- Etiology/Pathophysiology
- Inheritance: Autosomal recessive.
- Genetic Basis: Caused by mutations in PEX genes (at least 12 different genes identified, PEX1 is most common), which encode for peroxins. Peroxins are proteins essential for the assembly and function of peroxisomes.
- Cellular Defect: Leads to absent or non-functional peroxisomes. This is a disorder of peroxisome biogenesis.
- Metabolic Consequences: Impaired peroxisomal function leads to the accumulation of substrates normally degraded in peroxisomes.
- ↑↑ Very-long-chain fatty acids (VLCFAs).
- ↑ Branched-chain fatty acids (e.g., phytanic acid).
- ↓ Plasmalogen synthesis (critical components of myelin).
- ↓ Bile acid synthesis.
- Clinical Features
- Zellweger syndrome is the most severe form of the Zellweger spectrum disorders (ZSD). The classic name is cerebrohepatorenal syndrome.
- Presentation: Severe symptoms are present at birth or in the early neonatal period.
- Neurologic:
- Profound hypotonia (“floppy baby”).
- Seizures (often neonatal).
- Impaired neuronal migration, leading to developmental delay and intellectual disability.
- Sensorineural hearing loss and vision problems (retinopathy, cataracts).
- Craniofacial Dysmorphism:
- High forehead, flattened face.
- Large anterior fontanelle.
- Low-set ears, broad nasal bridge.
- Hepatic:
- Hepatomegaly.
- Jaundice (conjugated hyperbilirubinemia).
- Liver dysfunction, can progress to cirrhosis.
- Renal:
- Small cysts in the kidneys.
- Diagnostics
- Labs:
- ↑ Serum VLCFAs (e.g., C26:0). This is a key diagnostic marker.
- Abnormal liver function tests.
- Genetic Testing: Confirmatory, detects mutations in PEX genes.
- Imaging:
- Cranial MRI can show neuronal migration defects (e.g., pachygyria, lissencephaly).
- Abdominal ultrasound may show hepatomegaly and renal cysts.
- Pathology
- Histology shows an absence of peroxisomes in hepatocytes and renal tubular cells.
- Brain pathology reveals characteristic neuronal migration defects.
- Treatment
- Supportive care is the only available option. There is no cure.
- Management of seizures, feeding difficulties (gastrostomy tube), and respiratory issues.
- Vitamin supplementation.
- Prognosis
- Extremely poor.
- Death typically occurs within the first year of life, usually from respiratory failure or seizures.