Learning Objective: By the end of this lesson, the student should be able to: Describe the major metabolic roles of peroxisomes and differentiate between disorders caused by defects in peroxisomal function.
Overview of Peroxisomes
Peroxisomes are membrane-enclosed organelles that play a crucial role in lipid metabolism and detoxification. They are especially active in the liver and the brain white matter.
Major Peroxisomal Functions
| Function | Description | Clinical Importance |
|---|---|---|
| β-oxidation of Very-Long-Chain Fatty Acids (VLCFA) | Degradation of fatty acids >22 carbons (strictly peroxisomal) | Defect → VLCFA accumulation in tissues (e.g., Adrenoleukodystrophy) |
| α-oxidation of Branched-Chain Fatty Acids | Degradation of phytanic acid | Defect → Refsum disease |
| Catabolism of Amino Acids & Ethanol | Detoxification and oxidative metabolism | Peroxisomal enzymes prevent the accumulation of toxic intermediates |
| Synthesis of Bile Acids & Plasmalogens | Plasmalogens are key membrane phospholipids, especially in myelin | Defect → Impaired myelination (e.g., Zellweger syndrome) |
Peroxisomal Disorders
- Zellweger Syndrome
- Inheritance: Autosomal recessive
- Defect: Mutations in PEX genes → defective peroxisome biogenesis
- Pathophysiology: Accumulation of pipecolic acid and VLCFAs due to absent functional peroxisomes
- Clinical Features:
- Hypotonia, seizures
- Craniofacial dysmorphia\
- Hepatomegaly, jaundice
- Early death
- Refsum Disease
- Inheritance: Autosomal recessive
- Defect: Impaired α-oxidation → accumulation of phytanic acid
- Clinical Features:
- Vision loss (retinitis pigmentosa)
- Anosmia, hearing loss
- Ataxia, peripheral neuropathy
- Ichthyosis, cardiac conduction defects
- Treatment: Dietary restriction of phytanic acid, plasmapheresis
- Adrenoleukodystrophy (ALD)
- Inheritance: X-linked recessive
- Defect: Mutation in the ABCD1 gene → defective transport of VLCFA into the peroxisome
- Pathophysiology: VLCFA accumulation in:
- Adrenal cortex → adrenal insufficiency
- White matter → demyelination
- Testes → hypogonadism
- Clinical Course: Progressive neurodegeneration, adrenal crisis, and death
Key Points for Step 1
- VLCFA metabolism → peroxisomal β-oxidation
- Phytanic acid metabolism → α-oxidation (peroxisome)
- Defective peroxisome biogenesis → Zellweger syndrome
- White matter involvement is common due to impaired plasmalogen synthesis
- Refsum = α-oxidation defect, ALD = transport defect, Zellweger = formation defect
