Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Cell Biology

Background:

• Neurological dysfunction is a hallmark of peroxisomal disorders.
• Significant advancements have been made in identifying gene defects, particularly peroxins (PEX).
• Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) represent a disease continuum.

Purpose of the Study:

• To review the gene defects and neuropathologic features of peroxisomal disorders.
• To elucidate the pathogenetic mechanisms underlying neuronal and white matter abnormalities.
• To highlight the role of abnormal fatty acids in cellular dysfunction.

Main Methods:

• Review of genetic and neuropathologic findings in peroxisomal disorders.
• Classification of neuropathologic lesions, including white matter abnormalities and neuronal degenerations.
• Postulation of pathogenetic mechanisms involving abnormal fatty acid metabolism.

Main Results:

• Five peroxisome (PEX) gene defects have been identified, confirming the ZS/NALD/IRD disease continuum.
• Adrenoleukodystrophy (ALD)/adrenomyeloneuropathy (AMN) involves a peroxisomal membrane protein defect.
• Neuropathologic lesions include neuronal migration/differentiation issues, white matter defects (demyelination, dysmyelination), and neuronal degenerations (axonopathy, cerebellar atrophy).

Conclusions:

• Abnormal fatty acids, such as very long chain fatty acids and phytanic acid, are implicated in cellular dysfunction and death.
• These abnormal lipids perturb cell membranes, leading to atrophy and dysfunction of vulnerable cells.
• Mouse models for ZS and ALD are expected to further unravel the pathogenesis of peroxisomal disorders.