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.