Menkes disease

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Menkes disease
Other namesTrichopoliodystrophy, copper transport disease, steely hair disease, kinky hair disease
Neurodegenerative Disease with Monilethrix 1.jpg
Child with Menkes disease, showing characteristic hair
Specialty Pediatrics, Medical Genetics
CausesMutations in genes coding for the copper-transport protein ATP7A
Frequency1 in 254,000 (Europe)
1 in 357,143 (Japan)

Menkes disease (MNK), also known as Menkes syndrome, [1] [2] is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, [3] leading to copper deficiency. [4] [5] Characteristic findings include kinky hair, growth failure, and nervous system deterioration. Like all X-linked recessive conditions, Menkes disease is more common in males than in females. The disorder was first described by John Hans Menkes in 1962. [6]

Contents

Onset occurs during infancy, with incidence of about 1 in 100,000 to 250,000 newborns; affected infants often do not live past the age of three years, though there are rare cases in which less severe symptoms emerge later in childhood. [7]

Signs and symptoms

Affected infants may be born prematurely. Signs of the disease appear during infancy, typically after a two- to three-month period of normal or slightly slowed development that is followed by a loss of early developmental skills and subsequent developmental delay. Patients exhibit hypotonia (weak muscle tone), failure to thrive, hypothermia (subnormal body temperature), sagging facial features, seizures, and metaphyseal widening. Hair appears strikingly peculiar: kinky, colorless or silvery, and brittle. There can be extensive neurodegeneration in the gray matter of the brain. [8] Arteries in the brain can also be twisted with frayed and split inner walls. This can lead to rupture or blockage of the arteries. Weakened bones (osteoporosis) may result in fractures. [9]

Occipital horn syndrome (sometimes called X-linked cutis laxa or Ehlers-Danlos type 9 [10] ) is a mild form of Menkes syndrome that begins in early to middle childhood. It is characterized by calcium deposits in a bone at the base of the skull (occipital bone), coarse hair, and loose skin and joints. [11]

Cause

Mutations in the ATP7A gene, located on chromosome Xq21.1, [12] lead to Menkes syndrome. [13] This condition is inherited in an X-linked recessive pattern. [14] About 30% of MNK cases are due to new mutations and 70% are inherited, almost always from the mother. [7] Even though the disease is more common in males, females can still be a carrier of the disease. As the result of a mutation in the ATP7A gene, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels and the nervous system such as lysyl oxidase. [15] As with other X-linked disorders, female children of a carrier mother have an even chance of carrying the disorder, but are normally well; male children have an even chance of having the disorder or of being free from it. A genetic counselor may have useful advice. [9]

Mechanism

Microscopic examination of hair, revealing classical sign of pili torti. Menkes disease3.jpg
Microscopic examination of hair, revealing classical sign of pili torti .

The ATP7A gene encodes a transmembrane protein that transport copper across the cell membranes. It is found throughout the body, except for the liver. In the small intestines, the ATP7A protein helps control the absorption of copper from food. In other cells, the protein travels between the Golgi apparatus and the cell membrane to maintain copper concentrations in the cell. The protein is normally found in the Golgi apparatus, which is important for modifying proteins, including enzymes. In the Golgi apparatus, ATP7A protein provides copper to certain enzymes that are critical for the structure and function of bone, skin, hair, blood vessels, and the nervous system. [16] One of the enzymes, lysyl oxidase, requires copper for proper function. This enzyme cross-links tropocollagen into strong collagen fibrils. The defective collagen contributes to many of the aforementioned connective tissue manifestations of this disease. [17]

If copper levels become excessive, the protein will travel to the cell membrane and eliminate excess copper from the cell. Mutations in the ATP7A gene such as deletions and insertions lead to parts of the gene being deleted, resulting in a shortened ATP7A protein. This prevents the production of a functional ATP7A protein, leading to the impaired absorption of copper from food and copper will not be supplied to certain enzymes. [9]

Diagnosis

Menkes syndrome can be diagnosed by blood tests of the copper and ceruloplasmin levels, skin biopsy, and optical microscopic examination of the hair to view characteristic Menkes abnormalities. X-rays of the skull and skeleton are conducted to look for abnormalities in bone formation. [7] Urine homovanillic acid/vanillylmandelic acid ratio has been proposed as a screening tool to support earlier detection. [18] [19] Since 70% of MNK cases are inherited, genetic testing of the mother can be performed to search for a mutation in the ATP7A gene. [20]

Treatment

There is no cure for Menkes disease. Early treatment with injections of copper supplements (acetate or glycinate) may be of some slight benefit. 11 of 12 newborns who were diagnosed with MNK were alive at age 4.6. [21] Other treatment is symptomatic and supportive. Treatments to help relieve some of the symptoms includes pain medication, anti-seizure medication, feeding tube when necessary, and physical and occupational therapy. [21] The earlier treatment is given, the better the prognosis. [22]

Epidemiology

One European study reported a rate of 1 in 254,000; [23] a Japanese study reported a rate of 1 in 357,143. [24] No correlation with other inherited characteristics, or with ethnic origin, is known.[ citation needed ]

See also

Related Research Articles

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<span class="mw-page-title-main">Occipital horn syndrome</span> Medical condition

Occipital horn syndrome (OHS), formerly considered a variant of Ehlers–Danlos syndrome, is an X-linked recessive mitochondrial and connective tissue disorder. It is caused by a deficiency in the transport of the essential mineral copper, associated with mutations in the ATP7A gene.

<span class="mw-page-title-main">Ceruloplasmin</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">ATP7A</span> Protein-coding gene in humans

ATP7A, also known as Menkes' protein (MNK), is a copper-transporting P-type ATPase which uses the energy arising from ATP hydrolysis to transport Cu(I) across cell membranes. The ATP7A protein is a transmembrane protein and is expressed in the intestine and all tissues except liver. In the intestine, ATP7A regulates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A shuttles between the Golgi apparatus and the cell membrane to maintain proper Cu(I) concentrations in the cell and provides certain enzymes with Cu(I). The X-linked, inherited, lethal genetic disorder of the ATP7A gene causes Menkes disease, a copper deficiency resulting in early childhood death.

<span class="mw-page-title-main">V-ATPase</span> Family of transport protein complexes

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<span class="mw-page-title-main">Cutis laxa</span> Skin which is abnormally inelastic and hangs loosely

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References

  1. ↑ Online Mendelian Inheritance in Man (OMIM): 309400
  2. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 765. ISBN   978-0-7216-2921-6.
  3. ↑ "Menkes syndrome" at Dorland's Medical Dictionary
  4. ↑ Rensing, Christopher; McDevitt, Sylvia Franke (2013). "The Copper Metallome in Prokaryotic Cells". Metallomics and the Cell. Metal Ions in Life Sciences. Vol. 12. pp. 417–450. doi:10.1007/978-94-007-5561-1_12. ISBN   978-94-007-5560-4.
  5. ↑ de Bie P, Muller P, Wijmenga C, Klomp LW (Nov 2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". J. Med. Genet. 44 (11): 673–688. doi:10.1136/jmg.2007.052746. PMC   2752173 . PMID   17717039.
  6. ↑ Menkes JH, Alter M, Steigleder GK, Weakley DR, Sung JH (1962). "A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration". Pediatrics. 29: 764–779. PMID   14472668.
  7. 1 2 3 "Research Overview". themenkesfoundation.org. Archived from the original on 2017-02-12. Retrieved 2015-12-10.
  8. ↑ Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S (2005). "The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum". J Biol Chem. 280 (10): 9640–5. doi: 10.1074/jbc.M413840200 . PMID   15634671.
  9. 1 2 3 "Menkes Disease". NORD (National Organization for Rare Disorders). Retrieved 2022-10-10.
  10. ↑ Menkes Disease at eMedicine
  11. ↑ "Menkes syndrome". MedlinePlus Genetics.
  12. ↑ Online Mendelian Inheritance in Man (OMIM): 300011
  13. ↑ Voskoboinik I, Camakaris J (2002). "Menkes copper-translocating P-type ATPase (ATPTA): biochemical and cell biology properties, and role in Menkes disease". J Bioenerg Biomembr. 34 (5): 363–71. doi:10.1023/A:1021250003104. PMID   12539963. S2CID   23109512.
  14. ↑ Kim BE, Smith K, Meagher CK, Petris MJ (November 2002). "A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation". J. Biol. Chem. 277 (46): 44079–84. doi: 10.1074/jbc.M208737200 . PMID   12221109.
  15. ↑ Scheiber, Ivo; Dringen, Ralf; Mercer, Julian F. B. (2013). "Chapter 11. Copper: Effects of Deficiency and Overload". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel (ed.). Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. Vol. 13. Springer. pp. 359–387. doi:10.1007/978-94-007-7500-8_11. ISBN   978-94-007-7499-5. PMID   24470097.
  16. ↑ "ATP7A gene". Genetics Home Reference. 2015-12-07. Retrieved 2015-12-10.
  17. ↑ Zeid, Cynthia Abou; Yi, Ling; Kaler, Stephen G. (2019). "Menkes Disease and Other Disorders Related to ATP7A". Clinical and Translational Perspectives on WILSON DISEASE. pp. 439–447. doi:10.1016/B978-0-12-810532-0.00043-4. ISBN   978-0-12-810532-0.
  18. ↑ Matsuo M, Tasaki R, Kodama H, Hamasaki Y (2005). "Screening for Menkes disease using the urine HVA/VMA ratio". J. Inherit. Metab. Dis. 28 (1): 89–93. doi:10.1007/s10545-005-5083-6. PMID   15702409. S2CID   32096977.
  19. ↑ Craiu, Dana; Kaler, Stephen; Craiu, Mihai (2014). "Role of optic microscopy for early diagnosis of Menkes disease". Romanian Journal of Morphology and Embryology = Revue Roumaine de Morphologie et Embryologie. 55 (3): 953–956. PMC   6456807 . PMID   25329126.
  20. ↑ MedlinePlus Encyclopedia : Menkes disease
  21. 1 2 Kaler SG, Holmes CS, Goldstein DS (February 2008). "Neonatal diagnosis and treatment of Menkes disease". N. Engl. J. Med. 358 (6): 605–14. doi:10.1056/NEJMoa070613. PMC   3477514 . PMID   18256395.
  22. ↑ "Research Overview". themenkesfoundation.org. Archived from the original on 2017-02-12. Retrieved 2018-04-08.
  23. ↑ Tønnesen T, Kleijer WJ, Horn N (February 1991). "Incidence of Menkes disease". Hum. Genet. 86 (4): 408–10. doi:10.1007/BF00201846. PMID   1999344. S2CID   1359203.
  24. ↑ Gu YH, Kodama H, Shiga K, Nakata S, Yanagawa Y, Ozawa H (2005). "A survey of Japanese patients with Menkes disease from 1990 to 2003: incidence and early signs before typical symptomatic onset, pointing the way to earlier diagnosis". J. Inherit. Metab. Dis. 28 (4): 473–8. doi:10.1007/s10545-005-0473-3. PMID   15902550. S2CID   1771596.
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