Review article
A systematic review and evidence-based guideline for diagnosis and treatment of Menkes disease

https://doi.org/10.1016/j.ymgme.2018.12.005Get rights and content

Abstract

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.

Introduction

Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance. The disease is caused by pathogenic variants in the ATP7A, which encodes a transmembrane copper-transporting P-type ATPase (ATP7A) [[1], [2], [3]]. Pathogenic variants with milder effects in ATP7A cause occipital horn syndrome or a distal form of motor neuropathy [4], entities that will not be covered in the present review.

The incidence of MD at birth is estimated at 1 in 300,000 live births in Europe [5]. In Australia, the incidence can be up to 1 in 40,000 live births [6]. Females are usually asymptomatic, except in rare reports of girls affected with attenuated forms of the disease [7,8].

The phenotype of MD results from decreased activities of enzymes that use copper as cofactor, such as dopamine-β-hydroxylase, cytochrome c oxidase, amongst others. The clinical picture is characterized by an early childhood cerebral/cerebellar neurodegenerative and connective tissue disorder, usually perceived around 3 months of age, when patients begin to lose skills, with regression of motor functions, seizures, and hypotonia. Skin laxity, pili torti, jowly appearance with sagging cheeks, frontal bossing, and vascular tortuosity are also common features of affected individuals [3,4]. The natural history of the disease is characterized by progressive degeneration of neurological functions leading to death in the first years of life [9].

The diagnosis of MD is classically based on clinical manifestations in association with reduced blood levels of copper and ceruloplasmin [2]. Parenteral copper supplementation is used as a potential disease-modifying treatment since the seventies of 20th century [10]. However, more recent evidence suggests that copper injections might only modify disease progression if initiated within days after birth [2]. Since both symptoms and conventional biochemical diagnosis are accurate for diagnostic confirmation of the disease only after 2–3 months of age, and since serum copper and ceruloplasmin levels in healthy newborns overlap with those in infants with MD [2], more reliable diagnostic tests should be available in the neonatal or even prenatal period in order to allow early therapy [3,11].

Possibly due to the rarity of MD, there are no published evidence-based guidelines for the care of these individuals and families. Therefore, we propose an approach for the diagnosis and treatment of MD, guided by a systematic review of the literature. We built our guideline based on questions regarding accuracy of prenatal and neonatal diagnostic methods for MD, and its impact on relevant clinical outcomes. We also tried to assess the efficacy of copper injections for the treatment of the disease and to evaluate potential predictors of treatment response.

Section snippets

Methods

The objectives and search strategies were built using the Population, Intervention, Comparator, Outcome format for i) neonatal diagnosis, ii) prenatal diagnosis, iii) treatment efficacy, and iv) prediction of treatment efficacy. For each question, two independent reviewers (FPV and SP) searched Medline, Embase, Cochrane Library and Scielo without restriction of publication date, with the last search carried out in June 03, 2018. We restricted our search to human studies written in English,

Results

Thirteen articles were used for building recommendations. The overall quality of evidence [14] for early neonatal diagnosis was considered high. Quality of evidence for prenatal diagnosis was judged as very low. Treatment question reached moderate quality of evidence. In this case, quality of evidence was rated up due to a large magnitude of effect and the presence of a dose-response gradient in the early versus late treatment. Finally, serious risk of bias and indirectness made treatment

Discussion

MD is not currently a curable disease. However, it may have a more favorable clinical course if diagnosed early, reducing disease burden for patients and families. The systematic and comprehensive assessment of all available evidence combined with clinicians and patients' perspectives provided a guideline for prenatal and neonatal diagnosis and for disease modifying therapies for MD that might influence and aid in the development of country based guidelines for management of this devastating

Acknowledgements

This study was started as a governmental initiative to build guidelines for rare diseases in Brazil. The initiative was part of a national program started in 2014 for the care of individuals and families with rare diseases in the Brazilian National Health System (SUS), organized by the National Committee for Health Technology Incorporation (CONITEC). We are grateful for the participation of Carmen Silvia Curiati Mendes, Daniel Zanetti Scherrer, Eugenia Ribeiro Valadares, Ida Schwartz, Janne

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      Citation Excerpt :

      Menkes disease, in its classic form, is characterized by severe neurodegeneration, poor long-term prognosis, and death before the patient turns three years old.1,6,12 Treatment of Menkes disease is effective only when it is commenced within several days from birth, and it consists in parenteral (subcutaneous or intravenous) administration of copper in complex forms, e.g. copper-L-histidine.13 Oral administration of copper is ineffective, as copper is not absorbed in the alimentary tract.

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