Pediatrics

Menkes syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Menkes disease? What are the typical findings for this disease?

Menkes is a lethal, X-linked, multisystemic, progressive disorder of copper metabolism that causes severe epilepsy, developmental delay, hypotonia, failure to thrive, and death in early childhood.

Boys with Menkes typically present at 2 to 4 months of life. The most common signs and symptoms are seizures, hypotonia, and failure to thrive. The patients will also develop distinctive hair that is short, sparse, and twisted or "kinky." The hair resembles steel wool. Viewing the hair shaft under a microscopic reveals rotation of the hair along its long axis (pili torti).

Neuroimaging shows cerebral and cerebellar atrophy and dysmyelination or demyelination. Subdural hemorrhages may also develop. The boys have abnormal connective tissue that manifests as skin laxity, herniae, bladder diverticula, vascular tortuosity and possible arterial rupture. Ophthalmologic changes include poor visual acuity, strabismus, and myopia. Other features of the disease include hypothermia, hypopigmentation, hypoglycemia, pectus excavatum, spontaneous fractures due to osteoporosis, and seborrheic dermatitis.

What other disease/condition shares some of these symptoms?

The differential diagnosis of Menkes disease includes other conditions that can cause epilepsy and developmental delay in infancy, including the epileptic encephalopathies (due to mutations in ARX, CDKL5, SLC25A22, STXBP1, SPTAN1, KCNQ2, ARHGEF9, PNKP, SCN2A, or PLCB1), inborn metabolic diseases (biotinidase deficiency, nonketotic hyperglycinemia, creatine deficiency syndromes, purine and pyrimidine disorders, mitochondrial cytopathies, sulfite oxidase deficiency, molybdenum cofactor deficiency), cerebral glucose transporter defect (due to mutations in GLUT1), and structural brain anomalies.

However, Menkes disease causes distinctive phenotypic features that are not usually present in these conditions (connective tissue abnormalities, hair abnormalities, subdural hemorrhages), and these other conditions are typically associated with additional signs and symptoms that do not occur in Menkes disease. Therefore, it is not usually difficult to make the diagnosis in affected individuals.

What caused this disease to develop at this time?

Menkes disease is caused by pathologic mutations in the ATP7A gene on the X chromosome. The gene encodes a protein that transports copper from the cytosol to the Golgi apparatus in all cells except hepatocytes. Defects in this enzyme lead to copper accumulation in the cytosol of the intestinal cells and subsequent copper deficiency in the body. Several enzymes require copper for proper functioning, and deficiency of these cuproenzymes leads to the multiple medical problems that occur in Menkes disease.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are three categories of laboratory studies for Menkes disease: biochemical testing, copper transport studies, and molecular testing. Biochemical testing includes serum copper and ceruloplasmin levels. These are typically low in individuals with Menkes disease. Affected individuals have a copper level of 0-55 microgram/dL (normal range is 20-70 in first 6 months of life) and a ceruloplasmin level of 10-160 mg/L (normal range is 50-220 mg/L). Since these levels are low in babies less than 6 years of age, these tests should not be used in isolation to make a diagnosis of Menkes disease.

Catechol levels are abnormal in individuals with Menkes disease because dopamine-beta-hydroxylase is a copper-dependent enzyme involved in catecholamine biosynthesis. The catechol levels will be abnormal in plasma and cerebrospinal fluid of affected individuals. This test helps to confirm the diagnosis in babies whose copper and ceruloplasmin levels are low.

Menkes is a disease of copper transport, and the functional capacity of fibroblasts to transport copper can be measured using radiolabelled copper. This test requires a skin biopsy to isolate and culture fibroblasts.

Molecular testing on the ATP7A gene identifies pathologic changes in nearly 100% of individuals with Menkes disease. This testing should include sequencing of the gene as well as deletion/duplication testing to identify a partial or complete gene deletion.

Specific information about genetic testing for Menkes is available at GeneTests.org: http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/207297?db=genetests

Would imaging studies be helpful? If so, which ones?

Imaging studies are not essential in individuals who have a confirmed diagnosis of Menkes. If performed, brain magnetic resonance imaging (MRI) typically shows cerebral and cerebellar atrophy and demyelination or dysmyelination. Subdural hemorrhages can also occur. Magnetic resonance angiography of the neck and brain may show tortuous vessels. Magnetic resonance spectroscopy shows an elevated lactate peak and a decreased N-acetylaspartate/creatinine + phosphocreatine ratio.

Confirming the diagnosis

In baby boys with a phenotype suggestive of Menkes disease, first obtain serum copper and ceruloplasmin levels. If these studies are abnormally low, then measurement of catechol levels (dopamine, norepinephrine, dihydroxyphenylacetic acid and dihydroxyphenylglycol) in the plasma can be performed. If these measurements are abnormal, then molecular testing of ATP7A should be performed. If a diagnostic lumbar puncture is being performed as part of the diagnostic work, then a cerebrospinal fluid sample should be collected for catechol metabolite measurements. Copper transport studies in fibroblasts are rarely necessary.

If you are able to confirm that the patient has Menkes disease, what treatment should be initiated?

Treatment for this lethal disease is primarily symptomatic and supportive. Most patients do not have significant benefit from copper treatment. However, in those rare patients with milder disease due residual enzyme activity, early parenteral copper-histidine injections may ameliorate the symptoms or slow the progression of the disease. Patients will frequently require gastrostomy tube placement. As the disease progresses, palliative care intervention is recommended.

What are the possible outcomes of Menkes disease?

Menkes is a progressive and lethal disease. Most boys with Menkes disease die within the first 3 to 5 years of life.

What causes this disease and how frequent is it?

Menkes disease is caused by pathologic mutations in the ATP7A gene on the X chromosome. The gene encodes a protein that transports copper from the cytosol to the Golgi apparatus in all cells except hepatocytes. Defects in this enzyme lead to copper accumulation in the cytosol of the intestinal cells and subsequent copper deficiency in the body. Copper deficiency causes impaired function of copper-requiring enzymes (cuproenzymes).

The incidence of the disease is about 1:250,000.

How does a pathologic mutation in ATP7A cause the disease?

Several enzymes require copper for proper functioning, and deficiency of these cuproenzymes leads to the multiple medical problems that occur in Menkes disease. For example, neurologic degeneration is related to decreased activity of cytochrome C oxidase in neurons. Connective tissue dysfunction and vascular abnormalities are due to dysfunction of lysyl oxidase, an enzyme critical for linking elastin and collagen in connective tissue.

What complications might you expect from the disease or treatment of the disease?

Menkes is a progressive and lethal disease. Most boys with Menkes disease die within the first 3 to 5 years of life.

How can Menkes disease be prevented?

Menkes disease cannot be prevented. If a disease-causing mutation has been identified in a family through molecular testing, then carrier testing for at-risk women, prenatal testing, and preimplantation genetic diagnosis may be offered. Copper transport studies in cultured chorionic villus cells or amniocytes can also be performed for prenatal testing.

If a pathologic mutation is identified in an affected boy, then the mother can be offered carrier testing. If the mother is a carrier, then she has a 50% chance of transmitting the pathologic mutation in each pregnancy. A son who inherits the mutation will be affected. A daughter who inherits the mutation will be a carrier. Females do not get Menkes disease, but they may have mild impairment in cognitive function, subtle skeletal abnormalities, or vessel tortuosity on neuroimaging.

What is the evidence?

Kaler, SG, Homes, CS, Goldstein, DS. "Neonatal diagnosis and treatment of Menkes". NEJM. vol. 358. 2008. pp. 605-614.

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