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Right arrow Metabolic disease (inherited)
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NEUROLOGY 2004;62:2077-2081
© 2004 American Academy of Neurology

Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder

J. Gootjes, MSc, F. Skovby, MD, E. Christensen, PhD, R. J.A. Wanders, PhD and S. Ferdinandusse, PhD

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 {alpha}-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.