Menkes disease

Abstract

Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar 'kinky' hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms.

Figure 1

Clinical appearance at age 3 weeks of a patient with classical MD. Note the lax skin.

Figure 2

Abnormal hair in a patient with classical MD. (a) Stubby appearance of depigmented scalp hair. (b) Hair microscopy ( × 100) of twisted hair shaft (pili torti) (below) and a normal hair strand (above) (courtesy of E Reske-Nielsen, Glostrup University Hospital, Denmark).

Figure 3

Lateral skull radiograph of a 23-year-old OHS patient. The occipital exostoses (arrow) are not present at birth and become prominent by age (courtesy of I Kaitila, Helsinki University Hospital, Finland).

Figure 4

Schematic illustration of cellular copper transport. Copper is taken up across the plasma membrane by the copper uptake transporter (CTR1) as cuprous ions (CuI). Within the cytoplasma, the copper is found attached to glutathione (GSH), metallothionein (MT), or copper chaperons, which deliver copper to enzymes and compartments. COX17 is the copper chaperone for COX, CCS is the copper chaperone for the cytoplasmic superoxide dismutase (SOD1), and HAH1 is the copper chaperone for ATP7A, which delivers copper to peptidyl-α-amidating enzyme (PAM), dopamine β-hydroxylase (DBH), tyrosinase (TYR), lysyl oxidase (LOX), and extracellular SOD3. ATP7A is also responsible for copper export from cells. At low copper concentrations, the localization of the protein is at the TGN, but at high copper concentrations it will be relocated to the plasma membrane. In the liver the role of ATP7A is performed by ATP7B.

Figure 5

Schematic 3D protein structure of ATP7A with the functionally important domains. At the N-terminal ATP7A has six MBDs with the copper-binding motifs (CXXC). The protein is anchored to the membrane with the transmembrane domains (TMDs) and within TMD6 resides the CPC motif, which is assumed to play a direct role in copper translocation. The activation domain (A) with the invariant TGE residues, the nucleotide-binding domain (N), and the phosphorylation domain (P) with the invariant aspartate residue (D) are important domains for the catalytic activity of ATP7A.

Figure 6

Flow chart for diagnosis. The DOPA/DHPG ratio (ratio of dihydroxyphenylalanine to dihydroxyphenylglycol) is indicative of dopamine β-hydroxylase, which is a copper-dependent enzyme. Gross deletions were previously investigated with the Southern blot method, which is now replaced by MLPA (multliplex ligation-dependent probe amplification) method (LBM, unpublished data).