What is the most likely diagnosis in a newborn presenting with profound hypotonia and sudden cardiac arrest?

Classic Infantile Pompe Disease (Glycogen Storage Disease Type II)

A newborn presenting with profound hypotonia and sudden cardiac arrest should be immediately evaluated for classic infantile Pompe disease, which characteristically presents with hypertrophic cardiomyopathy, generalized muscle weakness and hypotonia, and death from cardiorespiratory failure—typically by 1 year of age if untreated.

Clinical Presentation and Diagnosis

The constellation of profound hypotonia with sudden cardiac arrest in a newborn is pathognomonic for classic infantile Pompe disease 1. This lysosomal storage disorder presents in the first few months of life with:

• Hypertrophic cardiomyopathy (present in 76% at birth)
• Generalized muscle weakness and profound hypotonia (92% of newborns)
• Cardiomegaly and hepatomegaly
• Death from cardiorespiratory failure, with median age of death at 6-8.7 months without treatment 1

The cardiac involvement is critical: these infants develop massive ventricular hypertrophy with potential left ventricular outflow tract obstruction, placing them at extremely high risk for tachyarrhythmias and sudden death, especially during stress, infection, fever, dehydration, or anesthesia 1.

Immediate Diagnostic Workup

When confronted with this presentation, obtain:

• Acid α-glucosidase (GAA) enzyme activity on dried blood spot or fibroblasts—this is diagnostic
• ECG: Look for short PR interval (common in Pompe), left ventricular hypertrophy, and arrhythmias
• Echocardiogram: Assess for severe ventricular hypertrophy and left ventricular mass (calculate z-score)
• Chest X-ray: Massive cardiomegaly is typical
• Serum lactate and CK: May be elevated but not as dramatically as in mitochondrial disorders
• 24-hour Holter monitoring: Essential given arrhythmia risk 1

Critical Management Pitfalls

The cardiac management in Pompe disease is treacherous and differs fundamentally from standard heart failure treatment 1:

Avoid in early hypertrophic phase:

• Digoxin, inotropes, diuretics, and ACE inhibitors can worsen left ventricular outflow tract obstruction
• Beta-blockers have been associated with sudden death in anecdotal cases and should be used judiciously 1

Essential precautions:

• Avoid hypotension at all costs—these massively hypertrophied ventricles are at risk for subendocardial ischemia
• Maintain strict fluid balance; avoid both dehydration and fluid overload
• Aggressive infection management with low threshold for treatment 1
• Extreme caution with anesthesia due to hemodynamic instability 1

Differential Considerations

While Pompe disease is the classic diagnosis for this presentation, briefly consider:

• Mitochondrial disorders (TMEM70 mutation): Also presents with neonatal hypotonia and hypertrophic cardiomyopathy, but typically has more profound lactic acidosis (5-36 mmol/L) and hyperammonemia (100-520 μmol/L), plus 3-methylglutaconic aciduria 2
• Type IV glycogenosis: Presents with hypotonia and cardiomyopathy but typically shows dilated (not hypertrophic) cardiomyopathy 3
• Malonyl-CoA decarboxylase deficiency: Can cause hypotonia and cardiomyopathy but presents later (around 5 months) 4

The hypertrophic cardiomyopathy with profound hypotonia and early presentation strongly favors Pompe disease over these alternatives 1.

Prognosis and Treatment

Without treatment, the natural history is grim: median symptom onset at 1.6-4 months, first ventilator support at 5.9 months, and death at 6-8.7 months 1. Enzyme replacement therapy (ERT) with recombinant acid α-glucosidase is now available and can reduce cardiac mass and improve survival, though transient falls in ejection fraction may occur in the first 12-24 weeks of therapy, requiring close monitoring 1.

The incidence is approximately 1:40,000 overall, with higher rates in African-Americans and Chinese populations 1.