Practice question

Peroxisome biogenesis requires more than thirty PEX genes encoding peroxins that mediate membrane protein targeting, matrix protein import, proliferation and inheritance. Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease constitute Zellweger spectrum, recognized as prototypical peroxisomal biogenesis disorders inherited autosomal recessively with combined incidence about 1 in 50,000. Most commonly mutations in PEX1, PEX6, PEX26 members of AAA ATPase complex that recycles PEX5 receptor block both PTS1 and PTS2 import pathways, leading to cytosolic mislocalization of enzymes and peroxisome ghosts lacking matrix content. Consequences are multi-systemic: failure of very-long-chain fatty acid beta-oxidation causing accumulation of C26:0 hexacosanoic acid in plasma, defective alpha-oxidation of phytanic acid from dietary chlorophyll, deficient plasmalogen ether lipid synthesis causing neuronal migration defects and myelin abnormalities, and impaired bile acid conjugation with taurocholate accumulation leading to cholestasis. Clinical features include characteristic craniofacial dysmorphism with prominent forehead, profound hypotonia, seizures, hepatomegaly with fibrosis, retinal dystrophy, sensorineural deafness and early death usually within first year. Tay-Sachs, metachromatic leukodystrophy and Niemann-Pick arise from lysosomal hydrolase defects, not peroxisomal, highlighting diagnostic distinction via plasma VLCFA assay and plasmalogens.