Menkes Disease Clinical Presentation

  • Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD   more...
 
Updated: Feb 14, 2012
 

History

Children with the classic form of Menkes disease usually present at 2-3 months of age with the following:

  • Loss of developmental milestones
  • Profound truncal hypotonia
  • Epilepsy, divided into 3 periods by Bahi-Buisson et al[8] : Early stage, median age 3 months, with focal clonic status; intermediate stage, median age 10 months, with intractable infantile spasms; late state, median age 25 months, with multifocal seizures, tonic spasms, and myoclonus[9]
  • Failure to thrive

People with milder variants may have minimal neurological symptoms with normal intelligence or only mild mental retardation and autonomic dysfunction.

One third of the patients with Menkes disease in Japan from 1992-2002 were born before 37 weeks or weighed less than 2500 g. Seventeen percent of patients were born both before 37 weeks and weighing less than 2500 g.

Next

Physical

Findings include the following:

Abnormal kinky hair, eyebrows, and eyelashes (see the image below) as follows:

Four-month-old patient with classic Menkes diseaseFour-month-old patient with classic Menkes disease. His hair is depigmented and lusterless with pili torti and the skin is pale with eczema.
  • Short, sparse, coarse, twisted
  • Shorter and sparser on the sides and back
  • Often lightly or abnormally pigmented; can be white, silver, or gray (In ethnic groups with black hair, the hair can also be blonde or brown.)

Abnormal facies include the following:

  • Jowly with sagging cheeks and ears
  • Depressed nasal bridge
  • High arched palate
  • Delayed tooth eruption

Progressive cerebral degeneration includes the following:

  • Loss of developmental milestones
  • Seizures
  • Profound truncal hypotonia with appendicular hypertonia
  • Temperature instability

Ocular manifestations include the following:

  • Ptosis
  • Visual inattention
  • Optic disc pallor with decreased pupillary responses to light
  • Iris hypoplasia and hypopigmentation

Connective-tissue abnormalities include the following:

  • Loose skin at the nape of the neck and over the trunk
  • Joint hypermobility
  • Polypoid masses, which can be multiple, in the gastrointestinal tract
  • Umbilical and inguinal hernias, which can be bilateral
  • Bladder diverticula (see the following image)Diverticula of the bladder in a boy with Menkes diDiverticula of the bladder in a boy with Menkes disease.
  • Dilated ureters
  • Emphysema

Vascular defects include the following:

  • Arterial rupture
  • Brachial, lumbar, and iliac artery aneurysms
  • Internal jugular vein aneurysms
  • Thrombosis
  • Pulmonary artery hypoplasia

Skeletal changes include the following:

  • Multiple congenital fractures, deformities (see the following image)The clavicles are short with hammer-shaped distal The clavicles are short with hammer-shaped distal ends in a patient with Menkes disease.
  • Osteoporosis
  • Metaphyseal spurring and widening (see the following image)Flared metaphyses of the ulna and radius in a 5-moFlared metaphyses of the ulna and radius in a 5-month-old patient with classic Menkes disease.
  • Diaphyseal periosteal reaction
  • Scalloping of the posterior portion of the vertebral bodies
  • Pectus excavatum
  • Wormian bones

Bleeding diathesis and renal calculi are also noted.

Patients with occipital horn syndrome are affected predominantly by connective-tissue and bony changes, including hyperelastic and bruisable skin, hyperextensible joints, hernias, bladder diverticula, and multiple skeletal abnormalities, including occipital exostoses ("horns"), which are wedge-shaped calcifications within the occipital tendinous insertion of the trapezius and sternocleidomastoid muscles (see the following images).

Lax skin in a patient with occipital horn syndromeLax skin in a patient with occipital horn syndrome. Occipital horns (arrow) in a 14-year-old boy with Occipital horns (arrow) in a 14-year-old boy with occipital horn syndrome.

The horns may not be present in early childhood. These patients also may have mild mental retardation and autonomic dysfunction. Serum copper and ceruloplasmin levels are low but not to the same degree as in Menkes disease. Copper also accumulates in cultured fibroblasts but to a lesser degree than in Menkes disease. Occipital horns can also be present in patients with the classic form of Menkes disease and have been noted in patients as young as 2 years of age.

Other clinical variants referred to as mild Menkes disease are characterized by ataxia and mild mental retardation.

Previous
Next

Causes

Menkes disease is caused by mutations of the Xq13.3 gene (ATP7A).

Many of the gene defects are deletions that can be detected by Southern blot, but small duplications, nonsense mutations, and missense mutations have also been reported.

The mild variants of the disease in humans are generally caused by splicing defects.

Previous
Proceed to Workup
 
 
Contributor Information and Disclosures
Author

Celia H Chang, MD  Associate Health Sciences Clinical Professor, Department of Neurology, University of California, Davis, School of Medicine

Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Beth A Pletcher, MD  Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey

Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Kenneth J Mack, MD, PhD  Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD  Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose.

References

  1. Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet. May 2010;18(5):511-8. [Medline]. [Full Text].

  2. Hardman B, Michalczyk A, Greenough M, et al. Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells. Biochem J. Mar 1 2007;402(2):241-50. [Medline].

  3. Niciu MJ, Ma XM, El Meskini R, et al. Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Neuroscience. 2006;139(3):947-64. [Medline].

  4. Schlief ML, West T, Craig AM, et al. Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. Proc Natl Acad Sci U S A. Oct 3 2006;103(40):14919-24. [Medline].

  5. Linnebank M, Lutz H, Jarre E, et al. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiol Dis. Sep 2006;23(3):725-30. [Medline].

  6. Moller LB, Tumer Z, Lund C, et al. Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. Am J Hum Genet. Apr 2000;66(4):1211-20. [Medline].

  7. 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. Nov 2008;95(3):174-81. [Medline].

  8. Bahi-Buisson N, Kaminska A, Nabbout R, et al. Epilepsy in Menkes disease: analysis of clinical stages. Epilepsia. Feb 2006;47(2):380-6. [Medline].

  9. Prasad AN, Levin S, Rupar CA, Prasad C. Menkes disease and infantile epilepsy. Brain Dev. Nov 2011;33(10):866-76. [Medline].

  10. Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. Feb 7 2008;358(6):605-14. [Medline].

  11. Matsuo M, Tasaki R, Kodama H, Hamasaki Y. Screening for Menkes disease using the urine HVA/VMA ratio. J Inherit Metab Dis. 2005;28(1):89-93. [Medline].

  12. Lee ES, Ryoo JW, Choi DS, Cho JM, Kwon SH, Shin HS. Diffusion-weighted MR imaging of unusual white matter lesion in a patient with Menkes disease. Korean J Radiol. Jan-Feb 2007;8(1):82-5. [Medline].

  13. Geller TJ, Pan Y, Martin DS. Early neuroradiologic evidence of degeneration in Menkes' disease. Pediatr Neurol. Oct 1997;17(3):255-8. [Medline].

  14. Sheela SR, Latha M, Liu P, et al. Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. Clin Genet. Sep 2005;68(3):278-83. [Medline].

  15. Paulsen M, Lund C, Akram Z, Winther JR, Horn N, Møller LB. Evidence that translation reinitiation leads to a partially functional Menkes protein containing two copper-binding sites. Am J Hum Genet. Aug 2006;79(2):214-29. [Medline].

  16. Donsante A, Tang J, Godwin SC, Holmes CS, Goldstein DS, Bassuk A, et al. Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet. Aug 2007;44(8):492-7. [Medline].

  17. Adaletli I, Omeroglu A, Kurugoglu S, Elicevik M, Cantasdemir M, Numan F. Lumbar and iliac artery aneurysms in Menkes' disease: endovascular cover stent treatment of the lumbar artery aneurysm. Pediatr Radiol. Oct 2005;35(10):1006-9. [Medline].

  18. 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. Aug 1999;8(8):1547-55. [Medline].

  19. Aoki T. Wilson's disease and Menkes disease. Pediatr Int. Aug 1999;41(4):403-4. [Medline].

  20. Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem. Mar 11 2005;280(10):9640-5. [Medline].

  21. Borm B, Moller LB, Hausser I, et al. Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/occipital horn syndrome in three affected males in a single family. J Pediatr. Jul 2004;145(1):119-21. [Medline].

  22. Ferreira RC, Heckenlively JR, Menkes JH, Bateman JB. Menkes disease. New ocular and electroretinographic findings. Ophthalmology. Jun 1998;105(6):1076-8. [Medline].

  23. Gasch AT, Kaler SG, Kaiser-Kupfer M. Menkes disease. Ophthalmology. Mar 1999;106(3):442-3. [Medline].

  24. Gerard-Blanluet M, Birk-Moller L, Caubel I, et al. Early development of occipital horns in a classical Menkes patient. Am J Med Genet A. Oct 1 2004;130(2):211-3. [Medline].

  25. Godwin SC, Shawker T, Chang B, Kaler SG. Brachial artery aneurysms in Menkes disease. J Pediatr. Sep 2006;149(3):412-5. [Medline].

  26. Goodyer ID, Jones EE, Monaco AP, Francis MJ. Characterization of the Menkes protein copper-binding domains and their role in copper-induced protein relocalization. Hum Mol Genet. Aug 1999;8(8):1473-8. [Medline].

  27. Grange DK, Kaler SG, Albers GM, et al. Severe bilateral panlobular emphysema and pulmonary arterial hypoplasia: unusual manifestations of Menkes disease. Am J Med Genet A. Dec 1 2005;139(2):151-5. [Medline].

  28. Gu YH, Kodama H, Shiga K, et al. 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. 2005;28(4):473-8. [Medline].

  29. Hsi G, Cox DW. A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet. Jan 2004;114(2):165-72. [Medline].

  30. Kaler SG. Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr Dev Pathol. Jan-Feb 1998;1(1):85-98. [Medline].

  31. Kim BE, Smith K, Petris MJ. A copper treatable Menkes disease mutation associated with defective trafficking of a functional Menkes copper ATPase. J Med Genet. Apr 2003;40(4):290-5. [Medline].

  32. Kim OH, Suh JH. Intracranial and extracranial MR angiography in Menkes disease. Pediatr Radiol. Oct 1997;27(10):782-4. [Medline].

  33. Kodama H, Gu YH, Mizunuma M. Drug targets in Menkes disease - prospective developments. Expert Opin Ther Targets. Oct 2001;5(5):625-635. [Medline].

  34. Kodama H, Murata Y. Molecular genetics and pathophysiology of Menkes disease. Pediatr Int. Aug 1999;41(4):430-5. [Medline].

  35. Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int. Aug 1999;41(4):423-9. [Medline].

  36. Kodama H, Sato E, Yanagawa Y, et al. Biochemical indicator for evaluation of connective tissue abnormalities in Menkes' disease. J Pediatr. Jun 2003;142(6):726-8. [Medline].

  37. Krajacic P, Qian Y, Hahn P, et al. Retinal localization and copper-dependent relocalization of the Wilson and Menkes disease proteins. Invest Ophthalmol Vis Sci. Jul 2006;47(7):3129-34. [Medline].

  38. Lane C, Petris MJ, Benmerah A, et al. Studies on endocytic mechanisms of the Menkes copper-translocating P-type ATPase (ATP7A; MNK). Endocytosis of the Menkes protein. Biometals. Feb 2004;17(1):87-98. [Medline].

  39. Mandelstam SA, Fisher R. Menkes disease: a rare cause of bilateral inguinal hernias. Australas Radiol. Apr 2005;49(2):192-5. [Medline].

  40. Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol. 1999;3(4):147-58. [Medline].

  41. Mercer JF, Ambrosini L, Horton S, et al. Animal models of Menkes disease. Adv Exp Med Biol. 1999;448:97-108. [Medline].

  42. Munakata M, Sakamoto O, Kitamura T, et al. The effects of copper-histidine therapy on brain metabolism in a patient with Menkes disease: a proton magnetic resonance spectroscopic study. Brain Dev. Jun 2005;27(4):297-300. [Medline].

  43. Muz' NI, Matvienko AV. [Local injection of fraxiparine for the treatment of the lower extremity trophic ulcer]. Klin Khir. Nov-Dec 2002;51-2. [Medline].

  44. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 309400. Accessed 1/10/00. Available at http://www.ncbi.nlm.nih.gov/omim/309400.

  45. Pedespan JM, Jouaville LS, Cances C, et al. Menkes disease: study of the mitochondrial respiratory chain in three cases. Eur J Paediatr Neurol. 1999;3(4):167-70. [Medline].

  46. Petris MJ, Mercer JF. The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal. Hum Mol Genet. Oct 1999;8(11):2107-15. [Medline].

  47. Petris MJ, Mercer JF, Camakaris J. The cell biology of the Menkes disease protein. Adv Exp Med Biol. 1999;448:53-66. [Medline].

  48. Poulsen L, Moller LB, Plunkett K, et al. X-linked Menkes disease: first documented report of germ-line mosaicism. Genet Test. 2004;8(3):286-91. [Medline].

  49. Sasaki G, Ishii T, Sato S, et al. Multiple polypoid masses in the gastrointestinal tract in patient with Menkes disease on copper-histidinate therapy. Eur J Pediatr. Dec 2004;163(12):745-6. [Medline].

  50. Suzuki M, Gitlin JD. Intracellular localization of the Menkes and Wilson's disease proteins and their role in intracellular copper transport. Pediatr Int. Aug 1999;41(4):436-42. [Medline].

  51. Tang J, Robertson S, Lem KE, et al. Functional copper transport explains neurologic sparing in occipital horn syndrome. Genet Med. Nov 2006;8(11):711-8. [Medline].

  52. Tumer Z, Birk Moller L, Horn N. Screening of 383 unrelated patients affected with Menkes disease and finding of 57 gross deletions in ATP7A. Hum Mutat. Dec 2003;22(6):457-64. [Medline].

  53. Tumer Z, Moller LB, Horn N. Mutation spectrum of ATP7A, the gene defective in Menkes disease. Adv Exp Med Biol. 1999;448:83-95. [Medline].

  54. Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis. Aug 1999;6(4):221-30. [Medline].

  55. Zaffanello M, Fanos V. Rare urological abnormalities in 2 cases of Menkes' syndrome. J Urol. Oct 2003;170(4 Pt 1):1335. [Medline].

 
Previous
Next
 
Four-month-old patient with classic Menkes disease. His hair is depigmented and lusterless with pili torti and the skin is pale with eczema.
Diverticula of the bladder in a boy with Menkes disease.
The clavicles are short with hammer-shaped distal ends in a patient with Menkes disease.
Flared metaphyses of the ulna and radius in a 5-month-old patient with classic Menkes disease.
Lax skin in a patient with occipital horn syndrome.
Occipital horns (arrow) in a 14-year-old boy with occipital horn syndrome.
Magnetic resonance imaging of the brain of a patient with Menkes disease. Subdural effusion is evident in the left frontal lesion. Brain atrophy is also evident.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.