RESUMEN
Menkes disease (MD) is an X linked recessive multi-systemic disorder of copper metabolism, resulting from an ATP7A gene mutation. We report a male infant aged 4 months who presented with kinky hair, hypopigmented skin, epilepsy and delayed development. Magnetic resonance imaging (MRI) of brain demonstrated multiple tortuosities of intracranial vessels and brain atrophy. Investigation had showed markedly decreased serum copper and ceruloplasmin. The novel c.2172+1G>T splice-site mutation in the ATP7A gene confirmed MD. He was treated with subcutaneous administration of locally prepared copper-histidine (Cu-His). Following the therapy, hair manifestation was restored and serum ceruloplasmin was normalised 1 month later. Despite the treatment, epilepsy, neurodevelopment and osteoporosis still progressed. He died from severe respiratory tract infection at the age of 9.5 months. These findings suggest that the benefit of Cu-His in our case is limited which might be related to severe presentations and degree of ATP7A mutation.
Asunto(s)
Proteínas de Transporte de Catión , Epilepsia , Síndrome del Pelo Ensortijado , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Proteínas de Transporte de Catión/genética , Ceruloplasmina/análisis , Cobre , ATPasas Transportadoras de Cobre/genética , ATPasas Transportadoras de Cobre/metabolismo , Asia Oriental , Histidina/análogos & derivados , Histidina/genética , Humanos , Lactante , Masculino , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Síndrome del Pelo Ensortijado/genética , Mutación , Compuestos Organometálicos , Fragmentos de Péptidos/metabolismoRESUMEN
PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.
Asunto(s)
Complejos de Coordinación/farmacocinética , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Tiosemicarbazonas/farmacocinética , Administración Oral , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C3H , Tamaño de la PartículaRESUMEN
Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.
Asunto(s)
Cobre/metabolismo , Hidrazinas/uso terapéutico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Animales , Transporte Biológico/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Transportador de Cobre 1/genética , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Hidrazinas/farmacología , Masculino , Síndrome del Pelo Ensortijado/metabolismo , Síndrome del Pelo Ensortijado/patología , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/prevención & control , RatasRESUMEN
BACKGROUND: Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair texture. Menkes disease is an X-linked recessive inherited disease caused by pathogenic variants in ATP7A, which leads to profound copper deficiency. METHOD: We identified an infant male who presented with prematurity, hypotonia, and dysmorphic features for whom a family history of clinical Menkes disease was revealed after discussion with the clinical genetics team. RESULTS: Although initial first-tier genetic testing identified Kdv syndrome (17q21.31 syndrome), the family history led the team to consider a second diagnostic possibility, and testing of ATP7A revealed a pathogenic variant (c.601C>T, p.R201X). CONCLUSION: Menkes disease and KdV syndrome may both present with hypotonia and abnormal hair, in addition to seizures and failure to thrive. While these genetic conditions have overlapping clinical features, they have different natural histories and different therapeutic options. Here, we report on a patient affected with both disorders and review the diagnostic and therapeutic difficulties this presented.
Asunto(s)
Anomalías Múltiples/genética , ATPasas Transportadoras de Cobre/genética , Discapacidad Intelectual/genética , Síndrome del Pelo Ensortijado/genética , Anomalías Múltiples/diagnóstico , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Hibridación Genómica Comparativa , Análisis Mutacional de ADN , Resultado Fatal , Pruebas Genéticas , Histidina/análogos & derivados , Histidina/uso terapéutico , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/terapia , Recién Nacido , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Masculino , Anamnesis , Síndrome del Pelo Ensortijado/complicaciones , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Mutación , Óxido Nítrico/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Linaje , Insuficiencia Respiratoria/genéticaRESUMEN
Menkes diseases (MD) is an X-linked recessive neurodegenerative disorder of copper metabolism, characterized by progressive multisystemic involvement. Death in the early childhood is usually observed in classical patients. Although a definite cure has not been established, copper replacement therapy administered parenterally may modify the severity of MD and permitted survival into adolescence. Subcutaneous copper-histidine supplementation is the current choice of therapy, and long-term administration is not desirable because of the expected nephrotoxicity. We report here the case of a 29-year-old male with MD who tolerated long-term intravenous copper therapy initiated at 2 months. Molecular analysis revealed hemizygous deletion mutation of ATP7A previously reported in classical MD. Although neurodevelopement is poor, no major event of central nervous system is observed, and he enjoys a good social life by interacting using gestures. Optimum management is unknown, and closed follow-up is mandatory for clarification of this phenotype.
Asunto(s)
Administración Intravenosa/métodos , Cobre/administración & dosificación , Cobre/uso terapéutico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Adulto , Esquema de Medicación , Humanos , MasculinoRESUMEN
Menkes disease is a neurodegenerative and lethal pathology caused by gene mutations of the copper-transporting ATP-7A enzyme; it manifests itself by neurological symptoms and connective tissue changes of varying severity. Timely subcutaneous use of copper histidinate (Cu-His) is determinant for quality of life. We report the first experiences in Mexico on Cu-His synthesis and its safe use in 3 cases where hypocupremia and hypoceruloplasminemia were corroborated. With advice of the Hospital for Sick Children of Toronto Canada, we prepared a 500 µg/mL solution. In all three cases were 250 µg of Cu-His applied without relevant undesirable effects for 30 days. Serum copper (Cu, expressed in µg/L) and ceruloplasmin (Cp, in mg/dL) were determined: case 1, Cu days 0 and 30, 8 and 504 µg/L; Cp days 0 and 30, 4 and 10.75 mg/dL; case 2, Cu days 0 and 30, <50 and 502 µg/L; Cp days 0 and 30, 2 and 15 mg/dL; case 3, Cu days 0 and 30, 3 and 84.2 µg/L; Cp days 0 and 30, 4 and 10.7 mg/dL. In Mexico, it is possible to safely synthesize Cu-His and treat MD, which must be intentionally sought.
La enfermedad de Menkes es una patología neurodegenerativa y letal debida a mutaciones génicas de la enzima ATP-7A trasportadora de cobre; se manifiesta por síntomas neurológicos y alteraciones del tejido conectivo de severidad variable. El uso subcutáneo oportuno de histidinato de cobre (Cu-His) es determinante en la calidad de vida. Se reportan las primeras experiencias en México en la síntesis y uso seguro de Cu-His en tres casos en los que corroboramos hipocupremia e hipoceruloplasminemia. Bajo asesoramiento del Hospital for Sick Children, Toronto, Canadá, elaboramos una solución de 500 µg/mL. En los tres casos aplicamos 250 µg de Cu-His, sin efectos indeseables relevantes durante 30 días y observamos las siguientes determinaciones séricas de cobre (Cu en µg/L) y ceruloplasmina (Cp en mg/dL): caso 1, Cu días 0 y 30, 8 y 504 µg/L; Cp días 0 y 30, 4 y 10.75 mg/dL; caso 2, Cu días 0 y 30, < 50 y 502, µg/L; Cp días 0 y 30, 2 y 15 mg/dL; caso 3, Cu días 0 y 30, 3 y 84.2 µg/L; Cp días 0 y 30, 4 y 10.7 mg/dL. En México es posible la síntesis segura de Cu-His y tratar la enfermedad de Menkes, la cual debe ser intencionalmente buscada.
Asunto(s)
Composición de Medicamentos/métodos , Histidina/análogos & derivados , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Compuestos Organometálicos/administración & dosificación , Calidad de Vida , Preescolar , Cobre/sangre , Histidina/administración & dosificación , Histidina/efectos adversos , Humanos , Lactante , México , Compuestos Organometálicos/efectos adversos , Soluciones FarmacéuticasRESUMEN
Resumen La enfermedad de Menkes es una patología neurodegenerativa y letal debida a mutaciones génicas de la enzima ATP-7A trasportadora de cobre; se manifiesta por síntomas neurológicos y alteraciones del tejido conectivo de severidad variable. El uso subcutáneo oportuno de histidinato de cobre (Cu-His) es determinante en la calidad de vida. Se reportan las primeras experiencias en México en la síntesis y uso seguro de Cu-His en tres casos en los que corroboramos hipocupremia e hipoceruloplasminemia. Bajo asesoramiento del Hospital for Sick Children, Toronto, Canadá, elaboramos una solución de 500 µg/mL. En los tres casos aplicamos 250 µg de Cu-His, sin efectos indeseables relevantes durante 30 días y observamos las siguientes determinaciones séricas de cobre (Cu en µg/L) y ceruloplasmina (Cp en mg/dL): caso 1, Cu días 0 y 30, 8 y 504 µg/L; Cp días 0 y 30, 4 y 10.75 mg/dL; caso 2, Cu días 0 y 30, < 50 y 502, µg/L; Cp días 0 y 30, 2 y 15 mg/dL; caso 3, Cu días 0 y 30, 3 y 84.2 µg/L; Cp días 0 y 30, 4 y 10.7 mg/dL. En México es posible la síntesis segura de Cu-His y tratar la enfermedad de Menkes, la cual debe ser intencionalmente buscada.
Abstract Menkes disease is a neurodegenerative and lethal pathology caused by gene mutations of the copper-transporting ATP-7A enzyme; it manifests itself by neurological symptoms and connective tissue changes of varying severity. Timely subcutaneous use of copper histidinate (Cu-His) is determinant for quality of life. We report the first experiences in Mexico on Cu-His synthesis and its safe use in 3 cases where hypocupremia and hypoceruloplasminemia were corroborated. With advice of the Hospital for Sick Children of Toronto Canada, we prepared a 500 µg/mL solution. In all three cases were 250 µg of Cu-His applied without relevant undesirable effects for 30 days. Serum copper (Cu, expressed in µg/L) and ceruloplasmin (Cp, in mg/dL) were determined: case 1, Cu days 0 and 30, 8 and 504 µg/L; Cp days 0 and 30, 4 and 10.75 mg/dL; case 2, Cu days 0 and 30, <50 and 502 µg/L; Cp days 0 and 30, 2 and 15 mg/dL; case 3, Cu days 0 and 30, 3 and 84.2 µg/L; Cp days 0 and 30, 4 and 10.7 mg/dL. In Mexico, it is possible to safely synthesize Cu-His and treat MD, which must be intentionally sought.
Asunto(s)
Humanos , Lactante , Preescolar , Compuestos Organometálicos/administración & dosificación , Calidad de Vida , Composición de Medicamentos/métodos , Histidina/análogos & derivados , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Compuestos Organometálicos/efectos adversos , Cobre/sangre , Soluciones Farmacéuticas , Histidina/administración & dosificación , Histidina/efectos adversos , MéxicoRESUMEN
Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential disease-modifying treatment of Menkes disease for decades. However, recent evidence suggests its efficacy only when treatment is started within days after birth, which also has important implications related to the techniques that enable early diagnosis. We aim at proposing a guideline for prenatal and neonatal diagnosis and for disease-modifying treatment of Menkes disease, guided by a systematic review of the literature, and built in conjunction with medical experts, methodologists and patient representatives. Thirteen articles were used for our recommendations that were based on GRADE system. Reviewed evidence suggests that prenatal genetic diagnosis in families with previous diagnosis of Menkes disease is feasible; analysis of plasma catecholamine levels is accurate for neonatal diagnosis of Menkes disease; treatment with copper-histidine is effective to increase survival and reduce neurologic burden of the disease if initiated in the neonatal period; and, treatment indication should not be guided by patient's genotype. In conclusion, our guideline can contribute to standardize some aspects of the clinical care of patients with Menkes disease, especially reducing disease burden and mortality and providers' and families' anxiety.
Asunto(s)
Cobre/metabolismo , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Diagnóstico Prenatal , Catecolaminas/sangre , Ensayos Clínicos como Asunto , Cobre/uso terapéutico , Diagnóstico Precoz , Femenino , Humanos , Masculino , Síndrome del Pelo Ensortijado/genética , Mutación , EmbarazoRESUMEN
Dysregulation of copper homeostasis in humans is primarily found in two genetic diseases of copper transport, Menkes and Wilson diseases, which show symptoms of copper deficiency or overload, respectively. However, both diseases are copper storage disorders despite completely opposite clinical pictures. Clinically, Menkes disease is characterized by copper deficiency secondary to poor loading of copper-requiring enzymes although sufficient body copper. Copper accumulates in non-hepatic tissues, but is deficient in blood, liver, and brain. In contrast, Wilson disease is characterized by symptoms of copper toxicity secondary to accumulation of copper in several organs most notably brain and liver, and a saturated blood copper pool. It is a challenge to correct copper dyshomeostasis in either disease though copper depletion in Menkes disease is most challenging. Both diseases are caused by defective copper export from distinct cells, and we seek to give new angles and guidelines to improve treatment of these two complementary diseases. Therapy of Menkes disease with copper-histidine, thiocarbamate, nitrilotriacetate or lipoic acid is discussed. In Wilson disease combination of a hydrophilic chelator e.g. trientine or dimercaptosuccinate with a brain shuttle e.g. thiomolybdate or lipoate, is discussed. New chelating principles for copper removal or delivery are outlined.
Asunto(s)
Quelantes/uso terapéutico , Degeneración Hepatolenticular/tratamiento farmacológico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Quelantes/química , Quimioterapia Combinada , HumanosRESUMEN
INTRODUCTION: Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice. METHODS: Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. RESULTS: In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. CONCLUSION: Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.
Asunto(s)
Cobre/farmacología , Disulfiram/uso terapéutico , Portadores de Fármacos , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Animales , Autorradiografía , Barrera Hematoencefálica/metabolismo , Cobre/metabolismo , Modelos Animales de Enfermedad , Masculino , Síndrome del Pelo Ensortijado/sangre , Síndrome del Pelo Ensortijado/metabolismo , Ratones , Ratones Endogámicos C3HRESUMEN
BACKGROUND: Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. METHODS: CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. RESULTS: CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. CONCLUSION: Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.
Asunto(s)
Complejos de Coordinación/uso terapéutico , Cobre/farmacocinética , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Tiosemicarbazonas/uso terapéutico , Administración Oral , Animales , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/farmacología , Cobre/sangre , ATPasas Transportadoras de Cobre/genética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Mutación , Tasa de Supervivencia , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/farmacología , Distribución Tisular , Aumento de Peso/efectos de los fármacosRESUMEN
Menkes disease (MD) is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving MD patient (37 years) receiving early-onset and long-term copper treatment. He has few neurological symptoms without connective tissue disturbances; and a missense ATP7A variant, p.(Pro852Leu), which results in impaired protein trafficking while the copper transport function is spared. These findings suggest that some cuproenzymes maintain their function when sufficient copper is provided to the cells; and underline the importance of early initiated copper treatment, efficiency of which is likely to be dependent on the mutant ATP7A function.
Asunto(s)
ATPasas Transportadoras de Cobre/metabolismo , Cobre/uso terapéutico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Síndrome del Pelo Ensortijado/enzimología , Adolescente , Adulto , Preescolar , Humanos , Lactante , Recién Nacido , Masculino , Transporte de ProteínasRESUMEN
Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair appearance, neurodegeneration, developmental delay, seizures, failure to thrive and other connective tissue or organ abnormalities. Other than biochemical tests, DNA-based diagnosis is now playing an important role. More than two hundred mutations in ATP7A gene were identified. Early copper supplementation can help improve neurological symptoms, but not non-neurological problems. Further molecular studies are needed to identify additional mutation types and to understand the mechanism of pathogenesis. This may help in discovering the possible treatment measures to cure the disease. We present a case with the clinical features and biochemical findings, abnormal brain magnetic resonance imaging as well as the effects of treatment with copper-histidine. Direct sequencing of ATP7A gene revealed a de novo point mutation which resulted in an early stop codon with truncated protein.
Asunto(s)
Adenosina Trifosfatasas/genética , Proteínas de Transporte de Catión/genética , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/genética , Mutación Puntual/genética , ATPasas Transportadoras de Cobre , Histidina/análogos & derivados , Histidina/uso terapéutico , Humanos , Lactante , Masculino , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Compuestos Organometálicos/uso terapéuticoRESUMEN
The nineties witnessed the discovery of the copper ATPases, enzymes which transport copper across the cytoplasmic membranes of bacteria and eukaryotes. In the same decade, several other key components of copper homeostasis have also been discovered, like copper chaperones and plasma membrane copper transporters. This has finally led to a molecular understanding of two inherited human diseases related to copper: Menkes disease, manifested by systemic copper deficiency, and Wilson disease, caused by defective secretion of excess copper. A historic perspective and untold stories of the events leading up to these discoveries are presented here.
Asunto(s)
Cobre/uso terapéutico , Degeneración Hepatolenticular/historia , Síndrome del Pelo Ensortijado/historia , Proteínas de Transporte de Catión/genética , Cobre/deficiencia , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/genética , Historia del Siglo XX , Homeostasis , Humanos , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Síndrome del Pelo Ensortijado/genética , Mutación/genéticaRESUMEN
When we were asked to produce articles for this volume, it seemed appropriate to us to co-author an article on the history and impact of copper research in Melbourne. It is appropriate because over many years, decades in fact, we worked closely together and with Professor David Danks to identify the molecular defect in Menkes disease. This work was always carried out with the intention of understanding the nature of the copper homeostatic mechanisms and a "copper pathway" in the cell, that David had the prescience to predict must exist despite scepticism from granting agencies! He indeed inspired us to pursue research careers in this field. This article outlines some of this history.
Asunto(s)
Cobre/uso terapéutico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Animales , Proteínas de Transporte de Catión/genética , Cobre/deficiencia , Homeostasis , Humanos , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/genética , Mutación/genéticaRESUMEN
Copper is one of essential trace elements. Copper deficiency lead to growth and developmental failure and/or neurological dysfunction. However, excess copper is also problems for human life. There are two disorders of inborn error of copper metabolism, Menkes disease and Wilson disease. Menkes disease is an X linked recessive disorder with copper deficiency and Wilson disease is an autosomal recessive disorder with copper accumulation. These both disorders result from the defective functioning of copper transport P-type ATPase, ATP7A of Menkes disease and ATP7B of Wilson disease. In this paper, the author describes about copper metabolism of human, and clinical feature, diagnosis and treatment of Menkes disease and Wilson disease.
Asunto(s)
Cobre/metabolismo , Predisposición Genética a la Enfermedad , Degeneración Hepatolenticular/metabolismo , Síndrome del Pelo Ensortijado/metabolismo , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/genética , Humanos , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , Síndrome del Pelo Ensortijado/genética , PronósticoRESUMEN
Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis. Treatment is parenteral administration of copper histidine. We report a familial case with molecular confirmation. The proband had clinical and biochemical suspicious. Treatment with copper histidine was indicated, but initiated at the age of 2 months and 27 days only. He did not present improvements and died at 6 months. The mother became pregnant again, a male fetus was identified and copper histidine was manufactured during pregnancy. He was born healthy, biochemical markers were reduced and treatment was indicated. Molecular analysis was performed confirming mutation in both the mother and the proband, while the other son did not have mutation, so treatment was discontinued. We support the clinical relevance of molecular confirmation for the correct diagnosis and genetic counseling, once clinical findings in the neonatal period are nonspecific and early treatment with parenteral copper histidine must be indicated.
Asunto(s)
Histidina/análogos & derivados , Síndrome del Pelo Ensortijado/genética , Técnicas de Diagnóstico Molecular/métodos , Compuestos Organometálicos/uso terapéutico , Adenosina Trifosfatasas/genética , Proteínas de Transporte de Catión/genética , Ceruloplasmina/análisis , Cobre/análisis , ATPasas Transportadoras de Cobre , Resultado Fatal , Femenino , Enfermedades del Cabello/diagnóstico , Histidina/uso terapéutico , Humanos , Recién Nacido , Masculino , Síndrome del Pelo Ensortijado/diagnóstico , Síndrome del Pelo Ensortijado/tratamiento farmacológico , EmbarazoRESUMEN
Summary Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis. Treatment is parenteral administration of copper histidine. We report a familial case with molecular confirmation. The proband had clinical and biochemical suspicious. Treatment with copper histidine was indicated, but initiated at the age of 2 months and 27 days only. He did not present improvements and died at 6 months. The mother became pregnant again, a male fetus was identified and copper histidine was manufactured during pregnancy. He was born healthy, biochemical markers were reduced and treatment was indicated. Molecular analysis was performed confirming mutation in both the mother and the proband, while the other son did not have mutation, so treatment was discontinued. We support the clinical relevance of molecular confirmation for the correct diagnosis and genetic counseling, once clinical findings in the neonatal period are nonspecific and early treatment with parenteral copper histidine must be indicated.
Resumo A doença de Menkes é causada por uma alteração genética no metabolismo do cobre, por mutações no gene ATP7A. Caracteriza-se por alterações neurológicas e no exame físico. No período neonatal, essas alterações podem ser inespecíficas, o que torna o diagnóstico precoce um desafio. O diagnóstico pode ser suspeitado quando há baixos níveis séricos de cobre e ceruloplasmina. A análise molecular confirma o diagnóstico, e o tratamento deve ser feito com histidina de cobre. Nós relatamos um caso familial de doença de Menkes. O probando apresentava quadro clínico e alterações bioquímicas compatíveis com a doença de Menkes, em consulta com 1 mês de vida. O tratamento foi indicado, mas apenas iniciado com 2 meses e 27 dias. Ele não apresentou melhora clínica e veio a óbito com 6 meses. A mãe teve uma nova gestação, foi identificado um feto do sexo masculino e foi solicitada a manipulação da histidina de cobre ainda durante a gestação. O bebê nasceu saudável, os marcadores bioquímicos estavam diminuídos e o tratamento com histidina de cobre foi indicado. Realizamos a análise molecular, que confirmou mutação no gene ATP7A na mãe e no probando; porém, o outro filho não apresentava mutação e o tratamento foi interrompido. Nós defendemos a importância clínica da confirmação molecular para o correto diagnóstico e o aconselhamento genético da doença de Menkes, uma vez que os achados clínicos e as alterações bioquímicas no período neonatal são inespecíficos, e o tratamento com histidina de cobre parenteral deve ser rapidamente instituído.