RESUMO
Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.
Assuntos
Carcinoma Hepatocelular/genética , Hidrolases/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Mutação de Sentido Incorreto , Tirosinemias/diagnóstico , Adolescente , Animais , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Heptanoatos/metabolismo , Humanos , Hidrolases/química , Lactente , Cirrose Hepática/complicações , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Linhagem , Análise de Sequência de DNA , Tirosina/metabolismo , Tirosinemias/complicações , Tirosinemias/genéticaRESUMO
BACKGROUND: Celiac disease (CD) is a chronic inflammatory disease of the small intestine triggered by gluten ingestion. The objective of this study is to describe our experience with CD children in Kuwait. METHODS: The records of children with CD seen in the pediatric gastroenterology unit between February 1998 and December 2010 were retrospectively reviewed. Patients were referred because of symptoms or positive CD antibody screening of a high-risk group (type 1 diabetes and Down syndrome). RESULTS: Forty-seven patients were diagnosed: 53% were symptomatic and 47% were identified by screening. The median age at diagnosis was 66 (range 7-189) months. All cases were biopsy-proven except one. The symptomatic patients were significantly younger than those identified following screening (P<0.004). In the whole group, 66% were females and 77% were Kuwaitis; 9% had a positive family history of CD. The estimated cumulative incidence was 6.9/10(5). The median duration of symptoms before diagnosis was 8.5 (range 2-54) months. Failure to thrive was the most common presenting complaint (72%) followed by diarrhea (64%) and abdominal distension (56%). Atypical manifestations were seen in 60% of patients. Underweight and short stature were confirmed in 19% and 17% of patients, respectively. Overweight and obesity were detected in 14% and 6%, respectively. CD serology was based on a combination of antiendomysial and antigliadin antibodies. The median follow up was 24 (range 12-144) months. All patients were commenced on a gluten free diet, but good compliance was only achieved in 78%. CONCLUSION: The low frequency of childhood CD in Kuwait could probably be attributed to either an underestimation of the atypical presentations or failure of proper screening. Also, adherence to a gluten free diet is a major problem in our population.
RESUMO
Primary hyperoxaluria type-1 (PH-1) is a rare autosomal recessive metabolic disorder leading to excessive oxalate production, deposition of calcium oxalate crystals in the kidney, nephrocalcinosis, progressive renal failure and systemic deposition of oxalate (oxalosis). Combined liver and kidney transplantation (LKT), which has been accepted as the treatment of choice for PH-1, has considerably improved patient and graft survival. Herein, we report our experience of three children with PH-1 who underwent combined LKT, with a review of the literature.
Assuntos
Hiperoxalúria Primária/cirurgia , Transplante de Rim/métodos , Transplante de Fígado/métodos , Criança , Pré-Escolar , Consanguinidade , Feminino , Sobrevivência de Enxerto , Humanos , MasculinoRESUMO
Galactosemia is an autosomal recessive disorder with a wide range of clinical abnormalities. Cellular oxidative stress is considered as one of the pathogenic mechanisms of galactosemia. In this study, we examined the activity of NADPH oxidase (NOX), a major superoxide-generating enzyme system, in peripheral blood lymphocytes (PBL) from galactosemia patients. PBL were isolated from galactosemia patients and healthy control subjects and used for cell culture studies and biochemical assays. PBL were cultured in the presence or absence of galactose or galactose-1-phosphate (Gal-1-P), and enzyme activities and/or gene expression of NOX, catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured in the cell homogenates. PBL isolated from galactosemia patients showed significantly reduced (P < 0.01) activities of catalase and GPx; however SOD activity remained unaltered. Galactosemia patients were found to have significantly (P < 0.01) increased levels of malondialdehyde (MDA) in blood lymphocytes. Enzymatic activity of NOX was significantly (P < 0.001) reduced in galactosemia patients; however, Western blotting revealed that NOX-1 protein was not significantly altered. Interestingly, levels of NOX activity in lymphocytes isolated from galactosemia patients significantly increased but remained subnormal when cultured in galactose-deficient medium for two weeks, indicating a galactose-mediated inhibition of NOX. Lymphocytes isolated from control subjects were found to have significantly (P < 0.01) reduced NOX activity when cultured in the presence of galactose or Gal-1-P for two weeks. These results show that galactose-induced cellular oxidative stress is not NOX mediated. However, impairment of the NOX system might be responsible for some of the clinical complications in galactosemia patients.
Assuntos
Galactosemias/sangue , Galactosemias/enzimologia , NADPH Oxidases/sangue , Antioxidantes/metabolismo , Western Blotting , Estudos de Casos e Controles , Separação Celular , Células Cultivadas , Pré-Escolar , Galactose/farmacologia , Galactosefosfatos/metabolismo , Galactosefosfatos/farmacologia , Glucosefosfato Desidrogenase/metabolismo , Humanos , Lactente , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , Linfócitos/patologia , Malondialdeído/metabolismo , NADPH Oxidase 1 , NADPH Oxidases/metabolismo , Nitritos/metabolismo , Fosfoproteínas/metabolismoRESUMO
OBJECTIVES: In this study, we examined the activities of key peroxisomal enzymes in peripheral blood lymphocytes (PBLs) of pediatric liver transplant patients. SUBJECTS AND METHODS: Venous blood was drawn from 14 patients aged 5-16 years on FK-506 treatment and 18 healthy subjects for isolation of lymphocytes. ß-Oxidation of very long chain fatty acids (VLCFAs) and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), NADPH oxidase (NOX), catalase and peroxisomal enzyme acyl CoA oxidase (ACO) were measured in cellular homogenates. Levels of malondialdehyde (MDA) were measured as an index of lipid peroxidation. Protein content and mRNA levels of catalase, peroxisomal membrane protein-70 (PMP-70) and ACO were measured using Western blotting and PCR techniques. RESULTS: PBLs isolated from liver transplant patients showed significantly (p < 0.01) increased levels (226.9 ± 24.5 µmol/mg protein) of MDA as compared to the levels in controls (162.8 ± 19.6 µmol/mg protein), whereas enzyme activities of SOD and NOX remained unaltered in patients' cells. Enzyme activities of catalase and GPx were markedly (p < 0.01) decreased in cells isolated from liver transplant patients. ACO activity and ß-oxidation of VLCFAs in PBLs from liver transplant patients were however found to be significantly increased by 38 and 52% respectively when compared with controls. Gene expression of PMP-70 and ACO was also significantly increased (p < 0.01) in PBLs of patients. CONCLUSION: Our results clearly showed that peroxisomal metabolic activities are markedly altered in lymphocytes of liver transplant patients and might contribute to the development of cellular oxidative stress.
Assuntos
Peroxidação de Lipídeos , Transplante de Fígado/efeitos adversos , Fígado/metabolismo , Estresse Oxidativo , Pediatria , Peroxissomos/metabolismo , Adolescente , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Imunossupressores , Lactente , Fígado/enzimologia , Linfócitos , Masculino , NADPH Oxidases/metabolismo , Fatores de RiscoRESUMO
BACKGROUND/AIMS: Inflammatory bowel disease (IBD) was previously thought a rare disease among children in Kuwait since most diarrhea cases were attributed to infections. In the past few years we observed an increase in the number of patients presenting with IBD. In this study we aimed to determine the epidemiology of IBD among children in the State of Kuwait. PATIENTS AND METHODS: The charts of all children with IBD who were referred to the pediatric gastroenterology unit during the period February 1998 to January 2008 were retrospectively reviewed. RESULTS: Out of a total of 130 children with IBD, 92 (71%) had Crohn's disease, 36 (28%) had ulcerative colitis and two (1%) had indeterminate colitis. The estimated annual incidence for IBD was 2.16/10 5 /year. The age range was nine months-15 years (median: 11 years). Fifty-three percent of all patients were females and 77% were Kuwaiti nationals. Positive family history was found in 23%. The commonest presenting symptoms were abdominal pain (87%) and diarrhea (82%). Failure to thrive was detected in 35% and short stature in 20% at presentation. The ileocolonic region was the most common presentation site affected in Crohn's patients and pancolitis was the commonest in ulcerative colitis. CONCLUSION: Inflammatory bowel disease is not uncommon in our children. We found no differences regarding disease presentation and clinical features compared to the Western world.
Assuntos
Doenças Inflamatórias Intestinais/epidemiologia , Adolescente , Distribuição por Idade , Idade de Início , Criança , Pré-Escolar , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/epidemiologia , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Diagnóstico Diferencial , Endoscopia Gastrointestinal , Feminino , Humanos , Incidência , Lactente , Doenças Inflamatórias Intestinais/diagnóstico , Kuweit/epidemiologia , Masculino , Estudos Retrospectivos , Distribuição por SexoRESUMO
Mutations of the EPCAM gene have been recently identified in Congenital Tufting Enteropathy (CTE), a severe autosomal recessive gastrointestinal insufficiency of childhood requiring parenteral nutrition and occasionally intestinal transplantation. Studying seven multiplex consanguineous families from the Arabic peninsula (Kuwait and Qatar) we found that most patients were homozygote for a c.498insC mutation in exon 5. The others carried a novel mutation IVS4-2AâG. Both mutations were predicted to truncate the C-terminal domain necessary to anchorage of EPCAM at the intercellular membrane. Consistently, immunohistochemistry of intestinal biopsies failed to detect the EPCAM protein at the intercellular membrane level. The c.498insC mutation was found on the background of a minimal common haplotype of 473kb suggesting a very old founder effect (5000-6000 yrs).
Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Efeito Fundador , Enteropatias/genética , Antígenos de Neoplasias/metabolismo , Sequência de Bases , Moléculas de Adesão Celular/metabolismo , Consanguinidade , Análise Mutacional de DNA , Molécula de Adesão da Célula Epitelial , Éxons/genética , Saúde da Família , Feminino , Genótipo , Haplótipos , Humanos , Imuno-Histoquímica , Enteropatias/congênito , Mucosa Intestinal/metabolismo , Intestinos/patologia , Kuweit , Masculino , Mutação , Linhagem , CatarRESUMO
BACKGROUND: Hepatitis C is endemic in the Middle East where genotype 4 accounts for most cases. Data regarding the safety and efficacy of peginterferon plus ribavirin for the treatment of chronic hepatitis C in children and adolescents, particularly those infected with genotype 4 is limited. Aim. To evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in adolescents chronically infected with HCV genotype 4. PATIENTS AND METHODS: In an open-labeled, uncontrolled pilot study, 12 adolescents (range14-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 mg/kg body weight once per week plus oral ribavirin (15 mg/kg/day) for 48 weeks. Patients were followed for 24 weeks post-treatment. All patients had biopsy proven hepatitis without cirrhosis. RESULTS: One patient withdrew from the study due to developing insulin dependent diabetes mellitus 4 months into treatment. The remaining patients received at least 80% of the prescribed dose of pegylated interferon and ribavirin. Sustained viral response was observed in 9 patients (75%). The most frequent side effect was flu like illness which was reported in all patients. Sixty seven percent had leucopenia, but only one individual required adjuvant therapy with hematologic growth factor. Four patients had anemia requiring ribavirin dose reduction. One patient developed hypothyroidism. CONCLUSION: Combination treatment of peginterferon alfa-2b with ribavirin appears to be efficacious and relatively safe in adolescents with chronic hepatitis C genotype 4.B.