Inborn errors of copper metabolism

Abstract

Two copper-transporting ATPases are essential for mammalian copper homeostasis: ATP7A, which mediates copper uptake in the gastrointestinal tract and copper delivery to the brain, and ATP7B, which mediates copper excretion by the liver into bile. Mutations in ATP7A may cause three distinct X-linked conditions in infants, children, or adolescents: Menkes disease, occipital horn syndrome (OHS), and a newly identified allelic variant restricted to motor neurons called X-linked distal hereditary motor neuropathy. These three disorders show variable neurological findings and ages of onset. Menkes disease presents in the first several months of life with failure to thrive, developmental delay, and seizures. OHS features more subtle developmental delays, dysautonomia, and connective tissue abnormalities beginning in early childhood. ATP7A-related distal motor neuropathy presents even later, often not until adolescence or early adulthood, and involves a neurological phenotype that resembles Charcot-Marie-Tooth disease, type 2. These disorders may be treatable through copper replacement or ATP7A gene therapy. In contrast, mutations in ATP7B cause a single known phenotype, Wilson disease, an autosomal recessive trait that results from copper overload rather than deficiency. Dysarthria, dystonia, tremor, gait abnormalities, and psychiatric problems may be presenting symptoms, at ages from 10 to 40 years. Excellent treatment options exist for Wilson disease, based on copper chelation. In the past 2 years (2012-2013), three new autosomal recessive copper metabolism conditions have been recognized: 1) Huppke-Brendel syndrome caused by mutations in an acetyl CoA transporter needed for acetylation of one or more copper proteins, 2) CCS deficiency caused by mutations in the copper chaperone to SODI, and 3) MEDNIK syndrome, which revealed that mutations in the σ1A subunit of adaptor protein complex 1 (AP-1) have detrimental effects on trafficking of ATP7A and ATP7B.

Fig. 180.1

Diagnostic signs in inherited disorders of copper transport. (A) Kayser–Fleischer ring (arrow) in the cornea of a newly diagnosed adult patient with Wilson disease. (Reproduced from Kaler (2008). Wilson disease. In: L Goldman, D Ausiello (Eds.), Cecil’s Textbook of Medicine, 23rd edn. Saunders, Philadelphia, ch. 230, pp. 1593–1595.) (B) Hair and facial appearance in classical Menkes disease at 8 months of age. (Reproduced from Kaler (1994). Adv Pediatr 41:263–304.) (C) Occipital exostoses (thick arrow) and wormian bones (small arrow) in a 4-year-old patient with occipital horn syndrome. (Modified from Tang et al. (2006). Genet Med 8: 711–718.) (D) Pes cavus foot deformity in a 43-year-old patient with ATP7A-related hereditary distal motor neuropathy. (Reproduced from Kennerson et al. (2010). Am J Hum Genet 86: 343–352.)

Fig. 180.2

Molecular spectrum of ATP7A-related copper transport disorders. (A) Western analysis of fibroblast protein from patients with classical Menkes disease (Del ex20-23, Pt A, Pt B) show absent or reduced quantities of the 178 kDa ATP7A protein compared to two normal fibroblast cell lines (GM3562, GM3440). An antibody raised against the carboxyl-terminus of ATP7A was used. The membrane was stripped and re-probed with an anti-β-actin antibody to demonstrate equivalent loading. (Modified from Tang et al. (2008). Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R. PMID: 18752978. Molec Genet Metab 95:174–181.) (B) RNAse protection assay indicates a “leaky” splicing defect in an occipital horn syndrome patient (lane 4) whose cultured lymphoblasts contained some properly spliced ATP7A transcript (698 bp protected fragment) in addition to two mutant protected fragments (424 bp and 156 bp), in comparison to a normal control lymphoblast cell line GM3201 (lane 3). (Modified from Kaler et al. (1994). Nat Genet 8:195–202.) (C) ATP7A model indicating two missense mutations in unrelated families with X-linked distal hereditary motor neuropathy. These specific mutations have not been reported in Menkes disease or occipital horn syndrome. (Modified from Kennerson et al. (2010). Am J Hum Genet 86: 343–352.)