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Hospital de Órbigo, Spain

Alcalde-Martin C.,Hospital Universitario Rio Hortega | Muro-Tudelilla J.M.,Hospital Universitario Rio Hortega | Cancho-Candela R.,Hospital Universitario Rio Hortega | Gutierrez-Solana L.G.,Hospital Infantil Universitario Nino Jesus | And 4 more authors.
European Journal of Medical Genetics | Year: 2010

Hunter syndrome (mucopolysaccharidosis type II [MPS II], OMIM309900) is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulphatase, resulting in accumulation of glycosaminoglycans (GAGs), multisystem organ failure and early death. Enzyme replacement therapy (ERT) with idursulfase is commercially available since 2007. Early access programs were established since 2005. However, limited information on the effects of ERT in young children is available to date. The aim of this analysis was therefore to determine the effects of ERT on patients younger than 5 years of age. We report data from six Spanish patients with confirmed Hunter syndrome who were younger than 5 years at the start of ERT, and had been treated with weekly intravenous infusions of idursulfase between 6 and 14 months. Baseline and treatment data were obtained from the Hunter Outcome Survey (HOS). HOS is an international database of MPS II patients on ERT or candidates to be treated, that collects data in a registry manner. HOS is supported by Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA). At baseline, all patients showed neurological abnormalities, including ventriculomegaly, hydrocephaly, cerebral atrophy, perivascular changes and white matter lesions. Other signs and symptoms included thoracic deformity, otitis media, joint stiffness and hepatosplenomegaly, demonstrating that children under 5 years old can also be severely affected. ERT reduced urinary GAG levels, and reduced spleen (n = 2) and liver size (n = 1) after only 8 months. Height growth was maintained within the normal range during ERT. Joint mobility either stabilized or improved during ERT. In conclusion, this case series confirms the early onset of signs and symptoms of Hunter syndrome and provides the first evidence of ERT beneficial effects in patients less than 5 years of age. Similar efficacy and safety profiles to those seen in older children can be suggested, although further studies including a direct comparison with older patients would still be required. © 2010 Elsevier Masson SAS. Source

Albuquerque D.,University of Coimbra | Estevez M.N.,Unit of Genetic Paediatrics | Vibora P.B.,Endocrinologist Service | Giralt P.S.,Endocrinologist Service | And 11 more authors.
Annals of Human Genetics | Year: 2014

We screened for mutations in the MC4R and LEPR genes and investigated the genotype-phenotype correlation in obese individuals belonging to families with evident hereditary patterns of severe and early-onset obesity among the Iberian population. A total of 202 unrelated and severely obese patients since childhood, were enrolled in the study. Bidirectional sequencing of the MC4R gene was carried out in all patients; the LEPR gene was sequenced in 15 individuals based on additional clinical signals. Segregation analysis and/or genotype-phenotype description was performed for subjects with the new mutations and with presumably functional variants. Ten MC4R gene mutations were identified in the heterozygous state in 10 patients. Mutations p.R147G and p.G323E are new and mutations p.R7H, p.G32E, p.H76R, p.V103I, p.S127L, p.T150I, p.I251L and p.G252S were previously described. A new dinucleotide insertion -77_-76insTA in the promoter region of the LEPR gene was found in the heterozygous state in one patient. The new p.R147G and the previously published p.R7H, p.S127L, p.T150I and p.G252S MC4R mutations, cosegregate with obesity in our patients and were predicted to be deleterious. For the novel MC4R p.G323E and LEPR -77_-76insTA gene mutations, the genotype-phenotype correlation and bioinformatic analysis did not clarify whether these mutations are indeed implicated in obesity. © 2014 John Wiley & Sons Ltd/University College London. Source

Rodriguez-Lopez R.,Genetics Unit | Perez J.M.C.,Genetics Unit | Balsera A.M.,Genetics Unit | Rodriguez G.G.,University of Extremadura | And 9 more authors.
Gene | Year: 2013

Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4. Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926-36576388) x1 dn in a child with 3. years and 4. months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80. kb of exon 1 of BDNF. The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor (BDNF) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the haploinsufficiency of the BDNF gene could constitute an adequate model to study in depth their effects. © 2012 Elsevier B.V. Source

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