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Metabolic abnormalities in Williams–Beuren syndrome
  1. María Gabriela Palacios-Verdú1,2,3,
  2. Maria Segura-Puimedon2,3,4,
  3. Cristina Borralleras1,2,3,
  4. Raquel Flores1,2,3,
  5. Miguel Del Campo2,3,5,
  6. Victoria Campuzano1,2,3,
  7. Luis Alberto Pérez-Jurado1,2,3
  1. 1Genetics Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
  2. 2Hospital del Mar Research Institute (IMIM), Barcelona, Spain
  3. 3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
  4. 4Institut für Integrative und Experimentelle Genomik, Universitat zu Lübeck, Lübeck, Germany
  5. 5Area de Medicina Molecular i Genètica, Hospital dew Vall d'Hebron, Barcelona, Spain
  1. Correspondence to Professor Luis Alberto Pérez-Jurado, Genetics Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona 08003, Spain; luis.perez{at}upf.edu

Abstract

Background Williams–Beuren syndrome (WBS, OMIM-194050) is a neurodevelopmental disorder with multisystemic manifestations caused by a 1.55–1.83 Mb deletion at 7q11.23 including 26–28 genes. Reported endocrine and metabolic abnormalities include transient hypercalcaemia of infancy, subclinical hypothyroidism in ∼30% of children and impaired glucose tolerance in ∼75% of adult individuals. The purpose of this study was to further study metabolic alterations in patients with WBS, as well as in several mouse models, to establish potential candidate genes.

Methods We analysed several metabolic parameters in a cohort of 154 individuals with WBS (data available from 69 to 151 cases per parameter), as well as in several mouse models with complete and partial deletions of the orthologous WBS locus, and searched for causative genes and potential modifiers.

Results Triglyceride plasma levels were significantly decreased in individuals with WBS while cholesterol levels were slightly decreased compared with controls. Hyperbilirubinemia, mostly unconjugated, was found in 18.3% of WBS cases and correlated with subclinical hypothyroidism and hypotriglyceridemia, suggesting common pathogenic mechanisms. Haploinsufficiency at MLXIPL and increased penetrance for hypomorphic alleles at the UGT1A1 gene promoter might underlie the lipid and bilirubin alterations. Other disturbances included increased protein and iron levels, as well as the known subclinical hypothyroidism and glucose intolerance.

Conclusions Our results show that several unreported biochemical alterations, related to haploinsufficiency for specific genes at 7q11.23, are relatively common in WBS. The early diagnosis, follow-up and management of these metabolic disturbances could prevent long-term complications in this disorder.

  • Williams-Beuren syndrome
  • WBS murine models
  • Metabolic profile
  • Cholesterol
  • Bilirubin

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