Menkes disease: importance of diagnosis with molecular analysis in the neonatal period.

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.

Menkes disease: importance of diagnosis with molecular analysis in the neonatal period / Doença de Menkes: importância do diagnóstico com análise molecular no período neonatal

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.

The T1048I mutation in ATP7A gene causes an unusual Menkes disease presentation.

BACKGROUND: The ATP7A gene encodes the ATP7A protein, which is a trans-Golgi network copper transporter expressed in the brain and other organs. Mutations in this gene cause disorders of copper metabolism, such as Menkes disease. Here we describe the novel and unusual mutation (p.T1048I) in the ATP7A gene of a child with Menkes disease. The mutation affects a conserved DKTGT1048 phosphorylation motif that is involved in the catalytic activity of ATP7A. We also describe the clinical course and the response to copper treatment in this patient. CASE PRESENTATION: An 11-month-old male Caucasian infant was studied because of hypotonia, ataxia and global developmental delay. The patient presented low levels of serum copper and ceruloplasmin, and was shown to be hemizygous for the p.T1048I mutation in ATP7A. The diagnosis was confirmed when the patient was 18 months old, and treatment with copper-histidinate (Cu-His) was started immediately. The patient showed some neurological improvement and he is currently 8 years old. Because the p.T1048I mutation affects its catalytic site, we expected a complete loss of functional ATP7A and a classical Menkes disease presentation. However, the clinical course of the patient was mild, and he responded to Cu-His treatment, which suggests that this mutation leads to partial conservation of the activity of ATP7A. CONCLUSION: This case emphasizes the important correlation between genotype and phenotype in patients with Menkes disease. The prognosis in Menkes disease is associated with early detection, early initiation of treatment and with the preservation of some ATP7A activity, which is necessary for Cu-His treatment response. The description of this new mutation and the response of the patient to Cu-His treatment will contribute to the growing body of knowledge about treatment response in Menkes disease.

Liver transplantation using University of Wisconsin or Celsior preserving solutions in the portal vein and Euro-Collins in the aorta.

INTRODUCTION: Orthotopic liver transplantation (OLT) is today the gold standard treatment of the end-stage liver disease. Different solutions are used for graft preservation. Our objective was to compare the results of cadaveric donor OLT, preserved with the University of Wisconsin (UW) or Celsior solutions in the portal vein and Euro-Collins in the aorta. METHODS: We evaluated retrospectively 72 OLT recipients, including 36 with UW solution (group UW) and 36 with Celsior (group CS). Donors were perfused in situ with 1000 mL UW or Celsior in the portal vein of and 3000 mL of Euro-Collins in the aortia and on the back table managed with 500 mL UW or Celsior in the portal vein, 250 mL in the hepatic artery, and 250 mL in the biliary duct. We evaluated the following variables: donor characteristics, recipient features, intraoperative details, reperfusion injury, and steatosis via a biopsy after reperfusion. We noted grafts with primary nonfunction (PNF), initial poor function (IPF), rejection episodes, biliary duct complications, hepatic artery complications, re-OLT, and recipient death in the first year after OLT. RESULTS: The average age was 33.6 years in the UW group versus 41 years in the CS group (P = .048). There was a longer duration of surgery in the UW group (P = .001). The other recipient characteristics, ischemia-reperfusion injury, steatosis, PNF, IPF, rejection, re-OLT, and recipient survival were not different. Stenosis of the biliary duct occured in 3 (8.3%) cases in the UW group and 8 (22.2%) in the CS (P = .19) with hepatic artery thrombosis in 4 (11.1%) CS versus none in the UW group (P = .11). CONCLUSION: Cadaveric donor OLT showed similar results with organs preserved with UW or Celsior in the portal vein and Euro-Collins in the aorta.

Copper-histidine therapy for Menkes disease.

Menkes disease is an X-linked genetic disorder of copper transport that results in death from severe progressive neurodegeneration by the age of 3 years. We report here our 17 years' experience with the treatment of Menkes disease with subcutaneous administration of copper-histidine. Two patients (16 and 6 years of age) whose therapy was begun within 1 month of birth have done well neurologically. The other five patients have done poorly despite treatment initiated at 2 to 7 months of age. Copper-histidine therapy may be an effective treatment if started early.

Dieta hipoproteica associada a aminoácidos essenciais e histidina para pacientes com insuficiência renal crônica terminal: estudo piloto / Hypoproteic diet supplemented by essential aminoacids and histidire for patients with end stage chronic renal failure: a pilot study

Dezessete pacientes portadores de insuficiência renal crônica terminal de diferentes etiologias e com clearance de creatinina inicial de 7,2 ñ 0,8ml/min foram submetidos por tempo indeterminado a uma dieta restrita em proteínas e suplementada com aminoácidos essenciais e histidina por via oral. No momento da avaliaçäo, dois pacientes continuavam sob tratamento e 15 iniciaram tratamento dialítico após seguimento médio de quatro meses (um a 24 meses, perfazendo um total de 102 pacientes/mês). Três pacientes permaneceram sob tratamento por mais de 12 meses. Näo foram observadas variaçöes significativas do peso corporal, prega cutânea do tríceps e da circunferência muscular do braço. O inquérito alimentar durante o estudo revelou calórica baixa em torno de 27 kcal/kg/dia e ingestäo protéica média de 0,79g/kg/dia. Todos os pacientes experimentaram reduçäo ou desaparecimento dos sintomas urêmicos; a uréia plasmática passaou de 197,1 ñ 5,6mg/dl, no início do estudo, para 142,8 ñ 8,5mg/dl durante a avaliaçäo. Näo foi observada modificaçäo da funçäo renal dos pacientes. Os resultados desse estudo preliminar com esse tipo de dieta mostram que os aminoácidos essenciais, embora näo palatáveis, foram bem tolerados pelos pacientes e que a dieta empregada foi capaz de reduzir os sintomas urêmicos, com significativa reduçäo da uréia plásmatica, evitando um total de 102 pacientes/mês em programa dialítico

Neonatal citrllinemia: treatment with keto-analogues of essential amino acids.

A patient with neonatal onset citrullinemia survived to 8 months of age when treated with a mixture of essential amino acids and their keto-analogues. The initial plasma citrulline concentration was 2.7 mM; the blood ammonia concentration was greater than 500 muM. During the first week of therapy, the blood ammonia concentration became normal and that of plasma citrulline was reduced by almost 50%. It was possible to institute progressive increases in dietary calories and protein; growth and developmetn with resolution of almost all clinical signs of disease ensued. The patient died at 8 months of age after an episode of diarrhea and dehydration, probably of viral origin.