternal inheritance (trinucleotide repeat expansion in DMPK gene)
• ~25% of infants of affected mothers; mother's diagnosis may be unrecognized
• Facial diplegia, hypotonia, respiratory distress → later myotonia in adolescence

Diagnostic Workup

Tier 1 - All hypotonic infants

• Detailed history: pregnancy, perinatal period, family history, consanguinity
• Careful physical and neurological examination
• Chromosomal microarray (first-line genetic test)
• Serum CK (markedly elevated → muscular dystrophy/myopathy; normal → central or some myopathies)
• Metabolic screen: blood ammonia, plasma amino acids, acylcarnitine profile, urine organic acids, lactate/pyruvate, glucose

Tier 2 - Based on localization

Tier 3 - Targeted testing

• EEG if seizures suspected
• Echocardiogram if cardiomyopathy suspected (Pompe disease)
• Ophthalmology for structural CNS/eye diseases
• Thyroid function (hypothyroidism - treatable cause)

A systematic diagnostic approach yields a specific diagnosis in up to 85% of cases.

Management Principles

• SMA is a medical emergency - start genetic testing immediately; disease-modifying therapy is time-sensitive
• Metabolic emergencies: hold feeds, start IV glucose, investigate and treat empirically for sepsis while awaiting cultures
• Neonatal MG: resolves spontaneously; neostigmine if feeding/respiratory support needed
• Infant botulism: BabyBIG IV (human botulism immune globulin); ICU/ventilatory support
• Multidisciplinary care: neurology, genetics, physiotherapy, occupational therapy, speech/feeding therapy, respiratory support
• Arthrogryposis: physiotherapy, splinting, orthopaedic referral for contractures
• Genetic counselling for familial conditions (SMA, congenital myopathies, CMDs)