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ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism
  1. Sacha Ferdinandusse1,
  2. Kim D Falkenberg1,
  3. Janet Koster1,
  4. Petra A Mooyer1,
  5. Richard Jones2,
  6. Carlo W T van Roermund1,
  7. Amy Pizzino3,
  8. Michael Schrader4,
  9. Ronald J A Wanders1,
  10. Adeline Vanderver3,
  11. Hans R Waterham1
  1. 1Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Kennedy Krieger Institute, Baltimore, Maryland, USA
  3. 3Department of Neurology, Children's National Health System, Washington DC, USA
  4. 4College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter, Devon, UK
  1. Correspondence to Dr Sacha Ferdinandusse, Laboratory Genetic Metabolic Diseases, F0-220 Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; S.Ferdinandusse{at};
  2. Hans Waterham, Laboratory Genetic Metabolic Diseases, F0-220 Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; H.R.Waterham{at}


Background Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role.

Methods We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing.

Results We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation. No effect on pexophagy was found.

Conclusions Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent β-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease.

  • peroxisomal single enzyme deficiency
  • peroxisomal beta-oxidation
  • pexophagy
  • very long-chain fatty acids
  • acyl-CoA binding domain containing protein 5

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  • SF and KDF are co-first authors.

  • Contributors KDF, JK, PM, RJ and CWTR performed laboratory analyses. AP and AV were responsible for the clinical care of the patient, provided the patient’s clinical information and revised the manuscript. SF supervised the study and wrote the manuscript. HRW supervised the study and revised the manuscript. KDF, MS and RJAW revised the manuscript.

  • Funding Supported in part by funding through the Marie Curie Initial Training Networks (ITN) action to KDF, MS and HRW (FP7-2012-PERFUME-316-723). MS is supported by the Biotechnology and Biological Sciences Research Council (BB/K006231/1; BB/N01541X/1).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.