eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Menkes Kinky Hair Disease

Author: Stephen G Kaler, MD, MPH, Head, Unit On Pediatric Genetics, Laboratory of Clinical Genomics, and Clinical Director, Intramural Research Program, National Institute of Child Health & Human Development (NICHD), National Institutes of Health
Contributor Information and Disclosures

Updated: May 28, 2009

Introduction

Background

In the nearly 45 years since the original description of Menkes kinky hair disease (MKHD), advances in understanding the clinical, biochemical, and molecular aspects of this rare disorder of copper metabolism have outstripped progress in the design of effective therapies. The most promising therapy to date, very early subcutaneous copper injections, has normalized neurodevelopmental outcome in some individuals with Menkes kinky hair disease (approximately 30% in the author's experience) and mitigated the neurologic effects in others. However, some patients with Menkes kinky hair disease (nearly 50% in the author's experience) have not derived substantive benefit from this approach, despite very early institution of treatment.

Identification of the Menkes gene by positional cloning has enabled molecular diagnosis of females who carry the gene and at-risk fetuses in certain families, enhancing preventive efforts. Evidence that the gene encodes a highly conserved copper-transporting adenosine triphosphatase (ATPase) has stimulated investigation of the molecule's normal function in prokaryotic and eukaryotic systems. Knowledge gleaned from such efforts may ultimately suggest the novel therapeutic strategies needed to achieve normal neurologic outcomes in patients with Menkes kinky hair disease regardless of mutation severity. Although early recognition of infants with Menkes kinky hair disease prior to neurologic damage remains a fundamental requirement, the recent advances provide a glimmer of hope in efforts to improve matters for individuals with Menkes kinky hair disease and the families who care for them.^1,2

History of the disorder

History of this disorder can be traced to as early as 1937, when Australian veterinary scientists recognized the critical role of copper in mammalian neurodevelopment through the association of copper deficiency with demyelinating disease in ataxic lambs. These animals' mothers had grazed in copper-deficient pastures throughout their pregnancies, and their offspring consequently demonstrated symmetric cerebral demyelination and gross pathologic changes, such as porencephalic cyst formation and cavitation.

Based on this connection between copper deficiency and demyelinating disease, neurologists at Oxford in 1948 investigated copper metabolism in a group of patients with multiple sclerosis (MS), a demyelinating disease of adults. Those studies excluded defective copper metabolism as the cause of MS, and Professor David Danks later identified Menkes kinky hair disease as a human example of abnormal myelination due to copper deficiency.^3,4

Danks' discovery in 1972 was based on his recognition that the unusual hair of infants with Menkes kinky hair disease appeared similar in texture to the brittle wool of sheep raised on copper-deficient soil in Australia, where wool production remained a major industry.^3,4 He measured serum copper in 7 patients with Menkes kinky hair disease and found low levels in all 7 individuals. Serum levels of ceruloplasmin, an important copper enzyme, were also subnormal. Thus, observations made 35 years apart concerning the effects of copper deficiency in Australian sheep became extremely relevant to a human inborn error of metabolism.

This important biochemical finding sparked renewed interest in the phenotype that had been delineated meticulously 10 years earlier by John Menkes, MD, and colleagues at Columbia University in New York.⁵ Menkes had reported 5 male infants in a family of English-Irish heritage who were affected with a distinctive syndrome of neurologic degeneration, peculiar hair, and failure to thrive. The boys appeared healthy at birth and throughout the first several months of life, but then they experienced seizures and developmental regression and ultimately died when aged 7 months to 3.5 years. The pedigree of the family strongly suggested that the condition was an X-linked genetic disease. Subsequent case reports confirmed that Menkes "kinky hair" disease was a newly recognized syndrome with unique clinicopathologic features.

The association of this disorder with abnormal copper metabolism had a number of important effects. Clinical diagnosis was facilitated by the availability of a reliable biochemical marker (ie, low serum copper and ceruloplasmin). Treatment for a previously fatal disease could be considered by way of copper replacement, and physiologically suitable forms had been reported. Delineation of the basic defect appeared possible, particularly when an excellent mouse model for the human phenotype was recognized and when cultured cells of patients with Menkes kinky hair disease were demonstrated to have distinctive abnormalities in copper handling. The latter findings were applied rapidly as a method of prenatal detection by analysis of cultured amniocytes.

During the following 15 years, additional descriptions of clinical, biochemical, and pathologic features of patients with Menkes kinky hair disease brought attention to the phenotypic spectrum of the disorder. Reports of treatment with copper supplementation in the classic severe type generally indicated little impact on the dismal natural history. A mild form of the disease was noted in which neurologic abnormalities were far less profound. Recognition of a close biochemical relationship between Menkes kinky hair disease and type IX Ehlers-Danlos syndrome (ie, occipital horn syndrome [OHS]) suggested a gene locus comparable to that in the mouse, wherein similar differences in neurologic effects, connective tissue manifestations, and longevity had been reported between 2 apparently allelic variants.

Mapping studies localized the gene to the long arm of the X chromosome close to the centromere. Metallothionein, a copper protein overexpressed in Menkes cultured cells and suspected by some as the primary abnormality, was excluded from direct consideration by localization to chromosome 16 in somatic cell hybrid studies. Experience with prenatal detection increased, and biochemical tests that used chorionic villus samples were developed to enable earlier diagnosis in at-risk pregnancies. A Menkes parents and professionals association was formed in the United States.

In 1987, a female with classic Menkes kinky hair disease caused by an X-autosome chromosomal translocation was reported. This critical observation narrowed the cytogenetic region containing the Menkes locus to Xq13, and cell lines established from this patient ultimately led to cloning of the gene. From a medical perspective, improved outcomes in several patients treated from a very early age with a copper-histidine complex were reported, and a protocol at the National Institutes of Health (NIH) was established to further evaluate the clinical and biochemical effects of this agent in patients with Menkes kinky hair disease.

Identification of the Menkes gene by positional cloning was reported in 1993.⁶ This landmark discovery disclosed that the Menkes gene product is a member of a highly conserved family of cation-transporting ATPases, which are molecules that function in the transport of ions across cellular and intracellular membranes. In conjunction with previous data characterizing the biochemical abnormalities in patients with Menkes kinky hair disease and their cultured cells, this finding suggests that the basic defect in Menkes kinky hair disease is the failure of a plasma membrane pump that normally extrudes copper from cells or failure of a pump that normally transports copper into an intracellular organelle such as endoplasmic reticulum.

Thus, in the nearly 40 years since its initial description, Menkes kinky hair disease has been the subject of extensive clinical and scientific scrutiny. The attention culminated in the detection of the faulty gene product, a discovery that provided basic insight into mammalian copper metabolism and presaged a new era in the investigation and history of this disorder.

Animal models of kinky hair disease

The mottled mouse provides an excellent animal model for Menkes kinky hair disease. The mottled and Menkes loci are located in homologous regions of their respective X chromosomes, and several allelic variants have been recognized in the mouse, predicting the possibility of a similar situation in humans.

One of the best studied mottled mutants, the brindled (Mobr) male hemizygote, exhibits decreased coat pigmentation, tremor, general inactivity, death when aged 14 days, increased intestinal copper levels with low levels in the liver and brain, and decreased copper enzyme activities. Of great interest is the observation that healthy viability can be restored in these mutants if a single copper injection is provided during the first week of life, whereas treatment is ineffective when administered later (eg, when aged 12 d).

This response is also characteristic of the macular mouse, a biochemically similar model of Menkes kinky hair disease discovered in Japan. These findings suggest the following: (1) the existence of a critical period in murine neurodevelopment during which copper is essential, and (2) the brindled mutation does not completely impede proper use of copper when the block in intestinal absorption is bypassed.

Male mice hemizygous for other mottled alleles (eg, tortoise, dappled, viable-brindled) also exhibit reduced viability. In contrast, the blotchy mutant (Mo-blo) has healthy viability but more pronounced connective tissue abnormalities. Cultured fibroblasts from all the mutants tested demonstrate the abnormal copper accumulation characteristic of Menkes kinky hair disease.

Biochemical investigation of brindled and blotchy mutants has been extensive. These findings suggest that cytochrome c oxidase (CCO) may be affected more than other copper enzymes in the brindled mutant and that partial restoration of CCO activity in the brain may be responsible for the clinical improvement associated with early copper therapy.

In untreated brindled mice, CCO deficiency has been correlated with progressive neuropathologic changes. In the blotchy mutant, CCO deficiency is less severe than in the brindled mutant, whereas lysyl oxidase (LO) deficiency appears more pronounced, suggesting that the blotchy mutant may be analogous to the human occipital horn phenotype in which connective tissue manifestations predominate. Interestingly, LO response to copper treatment seems better in the brindled mutant than in the blotchy mutant. Also noteworthy is the apparent preservation of normal CCO and superoxide dismutase (SOD) activity in certain organs of both mutants, including the kidney, which is one organ that manifests the copper accumulation phenotype.

Direct measurement of dopamine beta-hydroxylase (DBH) activity in the mottled mutants is complicated by the fact that most assays for DBH require the addition of exogenous copper to samples being measured. The provision of copper presumably circumvents the basis for deficient DBH activity in vivo in tissues of these mutants. Brindled and blotchy mice in which low levels of norepinephrine (NE) in the brain indicated significant DBH deficiency actually demonstrated increased brain DBH when assayed in vitro. These findings suggested that DBH apoenzyme was available in adequate amounts, indeed amounts are perhaps increased in a compensatory manner, but that enzyme function was impaired because of unavailability of copper as a cofactor in vivo. Data on DBH response to copper therapy in the mottled mutants are limited.

Copper/zinc (Cu/Zn) SOD activity is not reduced in either mouse mutant to the same extent as the other copper enzymes studied, nor is its activity enhanced as much (if at all) by copper treatment. In one study of cultured blotchy fibroblasts, measurable SOD activity did not differ from controls. The consistent favorable clinical response to copper treatment in the brindled mutant represents a distinct difference from the experience in most patients with Menkes kinky hair disease.

Cloning of the mottled gene by 2 laboratories (Gitscher, Mercer) and identification of the mutants (ie, brindled, blotchy, dappled) and other alleles by several laboratories (ie, Gitscher, Mercer, Boyd) have improved the understanding of the relationship between mottled phenotype and genotype. Some of these mutant alleles may hold promise for evaluating potential new therapies for Menkes kinky hair disease.

Pathophysiology

Physical presentation

The scalp hair of infants with classic Menkes kinky hair disease is short, sparse, coarse, and twisted. The hair is often less abundant and even shorter on the sides and the back of the head than on the top. The twisted strands may be reminiscent of those in steel wool cleaning pads. The eyebrows usually share the unusual appearance. Light microscopy of patient hair illustrates pathognomonic pili torti (ie, 180° twisting of the hair shaft) and often other abnormalities, including trichoclasis (ie, transverse fracture of hair shaft) and trichoptilosis (ie, longitudinal splitting of shaft). Hair tends to be lightly pigmented and may demonstrate unusual colors, such as white, silver, or grey; however, in some individuals with Menkes kinky hair disease, the hair is pigmented normally.

The face of the individual with Menkes kinky hair disease has pronounced jowls, with sagging cheeks and ears that often appear large. The palate tends to be high-arched, and tooth eruption is delayed. Noisy sonorous breathing is often evident. Although findings on auscultation of the heart and lungs are usually unremarkable, pectus excavatum (chest deformity) is a common thoracic finding. Umbilical and/or inguinal herniae may be present. The skin often appears loose and redundant, particularly at the nape of the neck and on the trunk.

Biochemical phenotype

The biochemical phenotype in Menkes kinky hair disease involves (1) low levels of copper in plasma, liver, and brain because of impaired intestinal absorption, (2) reduced activities of numerous copper-dependent enzymes, and (3) paradoxical accumulation of copper in certain tissues (ie, duodenum, kidney, spleen, pancreas, skeletal muscle, placenta). The copper-retention phenotype is also evident in cultured fibroblasts and lymphoblasts, in which reduced egress of radiolabeled copper is demonstrable in pulse-chase experiments. This constellation of biochemical findings denotes a primary defect affecting copper transport that begins with impaired absorption at the intestinal level and continues with failed utilization and handling of whatever copper is conveyed to other cells in the body.

Certain clinical features of Menkes kinky hair disease can clearly be related to deficient activity of specific copper-requiring enzymes, and one can speculate on the effects that reduced activity of other copper enzymes would produce. Partial deficiency of DBH, a critical enzyme in the catecholamine biosynthetic pathway, is responsible for a distinctively abnormal plasma and cerebrospinal fluid (CSF) neurochemical pattern in patients with Menkes kinky hair disease. In the author's experience, the ratio of a proximal compound in the pathway, (dihydroxyphenylalanine [DOPA]), to a distal metabolite (dihydroxyphenylglycol [DHPG]) provides a better index of DBH deficiency in patients with Menkes kinky hair disease than NE levels alone.

Plasma and especially CSF levels of NE, the direct product of DBH, are maintained relatively well in some patients with Menkes kinky hair disease, presumably because of suitable compensatory mechanisms. Clinical features of patients with Menkes kinky hair disease potentially attributable to DBH deficiency include temperature instability, hypoglycemia, and eyelid ptosis, which are autonomic abnormalities that may result from selective loss of sympathetic adrenergic function. Similar clinical problems have been reported in patients with Riley-Day dysautonomia, in which DBH deficiency has been documented, and/or in patients with congenital absence of DBH.

A copper-dependent enzyme, peptidylglycine alpha-amidating monooxygenase (PAM), is required for removal of the carboxy-terminal glycine residue characteristic of numerous neuroendocrine peptide precursors (eg, gastrin, cholecystokinin, vasoactive intestinal peptide, corticotropin-releasing hormone, thyrotropin-releasing hormone, calcitonin, vasopressin). Failure to amidate these precursors can result in 100-fold to 1000-fold diminution of bioactivity compared with the mature amidated forms. Although deficiency of tyrosinase, a copper enzyme needed for melanin biosynthesis, is considered responsible for reduced hair and skin pigmentation in patients with Menkes kinky hair disease, PAM deficiency may also contribute to this feature through reduced bioactivity of melanocyte-stimulating hormone, an alpha-amidated compound. PAM deficiency may have more important and wide-ranging physiologic effects that contribute to the Menkes phenotype.

Deficient CCO activity is probably a major factor in the neuropathology of Menkes kinky hair disease. Effects on the brain are quite similar to those in individuals with Leigh disease (ie, subacute necrotizing encephalomyelopathy), in whom CCO deficiency is caused by complex IV respiratory chain defects. As in Leigh disease, patients with Menkes kinky hair disease do not have the severe lactic acidemia associated with other complex IV defects. CCO deficiency peripherally probably also contributes to the hypotonia and muscle weakness evident in patients with Menkes kinky hair disease.

Reduced activity of LO, another copper enzyme, also has major clinical consequences in Menkes kinky hair disease. This enzyme normally acts to deaminate lysine and hydroxylysine as the first step in collagen cross-link formation. Decreased LO activity significantly reduces the strength of connective tissue investing numerous organs and tissues. In patients with Menkes kinky hair disease, vascular tortuosity, bladder diverticula, and gastric polyps are all believed to result from LO deficiency.

Deficiency of Cu/Zn SOD in Menkes kinky hair disease may lower protection against oxygen free radicals and theoretically have cytotoxic effects. Localized brain damage due to such oxidant stress has been postulated as the pathogenetic basis of Parkinson disease. Mutations in the Cu/Zn SOD gene on chromosome 21 have been associated with amyotrophic lateral sclerosis, a motor neuron disease of adult onset. The relative contribution of partial SOD deficiency to the neurodegenerative changes in patients with Menkes kinky hair disease is difficult to assign.

Further pathology

Interesting and varied ocular pathology has been reported, including retinal hypopigmentation and vessel tortuosity, macular dystrophy, congenital cataracts, partial optic nerve atrophy and decreased retinal ganglion cells, and microcysts in the pigment epithelium of the iris.

On occasion, thymic atrophy and impaired T-cell function has been demonstrated in patients with Menkes kinky hair disease and warrants investigation in a larger group, given the apparent predisposition to infectious illness in some patients with the syndrome. Decreased T-cell function has been reported in the macular mouse, an animal model of Menkes disease.

Frequency

United States

Menkes kinky hair disease is a relatively rare condition with incidence estimates ranging from 1 case per 100,000 live births to 1 case in 250,000. Based on the recent number of annual births in the United States (approximately 3.9 million), an estimated 16-40 infants with Menkes kinky hair disease are expected to be born in this country each year. One third of these infants are predicted to be nonfamilial, representing new mutations.

International

Mutations in the Menkes gene occur in all racial and ethnic groups, presumably at the same frequency as occurs in the United States. Therefore, based on recent estimates of annual world births (approximately 135 million per year), an estimated 540-1350 infants with Menkes kinky hair disease are expected to be born each year worldwide.

Mortality/Morbidity

The life span of children with Menkes kinky hair disease cannot be reliably predicted, although most of these children die by the time they are aged 3 years. Pneumonia, leading to respiratory failure, is a common cause of death, although some patients with Menkes kinky hair disease die suddenly in the absence of any apparent acute medical process. The major morbidity associated with Menkes kinky hair disease involves the neurologic, GI, and connective tissue (including vasculature) systems (see Pathophysiology).

Race

No particular racial or ethnic predilection for Menkes kinky hair disease is noted. For X-linked recessive lethal traits, such as in individuals with Menkes kinky hair disease, genetic theory suggests that one third of infants with Menkes kinky hair disease represent new mutations. Such de novo mutations are expected to occur at equal frequency among all Homo sapiens racial and ethnic groups.

Sex

Menkes kinky hair disease affects males nearly exclusively because it is an X-linked recessive trait. Female carriers generally do not manifest symptoms unless unusual genetic circumstances are present. These include unfavorable lyonization due to skewed X-inactivation, balanced chromosomal translocations with breakpoints lying within the Menkes gene, or sex chromosome aneuploidy (ie, Turner syndrome ([45, XO karyotype]) with a Menkes gene mutation on the sole X chromosome).

Age

As noted above, individuals with Menkes kinky hair disease typically present when aged 6-8 weeks, with parents noticing a delay in developmental progress or the appearance of unusual eye or extremity movements suggestive of seizure activity.

Clinical

History

The typical history of a patient with Menkes kinky hair disease (MKHD) includes healthy pregnancy and delivery. Birth frequently occurs several weeks in advance of the estimated date of confinement or due date.

• Classic Menkes kinky hair disease often escapes attention in the neonatal period because of its very subtle manifestations in neonates. However, several nonspecific physical and metabolic findings are commonly cited when birth histories of these babies are reviewed.
  • These findings include premature labor and delivery, large cephalohematomas in individuals born by abdominal delivery, hypothermia that necessitates warming lights or an isolette, hypoglycemia for which early feeding or support with intravenous (IV) glucose is instituted, and jaundice that requires several days of phototherapy.
  • Pectus excavatum and inguinal or umbilical herniae are found at birth in some patients with Menkes kinky hair disease.
  • Occasionally, unusual hair pigmentation may suggest the diagnosis in newborns. However, the appearance of the hair is often unremarkable. As in healthy babies, newborns with Menkes kinky hair disease may exhibit no hair or have normally pigmented hair. The pili torti Menkes kinky hair disease on microscopic examination of hair from older patients with Menkes kinky hair disease is not usually evident in the hair of newborns with Menkes kinky hair disease.
• Neurologically, newborns with Menkes kinky hair disease generally appear to be healthy. Excessive jitteriness was noted in one patient at age 1 week.
• Transient neonatal hypothermia and hypoglycemia are not uncommon; however, infants with Menkes kinky hair disease appear essentially healthy at birth and for the first 4-6 weeks of life.
• When the infant is aged approximately 2-2.5 months, the parents usually first suspect that something is wrong and voice their concerns to the healthcare provider.
• A steady downward spiral continues clinically, with development of progressive hypotonia, seizures, failure to thrive, and appearance of the characteristic coarse wiry hair by the time the individual with Menkes kinky hair disease is aged 4-5 months.

Physical

As noted previously, major clinical manifestations of persons with Menkes kinky hair disease include loss of early developmental milestones, truncal hypotonia, seizures, poor weight gain, abnormal hair, loose skin, pectus excavatum, and urinary bladder diverticula.

The severity widely varies in patients with Menkes kinky hair disease and certain disorders; although once considered distinct genetic entities, they most likely represent allelic variants.

• Patients with the classic phenotype may differ in certain respects (eg, presence of functional vision, level of infant personal-social development, severity of seizures), but they invariably demonstrate profound hypotonia and motor impairment. In contrast, patients with variants of the classic phenotype demonstrate less severe overall developmental outcomes.
  • One such child evaluated at the NIH was aged approximately 7 months when developmental delay was first noted.
    • When aged 9 months, the child required surgery for bladder outlet obstruction due to massive diverticula.
    • He was diagnosed with Menkes kinky hair disease when aged 22 months.
    • When aged 27 months, he was able to sit alone, crawl, play with toys, indicate his needs, and voice approximately 20 words with poor articulation. He was ataxic with head bobbing and tremor, and his brain MRI exhibited mild cerebellar hypoplasia. He had normal findings on EEG and no clinical seizures. His growth exhibited height between the 25th and 50th percentile for age, with weight and head circumference both slightly below the fifth percentile. His biochemical parameters (eg, plasma copper, plasma catecholamines, copper accumulation in cultured fibroblasts) did not differ significantly from values in infants with classic Menkes kinky hair disease.
    • Apart from his asymmetric growth retardation and history of bladder diverticula, this patient resembles a reported example of mild Menkes kinky hair disease.
  • Another atypical patient has been reported in whom motor development was relatively better, ataxia less severe, and connective tissue problems more prominent than the initially reported mild patient.
  • Because the neurologic impairment is less profound, other patients with conditions such as these seem unlikely to be suspected of having a condition related to Menkes kinky hair disease. Of note, both of the patients reported above had pili torti, which aided in establishing their diagnosis.
• Another probable Menkes variant is type IX Ehlers-Danlos syndrome, otherwise known as X-linked cutis laxa or occipital horn syndrome (OHS), in reference to the pathognomonic wedge-shaped calcification that forms within the trapezius and sternocleidomastoid muscles at their attachment to the occipital bone in affected individuals.
  
  

  

  Adolescent patient with typical occipital horn syndrome. Note elbow dislocations and genu valgum. Radiographs exhibited bilateral occipital exostoses of the skull and club-shaped distal clavicles.

  [ CLOSE WINDOW ]

  

  Adolescent patient with typical occipital horn syndrome. Note elbow dislocations and genu valgum. Radiographs exhibited bilateral occipital exostoses of the skull and club-shaped distal clavicles.

  • This protuberance can be palpated in some patients and is demonstrable radiographically on Towne view or on appropriate sagittal CT scanning or MRI cuts. Radiologic abnormalities of the clavicles and long bones have also been noted.
  • Clinical findings include lax skin and joints, bladder diverticula, inguinal herniae, vascular tortuosity, and normal or slightly subnormal intelligence.
  • Biochemically, plasma copper and ceruloplasmin levels are in the low reference range, copper egress in cultured fibroblasts is impaired to the same degree as in classic Menkes kinky hair disease, and activity of fibroblast lysyl oxidase (LO) is markedly reduced.
  • Additionally, some patients have signs of autonomic dysfunction (eg, syncope, episodic diarrhea) suggestive of dopamine beta-hydroxylase (DBH) deficiency. Neurologic findings are otherwise essentially normal.
• Other clinical variants have been reported that involve features of both the classic Menkes and the occipital horn phenotypes.
  • One kindred study included 4 males aged 15 months to 35 years who had low or low-normal plasma copper; abnormal plasma catecholamines; and a syndrome of mental retardation, childhood-onset seizures (aged 3-8 y), neuromuscular weakness, joint abnormalities, and bladder diverticula.
  • Occipital exostoses were detected in the 15-year-old patient during radiologic studies performed after a sudden cerebral hemorrhage.
  • The 35-year-old man developed seizures when aged 3-4 years and required vesicostomy when aged 9 years for bladder outflow problems caused by diverticula. He learned to walk with the aid of crutches. His elbows became dislocated. He had the estimated intellectual capacity of an individual aged 8 years, and his speech was extremely inarticulate. His size was that of a small adult.
  • The members of this family who were affected with Menkes kinky hair disease were found to have splice site mutations in the 3' region of the Menkes/OHS gene that impaired but did not eliminate proper RNA splicing; a similar type of splicing mutation was found in an unrelated patient with typical OHS.
  • In 1994, Kaler et al quantitated the amount of proper splicing in cultured cells associated with these mutations at approximately 20-30% of normal.⁸

Causes

Mutations in the Menkes/OHS gene underlie both classic and milder phenotypes. The severity of mutations and amount of possible residual copper ATPase activity appear to be relevant to the variable clinical outcomes.⁹ Secondary deficiencies of copper-dependent enzymes are believed to cause certain of the clinical manifestations, as reviewed earlier (see Pathophysiology).

• Menkes/OHS gene: Location of the Menkes/OHS gene on the X chromosome was indicated by pedigree analysis from the time of its earliest descriptions.
  • Progressively refined localization to Xq13 was enabled by linkage studies and characterization of X chromosomal rearrangements in 2 unrelated patients.
  • Genomic DNA from the chromosomal breakpoint region was used to identify portions of the Menkes locus by screening complementary DNA (cDNA) libraries or by exon trapping.
  • The candidate gene thus identified was found to be expressed abnormally in more than 70% of patients with Menkes kinky hair disease who were studied, and gene deletions were detectable by Southern blotting in more than 15% of these patients.
  • The Menkes/OHS gene is expressed in all human tissues tested, with the liver being a prominent exception. The messenger RNA (mRNA) transcript is approximately 8.5 kilobases (kb), with a long 3' noncoding portion and a coding sequence of 4.5 kb.
  • The predicted gene product is a 1500–amino acid molecule that is similar to numerous ion-motive ATPase molecules, including a pair of copper-transporting ATPases (copA and copB) in the bacterium Enterococcus hirae, an intracellular copper transporter (CCC2) in Saccharomyces cerevisiae, and the Wilson disease gene product.
• Menkes/OHS copper ATPase: A wide array of ion-motive ATPases has been characterized, and they are divided into 3 classes (ie, P, V, F).
  • The P-type ATPases, of which the Menkes gene product is an example, are so named because they form a covalently phosphorylated intermediate from transfer of the gamma-phosphate of ATP to a specific aspartate residue at the catalytic site of the protein.
  • V-type ATPases are those associated with vacuolar organelles (eg, lysosomes, endosomes, storage granules, Golgi vesicles).
  • The F-type ATPases are found in most bacteria and are associated with mitochondria in higher organisms.
  • The overall sequence similarity among prokaryotic and eukaryotic cation-transporting ATPases suggests that these proteins have been modified throughout evolution in response to the need for import and export of various cations across different cellular membranes.
  • P-type ATPases function in the regulation of intracellular ion concentrations. Those imbedded in plasma membranes function to extrude their respective ions from the cell. Other P-type ATPases are localized to the membranes of intracellular organelles (eg, sarcoplasmic reticulum, endoplasmic reticulum) and act to sequester ions within their lumens. Interaction with ATP at a specific site is believed to induce multiple conformational adjustments that reorient the molecule with respect to the membrane, creating channels for cation translocation from high-affinity binding sites on one membrane side to low-affinity binding domains oriented toward the other side. Alternative splicing that generates multiple isoforms with potential functional differences has been demonstrated for certain ATPases of this class.
• Menkes gene product: In the Menkes gene product, the N-terminal portion has a distinctive recurring amino acid pattern, cysteine-X-serine-cysteine, which is comparable to putative metal binding sites in the bacterial ATPases involved in transport of copper, cadmium, and mercury, respectively. Hydrophobicity analysis indicates 6-8 transmembrane domains, and the predicted protein demonstrates all the other functional domains expected of P-type ATPases. The expression of the Menkes gene in nearly all human tissues, the severe consequences of impaired function (ie, MKHD) and the high degree of evolutionary conservation all indicate the fundamental importance of the copper transport process that this gene encodes.
  • With the discovery of the Menkes gene, investigating the basic cell biological defect in greater depth became possible. Elegant studies in several laboratories (ie, Camakaris, Francis, Gitlin, Glover, Mercer) localized the Menkes/OHS gene product to the trans-Golgi apparatus, where it is involved in the delivery of copper to copper-dependent enzymes processed in the secretory pathway of cells. In addition, the Menkes/OHS ATPase appears to relocate in response to increased copper exposure, moving to the plasma membrane of cells where it presumably functions as a pump directly mediating copper exodus from cells.
  • This model of the gene product's locations (trans-Golgi and plasma membrane) is consistent with the copper retention phenotype of cultured Menkes cells and with induction of metallothionein (MT) in these cells at much lower experimental copper exposures than in healthy cells.
    • MT, a cysteine-rich heavy metal–binding protein, may represent a secondary line of defense against the toxicity of high intracellular copper that is required sooner than usual in Menkes cells because of a defect in the primary regulatory mechanism (ie, removal of copper).
    • The efficiency with which MT performs its detoxifying role and the extremely avid binding of MT to copper restricts the availability of the metal to cytosolic copper enzymes (eg, Cu/Zn SOD), as well as those synthesized or located in cellular compartments. Under normal conditions, MT presumably helps maintain low intracellular levels of free copper while permitting activation of the copper enzymes. However, in Menkes kinky hair disease, chronic MT induction due to failure of normal copper transport disrupts this balance.
    • Failure to extrude copper from intestinal mucosal cells into the blood explains the accumulation of copper in these cells and the consequent reduced delivery of copper to the liver in individuals with Menkes kinky hair disease. Similarly, failed copper export by placental cells accounts for the placental copper accumulation observed in pregnancies affected by Menkes kinky hair disease and the low hepatic copper levels in fetuses with Menkes kinky hair disease. Failure of copper export by vascular endothelial and glial cells comprising the blood-brain barrier explains low copper levels and reduced copper enzyme activities in the brain. Because the Menkes gene is weakly expressed in the liver, this organ must possess alternative mechanisms for copper excretion (ie, Wilson copper ATPase) and thus does not manifest the copper accumulation, MT induction, or copper enzyme deficiencies found in other tissues.
• Mutational analysis of the Menkes/OHS gene: Identification of the Menkes/OHS gene provided the opportunity for molecular analysis of patients with Menkes kinky hair disease. Before the genomic organization of the gene was characterized completely, the reverse transcription–polymerase chain reaction method (RT-PCR) offered a particularly useful approach to mutation analysis.
  • RT-PCR involves isolation of intact RNA from cultured fibroblasts or lymphoblasts and reverse transcription of the 8.5-kb Menkes message using oligodeoxythymidine as a primer. This reaction generates a full-length cDNA that is suitable as a template for PCR using gene-specific primers. The entire cDNA from patients with Menkes kinky hair disease thus may be obtained for direct sequence analysis.
  • Menkes/OHS gene mutation analysis by this method, and more recently from genomic DNA directly, has been conducted in several laboratories (ie, Horn, Kaler, Mercer, Ogawa), contributing important information about the molecular correlates of certain clinical and biochemical phenotypes and about functional aspects of this copper-ATPase. Molecular diagnosis also provides practical benefit to Menkes families with regard to detection of fetuses with Menkes kinky hair disease and females who are carriers.

• Search for CME/CE on This Topic »

• Menkes Kinky Hair Disease (Dermatology)