Clinical Scenario: Floppy | Seizures | dysmorphism | Pigmentary retinopathy
A 10-day-old male neonate is admitted with poor feeding, lethargy, hypotonia, and multifocal seizures since birth. Pregnancy was uncomplicated, and he was delivered at term. Examination shows a large anterior fontanelle, broad forehead, flattened facial profile, broad nasal bridge, low-set ears, hepatomegaly, and generalized hypotonia. Fundoscopy reveals pigmentary retinopathy.
Laboratory investigations demonstrate:
- Mild conjugated hyperbilirubinemia
- Elevated AST and ALT
- Normal plasma ammonia
- Normal blood lactate
- Normal plasma amino acid profile
Brain MRI demonstrates bilateral polymicrogyria.
Which of the following investigations is most likely to establish the diagnosis?
A. Plasma very-long-chain fatty acid assay
B. Urinary organic acid analysis
C. Plasma acylcarnitine profile
D. Leukocyte arylsulfatase A activity
E. Urinary glycosaminoglycan analysis
Correct answer & Explanation:
Correct Answer: A. Plasma very-long-chain fatty acid assay
Explanation
The infant has classical Zellweger syndrome, the most severe disorder in the Zellweger spectrum disorders, caused by mutations in PEX genes, leading to absence of functional peroxisomes.
Important clues include:
- Neonatal presentation
- Severe hypotonia (“floppy infant”)
- Poor feeding
- Refractory seizures
- Characteristic facial dysmorphism
- Hepatomegaly with cholestatic liver disease
- Pigmentary retinopathy
- Neuronal migration defect (polymicrogyria)
Peroxisomes are required for oxidation of very-long-chain fatty acids (VLCFAs). Their absence causes marked elevation of VLCFAs in plasma, making this the most useful diagnostic biochemical test.
Why the Other Options Are Incorrect
B. Urinary organic acid analysis
- Useful for organic acidemias, not peroxisomal disorders.
C. Plasma acylcarnitine profile
- Screens for fatty acid oxidation defects such as MCAD deficiency.
D. Leukocyte arylsulfatase A activity
- Confirms metachromatic leukodystrophy.
E. Urinary glycosaminoglycan analysis
- Used in mucopolysaccharidoses.
High-Yield Pearls
- Gene: PEX (peroxisome biogenesis genes)
- Inheritance: Autosomal recessive
- Diagnostic test: ↑ Plasma very-long-chain fatty acids (especially C26:0)
- Other abnormalities:
- ↑ Phytanic acid
- ↑ Pipecolic acid
- ↓ Plasmalogens
- MRI:
- Polymicrogyria
- Pachygyria
- Delayed myelination
- Prognosis is poor, with most affected infants dying during the first year of life.
Exam Pearl
If you see a floppy neonate with:
- Dysmorphic facies
- Hepatomegaly
- Pigmentary retinopathy
- Seizures
- Normal ammonia and lactate
- Neuronal migration abnormalities on MRI
→ Think Zellweger syndrome and order plasma very-long-chain fatty acids.
