title: Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation.
abstract: BACKGROUND
  Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability.
  
  
  OBJECTIVE
  To update disease-causing mutations and current clinical knowledge of the disease.
  
  
  METHODS
  Genetic and clinical information were obtained from a collection of both unreported and previously reported cases.
  
  
  RESULTS
  We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation.
  
  
  CONCLUSIONS
  Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.
authors.affiliation: Department of Pediatrics, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain.|CIBER OBN, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Peña-Quintana
authors.affiliation: Institute of Human Genetics, University of Freiburg, Freiburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Scherer
authors.affiliation: Department of Pediatrics, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: Curbelo-Estévez
authors.affiliation: Mediteknia Dermatology and Hair Transplant Clinic, Medical Pathology Group, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Jiménez-Acosta
authors.affiliation: Institute of Human Genetics, University of Freiburg, Freiburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain.
authors.forename: F
authors.initials: F
authors.lastname: La Roche
authors.affiliation: Section of Gastroenterology, Hepatology and Nutrition, Metabolopathies Unit Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Meavilla-Olivas
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid, CIBERER, IdiPAZ, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.affiliation: Center for Molecular Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: García-Segarra
authors.affiliation: Programme québécois de dépistage néonatal sanguin, CHU de Québec, and Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Quebec, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Giguère
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Huppke
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Canada.
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
authors.affiliation: Charité University Medical Center, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Mönch
authors.affiliation: Department of Medical Genetics, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: D
authors.initials: D
authors.lastname: Trump
authors.affiliation: Centre de Biologie Est, CHU Lyon, Bron, France.
authors.forename: C
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: Department of Clinical Biochemistry, Royal Victoria Hospital, Belfast, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Trimble
authors.affiliation: Unidad de Nutrición y Metabolopatías, Hospital La Fe, Valencia, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Vitoria-Miñana
authors.affiliation: Department of Pediatrics, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Reyes-Suárez
authors.affiliation: Research Unit, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Ramírez-Lorenzo
authors.affiliation: Research Unit, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-1849-9239
authors.initials: A
authors.lastname: Tugores
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014444:Tyrosine Transaminase / Q000235:genetics; D020176:Tyrosinemias / Q000175:diagnosis* / Q000178:diet therapy / Q000235:genetics*; D055815:Young Adult
chemical_list: D014444:Tyrosine Transaminase
keywords: Richner-Hanhart; TAT; genetics; tyrosinemia