A pathognomonic MRI pattern can be the major clue to a peroxisomal disorder in case of pitfalls in metabolic screening

Peroxisomal β-oxidation defects are a clinically and genetically heterogenous group of fatal autosomal recessive and X-linked diseases that are due to enzymatic deficiencies in the oxidation of branched chain fatty acids, saturated very long chain fatty acids (VLCFAs) and their derivatives. Known diseases are X-linked adrenoleukodystrophy, Acyl-CoA oxidase deficiency, D-bifunctional protein deficiency and 2-Methyl-acyl-CoA racemase deficiency. So far, measuring the concentration of VLCFAs in plasma or serum has been considered as a reliable screening method for peroxisomal disorders in general.

Here we describe a male infant with facial dysmorphism, progressive psychomotor deterioration, deafness, retinopathy, peripheral neuropathy and infantile seizures. The patient died at the age of 5 years and 1 month. His cerebral MRI at the age of 2 months and 3 years showed severe neuronal migration defects including pachygyria and perisylvian polymicrogyria. In addition, he had white matter abnormalities in the cerebrum and cerebellum. This pattern of brain involvement has only been described for peroxisomal disorders. Extensive and repetitive biochemical screening of peroxisomal functions did not reveal elevated plasma levels of VLCFAs. Nevertheless, the pathognomonic MRI findings and the clinical phenotype of this patient were highly suggestive for a β-oxidation defect or a peroxisome biogenesis defect like Zellweger syndrome. Biochemical analyses in cultured skin fibroblasts as well as molecular analyses in blood and cultured skin fibroblasts revealed a peroxisomal acyl-CoA oxidase deficiency and a homozygous splice site mutation IVS3–1G>A in the ACOX1 gene.

In conclusion, measuring normal VLCFAs in plasma does not exclude peroxisomal disorder. A pathognomonic MRI pattern should lead to biochemical analyses of peroxisomal functions in cultured skin fibroblasts and molecular analyses even if screening results in plasma are not indicative for a peroxisomal disorder.