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Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
The facial appearance is highly characteristic, with a pale complexion, sagging jowls, wide nasal bridge and abnormal hair. The hair is striking; it is lustreless, brittle and has an unkempt appearance (Figs 14.23, 14.24). Microscopically it shows pili torti. Menke patients, because of the role of copper in elastin and collagen synthesis, can also have problems with joint laxity, bladder diverticulum and rupture, arterial bleeds and bony abnormalities. These features are also seen in the milder forms of the disease such as the occipital horn syndrome.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Allelic conditions: occipital horn syndrome is caused by mutations in the same gene and presents later. Affected individuals are long and thin with bilateral herniae, chronic diarrhoea, redundant skin as in cutis laxa, bladder diverticula causing obstruction and hydronephrosis. The digits are hypermobile, but elbows and knees have limited extension. There is carpal fusion and the clavicles are short with a hammer-shaped distal end.
Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders
Published in Expert Opinion on Investigational Drugs, 2021
Copper serves as a structural and catalytic cofactor for a variety of enzymes in aerobic organisms. Though present in trace amounts, copper is essential for numerous biochemical processes including mitochondrial energy generation, free radical eradication, neurotransmitter synthesis, neuropeptide maturation, connective tissue formation, iron homeostasis, and pigment production [1]. Owing to its diverse roles in cellular and organismal physiology, it is not surprising that copper deficiency can result in multi-systemic diseases. Indeed, loss-of-function mutations in copper transport proteins result in debilitating and frequently fatal infantile disorders [2]. Amongst the many rare genetic disorders of copper deficiency, the most prevalent and best studied is Menkes disease, which is an X-linked disease caused by mutations in the copper transporting ATPase, ATP7A [3]. Menkes is a relatively rare disease with incidence estimates ranging from 1/50,000 to 1/360,000 live births depending on the population surveyed [3]. Loss of functional ATP7A, which is required for directional transport across polarized epithelial cells such as the intestinal enterocytes, results in systemic copper deficiency due to impaired absorption of dietary copper. Copper deficiency in Menkes children manifests in characteristic kinky hair, hypopigmentation, connective tissue abnormalities, seizures, and progressive neurodegeneration, with death typically occurring by the third year of life [3]. Partial loss-of-function ATP7A variants have been identified in patients with occipital horn syndrome (OHS), which is a milder form of Menkes disease [4]. Like Menkes patients, OHS patients display hair and connective tissue abnormalities, but their neurological symptoms are milder [4]. Additionally, missense mutations in the carboxyl half of ATP7A have been associated with X-linked distal hereditary motor neuropathy, and mutations in AP1S1 (σ1A subunit of the adaptor protein complex I), which disrupt intracellular trafficking of copper transporters ATP7A and ATP7B, have been found in patients with MEDNIK syndrome [2]. Currently, no effective therapy exists for these disorders, though early administration of copper-histidine could be beneficial to a subset of Menkes patients, especially, if the mutant ATP7A retains some residual activity [5].