RESUMO
Citrin deficiency is characterized by a wide range of symptoms from infancy through adulthood and presents a distinct preference for a diet composed of high protein, high fat, and low carbohydrate. The present study elucidates the important criteria by patients with citrin deficiency for food selection through detailed analysis of their food preferences. The survey was conducted in 70 citrin-deficient patients aged 2-63 years and 55 control subjects aged 2-74 years and inquired about their preference for 435 food items using a scale of 1-4 (the higher, the more favored). The results showed that the foods marked as "dislike" accounted for 36.5% in the patient group, significantly higher than the 16.0% in the controls. The results also showed that patients clearly disliked foods with 20-24 (% of energy) or less protein, 45-54% (of energy) or less fat, and 30-39% (of energy) or more carbohydrate. Multiple regression analysis showed carbohydrates had the strongest influence on patients' food preference (ß = -0.503). It also showed female patients had a stronger aversion to foods with high carbohydrates than males. The protein, fat, and carbohydrate energy ratio (PFC) of highly favored foods among patients was almost the same as the average PFC ratio of their daily diet (protein 20-22: fat 47-51: carbohydrates 28-32). The data strongly suggest that from early infancy, patients start aspiring to a nutritional balance that can compensate for the metabolism dissonance caused by citrin deficiency in every food.
Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Dieta/psicologia , Ingestão de Alimentos/psicologia , Preferências Alimentares/psicologia , Transportadores de Ânions Orgânicos/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Inquéritos sobre Dietas , Carboidratos da Dieta , Gorduras na Dieta , Proteínas Alimentares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Adulto JovemRESUMO
We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62- positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.
RESUMO
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
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
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
BACKGROUND: Phenylketonuria (PKU) possibly leads to hypocholesterolemia and lowered vitamin D (VD) status. Metabolism of oxysterols linking with those of cholesterol and VD has never been examined in PKU. METHODS: Blood oxysterols along with blood phenylalanine, lipids and VD were examined for 33 PKU adults aged 21-38 years and 20 age-matched healthy controls. RESULTS: Total- and low-density cholesterols, and 25-hydroxy VD(3) were decreased significantly in the PKU group (cholesterols, 10% decrease; 25-hydroxy VD(3) 35% decrease vs. the control group). 24S-hydroxycholesterol (24S-OHC) eliminating brain cholesterol, and 27-OHC and 7α-hydroxycholesterol (7α-OHC) representing peripheral and hepatic cholesterol elimination, respectively, were significantly decreased in PKU group: 24S-OHC, 25% decrease, p<.01; 27-OHC and 7α-OHC, 35-40% decrease, p<.001. 7ß-Hydroxycholesterol (7ß-OHC) reflecting oxidative stress was increased significantly in PKU group (p<.05). 7α-OHC and 27-OHC levels in PKU group always showed similar values, regardless of other parameters while the 24S-OHC and 7ß-OHC levels decreased and increased, respectively, showing significant correlations with phenylalanine level (p<.005). 27-OHC level showed a significant positive correlation with the 25-hydroxy VD(3) level in this group (p<.001). CONCLUSION: Blood oxysterol changes predominate over blood cholesterol changes and influence on VD status in adult PKU patients.
Assuntos
Colesterol/sangue , Cetocolesteróis/sangue , Fenilcetonúrias/sangue , Vitamina D/sangue , Adulto , Feminino , Humanos , Masculino , Programas de Rastreamento , Fenilcetonúrias/diagnósticoRESUMO
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
Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.
Assuntos
Senescência Celular/genética , Síndrome de Costello/genética , Síndrome de Costello/fisiopatologia , Fibroblastos/metabolismo , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Adulto , Animais , Linhagem Celular , Criança , Pré-Escolar , Códon/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Masculino , Camundongos , Células NIH 3T3 , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/genética , Regulação para CimaRESUMO
AIM: To characterize the histological features of the livers of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), we studied specimens from 30 patients diagnosed with NICCD by genetically analyzing the SLC25A13 gene. METHODS: Liver biopsy specimens were subjected to hematoxylin-eosin, Azan, and Berlin-blue staining. RESULTS: Most specimens showed varying degrees of fibrosis. The degree of inflammation varied among the specimens, with half showing moderate or severe inflammatory changes. Fat deposition in hepatocytes was observed in almost all of the specimens, and severe fatty liver was noted in 20 (67%) of them. There was a mixture of two types of hepatocytes with macrovesicular or microvesicular fat droplets, and cholestasis was observed at a rate of 77%. Hemosiderin deposition, mostly mild and localized in periportal hepatocytes and macrophages in portal areas, was observed in 57% of the specimens. CONCLUSION: A combination of mixed macrovesicular and microvesicular fatty hepatocytes and the above-described findings, such as fatty liver, cholestasis, necroinflammatory reaction and iron deposition, are almost never observed in other liver diseases in infants and adults. We believe that NICCD is a disease with characteristic hepatopathological features.
RESUMO
Renal tubular dysgenesis is a critical disorder characterized by the Potter phenotype and severe hypotension in the early neonatal period. We herein report a 3-year-old female with renal tubular dysgenesis. Endocrinological studies showed a high plasma renin activity (over 49.2 ng/ml/h; normal range 2.0-15.2), high active renin concentration (1,823.5 pg/ml; normal range 2.4-21.9), and low angiotensin-converting enzyme (ACE) concentration (1.7 U/l; normal range 8.3-21.4). Taken together, these findings suggested an abnormality of the ACE gene, ACE. Direct sequencing analysis revealed two novel deletions in the coding region of ACE. We conclude that hormonal analysis of the renin-angiotensin system can aid in identifying the responsible genes and help with efficient gene analysis and pathophysiological considerations.
Assuntos
Deleção Cromossômica , Doenças do Prematuro/genética , Falência Renal Crônica/genética , Túbulos Renais Proximais/anormalidades , Peptidil Dipeptidase A/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anuria/diagnóstico , Anuria/genética , Anuria/patologia , Anuria/terapia , Biópsia , Pré-Escolar , Códon/genética , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Recém-Nascido , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/patologia , Rim/patologia , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Túbulos Renais Proximais/patologia , Oligo-Hidrâmnio/etiologia , Fases de Leitura Aberta/genética , Diálise Peritoneal , Gravidez , Renina/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNARESUMO
Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 x 10(-3)), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68-bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C-bearing chromosomes and to determine whether the pathogenic c.[833C; -] chromosomes are identical-by-descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub-Saharan African wild-type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; -] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild-type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; -] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates.
Assuntos
Cistationina beta-Sintase/genética , Conversão Gênica/fisiologia , Variação Genética , Haplótipos , Homocistinúria/genética , África , Sequência de Bases , Europa (Continente) , Frequência do Gene , Testes Genéticos , Humanos , Dados de Sequência MolecularRESUMO
OBJECTIVE: It is currently problematic to confirm the clinical diagnosis of glycine encephalopathy, requiring either invasive liver biopsy for enzymatic analysis of the glycine cleavage system or exhaustive mutation analysis. Because the glycine cleavage system breaks down glycine generating carbon dioxide, we suppose that the glycine cleavage system activity could be evaluated in vivo by measuring exhaled (13)CO(2) after administration of [1-(13)C]glycine. METHODS: The [1-(13)C]glycine breath test was performed in 10 control subjects and 5 glycine encephalopathy patients with GLDC mutation, including 1 patient with mild glycine encephalopathy. RESULTS: All the patients showed lower (13)CO(2) excretion than any control subject. INTERPRETATION: Not only typical GE but also atypical GE can be reliably diagnosed by the (13)C-glycine breath test. Because it is rapid, non-invasive, and requires little expertise, the breath test could be useful as a standard test for diagnosing GE.
Assuntos
Dano Encefálico Crônico/diagnóstico , Glicina/análise , Glicina/fisiologia , Hiperglicemia/diagnóstico , Adolescente , Dano Encefálico Crônico/genética , Testes Respiratórios , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Criança , Pré-Escolar , Feminino , Glicina/metabolismo , Humanos , Hiperglicemia/genética , Lactente , Masculino , Oxirredução , Reprodutibilidade dos TestesRESUMO
Cystathionine beta-synthase (CBS) deficiency is the most common cause of homocystinuria. More than 130 pathogenic mutations, mostly in the Caucasian populations, have been described. Recently, our group reported a mutation analysis of Japanese homocystinuric patients. In the present paper, we report an expression study of several mutant CBS enzymes in Escherichia coli, i.e., R121H, G148R, G151R, S217F, H232D, R266G, 1591delTTCG, and K441X. All of the mutants except K441X exhibited severely decreased activity, and the capability to form tetramers of most mutants was severely impaired. The K441X mutant, on the other hand, exhibited relatively high activity (63% of the wild type activity). This was probably due to two factors. First, the high abundance of the full-length CBS protein, a likely K441Q mutant, which was produced through suppression of the amber termination codon by glutamine tRNA in E. coli. And second, the presence of a C-terminally truncated protein, which was previously shown to be constitutively activated. Patient-derived lymphocytes, however, showed no detectable CBS subunits. As previously hypothesized, the increased aggregation of mutant CBS subunits might be a common pathogenic mechanism in CBS deficiency.
Assuntos
Cistationina beta-Sintase/biossíntese , Homocistinúria/enzimologia , Adulto , Povo Asiático , Pré-Escolar , Cistationina beta-Sintase/genética , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , MutaçãoRESUMO
We report the case of a 7-year-old girl with ornithine transcarbamylase deficiency whose quality of life (QOL) improved greatly after a living donor liver transplantation (LDLT). Ornithine transcarbamylase deficiency had been diagnosed when she was 2 years old and she finally underwent LDLT, with her father as the donor, when she was 7 years old. The patient had suffered episodes of hyperammonemic encephalopathy ranging from lethargy to coma, treated by hemodialysis twice before LDLT, and her intelligence quotient was borderline for her age. Preoperative magnetic resonance imaging (MRI) showed an atrophic area in the subcortical white matter of the frontal lobe. After LDLT, the patient suffered acute rejection with hyperamylasemia, but not hyperammonemia. Postoperative MRI and quantitative MR spectroscopy showed no changes in the subcortical lesion. She has been followed up carefully for 16 months and has had no further complications or any sign of hyperammonemia.
Assuntos
Encéfalo/patologia , Transplante de Fígado , Doença da Deficiência de Ornitina Carbomoiltransferase/cirurgia , Qualidade de Vida , Atrofia , Criança , Feminino , Humanos , Doadores Vivos , Imageamento por Ressonância MagnéticaAssuntos
Doença de Darier/tratamento farmacológico , Ceratodermia Palmar e Plantar/tratamento farmacológico , Unhas Malformadas/tratamento farmacológico , Adulto , Cloreto de Alumínio , Compostos de Alumínio/uso terapêutico , Cloretos/uso terapêutico , Doença de Darier/complicações , Doença de Darier/congênito , Fármacos Dermatológicos/uso terapêutico , Feminino , Pé , Dermatoses do Pé/complicações , Dermatoses do Pé/congênito , Dermatoses do Pé/tratamento farmacológico , Humanos , Ceratodermia Palmar e Plantar/complicações , Ceratodermia Palmar e Plantar/congênito , Unhas Malformadas/complicações , Unhas Malformadas/congênito , Dor/etiologia , Ácido Salicílico/uso terapêutico , Resultado do TratamentoAssuntos
Proteínas de Ligação ao Cálcio/deficiência , Hepatomegalia/complicações , Hipoglicemia/complicações , Cetose/complicações , Transportadores de Ânions Orgânicos/deficiência , Acidose Láctica/complicações , Acidose Láctica/prevenção & controle , Pré-Escolar , Citrulina/análise , Feminino , Teste de Tolerância a Glucose , Hepatomegalia/prevenção & controle , Humanos , Hipoglicemia/prevenção & controle , Lactente , Proteínas de Membrana Transportadoras/genética , Proteínas de Transporte da Membrana Mitocondrial , Proteínas Mitocondriais/genética , Mutação , Irmãos , Amido/uso terapêuticoRESUMO
A deficiency of citrin, which is encoded by the SLC25A13 gene, causes both adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). We analyzed 16 patients with NICCD to clarify the clinical features of the disease. Severe intrahepatic cholestasis with fatty liver was the most common symptom, but the accompanying clinical features were variable, namely; suspected cases of neonatal hepatitis or biliary atresia, positive results from newborn screening, tyrosinemia, failure to thrive, hemolytic anemia, bleeding tendencies and ketotic hypoglycemia. Laboratory data showed elevated serum bile acid levels, hypoproteinemia, low levels of vitamin K-dependent coagulation factors, and hypergalactosemia. Hypercitrullinemia was detected in 11 out of 15 patients examined. Most of the patients were given a lactose-free and/or medium chain triglycerides-enriched formula and lipid-soluble vitamins. The prognosis of the 16 patients is going fairy well at present, but we should observe these patients carefully to see if they manifest any symptom of CTLN2 in the future.
Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/patologia , Fígado/patologia , Proteínas de Membrana Transportadoras/genética , Proteínas Mitocondriais/genética , Transportadores de Ânions Orgânicos/deficiência , Aminoácidos/sangue , Anemia Hemolítica/complicações , Anemia Hemolítica/patologia , Ácidos e Sais Biliares/sangue , Atresia Biliar/complicações , Atresia Biliar/parasitologia , Fatores de Coagulação Sanguínea , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/dietoterapia , Citrulinemia/complicações , Citrulinemia/patologia , Análise Mutacional de DNA , Primers do DNA , Feminino , Alimentos Formulados , Galactose/sangue , Hepatite/complicações , Hepatite/patologia , Humanos , Hipoglicemia/complicações , Hipoglicemia/patologia , Hipoproteinemia/complicações , Hipoproteinemia/patologia , Lactente , Recém-Nascido , Masculino , Proteínas de Transporte da Membrana Mitocondrial , Tirosinemias/complicações , Tirosinemias/patologia , Vitaminas/uso terapêuticoRESUMO
Homocystinuria is a congenital metabolic disorder, and has been known as life-threatening risk factor of vascular disease including ischemic stroke. We report a case of cerebral infarction due to homocystinuria. The patient was a 21-year-old woman exhibiting left hemiparesis and a previous history of ectopia lentis. Magnetic resonance imaging showed multiple fresh infarctions in the right frontal and temporal lobes, basal ganglia, corona radiata, and internal capsule. The right common carotid angiogram demonstrated complete occlusion at the origin of the right internal carotid artery. Further investigation clarified increased level of serum methionine and homocysteine and urinary homocystin due to cystathionine beta-synthase deficiency. Homocystinuria was diagnosed as the cause of cerebral infarction. The patient was treated by low methionine diet and administration of folic acid, cobalamin, and aspirin. It should be recognized that some patients with homocystinuria are missed in the neonatal screening for congenital metabolic disorders. Recent studies indicated that the homocysteinemia is one of risk factors of ischemic stroke in the general population as well as in the patients of homocystinuria. We recommend metabolic screening for homocystinuria, when treating a juvenile patient with ischemic stroke of unknown etiology.
Assuntos
Infarto Cerebral/etiologia , Homocistinúria/complicações , Adulto , Angiografia Cerebral , Infarto Cerebral/diagnóstico , Feminino , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Methylmalonic acidemia (MMA) is caused by the deficient activity of l-methylmalonyl-CoA mutase, which is a vitamin B(12) (or cobalamin, Cbl)-dependent enzyme. MMA due to the effect of insufficient Cbl metabolism is classified into three forms (cblA, cblB, and cblH). Recently, the genes responsible for cblA and cblB were identified as MMAA and MMAB, respectively. The MMAA protein likely transports Cbl into the mitochondria for adenosylcobalamin synthesis, while the MMAB protein appears to be an adenosyltransferase. We performed a mutation analysis of 10 unrelated Japanese patients with vitamin B(12)-responsive MMA. Seven patients had mutations in MMAA, whereas the other three patients showed no disease-causing substitutions in either MMAA or MMAB. Five novel mutations were identified in MMAA (R22X, R145X, L217X, R359G, and 503delC). The 503delC mutation was observed in five of the seven MMAA patients, suggesting that the mutation is prevalent in Japanese patients. This finding may facilitate the DNA diagnosis of vitamin B(12)-responsive MMA within the Japanese population.