Dermatology

Menkes’ Syndrome (Menkes disease, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome)

Menkes’ Syndrome, Menkes disease, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome

Are You Confident of the Diagnosis?

What you should be alert for in the history

Affected infants may be born prematurely, but appear healthy at birth and develop normally for 6 to 8 weeks. Initial symptoms may include floppy muscle tone, subnormal body temperature, a cutis laxa-type appearance of the skin, seizures, and failure to thrive. After the normal-appearing newborn hair is shed, patients develop stubby, course, sparse and hypopigmented hair. The hair has been described as “steel wool” since it is unruly and easily fractures with friction. Tortuous blood vessels may be present in the brain.

Characteristic findings on physical examination

A bedside diagnosis can be made by light microscopic observation of hair. A hair mount will show hair twisted at 180º along its axis and occurring in groups of three to ten (Figure 1). Sometimes this twisting can be difficult to visualize with a hair mount due to the flattening of the hair; thus, if the diagnosis is suspected, the hair may be viewed by light micrscopy without mounting media.

Figure 1.

Hair mount showing twisted hair.

Expected results of diagnostic studies

Low serum copper and ceruloplasmin levels are diagnostic but are unreliable in infancy since the values in normal healthy infants can also be low during this time period. Neonatal diagnosis by measurement of serum and cerebrospinal neurochemicals has been advocated.

There are multiple catechols that can be measured (dopamine is high, norepinephrine is low and the various metabolites of dopamine are high while the metaboites of norepinephrine are low). It is not universally agreed upon which one has the best predictive ability or whether a ratio of the different levels may be most useful diagnostically. Abnormal catechol levels are seen in Menkes patients due to low dopamine-beta-hydroxylase activity. Low hepatic copper levels are seen, and serum copper and ceruloplasmin levels are decreased.

Who is at Risk for Developing this Disease?

Menkes’ syndrome is estimated or occurs in about 1 in 100,000 to 1 in 250,000 newborns. The condition is inherited in an X-linked recessive pattern; thus boys are almost exclusively affected.

What is the Cause of the Disease?

Etiology

Menkes’ syndrome is due to a mutation in the X-linked gene encoding Cu(2+)-transporting ATPase, alpha polypeptide (ATP7A) located on chromosome Xq12-q13, which encodes a copper-transporting ATPase.

Pathophysiology

The ATP7A gene regulates copper transport, resulting in abnormally low levels of copper in the brain and liver and excessive copper in the intestines and kidneys. Patients with Menkes’ syndrome have defective activity of copper-dependent enzymes, which affects multiple systems including bone, skin, hair, blood vessels and the nervous system . Copper plays a critical role in brain development and in the normal production of myelin.

It had been presumed that since normal copper transportation is essential to formation of disulfide bonds in hair keratin, defective keratin production was the cause of twisted hair. However, impaired copper transport is also known to lead to reactive oxygen species and mitochondrial dysfunction that can also lead to pili torti (Bjorndstad), thus, the cause of hair twisting in Menkes’ syndrome may be multifactorial. The light, or depigmented appearance of the hair is a result of abnormal tyrosinase function, which also requires copper-dependent enzymes.

Systemic Implications and Complications

Menkes’ disease affects multiple systems due to the crucial role of copper-dependent enzymes. Patients are typically managed by a multispecialty group including pediatricians and pediatric neurologists and urologists.

  • Neurological: Hypotonia, increased deep tendon reflexes, asymmetric neurodegeneration, seizures.

  • Skeletal: Osteoporosis, abnormal bone formation, fractures

  • Vascular: Tortuous blood vessels of the brain

  • Urologic: Diverticula of the urinary bladder

  • General: Failure to thrive, hypoglycemia

  • Untreated children will die, typically before the age of 5.

Treatment Options

Parenteral, subcutaneous, and intramuscular administration of copper-histidine have been reported to restore circulating copper and ceruloplasmin to normal levels. The route of administration and the dosage is not universally agreed upon, with the risk of treatment including iron overload and liver disease.

Optimal Therapeutic Approach for this Disease

The key to successful treatment is early diagnosis prior to the onset of any of the neurologic or other systemic defects. Prompt referral to a neurologist is required.

Early diagnosis and treatment with copper-histidine can lead to excellent clinical outcomes. It has been reported that about one-third of patients with Menkes’ syndrome who are treated within the first 10 days of life have normal neurodevelopmental outcomes.

The specific genetic mutation may account for differences in outcome. However clear phenotype-genotype correlations have not been identified. Studies to determine treatment dosages are ongoing and patients at risk of developing this condition should be referred to the National Institute of Health or other tertiary referral centers. The National Institutes of Health (NIH) has an ongoing study that is recruiting; information is available at clinicaltrials.gov.

Patient Management

Most mutations are de novo; however genetic counseling may be offered to parents who may be at increased risk, or if a woman is suspected of being a carrier. High placental copper levels or genetic analysis can be used for prenatal diagnosis. Women who are carriers may have evidence of pili torti on examination of hair.

Unusual Clinical Scenarios to Consider in Patient Management

A clinical variant of Menkes’ syndrome is type IX Ehlers-Danlos syndrome (aka, X-linked cutis laxa or occipital horn syndrome) which is also caused by a mutation in the ATP7A gene. In addition to the pathognomonic wedge-shaped calcification at the occipital bone, patients have other skeletal abnormalities, as well as hyperelastic and bruisable skin, hyperextensible joints, varicosities, bladder diverticula.

Over 160 other genetic mutations have been reported with phenotypic variability. When patients have small amounts of normal protein, or partly functional protein variants, they may display a milder, atypical phenotype. However a clear phenotype-genotype correlation has been difficult to establish.

What is the Evidence?

Menkes, JH, Alter, M, Steigleder, GK, Weakley, DR, Sung, JH. "A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration". Pediatrics. vol. 29. 1962. pp. 764-79.

(Original paper describing the syndrome.)

Vulpe, C., Levinson, B., Whitney, S., Packman, S., Gitschier, J. "Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase". Nature Genet.. vol. 3. 1993. pp. 7-13.

(The original description of the genetic mutation in Menkes.)

Ambrosini, L, Mercer, JF. "Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease". Hum Mol Genet. vol. 8. 1999. pp. 1547-55.

(Article that describes the protein function of the Menkes syndrome protein that is defective.)

De Bie, P, Muller, P, Wijmenga, C, Klomp, LWJ. "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". J Med Genet. vol. 44. 2007. pp. 673-88.

(A detailed review of the molecular pathogenesis.)

Tang, J, Donsante, A, Desai, V, Patronas, N, Kaler, SG. "Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R". Mol Genet Metab. vol. 95. 2008. pp. 174-81.

(Discussion, characterization, and study of the clinical outcomes of a subset of Menkes patients.)

Kaler, SG, Holmes, CS, Goldstein, DS. "Neonatal diagnosis and treatment of Menkes disease". N Engl J Med. vol. 358. 2008. pp. 605-14.

(The authors propose more extensive screening in neonates, and report positive outcomes when the disease is recognized early.)

Moller, LB, Mogensen, M, Horn, N. "Molecular diagnosis of Menkes disease: Genotype-phenotype correlation". Biochimie. vol. 91. 2009. pp. 1273-1277.

(A review of the many genotype and phenotype variations with a focus on mutations reported in milder forms of Menkes.)

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