Menkes Disease 

Updated: Oct 29, 2014
Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD 

Overview

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.

The image below depicts an infant with Menkes disease.

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

See 21 Hidden Clues to Diagnosing Nutritional Deficiencies, a Critical Images slideshow, to help identify clues to conditions associated with malnutrition.

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.[1]

Hardman et al found that insulin and estrogen increased the level of MNK mRNA and protein levels in the placenta.[2] The MNK protein also became localized toward the basolateral membrane and increased copper transport. Hardman et al found levels of the Wilson disease ATPase decreased in response to insulin and was perinuclear. His conclusion was 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.[3] 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.[4]

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 in 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 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) activity probably accounts for most of the neurologic 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.[5] 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.[6] 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.[7]

Etiology

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.

Epidemiology

In the United States, 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.

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.

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

Prognosis

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

Kaler et al noted that infants who received treatment early (within 10 +/- 4 days) had a 92% survival after a median follow-up of 4.6 years. Historical controls that were diagnosed at 163 +/- 113 days and treated only had a 13% survival after a median follow-up of 1.8 years. In fact, 2 of their patients (one with a missense mutation and one with a splice junction alteration) who were treated within 10 days of life had normal neurodevelopmental outcomes at age 5 and 7. A child with the same mutation as the 5-year-old but treated later at 22 days of age did have neurologic sequelae but could walk with support and ride a tricycle. Patients with mutations that disrupt the translational reading frame or have a premature termination codon did not do as well. Their treatment regimen consisted of subcutaneous copper histidine injections of 250 micrograms twice a day to 1 year of age and then daily injections to 3 years of age.[10]

Tang et al also reported that 2 infants treated within 25 days of age had near normal neurodevelopment at 7 months and 3 years of age. However, another infant with an identical missense mutation who began treatment at 228 days of age remained at a 2- to 4-month neurodevelopmental level at a chronological age of 2.5 years. This mutation resulted in normal levels of ATP7A transcript, but the mutated protein had abnormally high posttranslational degradation.[7]

Paulsen et al caution that the biochemical profile needs to be examined as reinitiation of protein translation may ameliorate the effects of a large frameshift deletion with a premature termination codon.[15]

Donsante et al also reported that 3 untreated brothers had differing courses of their disease. The 2 older brothers had mild disease and were able to ambulate independently and did not have seizures. The youngest brother was more delayed and had epilepsy, but he also had a cardiac arrest as a neonate. The cardiac arrest may be the cause of the more severe problems in the youngest brother, but he also had lower serum copper levels and the highest DOPA:DHPG ratio. Furthermore, Donsante et al also reported 2 untreated brothers who had different courses. The older brother also had a milder course with the occipital horn phenotype but the younger brother had profound delay and epilepsy. The less affected sibling had higher ATP7A levels but it was not clear why. There was no somatic mosaicism detected in either family.[16]

 

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[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.

Physical Examination

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

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

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 di Diverticula 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-mo Flared 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 syndrome Lax 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.

 

DDx

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

Pili torti (twisted hair shafts)

  • 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

Other Problems to be Considered

  • Leigh disease

  • Phenylketonuria (PKU)

Differential Diagnoses

  • Non accidental trauma

 

Workup

Copper and Ceruloplasmin Levels

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 are considered 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.

Diagnostic findings are as follows:

  • 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 may be noted. Elevated hydroxyphenylalanine (DOPA) and dihydroxyphenylglycol (DHPG) ratio due to decreased activity of dopamine beta-hydroxylase may be observed, with higher values reflecting more severe disease. Diagnostic findings are as follows:

  • Greater than 5 in serum (normal 1.7-3.3)

  • Greater than 1 in cerebrospinal fluid (normal 0.3-0.7

Kaler et al found that asymptomatic infants at risk for Menkes disease could be separated into affected and unaffected based on plasma neurochemical profiles. Although there was potential overlap for the absolute levels of dopamine, dihydroxyphenylacetic acid, norepinephrine, and DHPG, 2 ratios clearly separated affected from unaffected infants. The differences were more distinct for older infants but were present in infants younger than 1 month.[10]

Diagnostic ratios

The ratio of dihydroxyphenylacetic acid to DHPG is as follows:

  • 13 +/- 6.6 for affected infants

  • 1.5 +/- .4 for unaffected infants

Ratio of dopamine to norepinephrine is as follows:

  • .83 +/- .71 for affected infants

  • .04 +/- .03 for unaffected infants

Urine homovanillic acid/vanillylmandelic acid (HVA/VMA) ratios above 4 may be noted. In once study, only 0.18% of controls had an HVA/VMA ratio greater than 4.[11]

Other findings

Other findings may include the following:

  • Increased intestinal and kidney copper

  • Decreased hepatic copper

  • Hypoglycemia

  • Deoxypyridinoline (D-Pyr): D-Pyr is synthesized by lysyl oxidase, which is defective in Menkes disease. D-Pyr levels in urine may remain low despite treatment.

CT and MRI

The following may be noted:

  • White matter dysmyelination

  • Other white matter lesions may be symmetrical and involve the corpus callosum[12]

  • 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.[13]

  • Subdural hematomas and effusions (see following image)

    Magnetic resonance imaging of the brain of a patie 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.
  • Cerebrovascular accidents

Proton Magnetic Rresonance Spectroscopy

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.

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 may be noted.

EEG

Early stage findings include the following:

  • 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 findings may include the following:

  • Interictal EEG - Modified hypsarrhythmia or diffuse irregular slow waves and spike-waves

Late stage findings may include the following:

  • Interictal EEG - Multifocal high amplitude activity mixed with irregular slow waves

Electroretinogram

Reduced amplitude and scotopic responses (rod isolated) may be noted in more severely affected than photopic responses (cone isolated).

Histologic Findings

Light microscopy of the hair shaft

See the list below:

  • 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

See the list below:

  • 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

See the list below:

  • Thin strand of amorphous elastin associated with numerous microfibrils

Cerebral and systemic arteries

See the list below:

  • Tortuous with irregular lumens

  • Frayed and split intimal linings

  • Disrupted elastin fibers on electron microscopy

Muscle

See the list below:

  • Accumulation of glycogen

  • Predominance of type 2 fibers

 

Treatment

Approach Considerations

In families with a previous affected child, genetics consultation and counseling with prenatal testing can be done for future pregnancies.

Medical Care

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 neurologic symptoms. Unfortunately, the neurologic 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.[14]

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.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Infants that carry the mutation must be identified and treated very early in life before irreparable neurodegeneration occurs.

Trace Elements

Class Summary

Copper histidine used in this class has been shown to prevent neurodegeneration when administered early in life.

Copper histidine

Copper histidine is a copper replacement administered parenterally to avoid absorption through the gastrointestinal tract. Patients with a genetic abnormality that are still able to produce limited amounts of enzymes, involved in copper metabolism, may receive benefit from early treatment. A dose of 350-500 µg IV/SC qDay or qod has been shown to be effective.