Clinical consequences of defects in peroxisomal beta-oxidation

The disorders of peroxisomal beta -oxidation, which have been well characte rised at the molecular level, include defects of acyl-CoA oxidase, defects of the D-bifunctional protein (D-BP) (including specific defects of its eno yl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase components), defects of the very-long-chain fatty acid (VLCFA)-CoA importer [X-linked adrenoleu kodystrophy (ALD)] and alpha -methylacyl-CoA racemase deficiency. A survey of the clinical consequences of these defects indicates that defects in the acyl-CoA oxidase and D-BP can produce neonatal hypotonia, seizures in earl y infancy retinopathy and progressive neurological dysfunction with leukody strophy on imaging. Defects in the VLCFA-CoA importer and in the racemase d o not produce disease until a long time after the neonatal period. However, again the clinical picture is dominated by neurological disease: impaired cognitive function with leukodystrophy in childhood X-linked ALD and retino pathy and neuropathy in racemase deficiency. It is difficult to escape the conclusion that defective peroxisomal alpha -oxidation has effects (such as impaired neuronal migration in the developing brain), which are more serio us than those produced by the accumulation of substrates (VLCFAs, pristanic acid) alone.