AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

DIFFERENTIALS

Section 4 of 11  

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• Follow-up
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Other Problems to be Considered

Leigh disease
Phenylketonuria (PKU)

Other diagnostic considerations - Differential diagnosis for specific hair findings is as follows:

Trichorrhexis nodosa (ie, beaded, fractured hair shafts)

• Biotin deficiency
• Argininosuccinic aciduria - A urea cycle defect with elevated ammonia and argininosuccinic acids
• Pollitt syndrome - Nonprogressive autosomal recessive disease with mental retardation, spasticity, and seizures

• Isolated finding
• Pollitt syndrome
• A syndrome associated with dental abnormalities, corneal opacities, deafness, and ichthyosis
• Autosomal dominant mental retardation and postpubertal pili torti
• Citrullinemia - A urea cycle defect
• Trichothiodystrophy - A defect of DNA repair with photosensitivity, ichthyosis, and mental retardation
• In heterozygotes, possibly areas of hair with 30-50% pili torti or skin depigmentation

WORKUP

Section 5 of 11  

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• Clinical
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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum copper level less than 70 mg/dL (reference 80-160)
• Serum ceruloplasmin level less than 20 mg/dL (reference 20-60)
• Plasma catecholamines
• • Decreased norepinephrine level
  • Elevated hydroxyphenylalanine (DOPA) and dihydroxyphenylglycol (DHPG) ratio due to decreased activity of dopamine beta-hydroxylase (higher values may reflect more severe disease)
    • Greater than 5 in serum (normal 1.7-3.3)
    • Greater than 1 in cerebrospinal fluid (normal 0.3-0.7)
  • Urine homovanillic acid/vanillylmandelic acid (HVA/VMA) ratios above 4 (Only 0.18% of controls had a HVA/VMA ratio greater than 4 noted in one study [Matsuo, 2005].)
• Increased intestinal and kidney copper
• Decreased hepatic copper
• Hypoglycemia
• Deoxypyridinoline (D-Pyr) is synthesized by lysyl oxidase, which is defective in Menkes disease. D-Pyr can be measured in urine with low levels despite treatment.
• Copper and ceruloplasmin levels may be normal in the milder variants and in the neonatal period. The total body copper content can be normal in the infant until 2 weeks after birth or later. Ceruloplasmin levels are 6-12 mg/dL initially and only later become pathologically low. Normal term newborns also have lower serum copper (32 mcg +/- 21 mcg/dL) with even lower levels in preterm infants. The fetal hair also may be normal.

Imaging Studies

• Computerized tomography (CT) and magnetic resonance imaging (MRI)
• • White matter dysmyelination
  • Tortuous blood vessels
  • Atrophy: This was reported by Geller et al in a 5-week-old who was flaccid, without pupillary responses or Moro reflex when born at term. Cranial ultrasound and CT prior to that had demonstrated prominent fluid spaces.
  • Subdural hematomas and effusions (see Image 7)
  • Cerebrovascular accidents
• Angiography and magnetic resonance angiography - Elongated and tortuous vessels, both intracranially and extracranially
• Proton magnetic resonance spectroscopy shows elevated lactate and reduced N-acetyl aspartate (NAA)– total creatine (tCr) ratio with a z score of -3.0. After 120 days of treatment, the lactate signal disappeared, and the NAA signal increased to a z score of -1.5. The choline/Cr ratio also markedly decreased during treatment. Although, neuronal metabolism appeared improved, the neurologic symptoms and imaging abnormalities on MRI did not change.

Other Tests

• Cultured fibroblasts and lymphoblasts: These exhibit impaired copper metabolism, increased copper accumulation, and decreased copper release. Heterozygotic carriers also have abnormalities of fibroblast copper metabolism.
• Increased placental copper
• EEG
• • Early stage
    • Ictal EEG - Runs of slow spike waves and slow waves in the posterior regions
    • Interictal EEG - Multifocal and polymorphic slow waves or mixed slow spike-waves and slow waves
  • Intermediate stage
    • Interictal EEG - Modified hypsarrhythmia or diffuse irregular slow waves and spike-waves
  • Late stage
    • Interictal EEG - Multifocal high amplitude activity mixed with irregular slow waves
• Visual-evoked potential - Low amplitude or absent
• Electroretinogram - Reduced amplitude; scotopic responses (rod isolated) more severely affected than photopic responses (cone isolated)

Histologic Findings

Light microscopy of the hair shaft

• Pili torti - 180° twisting
• Trichoclasis - Transverse fracture
• Trichoptilosis - Longitudinal splitting
• Trichorrhexis nodosa - Small, beaded swelling with fractures at regular intervals
• Monilethrix elliptica - Swelling with intervening tapered constrictions

Autopsy of brain

• Diffuse atrophy
• Focal degeneration of neurons
• Prominent neuronal loss in the cerebellum affecting the Purkinje cells
• Abnormal dendritic arborization (so called "weeping willow") and perisomatic processes
• Focal axonal swelling ("torpedoes")
• Increased number and size of mitochondria on electron microscopy with electron-dense inclusions
• Marked reduction of internal granule cells
• Eosinophilic spheroid bodies (probably proliferated smooth endoplasmic reticulum) in the molecular layer

Skin

• Thin strand of amorphous elastin associated with numerous microfibrils

Cerebral and systemic arteries

• Tortuous with irregular lumens
• Frayed and split intimal linings
• Disrupted elastin fibers on electron microscopy

Muscle

• Accumulation of glycogen
• Predominance of type 2 fibers

TREATMENT

Section 6 of 11  

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Consultations

• Genetics: In families with a previous affected child, genetics consultation and counseling with prenatal testing can be done for future pregnancies.
• Physical medicine and rehabilitation: The patient may have skeletal deformities and a continued high risk of fractures as well as malformed connective tissues.

MEDICATION

Section 7 of 11  

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• Miscellaneous
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Oral treatment with copper salts such as the sulfate, acetate, or chloride does not alter serum copper and ceruloplasmin levels. Parenteral copper induces synthesis of apoceruloplasmin and the WND gene, resulting in increase of serum copper and ceruloplasmin levels; however, the cerebral copper levels do not change and no clinical improvement ensues.

Treatment with copper chloride and/or L-histidine should be provided by a clinician familiar with their use. Copper chloride and L-histidine solutions of 350-500 µg/d or qod injected intravenously or subcutaneously increase the serum and cerebrospinal fluid copper levels to the normal range after 6 weeks. This treatment seems to improve symptoms related to copper efflux from the cell. Metaphyseal widening and spurring and periosteal thickening regress. Bone maturation progresses, although mineralization is still defective. The ratio of DOPA/DHPG normalizes. However, the connective-tissue defects do not respond to parenteral copper histidine treatment. Newborns and fetuses treated in utero with copper histidine can avoid neurological symptoms. Unfortunately, the neurological symptoms, once present, are less amenable to treatment. Sheela et al reported that a 15 month old who was treated with subcutaneous copper supplementation for 30 months became seizure free and the skin and

hair darkened, but the child continued to have severe developmental delay (Sheela, 2005).

Early treatment of the brindled mouse prevents neurological symptoms, but if therapy is delayed beyond 10 days of life, the animal dies. The brindled mouse responds to therapy at a stage of brain development that corresponds to the third trimester in humans.

FOLLOW-UP

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Prognosis

• Most untreated patients with the classic form of Menkes disease die by age 3 years.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• In a family with a previous affected child, prenatal diagnosis may be available for future pregnancies.

MULTIMEDIA

Section 10 of 11  

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• Multimedia
• References

Media file 1:  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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Media type:  Photo

Media file 2:  Diverticula of the bladder in a boy with Menkes disease.
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Media type:  X-RAY

Media file 3:  The clavicles are short with hammer-shaped distal ends in a patient with Menkes disease.
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Media type:  X-RAY

Media file 4:  Flared metaphyses of the ulna and radius in a 5-month-old patient with classic Menkes disease.
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Media type:  X-RAY

Media file 5:  Lax skin in a patient with occipital horn syndrome.
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Media type:  Photo

Media file 6:  Occipital horns (arrow) in a 14-year-old boy with occipital horn syndrome.
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Media type:  X-RAY

Media file 7:  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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Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• 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].
• Petris MJ, Mercer JF, Camakaris J. The cell biology of the Menkes disease protein. Adv Exp Med Biol. 1999;448:53-66. [Medline].
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Article Last Updated: Apr 9, 2007