Sections

Menkes Disease

Presentation

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^[13]: 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^[14]
Failure to thrive

People with milder variants may have minimal neurological symptoms with normal intelligence or only mild intellectual disabilityand autonomic dysfunction. Individuals with occipital horn syndrome are predominantly affected by connective tissue and bony abnormalities (see Physical Examination for more details).

An ATP7A variant with a missense mutation T994I in the sixth transmembrane domain is associated with a distal motor neuropathy.^[15]

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 weighed less than 2500 g.

Physical Examination

Findings include abnormal kinky hair, eyebrows, and eyelashes (see the image below) as follows:

Four-month-old patient with classic Menkes disease. His hair is depigmented and lusterless with pili torti and the skin is pale with eczema.

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See the list below:

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 disease.
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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 ends in a patient with Menkes disease.
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Osteoporosis
Metaphyseal spurring and widening (see the following image)

Flared metaphyses of the ulna and radius in a 5-month-old patient with classic Menkes disease.
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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 syndrome.

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

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The horns may not be present in early childhood. These patients also may have mild intellectual disability 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 intellectual disability.

Complications

Spontaneous retroperitoneal hemorrhage was reported in a 4-year-old.^[16]

Differential Diagnoses

Tumer Z, Moller LB. Menkes disease. Eur J Hum Genet. 2010 May. 18(5):511-8. [QxMD MEDLINE Link]. [Full Text].
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. 2007 Mar 1. 402(2):241-50. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. 2006 Oct 3. 103(40):14919-24. [QxMD MEDLINE Link].
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. 2006 Sep. 23(3):725-30. [QxMD MEDLINE Link].
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. 2000 Apr. 66(4):1211-20. [QxMD MEDLINE Link].
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. 2008 Nov. 95(3):174-81. [QxMD MEDLINE Link].
Gu YH, Kodama H, Shiga K, Nakata S, Yanagawa Y, Ozawa H. 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. [QxMD MEDLINE Link].
Kaler SG, Holmes CS, Goldstein DS, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008 Feb 7. 358(6):605-14. [QxMD MEDLINE Link].
Paulsen M, Lund C, Akram Z, Winther JR, Horn N, Moller LB. Evidence that translation reinitiation leads to a partially functional Menkes protein containing two copper-binding sites. Am J Hum Genet. 2006 Aug. 79(2):214-29. [QxMD MEDLINE Link].
Donsante A, Tang J, Godwin SC, et al. Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet. 2007 Aug. 44(8):492-7. [QxMD MEDLINE Link].
Tümer Z, Petris M, Zhu S, Mercer J, Bukrinski J, Bilz S, et al. A 37-year-old Menkes disease patient-Residual ATP7A activity and early copper administration as key factors in beneficial treatment. Clin Genet. 2017 Nov. 92 (5):548-553. [QxMD MEDLINE Link].
Bahi-Buisson N, Kaminska A, Nabbout R, et al. Epilepsy in Menkes disease: analysis of clinical stages. Epilepsia. 2006 Feb. 47(2):380-6. [QxMD MEDLINE Link].
Prasad AN, Levin S, Rupar CA, Prasad C. Menkes disease and infantile epilepsy. Brain Dev. 2011 Nov. 33(10):866-76. [QxMD MEDLINE Link].
Yi L, Kaler SG. Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration. J Biol Chem. 2018 May 18. 293 (20):7606-7617. [QxMD MEDLINE Link].
Peng CH, Hsu CH, Wang NL, Lee HC, Lin SP, Chan WT, et al. Spontaneous retroperitoneal hemorrhage in Menkes disease: A rare case report. Medicine (Baltimore). 2018 Feb. 97 (6):e9869. [QxMD MEDLINE Link].
Lorincz MT. Wilson disease and related copper disorders. Handb Clin Neurol. 2018. 147:279-292. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. 2007 Jan-Feb. 8(1):82-5. [QxMD MEDLINE Link]. [Full Text].
Geller TJ, Pan Y, Martin DS. Early neuroradiologic evidence of degeneration in Menkes' disease. Pediatr Neurol. 1997 Oct. 17(3):255-8. [QxMD MEDLINE Link].
Sheela SR, Latha M, Liu P, et al. Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. Clin Genet. 2005 Sep. 68(3):278-83. [QxMD MEDLINE Link].
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. 2005 Oct. 35(10):1006-9. [QxMD MEDLINE Link].
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. 1999 Aug. 8(8):1547-55. [QxMD MEDLINE Link].
Aoki T. Wilson's disease and Menkes disease. Pediatr Int. 1999 Aug. 41(4):403-4. [QxMD MEDLINE Link].
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. 2005 Mar 11. 280(10):9640-5. [QxMD MEDLINE Link].
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. 2004 Jul. 145(1):119-21. [QxMD MEDLINE Link].
Ferreira RC, Heckenlively JR, Menkes JH, Bateman JB. Menkes disease. New ocular and electroretinographic findings. Ophthalmology. 1998 Jun. 105(6):1076-8. [QxMD MEDLINE Link].
Gasch AT, Kaler SG, Kaiser-Kupfer M. Menkes disease. Ophthalmology. 1999 Mar. 106(3):442-3. [QxMD MEDLINE Link].
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. 2004 Oct 1. 130(2):211-3. [QxMD MEDLINE Link].
Godwin SC, Shawker T, Chang B, Kaler SG. Brachial artery aneurysms in Menkes disease. J Pediatr. 2006 Sep. 149(3):412-5. [QxMD MEDLINE Link].
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. 1999 Aug. 8(8):1473-8. [QxMD MEDLINE Link].
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. 2005 Dec 1. 139(2):151-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Hsi G, Cox DW. A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet. 2004 Jan. 114(2):165-72. [QxMD MEDLINE Link].
Kaler SG. Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr Dev Pathol. 1998 Jan-Feb. 1(1):85-98. [QxMD MEDLINE Link].
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. 2003 Apr. 40(4):290-5. [QxMD MEDLINE Link].
Kim OH, Suh JH. Intracranial and extracranial MR angiography in Menkes disease. Pediatr Radiol. 1997 Oct. 27(10):782-4. [QxMD MEDLINE Link].
Kodama H, Gu YH, Mizunuma M. Drug targets in Menkes disease - prospective developments. Expert Opin Ther Targets. 2001 Oct. 5(5):625-635. [QxMD MEDLINE Link].
Kodama H, Murata Y. Molecular genetics and pathophysiology of Menkes disease. Pediatr Int. 1999 Aug. 41(4):430-5. [QxMD MEDLINE Link].
Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int. 1999 Aug. 41(4):423-9. [QxMD MEDLINE Link].
Kodama H, Sato E, Yanagawa Y, et al. Biochemical indicator for evaluation of connective tissue abnormalities in Menkes' disease. J Pediatr. 2003 Jun. 142(6):726-8. [QxMD MEDLINE Link].
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. 2006 Jul. 47(7):3129-34. [QxMD MEDLINE Link].
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. 2004 Feb. 17(1):87-98. [QxMD MEDLINE Link].
Mandelstam SA, Fisher R. Menkes disease: a rare cause of bilateral inguinal hernias. Australas Radiol. 2005 Apr. 49(2):192-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Mercer JF, Ambrosini L, Horton S, et al. Animal models of Menkes disease. Adv Exp Med Biol. 1999. 448:97-108. [QxMD MEDLINE Link].
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. 2005 Jun. 27(4):297-300. [QxMD MEDLINE Link].
Muz' NI, Matvienko AV. [Local injection of fraxiparine for the treatment of the lower extremity trophic ulcer]. Klin Khir. 2002 Nov-Dec. 51-2. [QxMD MEDLINE Link].
Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 309400. [Full Text].
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. [QxMD MEDLINE Link].
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. 1999 Oct. 8(11):2107-15. [QxMD MEDLINE Link].
Petris MJ, Mercer JF, Camakaris J. The cell biology of the Menkes disease protein. Adv Exp Med Biol. 1999. 448:53-66. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. 2004 Dec. 163(12):745-6. [QxMD MEDLINE Link].
Suzuki M, Gitlin JD. Intracellular localization of the Menkes and Wilson's disease proteins and their role in intracellular copper transport. Pediatr Int. 1999 Aug. 41(4):436-42. [QxMD MEDLINE Link].
Tang J, Robertson S, Lem KE, et al. Functional copper transport explains neurologic sparing in occipital horn syndrome. Genet Med. 2006 Nov. 8(11):711-8. [QxMD MEDLINE Link].
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. 2003 Dec. 22(6):457-64. [QxMD MEDLINE Link].
Tumer Z, Moller LB, Horn N. Mutation spectrum of ATP7A, the gene defective in Menkes disease. Adv Exp Med Biol. 1999. 448:83-95. [QxMD MEDLINE Link].
Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis. 1999 Aug. 6(4):221-30. [QxMD MEDLINE Link].
Zaffanello M, Fanos V. Rare urological abnormalities in 2 cases of Menkes' syndrome. J Urol. 2003 Oct. 170(4 Pt 1):1335. [QxMD MEDLINE Link].
Gu YH, Kodama H, Ogawa E, Izumi Y. Lactate and pyruvate levels in blood and cerebrospinal fluid in patients with Menkes disease. J Pediatr. 2014 Apr. 164(4):890-4. [QxMD MEDLINE Link].

Media Gallery

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.

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Menkes Disease Clinical Presentation

History

Physical Examination

Complications

References

Tables

Contributor Information and Disclosures

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