Pitfall in Metabolic Screening in a Patient with Fatal Peroxisomal β-Oxidation Defect

Abstract

We present a rare case of peroxisomal acyl-CoA oxidase deficiency that was not detected by the common metabolic screening program for peroxisomal disorders. The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly indicative for a peroxisomal disorder. Yet, repetitive measurements of very long-chain fatty acids (VLCFAs) and phytanic acid in serum and plasma as well as plasmalogens in erythrocytes revealed normal values apparently excluding a peroxisomal defect (methods of measurement published by Moser and co-workers in 1980 [[4]] and 1981 [[2]]). Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal de novo plasmalogen synthesis, indicative for a defect in the peroxisomal β-oxidation system. Enzymatic studies in these fibroblasts pointed to peroxisomal acyl-CoA oxidase deficiency and subsequent molecular analyses revealed a homozygous acceptor splice site mutation IVS3-1G>A in the ACOX1 gene (MIM *609 751).

Metabolic screening - β-oxidation defect - peroxisomes - MRI pattern recognition

References

• 1 Ferdinandusse S, Denis S, Clayton P T, Graham A, Rees J E, Allen J T, McLean B N, Brown A Y, Vreken P, Waterham H R, Wanders R J. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy.  Nat Genet. 2000;  24 188-191
• 4 Kurian M A, Ryan S, Besley G T, Wanders R J, King M D. Straight-chain acyl-CoA oxidase deficiency presenting with dysmorphia, neurodevelopmental autistic-type regression and a selective pattern of leukodystrophy.  J Inherit Metab Dis. 2004;  27 105-108
• 2 Moser H W, Moser A B, Kawamura N, Murphy J, Suzuki K, Schaumburg H, Kishimoto Y. Adrenoleukodystrophy: elevated C₂₆ fatty acid in cultured skin fibroblasts.  Ann Neurol. 1980;  7 542-549
• 3 Moser H W, Moser A B, Frayer K K, Chen W, Schulman J D, O'Neill B P, Kishimoto Y. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.  Neurology. 1981;  31 1241-1249
• 5 Poll-The B T, Roels F, Ogier H, Scotto J, Vamecq J, Schutgens R B, Wanders R J, van Roermund C W, van Wijland M J, Schram A W. et al . A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy).  Am J Hum Genet. 1988;  42 422-434
• 6 Suzuki Y, Shimozawa N, Yajima S, Tomatsu S, Kondo N, Nakada Y, Akaboshi S, Lai M, Tanabe Y, Hashimoto T. et al . Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional enzyme deficiency with detectable enzyme protein: identification by means of complementation analysis.  Am J Hum Genet. 1994;  54 36-43
• 7 Varanasi U, Chu R, Chu S, Espinosa R, LeBeau M M, Reddy J K. Isolation of the human peroxisomal acyl-CoA oxidase gene: organization, promoter analysis, and chromosomal localization.  Proc Natl Acad Sci USA. 1994;  91 3107-3111
• 8 Wanders R JA, Barth P G, Heymans H AS. Single peroxisomal enzyme deficiencies. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York; McGraw-Hill 2001: 3219-3256
• 9 Wanders R J. Metabolic and molecular basis of peroxisomal disorders: a review.  Am J Med Genet A. 2004;  126 355-375 [Review]