Eduardo Couchonnal1, Sophie Bouchard2, Thomas Damgaard Sandahl3, Cecile Pagan4, Laurence Lion-François5, Olivier Guillaud5, Dalila Habes6, Dominique Debray7, Thierry Lamireau8, Pierre Broué9, Alexandre Fabre10, Claire Vanlemmens11, Rodolphe Sobesky12, Frederic Gottrand13, Laure Bridoux-Henno14, Abdelouahed Belmalih5, Aurelia Poujois15, Anne Sophie Brunet16, Alain Lachaux17, Muriel Bost18. 1. Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany. Electronic address: eduardo.couchonnal-bedoya@chu-lyon.fr. 2. Claude Bernard Lyon 1 University Lyon, France. 3. European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark. 4. Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France. 5. Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany. 6. European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre, France. 7. European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Inserm U1193, Hepatinov, University of Paris Saclay, Orsay, France. 8. Children's Hospital, Paediatric Gastroenterology Unit, Bordeaux, France. 9. Children University Hospital, Metabolic Disease Department, Toulouse, France. 10. APH, Timone Enfant, Service de Pédiatrie Multidisciplinaire, Marseille, France; Aix Marseille Univ, INSERM, MMG, Marseille, France. 11. University Hospital of Besancon, Paediatric Gastroenterology Unit, Besacon, France. 12. European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Paul Brousse Hospital, Hepatobiliary Centre, Hepatobiliary Centre, France. 13. Univ- Lille, CHU Lille, UMR1286 Department of Pediatric Gastroenterology Hepatology and Nutrition, Lille, France. 14. CHU Rennes, Department of Pediatric Gastroenterology, Rennes, France. 15. European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; French National Rare Disease Reference Centre "Wilson's Disease and Other Copper-related Rare Diseases", Rothschild Foundation Hospital, Neurology Department, Paris, France. 16. Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France. 17. Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Claude Bernard Lyon 1 University Lyon, France. 18. Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany; Department of Biochemistry and Molecular Biology, LBMMS, Hospices Civils de Lyon, France.
Abstract
BACKGROUND/AIM: The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS: Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS: Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION: p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.
BACKGROUND/AIM: The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS: Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS: Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION: p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.
Authors: Miguel Trindade; Joana Carvalho; Mariana Barosa; João Serôdio; Ricardo Oliveira; Ana Furtado; Catarina Favas; José Delgado Alves Journal: Eur J Case Rep Intern Med Date: 2022-01-25