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Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder

From the Laboratory Genetic Metabolic Diseases (Drs. Wanders and Ferdinandusse, J. Gootjes), Academic Medical Center, University of Amsterdam, The Netherlands; and the Department of Clinical Genetics (Drs. Skovby and Christensen), Copenhagen University Hospital, Denmark.

Address correspondence and reprint requests to Dr. Sacha Ferdinandusse, Laboratory Genetic Metabolic Diseases (F0-224), Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands; e-mail: s.ferdinandusse{at}amc.uva.nl

Objective: To determine the enzymatic defect in a patient with ataxia, dysarthric speech, dry skin, hypotonia, and absent reflexes. The patient was previously diagnosed with a presumed deficiency of trihydroxycholestanoyl-CoA oxidase.

Background: Peroxisomes harbor a variety of metabolic functions, including fatty acid ß-oxidation, etherphospholipid biosynthesis, phytanic acid -oxidation, and L-pipecolic acid oxidation. This patient was previously described with an isolated peroxisomal ß-oxidation defect caused by a deficiency of the enzyme trihydroxycholestanoyl-CoA oxidase. This was based on the pattern of accumulating metabolites.

Methods: Measurement of ß-oxidation enzymes, peroxisomal biochemical analysis in body fluids and cultured skin fibroblasts, and DNA analysis of the PEX12 gene were performed.

Results: An isolated ß-oxidation defect in this patient was excluded by measurement of the various ß-oxidation enzymes. The authors found that the patient had a peroxisome biogenesis disorder caused by mutations in the PEX12 gene, although all peroxisomal functions in cultured skin fibroblasts were normal.

Conclusions: The absence of clear peroxisomal abnormalities in the patient’s fibroblasts, including a normal peroxisomal localization of catalase, implies that even when all peroxisomal functions in fibroblasts are normal, a peroxisome biogenesis disorder cannot be fully excluded, and further studies may be needed. In addition, the authors’ findings imply that there is no longer evidence for the existence of trihydroxycholestanoyl-CoA oxidase deficiency as a distinct disease entity.

Received November 11, 2003. Accepted in final form January 29, 2004.