title: A novel ABCD1 mutation detected by next generation sequencing in presumed hereditary spastic paraplegia: A 30-year diagnostic delay caused by misleading biochemical findings.
abstract: OBJECTIVE
  To present a Greek family in which 5 male and 2 female members developed progressive spastic paraplegia. Plasma very long chain fatty acids (VLCFA) were reportedly normal at first testing in an affected male and for over 30 years the presumed diagnosis was hereditary spastic paraplegia (HSP). Targeted next generation sequencing (NGS) was used as a further diagnostic tool.
  
  
  METHODS
  Targeted exome sequencing in the proband, followed by Sanger sequencing confirmation; mutation segregation testing in multiple family members and plasma VLCFA measurement in the proband.
  
  
  RESULTS
  NGS of the proband revealed a novel frameshift mutation in ABCD1 (c.1174_1178del, p.Leu392Serfs*7), bringing an end to diagnostic uncertainty by establishing the diagnosis of adrenomyeloneuropathy (AMN), the myelopathic phenotype of X-linked adrenoleukodystrophy (ALD). The mutation segregated in all family members and the diagnosis of AMN/ALD was confirmed by plasma VLCFA measurement. Confounding factors that delayed the diagnosis are presented.
  
  
  CONCLUSIONS
  This report highlights the diagnostic utility of NGS in patients with undiagnosed spastic paraplegia, establishing a molecular diagnosis of AMN, allowing proper genetic counseling and management, and overcoming the diagnostic delay that can be rarely caused by false negative VLCFA analysis.
authors.affiliation: Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece. Electronic address: gkoutsi2@otenet.gr.
authors.forename: Georgios
authors.initials: G
authors.lastname: Koutsis
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Lynch
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Tucci
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Karadima
authors.affiliation: Neurogenetics Unit, 1st Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece.
authors.forename: Marios
authors.initials: M
authors.lastname: Panas
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D055815:Young Adult
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters
keywords: ABCD1; Adrenomyeloneuropathy; Hereditary spastic paraplegia; Next generation sequencing; Novel mutation; X-linked adrenoleukodystrophy