title: Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing.
abstract: OBJECTIVE
  To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic.
  
  
  METHODS
  The patients' initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively.
  
  
  RESULTS
  Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP's enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced.
  
  
  CONCLUSIONS
  Exome sequencing provides a powerful and elegant tool in the specific diagnosis of "mild" or "atypical" neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features.
authors.affiliation: From Metabolics and Newborn Screening (M.A.L.), University of Ottawa, Children's Hospital of Eastern Ontario; Clinical and Metabolic Genetics (R.J.), and The Centre for Applied Genomics and Program in Genetics and Genome Biology (C.R.M., S.W.S.), The Hospital for Sick Children, Toronto; Neuromuscular and Neuorometabolic Disorders (L.B., M.A.T.), and Department of Ophthalmology (A.R.R.), McMaster University, Hamilton; Department of Molecular Genetics, McLaughlin Centre (C.R.M., S.W.S.), and Division of Neurology, Sunnybrook Health Sciences Centre (L.L.), University of Toronto; Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease (A.E.L., T.A.M.), Toronto Western Hospital, Canada; and Laboratory Genetic Metabolic Diseases (R.J.A.W., S.F.), Academic Medical Center, University of Amsterdam, the Netherlands.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lines
authors.forename: Rebekah
authors.initials: R
authors.lastname: Jobling
authors.forename: Lauren
authors.initials: L
authors.lastname: Brady
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Amadeo R
authors.initials: AR
authors.lastname: Rodriguez
authors.forename: Liesly
authors.initials: L
authors.lastname: Lee
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.forename: Tiago A
authors.initials: TA
authors.lastname: Mestre
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D059472:Exome; D005227:Fatty Acids / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D064029:Peroxisomal Multifunctional Protein-2 / Q000172:deficiency*; D011488:Protein Deficiency / Q000235:genetics* / Q000378:metabolism*; D035781:Siblings
chemical_list: D005227:Fatty Acids; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human