Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment

Abstract

Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.

Fig. (1)

Copper metabolism in humans. ATP7B, copper-transporting P-type ATPase. Solid and dashed arrows show main and minor pathways in copper transport, respectively. Values in parentheses show amounts in adult males.

Fig. (2)

Copper metabolism in normal cells versus those affected by Menkes disease. CTR1, copper transporter 1; ATP7A, copper-transporting P-type ATPase ; ●, copper. Left, copper metabolism in normal cells. Right, copper metabolism in cells affected by Menkes disease. In cells affected by Menkes disease, copper cannot be transported from the cytosol to the Golgi apparatus. As a result, copper accumulates in the cytosol and cannot be excreted from the cells. Copper deficiency in the Golgi apparatus results in a decrease in the activities of secretory copper enzymes such as lysyl oxidase (LOX) and dopamine β-hydroxidase (DBH).

Fig. (3)

Copper metabolism in normal and abnormal (affected by Wilson’s disease) hepatocytes. CTR1, copper transporter 1; ATP7B, copper-transporting Ptype ATPase ; Cp●, ceruloplasmin; ●: copper. Left, copper metabolism in normal hepatocytes. Right, copper metabolism in hepatocyte of patient with Wilson’s disease. In hepatocytes affected by Wilson’s disease, copper cannot be transported from the cytosol to the Golgi apparatus due to a defect in ATP7B, so copper accumulates in the cytosol. Copper deficiency in the Golgi apparatus results in reduced secretion of copper into the blood as ceruloplasmin, during which biliary excretion of copper is disturbed. Accumulated copper in the hepatocyte is released into the blood as non-ceruloplasmin-bound copper, although the mechanism is unclear.

Fig. (4)

Domain organization and catalytic cycle of human copper-ATPases (ATP7A and ATP7B). A: membrane topology and domain organization of Cu-ATPase; MBDs, metal-binding domains; A-domain, the actuator domain; P-domain, phosphorylation domain; N-domain, nucleotide-binding domain. Modified from Lutsenko et al. Physiol Rev. 2007, 87: 1011. Used with permission.

Fig. (5)

Depigmented, lusterless, and kinky hair in a 3-month-old patient with Menkes disease. Hair abnormalities were improved by copper-histidine injections.

Fig. (6)

A 2 year-old patient with Menkes disease treated with copperhistidine injections since the age of 8 months. Despite treatment, he suffers from severe muscle hypotonia and cannot hold up his head.

Fig. (7)

Brain CT images of a patient with Menkes disease at 2, 8, and 11 months of age. The image was taken at the age of 2 months because of a head injury. This was prior to diagnosis of MD as no neurological symptoms were observed at that time. The patient was diagnosed with MD at the age of 8 months, with brain atrophy progressing despite copper-histidine treatment. Subdural hemorrhage was observed in the patient at 11 months of age.

Fig. (8)

Connective tissue abnormalities in the patient with Menkes disease shown in Fig 7. Images on the left and right were taken just before treatment and at 2 years of age (also during the treatment period), respectively. Bladder diverticula formation (upper) and osteoporosis (lower) progressed despite treatment. Arrows show bone fractures.

Fig. (9)

a) Skin laxity in a 18 year-old patient with occipital horn syndrome. b) MRA showing tortuosity of cerebral arteries (arrow). c-d) Occipital horns are shown in a skull X-ray (c) and MRI T1 WI (d) (arrows).

Fig. (10)

Chemical reaction of chelation by sodium N,N-diethyldithiocarbamate.

Fig. (11)

Copper concentrations (Cu) and cytochrome C oxidase (CCO) activity in the cerebrum of macular mice. MA, macular mice treated with copper and DEDTC; MB, macular mice treated with copper only; MC, macular mice without treatment. (*p<0.05; ** p<0.01.

Fig. (12)

Loss of left frontal cerebral white matter in a neurological patient with Wilson’s disease who suffered right hemiplegia.

Fig. (13)

Kayser-Fleischer rings.

Fig. (14)

Chemical reaction of chelation by trientine (upper) and tetrathiomolybdate (lower) [126].