Neck masses due to internal jugular vein phlebectasia: Frequency in Menkes disease and literature review of 85 pediatric subjects.

Classic Menkes disease is a rare X-linked recessive disorder of copper metabolism caused by pathogenic variants in the copper transporter gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that begin at 6-8 weeks of age and progress inexorably to death, often within 3 years. Subcutaneous injections of Copper Histidinate (US Food and Drug Administration IND #34,166, Orphan product designation #12-3663) are associated with improved survival and neurological outcomes, especially when commenced within a month of birth. We previously identified internal jugular vein phlebectasia (IJP) in four Menkes disease subjects. This feature and other connective tissue abnormalities appear to be consequences of deficient activity of lysyl oxidase, a copper-dependent enzyme. Here, we report results from a prospective study of IJP based on 178 neck ultrasounds in 66 Menkes subjects obtained between November 2007 and March 2018. Nine patients met the criterion for IJP (one or more cross-sectional area measurements exceeding 2.2 cm2 ) and five subjects had clinically apparent neck masses that enlarged over time. Our prospective results suggest that IJP occurs in approximately 14% (9/66) of Menkes disease patients and appears to be clinically benign with no specific medical or surgical actionability. We surveyed the medical literature for prior reports of IJP in pediatric subjects and identified 85 individuals and reviewed the distribution of this abnormality by gender, sidedness, and underlying etiology. Taken together, Menkes disease accounts for 16% (15/94) of all reported IJP individuals. Neck masses from IJP represent underappreciated abnormalities in Menkes disease.

Intervenção da fisioterapia na síndrome de Menkes: relato de caso / Intervention of physiotherapy in Menkes syndrome: case report

Objetivo: Descrever a intervenção da fisioterapia motora e respiratória no caso de uma criança com Síndrome de Menkes. Método: Relato de caso, com base em registros retrospectivos, no qual são apresentados dados referentes ao acompanhamento fisioterapêutico de uma criança com o diagnóstico de Síndrome de Menkes. Os dados foram obtidos por meio do prontuário, entrevista com familiares e informações dos profissionais envolvidos. O referido paciente foi encaminhado para assistência fisioterapêutica aos 5 meses de vida, devido ao quadro de pneumonia com presença de atelectasia, associado as manifestações típicas da Síndrome, sendo então acompanhado por um período de 04 meses. Foram realizados 76 atendimentos, de um total de 91 agendamentos, os quais incluíram fisioterapia motora e respiratória, sendo aplicados métodos, técnicas, manuseios e posturas, para estimulação do desenvolvimento neuropsicomotor, e realizadas técnicas e recursos fisioterapêuticos para desobstrução e reexpansão pulmonar. Resultados: A cada sessão, a criança apresentou evidente melhora imediata no padrão e tipo respiratório, na frequência respiratória, na ausculta pulmonar e nos sinais de desconforto respiratório. Além disso, a estimulação motora e manutenção do quadro músculo esquelético, impediram agravos e deformidades. Segundo relato da mãe, a criança mostrava-se menos agitada após as sessões, com melhora no padrão e conforto respiratório, o que impactou de forma positiva na sua qualidade de vida. Conclusão: A fisioterapia motora e respiratória se apresentam como terapêuticas favoráveis para condição de saúde geral de pacientes com Síndrome de Menkes e novos estudos devem ser conduzidos no sentido de elucidar essa intervenção, com amostras maiores.

Objective: To describe the intervention of motor and respiratory physiotherapy in the case of a child with Menkes Syndrome. Method: Case report based on retrospective registers in which data are presented regarding the physical therapy accompaniment of a child with the diagnosis of Menkes Syndrome. The data were obtained based on the records of the child's chart, interview with relatives and information of the professionals involved. The patient was referred for physiotherapeutic assistance at 5 months of age, due to the presence of atelectasis pneumonia associated with the typical manifestations of Menkes' Syndrome, followed by a period of 4 months. A total of 76 appointments were performed, including motor and respiratory physiotherapy, and methods, techniques and manipulations were used to stimulate neuropsychomotor development, as well as techniques and physiotherapeutic resources were used to clear and reexpans the lungs. Results: At each session, the child showed evident immediate improvement in respiratory pattern and type, respiratory rate, pulmonary auscultation, and signs of respiratory discomfort. In addition, the motor stimulation and maintenance of the skeletal muscle of the child, prevented injuries and deformities. According to the mother's report, the child was less agitated after the sessions, with improved breathing pattern and comfort, which positively impacted his quality of life. Conclusion: Motor and respiratory physiotherapy are presented as favorable therapies for the general health condition of patients with Menkes-Syndrome, and further studies should be conducted to elucidate this intervention in a bigger sample.

Giant axonal neuropathy: The first Iranian case with a variation in the gigaxonin gene and a glance to the other cases.

Background: Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN (gigaxonin) gene. Herein, we reported the clinical presentations and results of genetic analysis of the first Iranian GAN case. Methods: Phenotypic data were obtained by neurologic examination, brain magnetic resonance imaging (MRI), electromyography (EMG), electroencephalography (EEG), and sonography from the proband. Deoxyribonucleic acid (DNA) was isolated from peripheral blood leucocytes and whole exome sequencing (WES) was performed. The candidate variant was screened by Sanger sequencing in the proband and her family members. Results: The proband was a 7-year-old girl who was admitted with a chief complaint of ataxia, muscle weakness, delayed developmental milestones, and history of psychiatric disorders. She was very moody and had clumsy gait, decreased deep tendon reflexes (DTRs) of lower limbs, and kinky hair. The brain MRI revealed white matter abnormality. The EMG revealed that her disease was compatible with the chronic axonal type of sensorimotor polyneuropathy; however, her EEG was normal. Results of the WES revealed a homozygous variant; c.G778T:p.E260* in the GAN gene, indicating the GAN disorder. Conclusion: The present study affirmed GAN allelic heterogeneity and resulted in the expansion of the phenotypic spectrum of GAN pathogenic variants. Identification of more families with mutations in GAN gene helps to further understand the molecular basis of the disease and provides an opportunity for genetic counseling especially in the populations with a high degree of consanguineous marriage such as the Iranian population.

El metabolismo del cobre. Sus consecuencias para la salud humana / Metabolism of copper. Its consequences for human health

Diversas enfermedades que constituyen problemas para la salud humana a nivel mundial, son el resultado de fallos en la homeostasis del cobre en la célula. El mecanismo de transporte del cobre no está completamente dilucidado; de ahí la necesidad de continuar profundizando en este tema. La presente revisión bibliográfica, sustentada en el análisis de 40 artículos científicos, describe los procesos de captación, distribución y eliminación del cobre en la célula; se refiere además a las enfermedades relacionadas con alteraciones en el metabolismo de dicho elemento y a su tratamiento, tales como, la enfermedad de Menkes y la de Wilson; y por último, a los estudios moleculares realizados en pacientes cubanos. Se concluye que el trabajo aporta información relevante que contribuye a la actualización y preparación del personal médico, respecto a estas afecciones a nivel molecular, celular y de organismo.

Several diseases which constitute a health problem for humans worldwide result from failure of copper cellular homeostasis. The mechanism of copper transportation in not completely defined therefore it is necessary to continue deepening on the topic. The present bibliographical review, based on the analysis of 40 scientific articles, describes the processes of copper catchment, distribution and elimination of copper in the cell; it refers, in addition to the diseases related to the metabolic disturbances of this element and its treatment, such as Menkes and Wilson diseases and lastly the molecular studies performed in Cuban patients. It is concluded that this work offers a significant information which contribute to the updating and preparation of the medical personnel regarding these illnesses at the molecular, cellular levels so as in the organism.

Clinical Findings of Menkes Disease and the Treatment of Epilepsy / 대한소아신경학회지

Menkes disease (also known as kinky hair disease) is an X-linked recessive neurodegenerative disorder caused by diverse mutations in a copper-transport gene, ATP7A. Affected patients are characterized by kinky hair, hypotonia, and generalized myoclonic seizures. Here, we report a case of Menkes disease in which the patient presented with progressive hypotonia and intractable seizures. A 4-month-old male infant visited our pediatric clinic for focal seizures with blinking eyes. He was generally hypotonic and suffered from malnutrition. The focal seizures became more frequent, and the patient became intractable to anti-seizure medications. An electroencephalogram (EEG) indicated diffuse cerebral dysfunction with focal seizure, and a brain magnetic resonance imaging (MRI) showed tortuous and ectatic intracranial arteries, as well as several ischemic lesions. A genetic analysis was performed, and a c.2473_2474del (p.Leu825fsX1) of the ATP7A gene was detected.

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.

A case of Menkes disease caused by novel mutation in the ATP7A gene with infantile hypertrophic pyloric stenosis

Menkes disease is caused by mutations in the ATP7A gene that lead to intracellular copper transport defects and characterized by brownish twisted (kinky) hair accompanied by growth retardation and intellectual disability. Reduced nitric oxide (NO) production contributes to infantile hypertrophic pyloric stenosis (IHPS) because NO plays an important role in smooth muscle relaxation. Here we describe a case of Menkes disease and IHPS in a 72-day-old male patient with severe persistent vomiting and convulsions with a novel ATP7A mutation.

Neurodegenerative disorders with hair abnormalities: an emergency room consultation for dermatologists.

Menke's syndrome and Elejalde disease are the two neurodegenerative disorders of dermatological interest. These patients present with characteristic hair changes which may be of diagnostic value in resource-poor setup where facilities for specific genetic analysis are not available. Simple light microscopic examination of hair may be a helpful diagnostic tool to pick up such cases.