RESUMEN
Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.
Asunto(s)
Cromosomas Humanos Par 7/genética , Cromosomas Humanos Y/genética , Trastornos del Desarrollo Sexual/genética , Genes sry/genética , Enfermedades Testiculares/genética , Translocación Genética/genética , Adulto , Puntos de Rotura del Cromosoma , Femenino , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipo , Masculino , Adulto JovenRESUMEN
BACKGROUND: Given that nutritional biotin deficiency in Japanese infants has been reported, a straightforward method for estimating biotin level is needed. The biotin content in infant formula, breast milk, and the sera of infants fed with various types of formula were measured using avidin-binding assay. METHODS: A commercially available ELISA kit was used for the measurement of biotin in 54 types of formula, including hydrolysate formulas for milk allergy, as well as in breast milk and in the sera of 27 infants fed with these formulas. RESULTS: The biotin content reached the recommended value in only five formulas. All of the hydrolysate formulas and more than half of the special formulas contained biotin <0.1 µg/dL. Serum biotin was low in infants fed only with the hydrolysate formulas, and one of them had alopecia related to biotin deficiency. CONCLUSION: While many were asymptomatic, infants fed with formulas lacking biotin are at risk of developing symptomatic disease. The addition of biotin to breast milk substitutes was finally approved in the middle of 2014, however pediatricians in Japan should still be vigilant with regard to nutritional biotin deficiency in infants for the time being.
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Biotina/sangre , Fórmulas Infantiles/química , Fenómenos Fisiológicos Nutricionales del Lactante/fisiología , Estado Nutricional , Hidrolisados de Proteína/administración & dosificación , Adulto , Biotina/farmacocinética , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Japón , MasculinoRESUMEN
BACKGROUND: Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults. METHODS: Serum biotin in 188 healthy Japanese children aged 0-4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined. RESULTS: Median biotin in children aged 0-4 years was 10.4 ng/dL (IQR, 7.9-13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8-15.8 ng/dL). Normal range was 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze-thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples. CONCLUSIONS: Serum biotin was significantly lower in children than in adults, with the normal range being 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency.
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Biotina/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Hipersensibilidad a la Leche/sangre , Adulto , Compuestos de Cetrimonio , Preescolar , Combinación de Medicamentos , Femenino , Humanos , Lactante , Recién Nacido , Japón/epidemiología , Masculino , Hipersensibilidad a la Leche/diagnóstico , Hipersensibilidad a la Leche/epidemiología , Miristatos , Ácidos Nicotínicos , Reproducibilidad de los Resultados , Simeticona , Ácidos EsteáricosRESUMEN
Zellweger syndrome, one of the peroxisome biogenesis disorders, is an autosomal recessive disease caused by mutations in PEX genes. It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. PEX14 is the 13th PEX gene responsible for peroxisome biogenesis disorders. Thus far, only two patients with PEX14 deficiency have been reported. Here, we report the first case of a Japanese patient with a PEX14 mutation who showed severe hypotonia, psychomotor retardation, demyelination, and developed rickets at the age of 5 months. An increased excretion of 3,6-epoxydicarboxylic acids leads to the diagnosis of Zellweger syndrome and a mutation analysis of PEX14 revealed a homozygous mutation of c.538C>T (p.Q180X). The patient survived for a prolonged period of time but died of liver failure at the age of 46 months.
Asunto(s)
ADN/genética , Proteínas de la Membrana/genética , Mutación , Proteínas Represoras/genética , Síndrome de Zellweger/genética , Análisis Mutacional de ADN , Resultado Fatal , Humanos , Recién Nacido , Japón , Masculino , Proteínas de la Membrana/metabolismo , Proteínas Represoras/metabolismo , Síndrome de Zellweger/metabolismoRESUMEN
OBJECTIVE: To examine levels of lactate (LA) and pyruvate (PA) in both blood and cerebrospinal fluid (CSF) in patients with Menkes disease (MNK). STUDY DESIGN: A nationwide survey involving a retrospective review of medical records or medical record summaries of 42 male patients with MNK born between 1993 and 2008 were performed, and the genetic analysis of their ATP7A gene was reviewed. RESULTS: In these patients, LA and PA levels and the lactate vs pyruvate ratio (L/P ratio) at diagnosis in both blood and CSF were abnormally high. There were no significant differences in LA levels, PA levels, and the L/P ratio between blood and CSF at diagnosis (P > .05). There was also no correlation between LA levels, PA levels, and the L/P ratio, and age at measurement (P > .05). There was no or slight metabolic acidosis, as analyzed by blood gas analysis, in 7 patients. During treatment with subcutaneous injections of copper-histidine, LA and PA levels and the L/P ratio in both the blood and CSF decreased. CONCLUSION: Our findings suggest that LA and PA levels, and in particular, the L/P ratio, and blood gas analysis can be used to guide the diagnosis and management of MNK.
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Ácido Láctico/sangre , Ácido Láctico/líquido cefalorraquídeo , Síndrome del Pelo Ensortijado/sangre , Síndrome del Pelo Ensortijado/líquido cefalorraquídeo , Ácido Pirúvico/sangre , Ácido Pirúvico/líquido cefalorraquídeo , Niño , Preescolar , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.
Asunto(s)
Exoma , Ligamiento Genético , Bocio/genética , Análisis de Secuencia de ADN/métodos , Secuencia de Aminoácidos , Pueblo Asiatico/genética , Estudios de Casos y Controles , Clonación Molecular , Hipotiroidismo Congénito/genética , Bases de Datos Genéticas , Femenino , Frecuencia de los Genes , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Japón , Masculino , Datos de Secuencia Molecular , Linaje , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de SecuenciaRESUMEN
Release of growth hormone (GH) from the somatotroph is regulated by binding GH-releasing hormone (GHRH) to its cognate receptor (GHRHR), one of the members of the G protein-coupled receptor (GPCR) superfamily. Proteins bound to the carboxy (C)-terminus of GPCR have been reported to regulate intracellular trafficking and function of the receptor; however, no functionally significant protein associated with GHRHR has been reported. We have identified a protein interacting with C-kinase 1 (PICK1) as a binding partner of GHRHR. In vitro binding assay revealed the PDZ-domain of PICK1 and the last four amino acid residues of GHRHR were prerequisite for the interaction. Further, in vivo association of these proteins was confirmed. Immunostaining data of a stable cell line expressing GHRHR with or without PICK1 suggested the C-terminus of GHRHR promoted cell surface expression of GHRHR and PICK1 affected the kinetics of the cell surface expression of GHRHR. Furthermore, cAMP production assay showed the C-terminus of GHRHR is involved in the regulation of receptor activation, and the interaction of GHRHR with PICK1 may influence intensities of the signal response after ligand stimulation. Thus, the interaction of the C-terminus of GHRHR with PICK1 has a profound role in regulating the trafficking and the signaling of GHRHR. [Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.12287FP].
Asunto(s)
Proteínas Portadoras/fisiología , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hormona Liberadora de Hormona del Crecimiento/fisiología , Proteínas Nucleares/fisiología , Dominios PDZ/fisiología , Receptores de Hormona Reguladora de Hormona Hipofisaria/metabolismo , Receptores de Hormona Reguladora de Hormona Hipofisaria/fisiología , Transducción de Señal/fisiología , Animales , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto , Humanos , Masculino , Proteínas Nucleares/metabolismo , Unión Proteica , Transporte de Proteínas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Transient neonatal diabetes mellitus (TNDM) is a rare condition that is characterized by the presence of diabetes mellitus during the first 6 months of life and remission by 18 months of age. It usually relapses at a median age of 14 years. Hyperinsulinaemic hypoglycaemia is a relatively common complication during remission. Although ß-cell function is reported to be impaired at relapse, the clinical course of glycaemic profiles during remission in patients with TNDM remains largely unknown. CASE PRESENTATION: Longitudinal glycaemic profiles were investigated annually from remission (185 days) to relapse (14.5 years) in a patient with TNDM due to paternal 6q24 duplication using the oral glucose tolerance test (glucose intake: 1.75 g/kg to a maximum of 75 g). The patient's ß-cell function and insulin sensitivity were assessed by calculating the insulinogenic index, homeostasis model assessment of ß-cell function (HOMA-ß), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index, and Matsuda index. Early insulin response to glucose intake was impaired throughout remission, whereas fasting insulin and ß-cell function by HOMA-ß gradually increased in the first few years since remission, followed by a gradual decline in function. In contrast, HOMA-IR fluctuated and peaked at 6.5 years of age. CONCLUSION: This is the first report of annual longitudinal glycaemic profiles in a patient with 6q24-related TNDM during remission. We identified fluctuations in ß-cell function and insulin resistance during remission.
Asunto(s)
Glucemia/fisiología , Diabetes Mellitus/fisiopatología , Hiperinsulinismo , Resistencia a la Insulina , Adolescente , Glucemia/análisis , Diabetes Mellitus/congénito , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo/complicaciones , Lactante , Recién Nacido , Enfermedades del Recién Nacido , Masculino , Enfermedades Raras , Remisión EspontáneaRESUMEN
The essential trace element zinc maintains liver functions. Liver diseases can alter overall zinc concentrations, and hypozincemia is associated with various hepatic pathologies. Modulating systemic zinc through dietary supplementation is potentially useful for liver diseases. We evaluated the usefulness of zinc (NPC-02; acetate formulation) supplementation. We conducted two NPC-02 studies on zinc-deficient patients (serum zinc < 70 µg/dL). Study 1: double-blind, randomized, placebo-controlled trial on 57 subjects with chronic liver diseases comparing serum zinc in patients given NPC-02 (NPC-02 group) versus placebo (Placebo group). Study 2: dose adjustment study on 43 subjects with/without liver diseases to determine proportions maintaining serum zinc target (≥ 80 µg/dL but < 200 µg/dL). In study 1, NPC-02 subjects had higher serum zinc concentrations at week 8 than Placebo subjects (83.2 ± 20.2 and 61.3 ± 12.0, respectively; P < 0.0001), and more NPC-02 than Placebo subjects achieved the serum zinc target (15/27 vs. 1/26). In study 2, the NPC-02-induced serum zinc increase was dose-dependent in subjects both with and without liver diseases (r = 0.5143, P = 0.0022 and r = 0.5753, P = 0.0005, respectively). Interestingly, there was a marginally positive correlation between serum zinc and albumin levels in subjects with but not in those without liver diseases (r = 0.4028, P = 0.0631 and r = 0.1360, P = 0.5567, respectively). NPC-02 dose-dependently increases serum zinc in hypozincemic patients, regardless of liver disease. NPC-02 is a potentially effective therapy for liver cirrhosis, in which zinc deficiency is common. Clinical trial registry number: NCT02337569, NCT02321865.
Asunto(s)
Hepatopatías/sangre , Acetato de Zinc/sangre , Zinc/sangre , Anciano , Enfermedad Crónica , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Acetato de Zinc/administración & dosificaciónRESUMEN
OBJECTIVE: To identify those infants who need a higher starting dose of levothyroxine (l-T4) for early normalization of thyroid-stimulating hormone (TSH) level. STUDY DESIGN: TSH levels at 2 time points (1 to 3 weeks and 3 to 5 weeks) after l-T4 therapy at a starting dose of 8 to 12 microg/kg/day were evaluated retrospectively in 22 hypothyroid infants screened for congenital hypothyroidism (CH) in terms of etiology as determined by ultrasonography (US), the size of distal femoral epiphysis (DFE), and initial thyroid function. RESULTS: The infants with a noneutopic thyroid or small DFE exhibited significantly higher posttherapeutic TSH levels compared with the other infants. Eight of the 9 infants who failed to achieve normalized TSH values at 1 to 3 weeks had noneutopic thyroid. All of the infants with eutopic thyroid exhibited normalized TSH at 3 to 5 weeks, and a significantly greater proportion of the infants with eutopic thyroid exhibited normalized TSH at 1 to 3 weeks compared with those with noneutopic thyroid. Stepwise regression analysis demonstrated that US etiology was a significant independent variable for normalization of TSH at 1 to 3 weeks. CONCLUSIONS: US examination to identify eutopic or noneutopic thyroid provides useful information for determining the starting dose of l-T4 in hypothyroid infants.
Asunto(s)
Hipotiroidismo Congénito/diagnóstico por imagen , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/patología , Tirotropina/sangre , Tiroxina/uso terapéutico , Ultrasonografía/métodos , Huesos/metabolismo , Hipotiroidismo Congénito/diagnóstico , Femenino , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , Pediatría/métodos , Estudios Retrospectivos , Pruebas de Función de la Tiroides/métodosRESUMEN
A 17-day-old Japanese boy was transferred to the hospital because of vomiting and impaired consciousness. His external genitalia was pigmented associated with small penis and penoscrotal hypospadias. He was diagnosed as suffering from adrenal deficiency according to severe electrolyte abnormality, moderate hypoglycemia, metabolic acidosis and extremely elevated 17-OHP and testosterone levels. He turned out to be a compound heterozygote of CYP21A2 mutations by genetic analysis. Through endocrinological evaluation, he seemed to have normal hypophyseal function, intact testosterone production and appropriate 5-alpha-reductase-2 activity. Partial androgen insensitivity could not be ruled out by slight decrease of SHBG in hCG loading test, although mutation was not detected on androgen receptor gene. This is a rare case of a male patient with 21-hydroxylase deficiency accompanied by hypospadias. As the cause of hypospadias in this case has yet to be elucidated, further investigation and careful follow-up are required.
Asunto(s)
Hiperplasia Suprarrenal Congénita/complicaciones , Hipospadias/complicaciones , Hipospadias/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Análisis Mutacional de ADN , Humanos , Hipospadias/genética , Recién Nacido , Masculino , Esteroide 21-Hidroxilasa/genética , Desequilibrio Hidroelectrolítico/etiología , Desequilibrio Hidroelectrolítico/genéticaRESUMEN
We describe the case of a girl diagnosed with Graves' disease (GD) at 2 yr of age, who developed early puberty. Preoperative examination for craniosynostosis revealed thyrotoxicosis. While she was tall and her bone age was advanced at GD onset, her linear growth attenuated after commencement of anti-thyroid treatment. However, at approximately 6 yr of age, breast budding was recognized. Hormonal analysis revealed pubertal levels of LH response to a GnRH stimulation test and serum E2. Gonadal suppression therapy with GnRH agonist was initiated, and her adult stature slightly exceeded the genetic potential. Although accelerated growth and skeletal maturation are often reported to occur at GD onset in prepubertal patients, early puberty is unusual, and this is the first reported case of sexual precocity in a girl with GD.
RESUMEN
Recent studies have demonstrated that gut microbiota development influences infants' health and subsequent host physiology. However, the factors shaping the development of the microbiota remain poorly understood, and the mechanisms through which these factors affect gut metabolite profiles have not been extensively investigated. Here we analyse gut microbiota development of 27 infants during the first month of life. We find three distinct clusters that transition towards Bifidobacteriaceae-dominant microbiota. We observe considerable differences in human milk oligosaccharide utilization among infant bifidobacteria. Colonization of fucosyllactose (FL)-utilizing bifidobacteria is associated with altered metabolite profiles and microbiota compositions, which have been previously shown to affect infant health. Genome analysis of infants' bifidobacteria reveals an ABC transporter as a key genetic factor for FL utilization. Thus, the ability of bifidobacteria to utilize FL and the presence of FL in breast milk may affect the development of the gut microbiota in infants, and might ultimately have therapeutic implications.
Asunto(s)
Bacterias/clasificación , Microbioma Gastrointestinal/fisiología , Oligosacáridos/metabolismo , Trisacáridos/metabolismo , Bacterias/genética , Bacterias/metabolismo , Heces/microbiología , Tracto Gastrointestinal/microbiología , Genoma Bacteriano , Humanos , Recién NacidoRESUMEN
Cholesterol side-chain cleavage enzyme (P450scc) catalyzes the conversion of cholesterol to pregnenolone in mitochondria, which is the first step in the biosynthesis of all steroid hormones. Until now, no homozygous or compound heterozygous mutations in CYP11A have been described in humans. Here we describe novel compound heterozygous mutations in CYP11A in a patient with congenital adrenal insufficiency born to healthy parents. One mutation, a maternally inherited R353W mutation, resulted in markedly reduced P450scc activity by the single amino acid substitution, indicating that Arg(353) is a crucial amino acid residue for P450scc activity. The other mutation, a de novo A189V mutation in the paternal allele, did not affect the P450scc activity by the single amino acid substitution and turned out to be a splicing mutation, which created a novel alternative splice-donor site. It resulted in a deletion of 61 nucleotides in the open reading frame and thus partially inactivated CYP11A. These experimental data are consistent with the clinical findings indicating that the patient had partially preserved ability to synthesize adrenal steroid hormones. This is the first report of the compound heterozygote for the CYP11A mutations with congenital adrenal insufficiency and the phenotypically normal heterozygote in humans.
Asunto(s)
Insuficiencia Suprarrenal/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Glándulas Suprarrenales/enzimología , Insuficiencia Suprarrenal/congénito , Sustitución de Aminoácidos , Análisis Mutacional de ADN , Femenino , Haplotipos , Heterocigoto , Humanos , Lactante , Repeticiones de Microsatélite , Mutación , FenotipoRESUMEN
Subacute thyroiditis is extremely rare during childhood. We treated a 10 year-old prepubertal girl who presented with typical clinical features of subacute thyroiditis. Considering this case and previous reports in children, we characterized the clinical features of this disorder as it occurs in childhood. In contrast to the predominance of subacute thyroiditis in adults, the incidence of subacute thyroiditis is lower than that of acute suppurative thyroiditis in children. This may cause difficulty with differential diagnosis, particularly when leukocytosis is present or the lesion is localized to the left lobe. Ultrasonography can be helpful in differentiation.
Asunto(s)
Tiroiditis Subaguda/patología , Antiinflamatorios no Esteroideos/uso terapéutico , Proteína C-Reactiva/metabolismo , Niño , Diagnóstico Diferencial , Femenino , Humanos , Dolor/etiología , Pruebas de Función de la Tiroides , Hormonas Tiroideas/sangre , Tiroiditis Subaguda/complicaciones , Tiroiditis Subaguda/diagnósticoRESUMEN
OBJECTIVE: To explore the changes in the body weight and height of Menkes disease (MNK) patients treated with long-term copper-histidine. METHODS: A survey involving a retrospective review of medical records or summaries of MNK patients was conducted. Patients were 44 males born after 1994, and their feeding method and genetic analysis of the ATP7A gene were reviewed. We compared the data of body weight and height from birth until 6 years between classical MNK patients and the general population obtained from national data and between patients who received early treatment and patients who received late treatment. RESULTS: Although five patients who received early treatment reached some developmental milestones, the body weight and height did not differ from patients who received late treatment in the mode of oral nutrition, and were lower in comparison to the national data (<3 percentile). CONCLUSION: We reported changes in the body weight and height of MNK patients who received early and late treatment. Although early treatment with copper-histidine had favorable effects on neurological development, it did not result in improvements in body weight and height. We suggest that the establishment of sufficient nutritional support is necessary along with early parenteral copper treatment to improve whole body condition in MNK patients.
Asunto(s)
Estatura/fisiología , Peso Corporal/fisiología , Síndrome del Pelo Ensortijado/fisiopatología , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
The clinical and biochemical effects of disulfiram were evaluated in three boys with the disorders characterized by copper deficiency due to the defect of ATP7A. Two suffered from Menkes disease (MD) and one from occipital horn syndrome. Disulfiram was orally given, in addition to a parenteral administration of copper-histidine in the case of MD patients. Serum levels of copper and ceruloplasmin slightly increased in one MD patient, and he showed favorable emotional expression and behavior more often than before according to his caretakers. However, no obvious changes were observed in the other two patients. Serum ratios of noradrenaline to dopamine, and adrenaline to dopamine, which are thought to be the indicators of dopamine ß-hydroxylase activity, one of the copper requiring enzymes, were unaltered after disulfiram treatment. No adverse effects were recognized during the treatment period in all patients. Although the major improvement was not observed clinically or biochemically by disulfiram treatment so far, the trial will be continued to see the possible effects in these disorders with copper transport defect.
Asunto(s)
Cutis Laxo/tratamiento farmacológico , Disulfiram/uso terapéutico , Síndrome de Ehlers-Danlos/tratamiento farmacológico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Adolescente , Adulto , Ceruloplasmina/metabolismo , Cobre/sangre , Cutis Laxo/sangre , Dopamina/sangre , Síndrome de Ehlers-Danlos/sangre , Humanos , Masculino , Síndrome del Pelo Ensortijado/sangre , Norepinefrina/sangre , Ácido Vanilmandélico/orina , Adulto JovenRESUMEN
Menkes disease (MD) is a genetic neurodegenerative disorder characterized by copper deficiency due to a defect in ATP7A. Standard treatment involves parenteral copper-histidine administration. However, the treatment is ineffective if initiated after two months of age, because the administered copper accumulates in the blood-brain barrier and is not transported to neurons. To resolve this issue, we investigated the effects of a combination therapy comprising copper and disulfiram, a lipophilic chelator, in the macular mouse, an animal model of MD. Seven-day-old macular mice treated subcutaneously with 50 µg of CuCl(2) on postnatal day 4 were used. The mice were given a subcutaneous injection of CuCl(2) (10 µg) with oral administration of disulfiram (0.3mg/g body weight) twice a week until eight weeks of age, and then sacrificed. Copper concentrations in the cerebellum, liver, and serum of treated macular mice were significantly higher than those of control macular mice, which received only copper. Mice treated with the combination therapy exhibited higher cytochrome c oxidase activity in the brain. The ratios of noradrenaline and adrenaline to dopamine in the brain were also increased by the treatment, suggesting that dopamine ß-hydroxylase activity was improved by the combination therapy. Liver and renal functions were almost normal, although renal copper concentration was higher in treated macular mice than in controls. These results suggest that disulfiram facilitates the passage of copper across the blood-brain barrier and that copper-disulfiram combination therapy may be an effective treatment for MD patients.
Asunto(s)
Cobre/uso terapéutico , Disulfiram/uso terapéutico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Síndrome del Pelo Ensortijado/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Cobre/sangre , Cobre/metabolismo , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Masculino , Síndrome del Pelo Ensortijado/sangre , RatonesRESUMEN
Combined 17alpha-hydroxylase/17,20-lyase deficiency is caused by a defect of P450c17 that catalyzes both 17alpha-hydroxylase and 17,20-lyase reactions in adrenal glands and gonads. In the present study, we analyzed the CYP17A1 gene in a Japanese girl with 17alpha-hydroxylase/17,20-lyase deficiency. The patient was referred to us for clitoromegaly at the age of 3 years. The karyotype was 46,XY. The patient was diagnosed as having 17alpha-hydroxylase/17,20-lyase deficiency based on the clinical and laboratory findings. Analysis of the CYP17A1 gene revealed a compound heterozygous mutation. One mutation was a deletion of codon 53 or 54 encoding Phe (TTC) in exon 1 (DeltaF54) on a maternal allele, which has been previously shown to partially abolish both 17alpha-hydroxylase and 17,20-lyase activities. The other was a novel missense mutation resulting in a substitution of Asn (AAC) for His (CAC) at codon 373 in exon 6 (H373N) on a paternal allele. Functional expression study demonstrated that the H373N mutation almost completely eliminates enzymatic activity. Previous studies have demonstrated that replacement of histidine by leucine at position 373 causes complete loss of both 17alpha-hydroxylase and 17,20-lyase activities with a defect in heme binding due to a global alteration of P450c17 structure, indicating the importance of H373 for P450c17 structure and function. Together, these results indicate that the patient is a compound heterozygote for the DeltaF54 and H383N mutations and that these mutations inactivate both 17alpha-hydroxylase and 17,20-lyase activities and give rise to clinically manifest combined 17alpha-hydroxylase/17,20-lyase deficiency.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Mutación , Esteroide 17-alfa-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/enzimología , Animales , Células COS , Preescolar , Chlorocebus aethiops , Femenino , Heterocigoto , Humanos , Mutación Missense , Eliminación de Secuencia , TransfecciónRESUMEN
We report on a 14 7/12-year-old Japanese female patient with CHARGE syndrome and CHD7 mutation who also exhibited Kallmann syndrome (KS) phenotype. She had poor pubertal development and apparently impaired sense of smell. A GnRH test showed severely compromised responses of LH (<0.5 --> <0.5 IU/L) and FSH (<0.5 --> 1.2 IU/L), and magnetic resonance imaging delineated hypoplastic olfactory bulbs. Mutation analysis revealed a heterozygous nonsense mutation at exon 33 of CHD7 (7027C>T, Q2343X). The results provide further support for the notion that KS phenotype can be included in the phenotypic spectrum of CHARGE syndrome, and indicate that CHARGE syndrome with KS phenotype is caused by a CHD7 mutation.