Very long-chain fatty acids-related diseases

Feature	Zellweger Syndrome	X-Linked Adrenoleukodystrophy
Inheritance	Autosomal Recessive	X-Linked Recessive
Mechanism	Absent peroxisomes (PEX mut)	Transport defect (ABCD1 mut)
Lab Finding	↑ VLCFAs, ↓ Plasmalogens	↑ VLCFAs
Patient	Neonate	Young Boy (4–10y)
Classic Sx	Hypotonia, Seizures, Craniofacial	Adrenal failure, Behavioral issues
Prognosis	Fatal < 1 year	CNS deterioration

Zellweger Syndrome

• Etiology/Pathophysiology
  • Autosomal Recessive peroxisome biogenesis disorder.
  • Mutations in PEX genes lead to absent or non-functional peroxisomes.
  • Results in accumulation of Very Long Chain Fatty Acids (VLCFAs) and branched-chain fatty acids (e.g., phytanic acid) due to inability to break them down.
  • Defective synthesis of plasmalogens (important for myelin) and bile acids.
• Clinical Features
  • Presents in neonates/early infancy.
  • Severe Hypotonia (“floppy baby”).
  • Seizures.
  • Hepatomegaly (often with jaundice).
  • Craniofacial dysmorphism: Widened sutures, large anterior fontanelle, broad nasal bridge.
  • Early death (usually within months to 1 year).
• Diagnostics
  • Labs: ↑ VLCFAs in blood; ↓ Plasmalogens.
• Treatment
  • Supportive care only. Prognosis is fatal.

---

X-Linked Adrenoleukodystrophy

• Etiology/Pathophysiology
  • X-Linked Recessive disorder.
  • Mutation in ABCD1 gene.
  • Defect in peroxisomal transport: Peroxisomes are present, but the transport protein required to move VLCFAs into the peroxisome for beta-oxidation is defective.
  • Accumulation of VLCFAs specifically damages:
    1. Adrenal Glands (Adrenal cortex)
    2. CNS White Matter (Demyelination)
    3. Testes (Leydig cells)
• Clinical Features
  • Typically affects young males (school age).
  • Adrenal Insufficiency: Hypotension, skin hyperpigmentation, electrolyte abnormalities (often the initial sign).
  • Neurological Decline: Behavioral changes, vision/hearing loss, ataxia, dementia, eventually vegetative state.
• Diagnostics
  • Labs: ↑ VLCFAs in plasma.
  • MRI Brain: White matter demyelination (posterior predominant).
  • Adrenal function tests: ACTH stimulation test (impaired response).
• Treatment
  • Adrenal insufficiency: Steroid replacement (Glucocorticoids/Mineralocorticoids).
  • Lorenzo’s oil: Mixture of oleic and erucic acid (may lower VLCFA levels but clinical efficacy is variable/limited).
  • Hematopoietic Stem Cell Transplant: Can arrest progression if performed early in cerebral forms.