title: Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease.
abstract: OBJECTIVE
  3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS).
  
  
  METHODS
  Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals.
  
  
  RESULTS
  Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients' fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals.
  
  
  CONCLUSIONS
  We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient's NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
authors.forename: Ashlee R
authors.initials: AR
authors.lastname: Stiles
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besse
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Appadurai
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
authors.forename: Karen B
authors.initials: KB
authors.lastname: Leydiker
authors.affiliation: Division of Diagnostic Radiology, CHOC Children's, Orange, CA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Cambray-Forker
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Bonnen
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Pediatrics, University of California Irvine, Orange, CA, USA. Electronic address: jabdenur@choc.org.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000378:metabolism; D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D015997:Neonatal Screening; D011379:Prognosis; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D035781:Siblings; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism
chemical_list: C513202:hydroxybutyrylcarnitine; D013869:Thiolester Hydrolases; D002331:Carnitine
keywords: HIBCH deficiency; Hydroxy-C4-carnitine; Leigh syndrome; Newborn screening; Valine metabolism