Journal of Multidisciplinary Healthcare Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Menkes disease: what a multidisciplinary approach can do Rahul Ojha1 Abstract: Disorders of copper homeostasis are currently recognized across the life span. Their Asuri N Prasad1–4 recognition and links to human disease have spanned several decades, beginning with the recog- nition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, 1Department of Pediatrics, 2Section of Pediatric Neurology, 3Division of through to the description of infants suffering from a progressive neurodegenerative disorder Clinical Neurological Sciences, 4Child characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair Health Research Institute, Schulich School of Medicine and Dentistry, quality (giving the condition its distinctive label of “kinky hair disease”). In this review, we trace University of Western Ontario, the historical background and describe the biochemistry and physiology of copper metabolism and London, ON, Canada transport, inheritance patterns, molecular genetics, and genotype–phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions. Keywords: Menkes disease, kinky hair, ceruloplasmin, neurodegenerative, copper homeostasis Introduction and historical background The focus of this review is to highlight the role a multidisciplinary approach can play in optimizing care of this multisystem lethal disease (Figure 1). The history of Menkes disease (MD) dates back to as early as 1937 when Australian veterinary scientists recognized an association between copper deficiency and a demyelinating disease of the brain in the offspring of sheep grazing in copper-deficient pastures. Researchers in the 1960s observing defective wool in affected sheep turned to the Australian Wool Research Laboratories to establish a link between a copper-deficient diet and defective hair formation. However, efforts to establish a causal relationship between a copper- deficient diet and wool quality remained inconclusive. Correspondence: Asuri N Prasad In 1962, Menkes et al at Columbia University, New York, NY, USA, described a London Health Science Centre, B1-174 distinctive clinical syndrome comprising neurological degeneration in five affected male Children’s Hospital, 800 Commissioners Road East, London, ON N6A 5W9, infants of English–Irish heritage who showed unusual hair quality and failure to thrive. Canada These male infants appeared normal at birth through early infancy; subsequently, they Tel +1 519 685 8814 developed epileptic seizures and regression of developmental milestones progressing Fax +1 519 685 8625 Email [email protected] to death between the age of 7 months and 3.5 years.1 submit your manuscript | www.dovepress.com Journal of Multidisciplinary Healthcare 2016:9 371–385 371 Dovepress © 2016 Ojha and Prasad. 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Ojha and Prasad Dovepress 2 1 Biochemistry 3 Historical and basic Genetics and background science molecular pathophysiology 8 4 Clinical Outcome and presentation survival Multidisciplinary approach to MD across life span 5 7 Multidisciplinary supportive care Diagnosis Biochemist/geneticist (laboratory Pediatrician and neonatologist and imaging) Neurologist Developmental pediatrician 6 Urologist Dermatologist Therapeutic management GI/nutritionist Current state Physiotherapist and occupational Other symptom therapist Management Experimental model Figure 1 Multidisciplinary approach to MD. Abbreviations: GI, gastrointestinal; MD, Menkes disease. O’Brien and Sampson2 coined the term “kinky hair dis- follicles deeply buried in the dermis with small, brittle, and ease” and performed biochemical studies on frozen brain broken hair shafts. tissues of two siblings, which demonstrated a reduction in MD, as it is currently known, is a lethal X-linked disorder docosahexaenoic acid, the most highly unsaturated fatty acid of copper metabolism with multisystem involvement. This in brain. Disruption of mitochondrial function was postulated disease shows wide variability and clinical heterogeneity in as playing a possible role in this disorder on account of its manifestations, ranging from a severe clinical course leading involvement in fatty acid oxidation. to death in early childhood to a milder form termed occipital Danks et al3 reported seven new cases of Menkes kinky horn syndrome (OHS) with connective tissue abnormalities hair syndrome from five families seen over a period of and longer survival.4 Patients with MD with intermediate phe- 3 years in Melbourne, Australia. The mode of inheritance notypes (5%–10%) characterized by later onset and milder in each pedigree was compatible with X-linked Mende- symptoms are also described.4,5 These variant presentations lian pattern. Hypothermia, developmental delay, growth are being better understood with evolving genotype–pheno- failure, and very low serum copper were noted along with type correlations. the unusual hair quality of infants. Hairs from the scalp in Danks et al6 who carried out further research on this dis- these infants appeared sparse, tangled, and lusterless with order used another term, “steely hair disease”. A number of rotational twists of “pili torti”, which were similar in texture other eponyms, such as Menkes steely hair disease, Menkes to the brittle wool of sheep raised on copper-deficient soil kinky hair disease, trichopoliodystrophy, and Menkes syn- in Australia (Figure 2). Sections of the scalp showed hair drome, have been used in scientific nomenclature. 372 submit your manuscript | www.dovepress.com Journal of Multidisciplinary Healthcare 2016:9 Dovepress Dovepress Menkes disease: what a multidisciplinary approach can do A B Normal hair Pili torti Figure 2 MD: (A) scalp shows “kinky hair”, (B) the inset shows “pili torti” and a normal hair strand under a high power microscope. Abbreviation: MD, Menkes disease. It is important to see how current understanding of differ- Xq21.1, truncating ATPA7, which results in clinical mani- ent aspects of this disorder has been shaped by developments festations and is attributed to random X inactivation.4,11 In in the fields of biochemistry, molecular genetics, pathology, addition, there are few reports of females with milder symp- clinical presentation, and therapeutic interventions. toms who carry exon deletions (exon 6, 6–9, 1) or base-pair substitutions.12–14 Epidemiology The overall incidence of MD is reported to be 1 in 100,000– Biochemistry 250,000 births.7 However, regional geographic variation The liver and kidney are the two organs in mammals that is recognized. The incidence in Australia is reported to be have the highest concentration of copper.15 A healthy adult much higher than elsewhere at 1:50,000–100,000.5 A large body contains ~110 mg of copper, which is distributed in the observational study reported the incidence as 1:300,000 in liver, kidney, brain, blood, and skeletal tissues.16 Vegetables, Europe and 1:360,000 in Japan.7,8 The true incidence rate animal proteins, and human breast milk are good sources of of OHS is not reported in the literature (to the authors’ copper.17,18 Under normal dietary conditions, the gastrointes- knowledge), but it is believed to be lower than that of MD. tinal (GI) tract in humans absorbs ~30%–40% of ingested Approximately 35–40 affected individuals are reported in copper.18 Copper is present in various GI fluids such as the literature, with the possibility that the condition may be salivary, gastric, pancreatic, duodenal, and bile. The absorp- underdiagnosed.9,10 tion of copper in humans occurs in two phases.15 In the first The vast majority of patients are male, while biologi- phase, copper is absorbed from the distal small intestine and cal mothers are heterozygotes or carriers. The population reabsorbed into the circulation in its protein-bound form to frequency of sporadic cases reported is compatible with the reach the liver and kidney. Once copper enters the body, it one-third expected for an X-linked lethal disease with