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1.
Am J Med Genet A ; 194(8): e63612, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38554024

RESUMO

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions.


Assuntos
Acondroplasia , Humanos , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Acondroplasia/patologia , Masculino , Feminino , Estudos Retrospectivos , Pré-Escolar , Japão/epidemiologia , Lactente , Hormônio do Crescimento Humano/uso terapêutico , Resultado do Tratamento , Criança , Estatura/efeitos dos fármacos , Gerenciamento Clínico , Prontuários Médicos , Imageamento por Ressonância Magnética , População do Leste Asiático
2.
Genet Med ; 24(12): 2444-2452, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36107167

RESUMO

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.


Assuntos
Acondroplasia , Criança , Masculino , Feminino , Humanos , Pré-Escolar , Estudos Prospectivos , Acondroplasia/epidemiologia , Acondroplasia/genética , Acondroplasia/diagnóstico , Estatura
3.
Am J Perinatol ; 39(11): 1236-1240, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-33374020

RESUMO

OBJECTIVE: The acylcarnitine profile is analyzed in dried blood spots (DBS) to screen for inborn errors of metabolism. Hematocrit (Ht) is known to affect the result of quantitative analyses of DBS samples; however, the effects of Ht on the acylcarnitine profiles in DBS have not been studied in actual samples from newborns. STUDY DESIGN: The acylcarnitine profiles in DBS for newborn screening tests and Ht levels of very-low-birth-weight infants were obtained from medical records. We investigated the relationship between Ht and each acylcarnitine using Pearson's correlation coefficient (r). RESULTS: We examined 77 newborns in this study. There was a significantly positive correlation between Ht and C0, C2, C12, C16, C18, C18:1, and C18:1-OH, respectively (p < 0.0025). The correlation was the greatest on C2 (r = 0.59). CONCLUSION: This study clarifies that Ht and C0, C2, C12, C16, C18, C18:1, and C18:1-OH are significantly correlated in DBS, which is consistent with previous studies. Hence, the effect of Ht should be considered when interpreting the results of acylcarnitine profiles in DBS. KEY POINTS: · Acylcarnitine profile in dried blood spots (DBS) is affected by the hematocrit (Ht) of the sample.. · There are positive correlations between Ht and C0, C2, C12, C16, C18, and C18:1-OH in DBS.. · We should be aware of the effects of Ht on acylcarnitine profiles in DBS..


Assuntos
Carnitina , Triagem Neonatal , Carnitina/análogos & derivados , Hematócrito , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso
4.
Lancet ; 396(10252): 684-692, 2020 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891212

RESUMO

BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.


Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Osteogênese , Absorciometria de Fóton , Acondroplasia/sangue , Adolescente , Biomarcadores/sangue , Estatura , Densidade Óssea , Criança , Pré-Escolar , Colágeno Tipo X/sangue , Método Duplo-Cego , Feminino , Humanos , Reação no Local da Injeção , Injeções Subcutâneas , Masculino , Peptídeo Natriurético Tipo C/uso terapêutico
5.
Genet Med ; 23(12): 2443-2447, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34341520

RESUMO

PURPOSE: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. METHODS: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 µg/kg/day. RESULTS: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. CONCLUSION: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.


Assuntos
Acondroplasia , Peptídeo Natriurético Tipo C , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Criança , Método Duplo-Cego , Humanos , Peptídeo Natriurético Tipo C/análogos & derivados , Peptídeo Natriurético Tipo C/uso terapêutico , Resultado do Tratamento
6.
J Inherit Metab Dis ; 44(4): 826-837, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33840128

RESUMO

Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 µmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 µmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.


Assuntos
Hiperamonemia/prevenção & controle , Transtornos do Neurodesenvolvimento/etiologia , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia , Distúrbios Congênitos do Ciclo da Ureia/terapia , Adolescente , Adulto , Amônia/sangue , Criança , Pré-Escolar , Feminino , Humanos , Hiperamonemia/etiologia , Japão/epidemiologia , Transplante de Fígado , Masculino , Diálise Renal , Taxa de Sobrevida , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/epidemiologia , Adulto Jovem
7.
Endocr J ; 66(3): 215-221, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30674755

RESUMO

Pseudohypoparathyroidism type 1A (PHP1A) is characterized by resistance to multiple hormones, the Albright Hereditary Osteodystrophy phenotype, obesity, and developmental delay. Developmental delay usually appears prior to hypocalcemia due to parathyroid hormone resistance and could be a clinically important feature for early diagnosis of PHP1A. To date, however, the details have not been documented. With regard to developmental delays, we conducted a multicenter retrospective study of 22 PHP1A patients from 18 families who were diagnosed clinically or genetically from 2005 to 2015. For quantitative analysis of their development, we calculated the ratios of the milestone ages of the patients to those in normal reference data. The ratio of the ages with respect to speech development, i.e., speaking a first meaningful word (median: 1.67), was significantly higher than that for gross motor development, walking unassisted (median: 1.34). The ratio of age at stringing a two-word sentence (median: 1.32) was significantly lower than that of saying a first word (median: 1.84). Ten out of 11 (91%) patients exhibited two or three of the following clinical phenotypes: developmental delay, obesity, and hyperthyrotropinemia. These results suggest two possible clinical features of developmental delays in PHP1A patients: developmental delay is more obvious in speech acquisition than in gross motor skills, and speech delays could be attenuated during later childhood. Further, the presence of multiple of three clinical symptoms could be an important indicator to differentiate the diagnosis of PHP1A during early childhood.


Assuntos
Transtornos do Desenvolvimento da Linguagem/etiologia , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Hipotireoidismo/etiologia , Lactente , Masculino , Obesidade/etiologia , Fenótipo , Estudos Retrospectivos
8.
Clin Endocrinol (Oxf) ; 87(1): 10-19, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28374482

RESUMO

OBJECTIVE: Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan. DESIGN: Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015. PATIENTS: Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1). MEASUREMENTS: Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development. RESULTS: Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved. CONCLUSION: Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.


Assuntos
Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/genética , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Fosfatase Alcalina/efeitos adversos , Fosfatase Alcalina/uso terapêutico , Cálcio/sangue , Criança , Pré-Escolar , Feminino , Humanos , Hiperfosfatemia/induzido quimicamente , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Lactente , Recém-Nascido , Japão , Masculino , Mutação , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
9.
Lancet Child Adolesc Health ; 8(1): 40-50, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37984383

RESUMO

BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.


Assuntos
Acondroplasia , Gastroenterite , Feminino , Humanos , Lactente , Masculino , Acondroplasia/tratamento farmacológico , Método Duplo-Cego , Peptídeo Natriurético Tipo C/uso terapêutico , Pré-Escolar
10.
J Inherit Metab Dis ; 36(1): 75-81, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22971957

RESUMO

Plasma mannose is suggested to be largely generated from liver glycogen-oriented glucose-6-phosphate. This study examined plasma mannose in glycogen storage disease type Ia (GSD Ia) lacking conversion of glucose-6-phosphate to glucose in the liver. We initially examined fasting--and postprandial 2 h--plasma mannose and other blood carbohydrates and lipids for seven GSD Ia children receiving dietary interventions using cornstarch and six healthy age-matched children. Next, one-day successive intra-individual parameter changes were examined for six affected and two control children. Although there were no significant differences in fasting--and postprandial 2 h--glucose and insulin levels, the mannose level of the affected group was invariably much higher than that of the control group (p < 0.001): the fasting level of the affected group was about two-fold that of the control group; the postprandial-2 h level remained almost unchanged in the affected group, although it was one-half of the fasting level in the control group. Inter-individual analyses revealed that the GSD Ia group mannose level was significantly and positively correlated with lactate and triglycerides levels at both time points (p < 0.01). In each control, mannose levels fluctuated greatly, maintaining strong and significant negative correlations with glucose and insulin levels (p < 0.001). Correlations were lower or nonexistent in GSD Ia children. In individuals with high lactate and triglycerides levels, strikingly high mannose levels never changed against glucose and insulin fluctuations. Plasma mannose is less sensitive to blood glucose and insulin in GSD Ia children. Its basal level and the fluctuation pattern differ by their metabolic activity.


Assuntos
Glicemia/metabolismo , Doença de Depósito de Glicogênio Tipo I/sangue , Manose/sangue , Adolescente , Criança , Jejum/sangue , Feminino , Glucose/metabolismo , Glucose-6-Fosfato/metabolismo , Doença de Depósito de Glicogênio Tipo I/metabolismo , Humanos , Ácido Láctico/sangue , Ácido Láctico/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Masculino , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo
11.
Pediatr Diabetes ; 13(1): 33-44, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22128760

RESUMO

OBJECTIVE: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. METHODS: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent-child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed. RESULTS: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1-09:01-DQB1-03:03 and heterozygosity for DRB1-04:05-DQB1-04:01 and DRB1-08:02-DQB1-03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1-09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. CONCLUSIONS: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes.


Assuntos
Povo Asiático/genética , Diabetes Mellitus Tipo 1/genética , Família , Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Adolescente , Povo Asiático/estatística & dados numéricos , Criança , Pré-Escolar , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/classificação , Diabetes Mellitus Tipo 1/etnologia , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino
12.
J Bone Miner Metab ; 29(6): 737-43, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21594581

RESUMO

The mechanism underlying the development of osteopenia or osteoporosis in longstanding phenylketonuria (PKU) remains to be clarified. We investigated the details of bone metabolism in 21 female and 13 male classical PKU patients aged 20-35 years. Vitamin D (VD), parathyroid hormone (PTH), bone turnover markers, and daily nutrient intake were examined. The patients had lower daily energy and protein intake than did the age-matched controls (22 women, 14 men), but their respective fat, VD, and calcium intake did not differ. Serum 1,25-dihydroxy VD and 25-hydroxy VD levels in female and male patient groups were significantly higher and lower than those in respective control groups (females, P < 0.001; males, P < 0.05 and P < 0.01, respectively). Serum intact PTH levels were significantly higher in the female patient group (P < 0.05). Urinary calcium levels in the patient groups were significantly higher than those of the control subjects (females, P < 0.001; males, P < 0.05). Bone resorption markers were significantly higher in patients than in controls, although bone formation markers were not different. Patient serum levels of osteoprotegerin-inhibiting bone resorption were significantly lower (females, P < 0.001; males, P < 0.01). None of the bone parameters correlated significantly with serum phenylalanine or nutrient intake. PKU patients exhibited lower VD status and more rapid bone resorption despite normal calcium-VD intakes.


Assuntos
Osso e Ossos/metabolismo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/metabolismo , Adulto , Doenças Ósseas Metabólicas/metabolismo , Reabsorção Óssea/sangue , Reabsorção Óssea/diagnóstico , Estudos Transversais , Feminino , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Hormônio Paratireóideo/sangue , Fenilcetonúrias/sangue , Vitamina D/sangue , Adulto Jovem
13.
Rinsho Shinkeigaku ; 51(8): 590-4, 2011 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-21878725

RESUMO

A 57 year-old man developed broad-based unsteady gait and memory loss over a period of one year. On admission, bradykinesia and impairment of postural reflex were evident. Mini-mental state examination scored 27/ 30. Urinary control was normal. MRI revealed symmetric dilatation of lateral and 3rd ventricles, but the 4th ventricle appeared normal. Partial obstruction of the aqueduct with a membranous structure was disclosed by fast imaging employing steady state acquisition (FIESTA), and the diagnosis of late-onset aqueductal membranous occlusion (LAMO) was made. The symptoms were ameliorated shortly after endoscopic aqueductoplasty (EAP) and endoscopic third ventriculostomy (ETV). Membranous occlusion of the aqueduct can be detected by FIESTA and it can be cured by neuro-endoscopic measures.


Assuntos
Encefalopatias/cirurgia , Aqueduto do Mesencéfalo/patologia , Neuroendoscopia , Encefalopatias/patologia , Aqueduto do Mesencéfalo/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ventriculostomia
14.
Mol Genet Metab ; 100(3): 269-73, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20409737

RESUMO

CONTEXT: Cytochrome P450 oxidoreductase (POR) is an electron donor for all microsomal P450 enzymes including CYP26 involved in inactivation of all-trans retinoic acid (atRA). Although previous studies in Por knockout mice suggest that atRA accumulation is relevant to various posterior organ abnormalities, a systematic analysis has not been performed for anorectal and urinary anomalies in patients with POR deficiency (PORD). OBJECTIVE: To report the frequencies of anorectal and urinary anomalies and plasma atRA values in PORD patients. PATIENTS: We studied 37 Japanese patients with PORD, consisting of 15 homozygotes for R457H (group A), 15 compound heterozygotes for R457H and one apparently null mutation (group B), and seven patients with other combinations of mutations (group C). Since R457H is a severe hypomorphic mutation, the residual POR function is predicted to be higher in group A than in group B. RESULTS: Imperforate anus was observed in four patients (10.8%) and vesicoureteral reflux was found in three patients (8.1%), with no significant difference in the frequencies of such anomalies between groups A and B. In addition, a complex urogenital malformation including penile agenesis was identified in one patient. Plasma atRA values were above the reference range in nine of 12 patients examined, and were similar between groups A and B and between patients with and without anomalies. CONCLUSIONS: The results imply that aberrant atRA metabolism due to CYP26 deficiency underlies various anorectal and urinary anomalies in patients with PORD. Clinical phenotypes may be primarily determined by maternal oral retinol intake during pregnancy, and plasma atRA values may be largely influenced by the amount of postnatal oral retinol intake in such patients.


Assuntos
Intestino Grosso/anormalidades , Mutação , NADPH-Ferri-Hemoproteína Redutase/deficiência , NADPH-Ferri-Hemoproteína Redutase/genética , Tretinoína/metabolismo , Sistema Urinário/anormalidades , Adolescente , Animais , Anus Imperfurado/enzimologia , Anus Imperfurado/genética , Criança , Pré-Escolar , Sistema Enzimático do Citocromo P-450/deficiência , Sistema Enzimático do Citocromo P-450/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Gravidez , Ácido Retinoico 4 Hidroxilase , Anormalidades Urogenitais/enzimologia , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/congênito , Refluxo Vesicoureteral/enzimologia , Refluxo Vesicoureteral/genética
15.
Clin Pediatr Endocrinol ; 29(1): 25-42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32029970

RESUMO

Achondroplasia (ACH) is a skeletal dysplasia that presents with limb shortening, short stature, and characteristic facial configuration. ACH is caused by mutations of the FGFR3 gene, leading to constantly activated FGFR3 and activation of its downstream intracellular signaling pathway. This results in the suppression of chondrocyte differentiation and proliferation, which in turn impairs endochondral ossification and causes short-limb short stature. ACH also causes characteristic clinical symptoms, including foramen magnum narrowing, ventricular enlargement, sleep apnea, upper airway stenosis, otitis media, a narrow thorax, spinal canal stenosis, spinal kyphosis, and deformities of the lower extremities. Although outside Japan, papers on health supervision are available, they are based on reports and questionnaire survey results. Considering the scarcity of high levels of evidence and clinical guidelines for patients with ACH, clinical practical guidelines have been developed to assist both healthcare professionals and patients in making appropriate decisions in specific clinical situations. Eleven clinical questions were established and a systematic literature search was conducted using PubMed/MEDLINE. Evidence-based recommendations were developed, and the guidelines describe the recommendations related to the clinical management of ACH. We anticipate that these clinical practice guidelines for ACH will be useful for healthcare professionals and patients alike.

16.
Clin Pediatr Endocrinol ; 29(1): 9-24, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32029969

RESUMO

Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.

17.
Endocr J ; 55(1): 97-103, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18202527

RESUMO

Mutations of DSS (dosage sensitive sex reversal)-AHC critical region on the X chromosome, gene 1 DAX-1(NROB1)] results in X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Here we report four Japanese patients with AHC and HHG caused by the mutations of the DAX-1 gene. All patients manifested adrenal crisis at early childhood. Three patients did not show any pubertal sign and were diagnosed as having HHG. One patient manifested spontaneous pubertal development at 17 years of age. Nevertheless, his puberty did not develop further and his gonadotropin and testosterone levels decreased thereafter. Therefore, he was also diagnosed as having HHG. We performed testicular biopsy in another patient with HHG. Histological examination demonstrated Sertoli cell hypoplasia and no sperm formation in the seminiferous tubules. Molecular analysis demonstrated two novel point mutations (V269D and L278R) in two patients. Transient transfection assays showed that all these mutations (V269D, L271X, L278R, and Q395X) abolished the repression activity to both StAR and LHbeta gene promoter activation. In conclusion, we reported patients with AHC and HHG caused by the loss of function mutations of the DAX-1 gene.


Assuntos
Doenças do Córtex Suprarrenal/genética , Proteínas de Ligação a DNA/genética , Regulação para Baixo/genética , Hipogonadismo/genética , Hormônio Luteinizante Subunidade beta/genética , Fosfoproteínas/genética , Regiões Promotoras Genéticas , Receptores do Ácido Retinoico/genética , Proteínas Repressoras/genética , Adolescente , Doenças do Córtex Suprarrenal/complicações , Doenças do Córtex Suprarrenal/congênito , Adulto , Animais , Sequência de Bases , Células Cultivadas , Receptor Nuclear Órfão DAX-1 , Análise Mutacional de DNA , Proteínas de Ligação a DNA/fisiologia , Humanos , Hipogonadismo/complicações , Japão , Masculino , Camundongos , Proteínas Mutantes/fisiologia , Mutação , Receptores do Ácido Retinoico/fisiologia , Proteínas Repressoras/fisiologia , Transfecção
18.
Clin Ophthalmol ; 12: 339-344, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29497274

RESUMO

PURPOSE: To evaluate the relationship between uncorrected visual acuity and refraction and binocular function using a vision screening protocol. METHODS: In total, 760 children (3-6 years old) who were enrolled in 4 nursery schools in Otawara, Japan, were recruited; a total of 1,520 eyes were examined. We assessed uncorrected near visual acuity, manifest refraction, stereopsis, and eye position. Subjects were divided into 4 subgroups according to the lowest uncorrected near visual acuity value compared between the 2 eyes: group 1 (visual acuity [VA] ≤0.00 [logarithm of the minimum angle of resolution]), group 2 (VA 0.15-0.05), group 3 (VA 0.52-0.22), and group 4 (VA >0.52). These parameters were compared among the groups. RESULTS: The sample number of each of the 4 sub-groups was as follows: group 1, 608; group 2, 114; group 3, 27; and group 4, 11. The median spherical equivalent values were -1.13 diopter (D) in group 1 and -1.00 in group 2, which were more myopic than group 4. Median cylindrical power in group 1 was 0.25 D, and was the lowest among all groups. In group 1, median anisometropia was 0.38 D and median corneal astigmatism value was 1.13 D; both values were lowest in group 1. With regard to binocular function, 89.6% of the subjects in group 1 had 60 arcseconds or better in near stereopsis and 98.8% had no detectable strabismus, which were significantly different from the findings in the other groups. The percentage of subjects in group 1 who had 80 arcseconds or worse in near stereopsis was 10.4%. In contrast, 90.9% of the subjects in group 4 had 80 arcseconds or worse in near stereopsis, and 18.2% had intermittent or manifest strabismus. CONCLUSION: We suggest that examination of refraction and stereopsis in preschool-age children undergoing vision screening is an important supplement to visual acuity testing.

19.
J Clin Endocrinol Metab ; 92(10): 4009-14, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17652215

RESUMO

CONTEXT: Natriuretic peptide receptor-B (NPR-B, GC-B in rodents; gene name NPR2) is a guanylyl cyclase-coupled receptor that mediates the effect of C-type natriuretic peptide. Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (OMIM 602875), an autosomal recessive skeletal dysplasia. NPR-B has an intracellular kinase homology domain (KHD), which has no kinase activity, and its functional significance in vivo is currently unknown. OBJECTIVE: We examined the functional significance of a novel NPR-B KHD mutation in humans. PATIENTS AND METHODS: A 28-yr-old Japanese male presented with marked short stature (118.5 cm, -9.3 sd). His limbs showed marked shortening in the middle and distal segments. His parents had relatively short stature with height z-scores of -2.75 and -0.98 (his father and mother, respectively). Direct sequencing of coding region of the NPR2 gene of the family was performed. The mutant receptor activity was investigated by saturation binding assay and cGMP measurement. Additionally, interaction between the mutant and wild type allele was investigated by the titration experiments. RESULTS: We identified a novel missense mutation L658F in KHD of NPR-B in homozygous and heterozygous states in the patient and his parents, respectively. The mutation conferred normal binding affinity for C-type natriuretic peptide but no discernible ligand-induced cGMP production. Furthermore, L658F mutant impaired wild-type NPR-B-mediated cGMP production in a dose-dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant-negative effect. CONCLUSIONS: This study provides the first evidence that intact KHD of NPR-B is essential for skeletal development.


Assuntos
Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/genética , Guanilato Ciclase/química , Guanilato Ciclase/genética , Mutação de Sentido Incorreto , Receptores do Fator Natriurético Atrial/química , Receptores do Fator Natriurético Atrial/genética , Adulto , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Células COS , Chlorocebus aethiops , Feminino , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fosfotransferases/química , Fosfotransferases/genética , Estrutura Terciária de Proteína , Radiografia , Transfecção
20.
Cornea ; 25(10 Suppl 1): S68-72, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17001197

RESUMO

PURPOSE: Low tear phospholipids levels are associated with tear film instability in soft contact lens wearers. We assayed levels of phospholipids and their degrading enzyme secretory phospholipase A2 (sPLA2) both in tears and deposited on contact lenses composed of 2 hydrophilic materials after 1 day of routine use. METHODS: Polymacon (Medalist; FDA group 1, low water/nonionic) and Etafilcon A (One Day Acuvue; group 4, high water/ionic) contact lenses were worn for 12 hours by 16 experienced contact lens wearers. Phospholipids in tear fluids and deposited on contact lenses were estimated by phosphorus determination with ammonium molybdate through enzymatic digestion. Double-antibody sandwich ELISA was used to determine group IIa sPLA2 concentrations, and sPLA2 activity was assayed using 1,2-diheptanoyl thio-phosphatidylcholine as substrate. RESULTS: Phospholipids concentrations in tears with Polymacon and Etafilcon A were 186 +/- 39 and 162 +/- 33 microg/mL, respectively. The latter concentration was significantly lower than that observed in the same subjects when not wearing contact lenses (P = 0.0023). In tears, both group IIa sPLA2 concentrations and enzymatic activity remained unchanged, regardless of lens wearing. However, Etafilcon A (0.57 +/- 0.09 microg/lens) showed more group IIa sPLA2 deposition than Polymacon (0.01 +/- 0.01 microg/lens; P < 0.001). Furthermore, group IIa sPLA2 deposited on Etafilcon A but not on Polymacon lenses retained its enzymatic activity. CONCLUSION: Significant differences of group IIa sPLA2 deposition were found in the 2 lenses tested. Such deposition might induce phospholipid hydrolysis in tears and thereby promote tear film instability in hydrophilic contact lens wearers.


Assuntos
Lentes de Contato Hidrofílicas , Proteínas do Olho/metabolismo , Fosfolipases A/metabolismo , Fosfolipídeos/metabolismo , Lágrimas/metabolismo , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Fosfolipases A2 do Grupo II , Humanos , Masculino , Fosfolipases A2
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