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Artigo em Inglês | MEDLINE | ID: mdl-32740538


OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.

J Inherit Metab Dis ; 43(6): 1254-1264, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32557644


5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH (ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA-riboside in urine. AICA-ribosiduria had been reported in only one individual, 15 years ago. In this article, we report three novel cases of AICA-ribosiduria from two independent families, with two novel pathogenic variants in ATIC. We also provide a clinical update on the first patient. Based on the phenotypic features shared by these four patients, we define AICA-ribosiduria as the syndromic association of severe-to-profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features were observed in all four cases, especially neonatal/infancy coarse facies with upturned nose. Early-onset epilepsy is frequent and can be pharmacoresistant. Less frequently observed features are aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis. Alteration of the transformylase activity of ATIC might result in a more severe impairment than the alteration of the cyclohydrolase activity. Data from literature points toward a cytotoxic mechanism of the accumulated AICA-riboside.

Hum Mutat ; 38(12): 1660-1665, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28945313


Exocrine pancreatic insufficiency (EPI) is rare in children, with most if not all cases occurring as part of syndromic conditions such as cystic fibrosis and Shwachman-Diamond syndrome. Here we report two cases, both presenting with severe EPI around 5 months of age. Characterized by diffuse pancreatic lipomatosis, they otherwise exhibited no remarkable deficiencies in other organs. Novel non-identical homozygous variants (a deletion removing the entire SPINK1 gene and an insertion of a full-length inverted Alu element into the 3'-untranslated region of the SPINK1 gene) resulting in the complete functional loss of the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) were identified in each patient. Having correlated our findings with current knowledge of SPINK1's role in exocrine pancreas pathophysiology, we propose that complete and partial functional losses of the SPINK1 gene are associated with quite distinct phenotypes, the former causing a new pediatric disease entity of severe infantile isolated EPI.

Doenças da Medula Óssea/genética , Fibrose Cística/genética , Insuficiência Pancreática Exócrina/genética , Lipomatose/genética , Inibidor da Tripsina Pancreática de Kazal/genética , Elementos Alu/genética , Doenças da Medula Óssea/diagnóstico por imagem , Doenças da Medula Óssea/fisiopatologia , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/fisiopatologia , Insuficiência Pancreática Exócrina/diagnóstico por imagem , Insuficiência Pancreática Exócrina/fisiopatologia , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Lipomatose/diagnóstico por imagem , Lipomatose/fisiopatologia , Imagem por Ressonância Magnética , Mutagênese Insercional , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/genética , Pancreatopatias/fisiopatologia , Fenótipo , Deleção de Sequência , Síndrome de Shwachman-Diamond , Inibidor da Tripsina Pancreática de Kazal/metabolismo
Clin Res Hepatol Gastroenterol ; 40(6): e65-e67, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27720179


Congenital short-bowel syndrome (CSBS) is a rare neonatal pathology associated with poor prognosis and high mortality rate. We describe a newborn presenting CSBS intestinal malrotation and chronic intestinal pseudo-obstruction syndrome (CIPS), compound heterozygous for two previously unreported heterozygous mutations in Coxsackie and adenovirus receptor-like membrane protein (CLMP) gene, one in intron 1 (c.28+1G>C), the other on exon 4 (c502C>T, p.R168X). Both mutations are predicted to be pathogenic, leading to impaired splicing and the appearance of a premature stop codon, respectively. Our case is remarkable in that it concerns two heterozygous truncating mutations associated with a good clinical prognosis with a favorable cerebral and gastrointestinal outcome and a substantial enteral input at 8 months of age, despite a small intestine measuring only 35cm.

Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Pseudo-Obstrução Intestinal/genética , Mutação , Éxons , Feminino , Heterozigoto , Humanos , Recém-Nascido , Volvo Intestinal/genética , Íntrons
Am J Hum Genet ; 94(3): 385-94, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24581742


Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1ß1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.

Acalasia Esofágica/metabolismo , Guanilato Ciclase/genética , Guanilato Ciclase/fisiologia , Doença de Moyamoya/metabolismo , Óxido Nítrico/química , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/fisiologia , Adolescente , Adulto , Plaquetas/metabolismo , Criança , Pré-Escolar , GMP Cíclico/metabolismo , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Mutação , Óxido Nítrico/metabolismo , Linhagem , Adesividade Plaquetária , Agregação Plaquetária , Guanilil Ciclase Solúvel , Adulto Jovem