Zellweger Syndrome (Cerebro-Hepato-Renal Syndrome)

1. DEFINITION AND CLASSIFICATION

• Definition: The prototype and most severe form of the Peroxisome Biogenesis Disorders (PBD).
• Classification (Zellweger Spectrum Disorders):
  • Zellweger Syndrome (ZS): Most severe; neonatal onset; fatal.
  • Neonatal Adrenoleukodystrophy (NALD): Intermediate severity.
  • Infantile Refsum Disease (IRD): Mildest form.

2. ETIOLOGY AND GENETICS

• Inheritance: Autosomal Recessive.
• Genetic Defect: Mutations in PEX genes (Peroxin genes) required for peroxisome assembly.
  • PEX1 mutation is the most common (approx. 70% of cases).
• Pathophysiology:
  • Failure to import proteins into peroxisomes leads to "Ghost Peroxisomes" (empty vesicles) and functional absence of peroxisomes.
  • Metabolic Consequences:
    • Accumulation: Very Long Chain Fatty Acids (VLCFA), Phytanic acid, Pipecolic acid, Bile acid intermediates.
    • Deficiency: Plasmalogens (essential for myelin), DHA.
  • Neuronal Migration Defect: Defective neuronal migration leads to pachygyria/polymicrogyria.

3. CLINICAL FEATURES

Presents in the neonatal period with a recognizable dysmorphic phenotype.

A. Craniofacial (Dysmorphic Facies)

• "Pear-shaped head": High, prominent forehead with flattened face.
• Large anterior fontanelle and widely split sutures.
• Eyes: Hypertelorism, epicanthal folds, shallow orbital ridges.
• Ears: Deformed ear lobes.

B. Neurologic (Severe)

• Profound Hypotonia: "Floppy infant" (often confused with Down syndrome or SMA).
• Seizures: Onset in neonatal period; often refractory.
• Sensory Deficits:
  • Vision: Cataracts, glaucoma, corneal clouding, "Leopard spot" pigmentary retinopathy.
  • Hearing: Sensorineural hearing loss.
• Development: Profound global developmental delay; little to no interaction.

C. Visceral (Hepato-Renal)

• Liver: Hepatomegaly with prolonged neonatal jaundice (cholestasis). Progresses to cirrhosis/fibrosis.
• Kidneys: Cortical renal cysts (microscopic or macroscopic) in >70% cases.

D. Skeletal

• Chondrodysplasia Punctata: Calcific stippling of the patella (distinctive sign) and epiphyses of long bones (seen on X-ray).

4. INVESTIGATIONS

• Biochemical Screening (Gold Standard):
  • Plasma VLCFA: Markedly elevated (C26:0 and C26:1 ratio).
  • RBC Plasmalogens: Reduced.
  • Plasma Pipecolic Acid & Phytanic Acid: Elevated.
• Imaging:
  • Ultrasound: Renal cortical cysts; Hepatomegaly.
  • MRI Brain: Neuronal migration defects (pachygyria, polymicrogyria), hypomyelination, and Germinolytic cysts (cysts in the germinal matrix).
  • Skeletal Survey: Stippled calcifications (chondrodysplasia punctata) in patella and hips.
• Molecular Genetics: Panel testing for PEX genes (PEX1, PEX6, PEX12, etc.).

5. DIFFERENTIAL DIAGNOSIS

• Down Syndrome (due to severe hypotonia/flat face).
• Other Peroxisomal disorders (X-linked Adrenoleukodystrophy).
• Smith-Lemli-Opitz Syndrome.
• Congenital infections (TORCH).

6. MANAGEMENT

• Curative: No cure exists. Management is strictly supportive and palliative.
• Supportive Care:
  • Gastrostomy for feeding difficulties.
  • Antiepileptics for seizure control.
  • Vitamin K and fat-soluble vitamin supplementation (due to cholestasis/bile acid defects).
  • Hearing aids and ophthalmology support.
• Experimental: Oral Cholic acid (to reduce toxic bile acid intermediates) and DHA therapy (limited efficacy).

7. PROGNOSIS

• Fatal: Death typically occurs in the first year of life (mean survival ~6 months).
• Cause of Death: Respiratory failure (aspiration/apnea), intractable seizures, or liver failure.