Luis García-Villarreal1, Andrea Hernández-Ortega2, Ana Sánchez-Monteagudo3, Luis Peña-Quintana2,4, Teresa Ramírez-Lorenzo1, Marta Riaño5, Raquel Moreno-Pérez6, Alberto Monescillo7, Daniel González-Santana2, Ildefonso Quiñones8, Almudena Sánchez-Villegas9, Vicente Olmo-Quintana10, Paloma Garay-Sánchez1, Carmen Espinós3, Jesús M González1, Antonio Tugores11. 1. Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain. 2. Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain. 3. Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. 4. Asociación Canaria Para Investigación Pediátrica. Centro de Investigación Biomédica en Red, Fisiopatología de La Obesidad y Nutrición (CIBER OBN), Instituto Universitario de Investigación en Ciencias Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 5. Department of Clinical Biochemistry and Clinical Analyses, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain. 6. Department of Nursery. Atencion Primaria, Las Palmas de Gran Canaria, Spain. 7. Department of Gastroenterology, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain. 8. Department of Gastroenterology. Hospital, Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain. 9. Department of Public Health, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 10. Department of Pharmacy, Atencion Primaria, Las Palmas de Gran Canaria, Spain. 11. Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain. atugores@yahoo.com.
Abstract
BACKGROUND: Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. METHODS: A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. RESULTS: Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. CONCLUSION: Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.
BACKGROUND:Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. METHODS: A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. RESULTS: Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. CONCLUSION: Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.
Authors: Alison J Coffey; Miranda Durkie; Stephen Hague; Kirsten McLay; Jennifer Emmerson; Christine Lo; Stefanie Klaffke; Christopher J Joyce; Anil Dhawan; Nedim Hadzic; Giorgina Mieli-Vergani; Richard Kirk; K Elizabeth Allen; David Nicholl; Siew Wong; William Griffiths; Sarah Smithson; Nicola Giffin; Ali Taha; Sally Connolly; Godfrey T Gillett; Stuart Tanner; Jim Bonham; Basil Sharrack; Aarno Palotie; Magnus Rattray; Ann Dalton; Oliver Bandmann Journal: Brain Date: 2013-03-21 Impact factor: 13.501
Authors: Peter D Stenson; Matthew Mort; Edward V Ball; Katy Evans; Matthew Hayden; Sally Heywood; Michelle Hussain; Andrew D Phillips; David N Cooper Journal: Hum Genet Date: 2017-03-27 Impact factor: 4.132