Presenter: Tyler Reimschisel, MD Preceptor: Harvey Singer, MD

Disclosures

October 07, 2002

Discussion

Like Wilson's disease, Menkes disease is also a defect in an ATPase-dependent membrane-associated copper transporter. In Menkes disease there is normal uptake of copper by enterocytes, but an abnormal extrusion of copper from these cells. This leads to a low level of copper in plasma, liver, and brain. Extrusion of copper from other cell lines is also blocked, and copper subsequently can build up in the duodenum, kidney, spleen, pancreas, skeletal muscle, and placenta. Copper-dependent enzymes (cuproenzymes) in the brain, retina, and connective tissue require copper as a cofactor. In Menkes disease, dysfunction of these enzymes leads to characteristic signs and symptoms.

Menkes disease predominantly affects boys because it is an X-linked recessive disorder.

Symptoms of Menkes disease usually begin at 2-3 months of age. The infant may present with developmental regression, seizures, and failure to thrive. Hypotonia is due to deficient function of cytochrome C oxidase, a cuproenzyme. The infant will usually have a typical dysmorphic pattern with full, rosy cheeks and a high-arched palate. The coarse, short, sparse, and twisted hair is distinctive and is due to tyrosine hydroxylase deficiency, another cuproenzyme. Pili torti, one of the hair abnormalities, can help the clinician make a prompt diagnosis (Figure 7).

Figure 7.

Hair from child in Case 2 with Menkes disease (top) compared to control hair (bottom).



Below is a list of the other clinical manifestations of Menkes disease. Deficiency of the cuproenzyme, in parentheses, is believed to be the etiology of the abnormality.

  • Temperature instability (dopamine-beta-hydroxylase)

  • Hypoglycemia (dopamine-beta-hydroxylase)

  • Autonomic instability

  • Ptosis (dopamine-beta-hydroxylase)

  • Hernias

  • Ophthalmology: retinal hypopigmentation, tortuous vessels, cataracts, microcysts, partial optic atrophy

  • Urinary bladder diverticula (lysyl oxidase)

The most important step toward making a diagnosis of Menkes disease is to consider it in the differential diagnosis of an infant boy with developmental delay and seizures. Serum copper and ceruloplasmin levels are low. Brain MRI shows impaired myelination (due to cytochrome C oxidase deficiency); diffuse atrophy from neuronal degeneration and gliosis; ventriculomegaly; and tortuous vessels (due to lysyl oxidase deficiency). Strokes are also relatively common.

Dopamine-beta-hydroxylase is an essential enzyme in the metabolism of catecholamines. Thus, Menkes disease can be confirmed by determining the concentration of catecholamine metabolites in the patient suspected of having the disease. Figure 8 shows the results of the evaluation of the patient in Case 2. Note that the catecholamines upstream from dopamine-beta-hydroxylase are elevated, and those downstream from the enzyme are reduced.

Figure 8.

Catecholamine metabolism in Menkes Disease. Key: Case 2 patient value (normal median).



Very early intravenous and intramuscular copper therapy may prevent severe neurologic outcome, but the treatment must begin before any symptoms develop. To this end, there is currently a study being conducted through the National Institutes of Health in which siblings of affected individuals are being treated with copper until Menkes disease can be ruled out.

Copper supplementation may provide limited benefit for controlling irritability, sleep patterns, and seizures in symptomatic patients, but this is controversial. Unfortunately, even with early treatment, subnormal neurodevelopment is unavoidable unless an affected individual has a mild form of the disease. This is possible because there is some phenotypic variability in the severity of the disease.

Children with Menkes disease require individualized management. Caloric intake must be maximized. Babies can receive immunizations, but one should consider withholding the acellular pertussis component of the DTaP series. Influenza immunization should be given each year. Seizures should be managed aggressively with anticonvulsant therapy. If the bladder ultrasound is abnormal, urinary tract infection prophylaxis should be considered. Finally, each child should receive physical and occupational therapy.

Since Menkes disease is uniformly fatal, physicians should discuss end-of-life preferences with the family. Thorough palliative care should be available to the patient and his family when necessary. Parents of children with Menkes disease should receive genetic counseling if they are planning to have more children.

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