Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder.
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 beta-oxidation, etherphospholipid biosynthesis, phytanic acid alpha-oxidation, and L-pipecolic acid oxidation. This patient was previously described with an isolated peroxisomal beta-oxidation defect caused by a deficiency of the enzyme trihydroxycholestanoyl-CoA oxidase. This was based on the pattern of accumulating metabolites.


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


RESULTS
An isolated beta-oxidation defect in this patient was excluded by measurement of the various beta-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.
Gootjes
J
J
Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, The Netherlands.
Skovby
F
F
Christensen
E
E
Wanders
R J A
RJ
Ferdinandusse
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000201:enzymology / Q000235:genetics; D002374:Catalase / Q000032:analysis; D002675:Child, Preschool; D002777:Cholestanols / Q000097:blood*; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D003951:Diagnostic Errors; D004401:Dysarthria / Q000201:enzymology / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D005658:Fungi / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics; D008322:Mammals / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000201:enzymology / Q000235:genetics; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000172:deficiency; D020675:Peroxisomes / Q000378:metabolism* / Q000502:physiology; D010831:Phytanic Acid / Q000009:adverse effects / Q000097:blood; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D002777:Cholestanols; D008565:Membrane Proteins; C105251:PEX12 protein, human; D010831:Phytanic Acid; C022069:3,7,12-trihydroxycholestan-26-oic acid; D010088:Oxidoreductases; D002374:Catalase; C066160:trihydroxycholestanoyl-CoA oxidase