RESUMO
PURPOSE: Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency. METHODS: This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023. RESULTS: We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM_138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency. CONCLUSION: GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.
Assuntos
Galactose , Galactosemias , Fenótipo , Humanos , Japão/epidemiologia , Galactosemias/genética , Galactosemias/epidemiologia , Feminino , Masculino , Pré-Escolar , Lactente , Estudos Retrospectivos , Criança , Adolescente , Adulto , Inquéritos e Questionários , Mutação/genética , Genótipo , Catarata/genética , Catarata/epidemiologia , Catarata/sangueRESUMO
BACKGROUND: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. METHODS: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. RESULTS: Sixty-six patients in 48 families (33 males/females; 0-59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype-phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. CONCLUSION: This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.
Assuntos
Anormalidades Múltiplas , Síndrome de Ehlers-Danlos , Anormalidades Múltiplas/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Fenótipo , Sulfotransferases/genéticaRESUMO
Patients with citrin deficiency during the adaptation/compensation period exhibit diverse clinical features and have characteristic diet of high protein, high fat, and low carbohydrate. Japanese cuisine typically contains high carbohydrate but evaluation of diet of citrin-deficient patients in 2008 showed a low energy intake and a protein:fat:carbohydrate (PFC) ratio of 19:44:37, which indicates low carbohydrate consumption rate. These findings prompted the need for diet intervention to prevent the adult onset of type II citrullinemia (CTLN2). Since the publication of the report about 10 years ago, patients are generally advised to eat what they wish under active dietary consultation and intervention. In this study, citrin-deficient patients and control subjects living in the same household provided answers to a questionnaire, filled-up a maximum 6-day food diary, and supplied physical data and information on medications if any. To study the effects of the current diet, the survey collected data from 62 patients and 45 controls comparing daily intakes of energy, protein, fat, and carbohydrate. Food analysis showed that patient's energy intake was 115% compared to the Japanese standard. The confidence interval of the PFC ratio of patients was 20-22:47-51:28-32, indicating higher protein, higher fat and lower carbohydrate relative to previous reports. The mean PFC ratio of female patients (22:53:25) was significantly different from that of male patients (20:46:34), which may explain the lower frequency of CTLN2 in females. Comparison of the present data to those published 10 years ago, energy, protein, and fat intakes were significantly higher but the amount of carbohydrate consumption remained the same. Regardless of age, most patients (except for adolescents) consumed 100-200 g/day of carbohydrates, which met the estimated average requirement of 100 g/day for healthy individuals. Finally, patients were generally not overweight and some CTLN2 patients were underweight although their energy intake was higher compared with the control subjects. We speculate that high-energy of a low carbohydrate diet under dietary intervention may help citrin-deficient patients attain normal growth and prevent the onset of CTLN2.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Citrulinemia/dietoterapia , Metabolismo Energético/fisiologia , Transportadores de Ânions Orgânicos/genética , Adolescente , Adulto , Proteínas de Ligação ao Cálcio/deficiência , Metabolismo dos Carboidratos/fisiologia , Carboidratos/administração & dosagem , Citrulinemia/epidemiologia , Citrulinemia/metabolismo , Citrulinemia/patologia , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/metabolismo , Ingestão de Alimentos/fisiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Proteínas de Transporte da Membrana Mitocondrial/genética , Transportadores de Ânions Orgânicos/deficiência , Proteínas/administração & dosagem , Proteínas/metabolismoRESUMO
IMPORTANCE: Sapropterin hydrochloride, a natural coenzyme (6R-tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin-responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin-responsive hyperphenylalaninemia. OBSERVATIONS: It is recommended that tetrahydrobiopterin-responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels. CONCLUSIONS AND RELEVANCE: If tetrahydrobiopterin-responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required.
Assuntos
Biopterinas/análogos & derivados , Fenilcetonúrias , Biopterinas/uso terapêutico , Feminino , Humanos , Japão , Fenótipo , Fenilalanina , Fenilalanina Hidroxilase , Fenilcetonúria Materna/prevenção & controle , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/terapia , GravidezRESUMO
For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible. If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used. Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association. Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status. In the future, it will be necessary to create a system to supply an exclusive human milk-based diet (EHMD), consisting of human milk with the addition of a human milk-derived human milk fortifier, to preterm and very low birthweight infants.
Assuntos
Nutrição Enteral/métodos , Recém-Nascido de muito Baixo Peso , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Recém-Nascido Prematuro , Japão , Bancos de Leite Humano/normas , Leite Humano , MãesRESUMO
Identification of the genes responsible for adult-onset type II citrullinemia (CTLN2) and citrin protein function have enhanced our understanding of citrin deficiency. Citrin deficiency is characterized by 1) neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); 2) adaptation/compensation stage with unique food preference from childhood to adulthood; and 3) CTLN2. The treatment of NICCD aims to prevent the progression of cholestasis, and it includes medium chain triglycerides (MCT) milk and lactose-free milk, in addition to medications (e.g., vitamin K2, lipid-soluble vitamins and ursodeoxycholic acid). Spontaneous remission around the age of one is common in NICCD, though prolonged cholestasis can lead to irreversible liver failure and may require liver transplantation. The adaptation/compensation stage (after one year of age) is characterized by the various signs and symptoms such as hypoglycemia, fatty liver, easy fatigability, weight loss, and neuropsychiatric symptoms. Some poorly-controlled patients show failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Diet therapy is the key in the adaptation/compensation stage. Protein- and fat-rich diet with a protein: fat: carbohydrate ratio being 15-25%: 40-50%: 30-40% along with the appropriate energy intake is recommended. The use of MCT oil and sodium pyruvate is also effective. The toxicity of carbohydrate is well known in the progression to CTLN2 if the consumption is over a long term or intense. Alcohol can also trigger CTLN2. Continuous intravenous hyperalimentation with high glucose concentration needs to be avoided. Administration of Glyceol® (an osmotic agent containing glycerol and fructose) is contraindicated. Because the intense treatment such as liver transplantation may become necessary to cure CTLN2, the effective preventative treatment during the adaptation/compensation stage is very important. At present, there is no report of a case with patients reported having the onset of CTLN2 who are on the diet therapy and under the appropriate medical support during the adaptation/compensation stage.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Citrulinemia/dietoterapia , Citrulinemia/prevenção & controle , Transportadores de Ânions Orgânicos/genética , Adulto , Colestase/etiologia , Fígado Gorduroso/etiologia , Humanos , Recém-Nascido , Transplante de Fígado , Proteínas de Transporte da Membrana Mitocondrial/genética , Triglicerídeos/sangue , Vitaminas/uso terapêuticoRESUMO
BACKGROUND: The amino acid l-citrulline is used as a therapeutic agent for urea cycle disorders (UCD) including ornithine transcarbamylase deficiency (OTCD), carbamoyl phosphate synthetase I deficiency (CPSD), and N-acetylglutamate synthase deficiency. There are few reports, however, on the use of l-citrulline in Japan and little consensus regarding the effects of l-citrulline. METHODS: We conducted a questionnaire survey of patients undergoing l-citrulline treatment for a UCD to evaluate the current status of this therapy. The survey included patient background, details of l-citrulline treatment, clinical examination data, treatment, frequency of vomiting, and liver transplantation. RESULTS: We retrospectively investigated 43 questionnaire respondents (OTCD, n = 33; CPSD, n = 10). The weight of male OTCD patients improved by +0.79 SD, and the ammonia level decreased by a mean of 44.3 µmol/L in all patients. The protein intake of all patients and of male OTCD patients increased by 0.14 g/kg/day and 0.17 g/kg/day, respectively. CONCLUSIONS: l-Citrulline effectively reduced ammonia level, increased protein intake, and improved weight gain in UCD patients. l-Citrulline should be considered a standard therapy in OTCD and CPSD patients.
Assuntos
Citrulina/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Dieta , Proteínas Alimentares , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Japão , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Aumento de PesoRESUMO
Kleine-Levin syndrome is a rare sleep disorder of unknown etiology characterized by repetitive episodes of hypersomnia between asymptomatic periods. We report the case of a 13-year-old girl who presented with drowsiness triggered by influenza A as the first episode. Magnetic resonance imaging (MRI) on day 6 showed transient reduction of diffusion in the corpus callosum splenium. The patient was diagnosed with encephalopathy with a reversible splenial lesion. The symptoms resolved after 10 days, but additional episodes of hypersomnia lasting 5-10 days occurred 1, 5, 6, 11, 13, and 25 months after the first episode. MRI during hypersomnia indicated no lesions, and sleep duration and cognition were normal between episodes. The patient was diagnosed with Kleine-Levin syndrome. Electroencephalographic and clinical findings during the first episode were similar to those during the other episodes. Encephalopathy with a splenial lesion and Kleine-Levin syndrome may have similar pathological mechanisms causing a disturbance in consciousness.
Assuntos
Corpo Caloso/diagnóstico por imagem , Encefalite Viral/complicações , Vírus da Influenza A , Influenza Humana/complicações , Síndrome de Kleine-Levin/etiologia , Imageamento por Ressonância Magnética , Neuroimagem , Adolescente , Encefalopatias , Encefalite Viral/diagnóstico por imagem , Feminino , Humanos , Influenza Humana/diagnóstico , Síndrome de Kleine-Levin/diagnóstico por imagemRESUMO
Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by repetitive seizures during the acute and chronic phases and has a poor neurological outcome. Burst-suppression coma via continuous i.v. infusion of a short-acting barbiturate is used to terminate refractory seizures, but the severe side-effects of short-acting barbiturates are problematic. We report on a 9-year-old boy with AERRPS who was effectively treated with very-high-dose phenobarbital (VHDPB) combined with intermittent short-acting barbiturates. VHDPB side-effects were mild, especially compared with those associated with continuous i.v. infusion of short-acting barbiturates (dosage, 40-75 mg/kg/day; maximum blood level, 290 µg/mL). Using VHDPB as the main treatment, short-acting barbiturates were used intermittently and in small amounts. This is the first report to show that VHDPB, combined with intermittent short-acting barbiturates, can effectively treat AERRPS. After treatment, convulsions were suppressed and daily life continued, but intellectual impairment and high-level dysfunction remained.
Assuntos
Barbitúricos/administração & dosagem , Encefalite/tratamento farmacológico , Fenobarbital/administração & dosagem , Convulsões/tratamento farmacológico , Doença Aguda , Anticonvulsivantes/administração & dosagem , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Eletroencefalografia , Encefalite/complicações , Encefalite/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Convulsões/diagnóstico , Convulsões/etiologiaRESUMO
Zellweger syndrome, one of the peroxisome biogenesis disorders, is an autosomal recessive disease caused by mutations in PEX genes. It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. PEX14 is the 13th PEX gene responsible for peroxisome biogenesis disorders. Thus far, only two patients with PEX14 deficiency have been reported. Here, we report the first case of a Japanese patient with a PEX14 mutation who showed severe hypotonia, psychomotor retardation, demyelination, and developed rickets at the age of 5 months. An increased excretion of 3,6-epoxydicarboxylic acids leads to the diagnosis of Zellweger syndrome and a mutation analysis of PEX14 revealed a homozygous mutation of c.538C>T (p.Q180X). The patient survived for a prolonged period of time but died of liver failure at the age of 46 months.
Assuntos
DNA/genética , Proteínas de Membrana/genética , Mutação , Proteínas Repressoras/genética , Síndrome de Zellweger/genética , Análise Mutacional de DNA , Evolução Fatal , Humanos , Recém-Nascido , Japão , Masculino , Proteínas de Membrana/metabolismo , Proteínas Repressoras/metabolismo , Síndrome de Zellweger/metabolismoRESUMO
OBJECTIVE: To assess the safety and efficacy of tetrahydrobiopterin therapy with sapropterin to treat tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency in children aged <4 years compared with those aged ≥4 years. STUDY DESIGN: We analyzed a longitudinal follow-up study conducted in all patients with BH4-responsive PAH deficiency throughout Japan. At the end of 2011, 43 patients were receiving sapropterin, of whom 21 were aged <4 years at the initiation of treatment. The starting dose of sapropterin was ≥10 mg/kg/day in 11 of these 21 patients. The duration of follow-up was ≥4 years in 6 of those 11 patients; 3 of these 6 were followed for ≥10 years. Nine patients were receiving sapropterin monotherapy at the end of 2011. RESULTS: Serum phenylalanine level was maintained within the recommended optimal control range in all 21 patients who started sapropterin treatment before age 4 years. Only 1 nonserious adverse drug reaction occurred, an elevated alanine aminotransferase level in 1 patient. No significant abnormal behavior related to nerve disorders was reported. CONCLUSION: Sapropterin therapy initiated before age 4 years was effective in maintaining serum phenylalanine level within the favorable range and was safe in Japanese patients with BH4-responsive PAH deficiency.
Assuntos
Biopterinas/análogos & derivados , Óxido Nítrico Sintase/uso terapêutico , Fenilcetonúrias/tratamento farmacológico , Adolescente , Biopterinas/efeitos adversos , Biopterinas/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Óxido Nítrico Sintase/efeitos adversos , Resultado do TratamentoRESUMO
Citrin-deficient children and adolescents between adult-onset type II citrullinemia and neonatal intrahepatic cholestasis by citrin deficiency do not have clear clinical features except for unusual diet of high-fat, high-protein, and low-carbohydrate food. The aims of the present study are to characterize fatigue and quality of life (QOL) in citrin-deficient patients during adaptation and compensation stage, and to define the relationship between fatigue and QOL. The study subjects were 55 citrin-deficient patients aged 1-22years (29 males) and 54 guardians. Fatigue was evaluated by self-reports and proxy-reports of the PedsQL Multidimensional Fatigue Scale. QOL was evaluated by the PedsQL Generic Core Scales. Both scale scores were significantly lower in child self-reports (p<0.01 and p<0.05, respectively) and parent proxy-reports (p<0.01 and p<0.01, respectively) than those of healthy children. Citrin-deficient patients with scores of 50 percentile or less of healthy children constituted 67.5% of the sample for the Fatigue Scale and 68.4% for the Generic Core Scales. The PedsQL Fatigue Scale correlated with the Generic Core Scales for both the patients (r=0.56) and parents reports (r=0.71). Assessments by the patients and their parents showed moderate agreement. Parents assessed the condition of children more favorably than their children. The study identified severe fatigue and impaired QOL in citrin-deficient patients during the silent period, and that such children perceive worse fatigue and poorer QOL than those estimated by their parents. The results stress the need for active involvement of parents and medical staff in the management of citrin-deficient patients during the silent period.
Assuntos
Adaptação Fisiológica , Metabolismo dos Carboidratos , Citrulinemia/metabolismo , Citrulinemia/patologia , Fadiga/metabolismo , Adolescente , Proteínas de Ligação ao Cálcio/deficiência , Criança , Pré-Escolar , Citrulinemia/terapia , Dieta Hiperlipídica , Fadiga/patologia , Fadiga/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transportadores de Ânions Orgânicos/deficiência , Qualidade de Vida , Adulto JovemRESUMO
Many reports have been published on the long-term outcome and treatment of hepatic glycogen storage diseases (GSDs) overseas; however, none have been published from Japan. We investigated the clinical manifestations, treatment, and prognosis of 127 hepatic GSD patients who were evaluated and treated between January 1999 and December 2009. A characteristic genetic pattern was noted in the Japanese GSD patients: most GSD Ia patients had the g727t mutation, and many GSD Ib patients had the W118R mutation. Forty-one percent (14/34) of GSD Ia patients and 18% (2/11) of GSD Ib patients of ages î¶13 years 4 months had liver adenoma. Among subjects aged 10 years, 19% (7/36) of the GSD Ia patients and none of the GSD Ib patients had renal dysfunction. The mean height of male GSD Ia patients aged î¶18 years was 160.8±10.6 cm (n=14), and that of their female counterparts was 147.8±3.80 cm (n=9). Patients with hepatic GSDs develop a variety of symptoms but can survive in the long term by diet therapy, corn starch treatment and supportive care. Liver transplantation for hepatic GSDs is an important treatment strategy and can help improve the patients'quality of life.
Assuntos
Doença de Depósito de Glicogênio/epidemiologia , Adolescente , Adulto , Fatores Etários , Idade de Início , Estatura , Criança , Pré-Escolar , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/terapia , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Transplante de Fígado , Masculino , Prognóstico , Adulto JovemRESUMO
Organic acidemias (OAs) are rare inborn errors of metabolism. The clinical presentations of methylmalonic acidemia (MMA) and propionic acidemia (PA) in Japan have not yet been examined in detail. We aimed to investigate the clinical presentations of OAs in Japan and evaluate current therapies for improving long-term outcomes, especially in MMA and PA cases. Questionnaires were sent to 928 institutions in 2009 inquiring about OAs, and secondary questionnaires were sent to those who confirmed that they had diagnosed and/or treated such cases; 119 cases were eventually included for analysis. In Japan, the majority of OAs was MMA, which was associated with a high mortality rate. The survival rates at 20 years of age in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA and PA patients were 69.8%, 94.4% and 95.8%, respectively. Factors associated with mortality in MMA were failure to thrive, hypoglycemia and pancreatitis. Factors associated with mental retardation in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA, and PA were seizure and liver dysfunction, seizure and failure to thrive, and failure to thrive, respectively. We advocated that avoiding failure to thrive due to too restricted protein diet, hypoglycemia and pancreatitis associated with mortality lead to improve outcome, especially in vitamin B12-unresponsive MMA patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Acidemia Propiônica/tratamento farmacológico , Vitamina B 12/uso terapêutico , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Acidemia Propiônica/mortalidade , Taxa de Sobrevida , Adulto JovemRESUMO
Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.
Assuntos
Exoma , Ligação Genética , Bócio/genética , Análise de Sequência de DNA/métodos , Sequência de Aminoácidos , Povo Asiático/genética , Estudos de Casos e Controles , Clonagem Molecular , Hipotireoidismo Congênito/genética , Bases de Dados Genéticas , Feminino , Frequência do Gene , Heterogeneidade Genética , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Japão , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de SequênciaRESUMO
BACKGROUND: Rotavirus is a leading worldwide cause of acute gastroenteritis in young children. This retrospective hospital-based study assessed the burden of rotavirus gastroenteritis in children younger than 6 years in Japan. METHODS: Children admitted to eight hospitals for acute gastroenteritis between 2008 and 2009 were identified from hospital admission databases. Diagnosis of acute gastroenteritis/rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis was confirmed based on either the International Classification of Diseases and Related Health Problems 10th revision (ICD10) codes (intestinal infectious diseases [AA00-AA09] and rotavirus gastroenteritis [A08.0]) or from rapid rotavirus diagnostic test results. RESULTS: Of 13,767 hospitalized children, 11.9% (1,644), 4.8% (665) and 0.6% (81) were diagnosed with acute gastroenteritis, rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis, respectively. Among acute gastroenteritis hospitalizations, 40.5% (665/1,644; ICD10 and rapid test) and 57.7% (645/1,118; rapid test only) were confirmed as rotavirus positive. Of 1,563 children with community-acquired acute gastroenteritis, 584 (37.4%) cases were confirmed as rotavirus positive. The median durations of hospitalization for all and community-acquired rotavirus gastroenteritis were 5.0 days (range: 2.0-133.0 days) and 5.0 days (range: 2.0-34.0 days), respectively. Among rotavirus gastroenteritis hospitalizations, 12.2% (81/665) of cases were hospital-acquired and the median duration of hospitalization was 10.0 days (range: 2.0-133.0 days). The median duration of additional hospitalization due to hospital-acquired rotavirus gastroenteritis was 3.0 days (range: 0-14 days). The overall incidence rate of hospital-acquired rotavirus gastroenteritis was 1.0 per 1,000 children hospital-days. The number of rotavirus gastroenteritis cases peaked between February and May in both 2008 and 2009, and the highest number of cases was reported in March 2008 (21.8%; 145/665). The highest number of rotavirus gastroenteritis hospitalizations (24.1%; 160/665) was observed in children aged 12-18 months. The proportion of hospital-acquired rotavirus gastroenteritis was higher in children aged below 18 months as compared to children at least 18 months of age (0.94 [95% CI: 0.71-1.21] vs. 0.39 [95% CI: 0.25-0.58]) and for children hospitalized for at least 5 days compared to those hospitalized for less than 5 days (0.91 [95% CI: 0.72-1.14] vs. 0.15 [95% CI: 0.05-0.32]). CONCLUSIONS: Both community- and hospital-acquired rotavirus gastroenteritis are significant public health problems in Japan. Data from this study justify the need for the introduction and implementation of rotavirus vaccination in the Japanese national immunization program. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01202201.
Assuntos
Gastroenterite/epidemiologia , Infecções por Rotavirus/epidemiologia , Doença Aguda , Distribuição por Idade , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/epidemiologia , Efeitos Psicossociais da Doença , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/epidemiologia , Bases de Dados Factuais , Feminino , Gastroenterite/diagnóstico , Inquéritos Epidemiológicos , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Lactente , Recém-Nascido , Japão/epidemiologia , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos Retrospectivos , Infecções por Rotavirus/diagnóstico , Estações do AnoRESUMO
Hartnup disorder, an autosomal recessive defect named after an English family described in 1956 (ref. 1), results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis. Using homozygosity mapping in the original family in whom Hartnup disorder was discovered, we confirmed that the critical region for one causative gene was located on chromosome 5p15 (ref. 3). This region is homologous to the area of mouse chromosome 13 that encodes the sodium-dependent amino acid transporter B(0)AT1 (ref. 4). We isolated the human homolog of B(0)AT1, called SLC6A19, and determined its size and molecular organization. We then identified mutations in SLC6A19 in members of the original family in whom Hartnup disorder was discovered and of three Japanese families. The protein product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine and renal proximal tubule and functions as a neutral amino acid transporter.
Assuntos
Doença de Hartnup/genética , Mutação , Sequência de Aminoácidos , Sistemas de Transporte de Aminoácidos Neutros/genética , Animais , Sequência de Bases , Mapeamento Cromossômico , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , LinhagemRESUMO
Hematopoietic stem cell transplantation (HSCT) has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome), while it is indicated for mucopolysaccharidosis I (MPS I) patients <2 years of age and an intelligence quotient (IQ) of ≥ 70. Even after the approval of enzyme replacement therapy for both of MPS I and II, HSCT is still indicated for patients with MPS I severe form (Hurler syndrome). To evaluate the efficacy and benefit of HSCT in MPS II patients, we carried out a nationwide retrospective study in Japan. Activities of daily living (ADL), IQ, brain magnetic resonance image (MRI) lesions, cardiac valvular regurgitation, and urinary glycosaminoglycan (GAG) were analyzed at baseline and at the most recent visit. We also performed a questionnaire analysis about ADL for an HSCT-treated cohort and an untreated cohort (natural history). Records of 21 patients were collected from eight hospitals. The follow-up period in the retrospective study was 9.6 ± 3.5 years. ADL was maintained around baseline levels. Cribriform changes and ventricular dilatation on brain MRI were improved in 9/17 and 4/17 patients, respectively. Stabilization of brain atrophy was shown in 11/17 patients. Cardiac valvular regurgitation was diminished in 20/63 valves. Urinary GAG concentration was remarkably lower in HSCT-treated patients than age-matched untreated patients. In the questionnaire analysis, speech deterioration was observed in 12/19 patients in the untreated cohort and 1/7 patient in HSCT-treated cohort. HSCT showed effectiveness towards brain or heart involvement, when performed before signs of brain atrophy or valvular regurgitation appear. We consider HSCT is worthwhile in early stages of the disease for patients with MPS II.
Assuntos
Encéfalo/patologia , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose II/patologia , Mucopolissacaridose II/terapia , Atividades Cotidianas , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Glicosaminoglicanos/urina , Pesquisas sobre Atenção à Saúde , Humanos , Iduronidase/uso terapêutico , Japão , Imageamento por Ressonância Magnética , Masculino , Insuficiência da Valva Mitral/enzimologia , Insuficiência da Valva Mitral/patologia , Insuficiência da Valva Mitral/prevenção & controle , Mucopolissacaridose II/enzimologia , Estudos Retrospectivos , Prevenção Secundária , Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Urea cycle disorders (UCDs) are one of the most frequently inherited metabolic diseases in Japan, with an estimated prevalence of 1 per 50,000 live births. Here, we investigated the clinical manifestations, treatment, and prognosis of 177 patients with UCDs who were evaluated and treated from January 1999 to March 2009. These included 77 cases of neonatal-onset UCDs and 91 cases of late-onset UCDs. The most common UCD was ornithine transcarbamylase deficiency (OTCD), which accounted for 116 out of 177 patients. This result is similar to a previous study performed between 1978 and 1995 in Japan: OTCD accounted for about two-thirds of the total number of UCD cases. We studied the relationship between prognosis and the peak blood ammonia level at the onset in 151 UCD patients. Compared with a previous survey conducted in Japan, we found that a greater number of patients survived without any mental retardation despite their peak blood ammonia levels being greater than 360 µmol/l. The 5-year survival rate of patients with OTCD improved to 86% for those with the neonatal-onset type and to 92% for those with the late-onset type. We hypothesize that the increased survival rate is due to early diagnosis and better treatments that are now available in Japan. It is very important to diagnose and treat UCDs, especially OTCD, when the blood ammonia levels in patients are low. The outcome in patients with low blood ammonia levels was better than that in patients with high blood ammonia levels.