eMedicine Specialties > Neurology > Pediatric Neurology

Menkes Disease

Author: Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Contributor Information and Disclosures

Updated: Apr 9, 2007

Introduction

Background

Menkes disease, also known as kinky hair disease, is an X-linked neurodegenerative disease of impaired copper transport. Menkes et al first described it in 1962. Danks et al first noted that copper metabolism is abnormal in 1972; in 1973, after noting the similarity of kinky hair to the brittle wool of Australian sheep raised in areas with copper-deficient soil, he demonstrated abnormal levels of copper and ceruloplasmin in these patients.

A girl with the Menkes disease phenotype and an X:autosome chromosomal translocation was described in 1987, which led to the identification of the locus on the X chromosome in 1993. Milder variants of Menkes disease, including occipital horn syndrome (also known as X-linked cutis laxa or Ehlers-Danlos type 9) have also been described. The brindled mouse, viable brindled mouse, and blotchy mouse are animal models of the classic form, the mild form, and the occipital horn syndrome, respectively.

Pathophysiology

Copper is a trace metal in many essential enzyme systems, including cytochrome C oxidase, superoxide dismutase, lysyl oxidase, tyrosinase, ascorbic acid oxidase, ceruloplasmin, and dopamine beta hydroxylase. The deficiency or impaired function of these enzyme systems is thought to be responsible for the clinical findings of Menkes disease. The Menkes gene is located on the long arm of the X chromosome at Xq13.3, and the gene product (ATP7A) is a 1500–amino acid P-type adenosine triphosphatase (ATPase) that has 17 domains—6 copper binding, 8 transmembrane, a phosphatase, a phosphorylation, and an ATP binding.

The Menkes and Wilson disease genes have 55% amino acid identity. Menkes and Wilson disease ATPases use common biochemical mechanisms, but the tissue-specific expression differs. The Wilson disease gene (WND) is expressed predominantly in the liver, whereas the Menkes disease gene (MNK) is not expressed in the liver. The predominant sites of Menkes gene expression are the placenta, GI tract, and blood-brain barrier. The Menkes protein is also in retinal pigment epithelial cells and the neurosensory retina.

Hardman et al found that insulin and estrogen increased the level of MNK mRNA and protein levels in the placenta (Hardman, 2007). The MNK protein also became localized toward the basolateral membrane and had increased copper transport. Hardman et al found levels of the Wilson disease ATPase decreased in response to insulin and was perinuclear. This suggests that the MNK protein delivers copper to the fetus and Wilson disease ATPase returns excess copper to the maternal circulation.

Niciu et al found that ATP7A is most abundant in the early postnatal period and peaks at P4 in the neocortex and cerebellum in the mouse brain (Niciu, 2006). ATP7A levels are highest in the ependymal cells of the lateral and third ventricles. ATP7A increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons but decreases in other cell populations postnatally. Schlief et al found that copper is protective and copper chelation exacerbates NMDA-mediated excitotoxic cell death in hippocampal neurons (Schlief, 2006).

All copper-transporting ATPases have a histidine residue in the large cytoplasmic loop adjacent to the ATP-binding domain. The histidine residue is the most common mutation site in Wilson disease, and this histidine residue is essential for the function of the Menkes ATPase, ATP7A. The Menkes protein is synthesized as a single-chain polypeptide localized to the trans-Golgi network of cells.

Under normal circumstances, ATP7A transports copper into the secretory pathway of the cell for incorporation into the cuproenzymes and excretion from the cell. An increase in intracellular copper causes ATP7A to move to the plasma membrane. As the copper is concentrated into vesicles for excretion from the cell, the cytosolic copper concentration decreases and ATP7A returns to the trans-Golgi network. The migration of ATP7A appears to involve amino acid sequences in the carboxyl terminus, utilizing both clathrin-dependent and clathrin-independent endocytosis. Menkes disease can be caused by both copper transport dysfunction and abnormal protein trafficking.

In Menkes disease, transport of dietary copper from intestinal cells is impaired, leading to the low serum copper levels. Abnormal copper transport in other cells leads to paradoxical copper accumulation in duodenal cells, kidney, pancreas, skeletal muscle, and placenta.

The Menkes gene product protein exists in both a truncated and a long form. The truncated form, which is located in the endoplasmic reticulum, is also present in the occipital horn syndrome. The partial preservation of the copper transport-ATPase activity may account for the milder phenotype. Exon skipping is common in Menkes disease. Normal splicing of mRNA depends on a highly conserved, 9-nucleotide splice donor sequence. Slight variations from the splice donor sequence are common, except for the invariant GT (guanine-thiamine) dinucleotide at the +1 and +2 intronic positions. Splice acceptor sites have an invariant AG (adenine-guanine) dinucleotide at intronic positions -1 and -2. Splice junction mutations of the invariant bases severely reduce correct splicing. Patients with the milder Menkes phenotypes have mutations at other sites so that proper splicing of some protein still occurs.

Gross gene deletions occur in about 15% of patients, usually with the classic form of Menkes disease. The point mutations in ATP7A are 23% at the splice site, 20.7% nonsense, 17.2% missense, and 39.1% small deletions/insertions. Variable expression of an identical mutation can be present within a family.

Deficient cytochrome C oxidase (CCO) probably accounts for most of the neurological symptoms, similar to patients with Leigh disease (subacute necrotizing encephalomyelopathy) who have reduced or absent CCO activity and similar neuropathologic changes. Linnebank et al found that copper supplementation in vitro helped to decrease homocysteine toxicity and preserved CCO activity (Linnebank, 2006). Decreased lysyl oxidase (LO) activity accounts for the connective-tissue fragility and vascular abnormalities in Menkes disease, since LO deaminates lysine and hydroxylysine in the first step for collagen cross-linkage. LO localizes to the trans-Golgi network so subcutaneous injections of copper-histidine do not improve the activity of LO as the copper is not delivered into the Golgi apparatus. Tyrosinase deficiency (involved in melanin biosynthesis) most likely accounts for the hypopigmentation of the hair and skin seen in Menkes disease.

Purkinje cell loss is profound in Menkes disease. During development, the expression of ATP7A switches from Purkinje cells to Bergmann glia, cells, which support Purkinje cell function in adults. ATP7A is a faster copper transporter and catalyses reactions faster than ATP7B, the deficient protein in Wilson disease. Peptidylglycine alpha-amidating mono-oxygenase (PAM) is necessary for the removal of the glycine residue from neuroendocrine precursors—corticotropin-releasing factor (CRH), thyrotropin-releasing hormone (TRH), calcitonin, and vasopressin. Deficiency of dopamine-beta-hydroxylase leads to reduced catecholamine levels. Decreased ascorbic acid oxidase activity leads to bone changes similar to those seen in scurvy.

Moller et al found that even a low level (2-5%) of normally spliced Menkes protein was sufficient to produce the milder occipital horn syndrome in one patient. In contrast, the classic phenotype was seen in 2 patients with a similar mutation who did not produce any normal Menkes protein. Tang et al found that a novel occipital horn syndrome mutation (N1304S) was associated with approximately 30% residual function of ATP7A (Tang, 2006).

Frequency

International

Incidence is 1 in 50,000 to 1 in 250,000; one third of cases result from new mutations. A study in Japan from 1993-2003 found that Menkes disease incidence was 1 per 2.8 million live births and 4.9 per million male live births.

Sex

• Menkes disease is an X-linked recessive condition and, therefore, usually affects boys through unaffected carrier women. The disease can be due to germ line mosaicism.
• A few affected females with X:autosome translocations, X0/XX mosaicism, or unfavorable lyonization have been reported.

Age

• The onset of the classic form is in infancy.
• The milder variants have their onset in childhood or early adulthood.

Clinical

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 (Bahi-Buisson, 2006)
    • 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
  • 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.

Physical

Findings include the following:

• Abnormal kinky hair, eyebrows, and eyelashes (see Image 1)
  • 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
  • Jowly with sagging cheeks and ears
  • Depressed nasal bridge
  • High arched palate
  • Delayed tooth eruption
• Progressive cerebral degeneration
  • Loss of developmental milestones
  • Seizures
  • Profound truncal hypotonia with appendicular hypertonia
  • Temperature instability
• Ocular manifestations
  • Ptosis
  • Visual inattention
  • Optic disc pallor with decreased pupillary responses to light
  • Iris hypoplasia and hypopigmentation
• Connective-tissue abnormalities
  • 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 Image 2)
  • Dilated ureters
  • Emphysema
• Vascular defects
  • Arterial rupture
  • Brachial, lumbar, and iliac artery aneurysms
  • Internal jugular vein aneurysms
  • Thrombosis
  • Pulmonary artery hypoplasia
• Skeletal changes
  • Multiple congenital fractures, deformities (see Image 3)
  • Osteoporosis
  • Metaphyseal spurring and widening (see Image 4)
  • Diaphyseal periosteal reaction
  • Scalloping of the posterior portion of the vertebral bodies
  • Pectus excavatum
  • Wormian bones
• Bleeding diathesis
• Renal calculi
• Patients with occipital horn syndrome are affected predominantly by connective-tissue and bony changes, including hyperelastic and bruisable skin (see Image 5), 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 Image 6). 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 age 2 years.
• Other clinical variants referred to as mild Menkes disease are characterized by ataxia and mild mental retardation.

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 also have been reported.
  • The mutation in each identified family has been unique, and all result in decreased ATP7A mRNA production.
  • The mild variants of the disease in humans generally are caused by splicing defects.

• Search for CME/CE on This Topic »

• Ehlers-Danlos Syndrome (Pediatrics: Genetics and Metabolic Disease)
• Arachnoid Cyst (Radiology)
• Trichorrhexis Nodosa (Dermatology)