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1.
Artículo en Inglés | MEDLINE | ID: mdl-31789783

RESUMEN

We have experienced 3 consecutive cases of familial hemophagocytic lymphohistiocytosis (FHL). All affected infants had mutations in exon 3 of the perforin gene. The first had a homozygous mutation, c.1168C>T (p.R390*), caused by maternal uniparental isodisomy. The second and third had compound heterozygous mutations: c.781G>A (p.E261K) and c.1491T>A (p.C497*); c.1724G>T (p.C242G) and p.R390*, respectively. FHL is very rare in Northern Japan but should be suspected if infants exhibit prolonged fever. This is the first report of a relationship of p.R390* with FHL caused by uniparental isodisomy, and the second reported case of FHL type 2 with this form of inheritance.

2.
J Clin Endocrinol Metab ; 104(12): 6229-6237, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504637

RESUMEN

CONTEXT: Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. OBJECTIVES: To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. PATIENTS AND METHODS: Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. RESULTS: Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. CONCLUSIONS: The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.

3.
J Inherit Metab Dis ; 42(3): 501-508, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30715743

RESUMEN

Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Owing to a defect in the NADH-shuttle, citrin deficiency impairs hepatic glycolysis and de novo lipogenesis leading to hepatic energy deficit. To investigate the physiological role of citrin, we studied the growth of 111 NICCD-affected subjects (51 males and 60 females) and 12 NICCD-unaffected subjects (five males and seven females), including the body weight, height, and genotype. We constructed growth charts using the lambda-mu-sigma (LMS) method. The NICCD-affected subjects showed statistically significant growth impairment, including low birth weight and length, low body weight until 6 to 9 months of age, low height until 11 to 13 years of age, and low body weight in 7 to 12-year-old males and 8-year-old females. NICCD-unaffected subjects showed similar growth impairment, including low birth weight and height, and growth impairment during adolescence. In the third trimester, de novo lipogenesis is required for deposition of body fat and myelination of the developing central nervous system, and its impairment likely causes low birth weight and length. The growth rate is the highest during the first 6 months of life and slows down after 6 months of age, which is probably associated with the onset and recovery of NICCD. Adolescence is the second catch-up growth period, and the proportion and distribution of body fat change depending on age and sex. Characteristic growth impairment in citrin deficiency suggests a significant role of citrin in the catch-up growth via lipogenesis.

4.
J Diabetes ; 11(1): 46-54, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29877041

RESUMEN

BACKGROUND: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. METHODS: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients. RESULTS: Four heterozygous missense mutations within the ß-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment. CONCLUSIONS: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.


Asunto(s)
Acantosis Nigricans/genética , Antígenos CD/genética , Diabetes Mellitus/genética , Resistencia a la Insulina/genética , Mutación Missense , Receptor de Insulina/genética , Acantosis Nigricans/patología , Adolescente , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Diabetes Mellitus/patología , Femenino , Heterocigoto , Humanos , Masculino , Linaje , Índice de Severidad de la Enfermedad , Síndrome
5.
Appl Clin Genet ; 11: 163-170, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30588060

RESUMEN

Citrin deficiency is a recessively inherited metabolic disorder with age-dependent clinical manifestations. It causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Patients with NICCD present with intrahepatic cholestasis in the neonatal period and usually respond to the treatment with medium-chain triglyceride (MCT) supplement and lactose-restricted formula. In adulthood, CTLN2 develops in <10 % of the patients showing hyperammonemic encephalopathy. Patients with CTLN2 required liver transplantation for the most promising prognosis; however, they were successfully treated with MCT supplement with a low carbohydrate formula. Citrin deficiency is caused by mutations in SLC25A13 on chromosome 7q21.3, with a high frequency in East Asia, including Japan. Citrin is aspartate/glutamate transporter in mitochondria, a component of malate-aspartate nicotinamide adenine dinucleotide hydrogen shuttle, and is essential for the hepatic glycolysis. Although the precise pathophysiology of citrin deficiency remains unclear, recent reports for the effective MCT supplement therapy and downregulation of peroxisome proliferator-activated receptor α suggest that citrin deficiency impairs hepatic de novo lipogenesis coupled with glycolysis leading to the energy deficit of hepatocytes. Herein, we review the current therapeutic and pathological understanding of CTLN2.

6.
J Inherit Metab Dis ; 41(5): 777-784, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29651749

RESUMEN

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.


Asunto(s)
Carbohidratos/administración & dosificación , Citrulinemia/dietoterapia , Encefalopatía Hepática/dietoterapia , Hiperamonemia/dietoterapia , Triglicéridos/administración & dosificación , Anciano , Amoníaco/sangre , Amoníaco/metabolismo , Argininosuccinato Sintasa/metabolismo , Citrulinemia/complicaciones , Suplementos Dietéticos , Hígado Graso/etiología , Femenino , Alimentos Formulados , Hepatocitos/metabolismo , Humanos , Hiperamonemia/sangre , Trasplante de Hígado , Masculino , Persona de Mediana Edad
7.
Horm Res Paediatr ; 89(3): 166-171, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29455197

RESUMEN

BACKGROUND/AIMS: We aimed to evaluate the incidence and characteristics of adrenal crisis in Japanese children with 21-hydroxylase deficiency (21-OHD). METHODS: We conducted a retrospective nationwide survey for the councilors of the Japanese Society for Pediatric Endocrinology (JSPE) regarding adrenal crisis in children under 7 years with 21-OHD, admitted to hospitals from 2011 through 2016. We defined adrenal crisis as the acute impairment of general health due to glucocorticoid deficiency with at least two of symptoms, signs, or biochemical abnormalities. RESULTS: The councilors of the JSPE in 83 institutions responded to this survey (response rate, 60.1%). Data analyses of 378 patients with 1,101.4 person-years (PYs) revealed that 67 patients (17.7%) experienced at least 1 episode of hospital admission for adrenal crisis at the median age of 2 years. The incidence of adrenal crisis was calculated as 10.9 per 100 PYs (95% confidence interval [CI] 9.6-12.2). Infections were the most common precipitating factors, while no factor was observed in 12.5%. Hypoglycemia occurred concomitantly in 27.4%. One patient died from severe hypoglycemia, resulting in a mortality rate of 0.09 per 100 PYs (95% CI 0.0-0.2). CONCLUSION: Adrenal crisis is not rare and can be accompanied by disastrous hypoglycemia in children with 21-OHD.


Asunto(s)
Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/epidemiología , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Incidencia , Lactante , Japón/epidemiología , Masculino
8.
J Steroid Biochem Mol Biol ; 178: 177-184, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29289577

RESUMEN

Although POR deficiency (PORD) is assumed to be accompanied by excessive placental androgen accumulation and enhanced adrenal and testicular androgen production via the backdoor pathway as well as compromised testicular androgen production via the frontdoor pathway, there is no direct evidence for the flux of excessive placental androgens into the fetal circulation and for the production of dihydrotestosterone (DHT) via the backdoor pathway. We examined longitudinal serum and urine steroid metabolite profiles in a 46,XY infant with PORD who was prenatally identified because of the progressive fetal masculinization and maternal virilization from the mid-gestation and the presence of fetal radio-humeral synostosis and was confirmed to have compound heterozygous mutations of POR (p.Q201X and p.R457H). The results showed (1) markedly and inappropriately elevated serum androstenedione and testosterone (T) values at birth, (2) a markedly increased serum DHT value with a normal DHT/T ratio at birth, (3) transient elevation of serum T and DHT values accompanied by a normal DHT/T ratio and concomitant elevations of intermediate steroid metabolites on both the frontdoor and backdoor pathways at 30 days of age, and (4) persistent PORD-compatible urine steroid profiles. Although the data obtained from a single infantile patient are too premature to be generalized, they imply: (1) the transfer of excessive placental androgens into the fetal as well as the maternal circulations from the mid-gestation, (2) lack of a clinically discernible amount of DHT production via the adrenal backdoor pathway around birth, and (3) the activation of both the frontdoor and backdoor pathways in the testis around the mini-puberty, with no production of a clinically discernible amount of DHT via the testicular backdoor pathway.


Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Trastorno del Desarrollo Sexual 46,XY/genética , Enfermedades Fetales/diagnóstico , Esteroide 17-alfa-Hidroxilasa/metabolismo , Esteroides/sangre , Esteroides/orina , Fenotipo del Síndrome de Antley-Bixler/sangre , Fenotipo del Síndrome de Antley-Bixler/genética , Fenotipo del Síndrome de Antley-Bixler/orina , Trastorno del Desarrollo Sexual 46,XY/patología , Femenino , Enfermedades Fetales/sangre , Enfermedades Fetales/genética , Enfermedades Fetales/orina , Humanos , Lactante , Estudios Longitudinales , Embarazo , Diagnóstico Prenatal , Pronóstico , Esteroide 17-alfa-Hidroxilasa/genética
9.
Clin Pediatr Endocrinol ; 26(4): 207-213, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29026269

RESUMEN

Septo-optic dysplasia (SOD) is a congenital anomaly in which agenesis of the septum pellucidum and optic nerve hypoplasia are accompanied by hypopituitarism. Typically, the symptoms develop in 3 organs, the brain, eyes, and pituitary, and approximately one third of the patients present with all of the three cardinal features. The diagnostic criteria for SOD were established in Japan in 2015. The purpose of this study is to review clinical features regarding SOD patients with hypopituitarism in Japan. In this study, 21 patients with SOD were identified by a questionnaire survey for congenital central hypothyroidism. All 3 symptoms of SOD, agenesis of the septum pellucidum, optic nerve hypoplasia, and endocrine abnormalities, were noted in 8 of the 21 patients. Various combinations of pituitary hormone deficiencies were observed in patients with SOD, although SOD is a rare, heterogeneous, and phenotypically variable disorder, some patients develop hypoglycemia and convulsions after birth, and early intervention with hormone replacement is necessary in severe cases. In addition, 14 cases were complicated by both developmental delay and epilepsy, and 16 cases involved eye abnormalities. Therefore, in addition to an early endocrinological diagnosis and hormone replacement, consultation with both pediatric neurologists and pediatric ophthalmologists is necessary.

10.
Genet Med ; 19(12): 1356-1366, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28640239

RESUMEN

PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14.MethodsWe performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported.ResultsWe identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader-Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS-like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older.ConclusionThese results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2.


Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 14 , Impresión Genómica , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Facies , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Gráficos de Crecimiento , Humanos , Lactante , Japón , Masculino , Persona de Mediana Edad , Embarazo , Adulto Joven
11.
Pediatr Diabetes ; 18(8): 917-924, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28181734

RESUMEN

BACKGROUND: Defects of the insulin receptor gene ( INSR ) cause wide spectra of congenital insulin resistance. Monoallelic defects result in milder insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN, type A). Whereas, leprechaunism (Donahue syndrome), the most severe condition with lethality during the infantile period is caused by biallelic defects of INSR . MATERIALS AND METHODS: We detected 2 missense mutations in 2 cases of leprechaunism and IRAN, type A, and reduced mRNA expression in the leprechaunism case. We performed an in vitro analysis to confirm that the 2 missense mutations are causative. RESULTS: The heterozygote mutations c.3436G>A (p.Gly1146Arg) and c.294C>A (p.Ser98Arg) were identified in a male patient with IRAN, type A and a female patient with leprechaunism, respectively. Gly1146Arg was previously reported in a diabetic case without precise functional analyses, and Ser98Arg is a novel mutation. Gly1146 and Ser98 are located on the tyrosine kinase domain and ligand-binding domain of INSR, respectively, and in vitro analyses (assay for insulin binding and phosphorylation) revealed that each mutation disrupted protein functions and properties. In the leprechaunism case, mutations in INSR other than Ser98Arg were not identified, and qRT-PCR analysis revealed that mRNA expression of INSR in lymphocytes was reduced in the leprechaunism case. CONCLUSION: Our study indicates that the 2 missense mutations of INSR , Gly1146Arg, and Ser98Arg, are responsible for insulin resistance, and, suggests that mutations not contained within INSR , but leading to decreased INSR expression should be considered for the patients who show insulin resistance without any mutations in the coding sequence of INSR.


Asunto(s)
Acantosis Nigricans/genética , Antígenos CD/genética , Diabetes Mellitus/genética , Síndrome de Donohue/genética , Resistencia a la Insulina/genética , Receptor de Insulina/genética , Antígenos CD/metabolismo , Niño , Femenino , Expresión Génica , Humanos , Recién Nacido , Masculino , Mutación Missense , Estabilidad Proteica , Receptor de Insulina/metabolismo
12.
Hum Mutat ; 38(6): 637-648, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28229514

RESUMEN

Weaver syndrome (WS) is a rare congenital overgrowth disorder caused by heterozygous mutations in EZH2 (enhancer of zeste homolog 2) or EED (embryonic ectoderm development). EZH2 and EED are core components of the polycomb repressive complex 2 (PRC2), which possesses histone methyltransferase activity and catalyzes trimethylation of histone H3 at lysine 27. Here, we analyzed eight probands with clinically suspected WS by whole-exome sequencing and identified three mutations: a 25.4-kb deletion partially involving EZH2 and CUL1 (individual 1), a missense mutation (c.707G>C, p.Arg236Thr) in EED (individual 2), and a missense mutation (c.1829A>T, p.Glu610Val) in SUZ12 (suppressor of zeste 12 homolog) (individual 3) inherited from her father (individual 4) with a mosaic mutation. SUZ12 is another component of PRC2 and germline mutations in SUZ12 have not been previously reported in humans. In vitro functional analyses demonstrated that the identified EED and SUZ12 missense mutations cause decreased trimethylation of lysine 27 of histone H3. These data indicate that loss-of-function mutations of PRC2 components are an important cause of WS.


Asunto(s)
Anomalías Múltiples/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Proteínas Cullin/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Deformidades Congénitas de la Mano/genética , Complejo Represivo Polycomb 2/genética , Anomalías Múltiples/patología , Adulto , Niño , Preescolar , Hipotiroidismo Congénito/patología , Anomalías Craneofaciales/patología , Proteínas de Unión al ADN/genética , Femenino , Deformidades Congénitas de la Mano/patología , Heterocigoto , Histonas/genética , Humanos , Masculino , Metilación , Mutación , Linaje , Mapas de Interacción de Proteínas
13.
J Pediatr Endocrinol Metab ; 30(1): 117-121, 2017 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-27935852

RESUMEN

Acromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) ß-binding protein-like domain 5 of the fibrillin 1 gene (FBN1), which is also mutated in Marfan syndrome. In the present study, we report and compare the highly varied clinical and radiological features of three Japanese AD/GD children. Our patients, harboring FBN1 mutations p.Tyr1699Cys, p.Ser1750Arg, and p.Gly1762Ser, shared common clinical symptoms such as severe short stature, acromelia and hepatomegaly. Short tubular bones of hands and deformities of femur heads are common radiological features of our patients.


Asunto(s)
Enfermedades del Desarrollo Óseo/genética , Fibrilina-1/genética , Hepatomegalia/genética , Deformidades Congénitas de las Extremidades/genética , Mutación/genética , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/patología , Niño , Preescolar , Femenino , Hepatomegalia/diagnóstico por imagen , Hepatomegalia/patología , Humanos , Japón , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/patología , Masculino , Pronóstico , Radiografía/métodos
14.
Tohoku J Exp Med ; 240(4): 323-328, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-28003588

RESUMEN

Citrin deficiency, an inherited defect of the liver-type mitochondrial aspartate/glutamate carrier isoform (citrin), may cause impairment of glycolysis because of an increase in the cytosolic NADH/NAD+ ratio. We report a Japanese boy whose main complaint was recurrent hypoglycemic episodes. He was suspected as having citrin deficiency because of his peculiar preference for protein- and fat-rich food. His young sister also had a similar food preference. Both siblings were diagnosed with citrin deficiency by genetic analysis. The brother and sister underwent an oral glucose tolerance test (OGTT) at 10 and 7 yr of age, respectively. Blood glucose, ammonia, lactic acid, pyruvic acid, and insulin levels were monitored before starting the test, and then every 30 min. During this test, they maintained blood glucose levels until 180 min. At 210 min, they experienced vomiting, feeling ill, and decreased blood glucose levels (2.9 and 2.8 mmol/l in the brother and sister, respectively). The sister and brother recovered uneventfully by intravenous glucose injection. In a second OGTT, 4 months after medium-chain triglyceride (MCT) oil supplementation, they had no major symptoms and normal glucose levels were maintained, even after 240 min. Additionally, after MCT oil therapy, their food preference slightly changed as they started eating more carbohydrates. Our OGTT data suggest excess carbohydrate intake has adverse consequences in patients with citrin deficiency, including hypoglycemia after a few hours. MCT oil therapy may be effective in preventing such hypoglycemia and improving metabolic derangement, even during the so-called apparently healthy period.


Asunto(s)
Proteínas de Unión al Calcio/deficiencia , Aceites/uso terapéutico , Transportadores de Anión Orgánico/deficiencia , Hermanos , Triglicéridos/uso terapéutico , Niño , Femenino , Preferencias Alimentarias , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Autoinforme , Encuestas y Cuestionarios
15.
Brain Nerve ; 67(6): 739-47, 2015 Jun.
Artículo en Japonés | MEDLINE | ID: mdl-26062589

RESUMEN

Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, a small number of adults with citrin deficiency develop adult-onset type II citrullinemia (CTLN2), which causes hyperammonemic encephalopathy leading to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. Hepatic glycolysis is coupled with hepatic lipogenesis via the NADH shuttles composed of the malate-aspartate shuttle and malate-citrate shuttle. Citrin deficiency is expected to impair glycolysis and lipogenesis in hepatocytes. We noticed that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. We extended this therapy for CTLN2 and found that an MCT supplementation therapy under a low-carbohydrate formula prevented the relapse of hyperammonemic encephalopathy, normalized the liver dysfunction (including the Fisher ratio), and gradually improved the level of plasma citrulline and fatty liver. An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to improvement of the cytosolic NAD+/NADH ratio via the malate-citrate shuttle. MCT supplementation could be a promising therapy for citrin deficiency.


Asunto(s)
Citrulinemia/tratamiento farmacológico , Triglicéridos/uso terapéutico , Adulto , Citrulinemia/metabolismo , Humanos , Lactante
16.
Diabetes Res Clin Pract ; 108(3): e53-5, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25819479

RESUMEN

The HNF4A p.R76W mutation causes congenital hyperinsulinism with Fanconi syndrome. Here, we report two cases who also presented with increased urinary calcium excretion and one had a transient hepatic dysfunction with hepatomegaly. Clinical variations including transient liver dysfunction is a likely mutation-specific clinical characteristic.


Asunto(s)
Calcio/orina , Hiperinsulinismo Congénito/complicaciones , Síndrome de Fanconi/complicaciones , Factor Nuclear 4 del Hepatocito/genética , Hepatomegalia/etiología , Hiperinsulinismo Congénito/genética , Hiperinsulinismo Congénito/orina , Síndrome de Fanconi/genética , Síndrome de Fanconi/orina , Hepatomegalia/diagnóstico , Humanos , Recién Nacido , Masculino , Mutación Missense , Nefrocalcinosis/complicaciones , Nefrocalcinosis/genética
17.
Bone Rep ; 3: 57-60, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28377967

RESUMEN

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was originally reported as a responsible gene for generalized arterial calcification in infancy (GACI). Though the prognosis of GACI patients is poor because of myocardial infarction and heart failure in relation to medial calcification of the coronary arteries, some patients rescued by bisphosphonate treatment have been reported. Recently, ENPP1 is also reported as responsible for autosomal recessive hypophosphatemic rickets type 2. We show here a boy with homozygous ENPP1 mutations diagnosed as having GACI in early infancy. After the diagnosis, he was treated with etidronate disodium (EHDP) in combination with antihypertensive drugs. The calcification of major arteries was diminished and disappeared by the age of eight months. He also showed mild hypophosphatemia (2.6-3.7 mg/dl) from the age of one year. After the treatment with EHDP for five years, he showed genu valgum with hypophosphatemia (2.6 mg/dl). He was diagnosed as having hypophosphatemic rickets at the age of seven years. The findings that hyper-mineralization of the arteries and hypo-mineralization of the bone observed in the same patient are noteworthy. ENPP1 could be regarded as a controller of the calcification of the whole body at least in part.

18.
Hum Genome Var ; 1: 15016, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-27081516

RESUMEN

Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth.

19.
Ann Clin Transl Neurol ; 1(2): 135-40, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25356393

RESUMEN

The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD.

20.
Am J Hum Genet ; 95(3): 294-300, 2014 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-25152455

RESUMEN

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.


Asunto(s)
Axones/fisiología , Enfermedad de Charcot-Marie-Tooth/genética , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/fisiología , Genes Recesivos/genética , Atrofia Muscular/genética , Mutación/genética , Adulto , Animales , Consanguinidad , Electrofisiología , Femenino , Ligamiento Genético , Humanos , Escala de Lod , Masculino , Ratones , Ratones Noqueados , Linaje , Fenotipo , Empalme del ARN/genética
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