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ATP7A-Related Copper Transport Disorders

, MD, MPH
Head, Unit on Human Copper Metabolism
Molecular Medicine Program
National Institute of Child Health and Human Development
National Institutes of Health
Rockville, Maryland

Initial Posting: ; Last Update: October 14, 2010.

Summary

Disease characteristics. Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders of copper transport caused by mutations in the copper-transporting ATPase gene (ATP7A).

Infants with classic Menkes disease appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, and often lightly pigmented). Temperature instability and hypoglycemia may be present in the neonatal period. Death usually occurs by age three years.

Occipital horn syndrome is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Intellect is normal or slightly reduced.

ATP7A-related distal motor neuropathy, an adult-onset disorder resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or OHS.

Diagnosis/testing. Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine beta hydroxylase (DBH) and lysyl oxidase. While serum copper concentration and serum ceruloplasmin concentration are low in Menkes disease and OHS, they are normal in ATP7A-related DMN.

Management. Treatment of manifestations: Classic Menkes disease: gastrostomy tube placement to manage caloric intake; surgery for bladder diverticulae.

Prevention of primary manifestations: Subcutaneous injections of copper histidine or copper chloride before age ten days normalizes developmental outcome in some children and improves the neurologic outcome in others.

Prevention of secondary complications: Antibiotic prophylaxis may prevent bladder infection.

Genetic counseling. The ATP7A-related copper transport disorders are inherited in an X-linked manner. Approximately one third of affected males have no family history of Menkes disease/OHS/DMN. If the mother is a carrier, the risk of transmitting the ATP7A mutation is 50% in each pregnancy: a male who inherits the mutation will be affected with the disorder present in his brother; females who inherit the mutation will be carriers and will not be affected. Males with OHS or ATP7A-related DMN will pass the disease-causing mutation to all of their daughters and none of their sons. Individuals with classic Menkes disease do not reproduce. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation has been identified in a family. Prenatal testing for Menkes disease is also possible by copper transport studies in cultured chorionic villus cells or amniocytes.

GeneReview Scope

ATP7A-Related Copper Transport Disorders: Included Disorders
  • Menkes disease
  • Occipital horn syndrome
  • ATP7A-related distal motor neuropathy

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Menkes disease is suspected in males who develop hypotonia, failure to thrive, and seizures between age six and ten weeks.

Shortly thereafter, hair changes become manifest: the scalp and (usually) eyebrow hair is short, sparse, coarse, twisted, and often lightly pigmented (white, silver, or gray). The hair is shorter and thinner on the sides and back of the head. The hair can be reminiscent of steel wool cleaning pads. Light microscopic hair analysis reveals pili torti (hair shafts twisting 180°), trichoclasis (transverse fracture of the hair shaft), and trichoptilosis (longitudinal splitting of the hair shaft). Because of the flattening of the normal cylindric structure, the periodicity of the twisting in pili torti is different from that found in naturally curly hair.

Specific clinical features include:

  • Distinctive facial features (jowly appearance with sagging cheeks)
  • Pectus excavatum (midline depression in the bony thorax)
  • Skin laxity particularly on the nape of the neck and trunk
  • Umbilical or inguinal herniae
  • Hypotonia, neurodevelopmental delays, and failure to thrive, typically manifest by age three to six months

Occipital horn syndrome is suspected in males with:

  • Occipital horns: distinctive wedge-shaped calcifications at the site of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. These calcifications may be clinically palpable or observed on skull radiographs.
  • Lax skin and joints
  • Bladder diverticula
  • Inguinal herniae
  • Vascular tortuosity
  • Dysautonomia (chronic diarrhea, orthostatic hypotension)
  • Mild cognitive deficits

ATP7A-related distal motor neuropathy, an adult-onset distal motor neuropathy resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or occipital horn syndrome.

It is characterized by:

  • Progressive distal motor neuropathy with minimal or no sensory symptoms
  • Distal muscle weakness and atrophy in feet and hands with occasional pes cavus foot deformities
  • Deep tendon reflexes vary from normal to diminished, with frequently absent ankle reflexes
  • Nerve conduction tests: reduced compound motor amplitudes with generally normal conduction velocities with positive waves and fibrillations on EMG

Testing

Serum concentration of copper and ceruloplasmin. Individuals with classic Menkes disease or occipital horn syndrome have low serum copper concentration and low serum ceruloplasmin concentration (see Table 1).

Table 1. Serum Copper and Serum Ceruloplasmin Concentration in Menkes Disease, Occipital Horn Syndrome, and ATP7A-Related Distal Motor Neuropathy

Serum ConcentrationMenkes Disease 1 Occipital Horn SyndromeATP7A-Related Distal Motor NeuropathyNormal
Copper 0-55 µg/dL40-80 µg/dL80-100 µg/dL70-150 µg/dL;
(birth - 6 mos: 20-70 µg/dL)
Ceruloplasmin 10-160 mg/L110-240 mg/L240-310 mg/L200-450 mg/L;
(birth - 6 mos: 50-220 mg/L)

1. Diagnosis of Menkes disease using these studies alone in children under age six months is problematic given the normally low serum concentration in all children at this age.

Copper transport studies in cultured fibroblasts. Impaired cellular copper exodus is demonstrated by increased cellular copper retention in pulse-chase experiments with radiolabelled copper in Menkes disease and OHS

Plasma and CSF catecholamine analysis. Plasma catechol concentrations are distinctively abnormal at all ages in Menkes disease and OHS (but normal in ATP7A-related distal motor neuropathy). Abnormal levels reflect partial deficiency of DBH (dopamine-beta-hydroxylase), a copper-dependent enzyme critical for catecholamine biosynthesis

Carrier females. Biochemical testing is generally unreliable for carrier detection because of overlap with normal ranges.

Molecular Genetic Testing

Gene. ATP7A is the only gene known to be associated with Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Menkes Disease and Occipital Horn Syndrome

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Affected Males Carrier Females
ATP7ASequence analysis 4, 5 or mutation scanning 6Sequence variants~80%~80%
Small intra-exon deletions and insertions
Deletion/duplication analysis 7(Multi)exon or whole-gene deletions~15% 8~15%

1. See Table A. Genes and Databases for chromosome locus and protein name

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis of genomic DNA cannot detect deletion of an exon(s) or a whole gene on the X chromosome in carrier females.

6. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.

7. Testing that identifies partial or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Deletion/duplication analysis can be used to confirm a putative exon/multiexon or whole-gene deletion in males after failure to amplify by PCR in sequence analysis or mutation scanning.

Testing Strategy

To confirm the diagnosis in a proband

  • Serum concentration of copper and ceruloplasmin for Menkes disease and OHS only.
  • Plasma and CSF catecholamine analysis for Menkes disease and OHS only
  • Molecular genetic testing for all three phenotypes
  • Copper transport studies in cultured fibroblasts for Menkes disease only

    Note: This method is reserved for urgent prenatal testing when a family’s mutation is unknown; however, this situation should become exceedingly rare with increased availability and efficiency of molecular genetic testing.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Female carriers are heterozygotes for these X-linked disorders and are typically asymptomatic, in some instances due to favorably skewed X-inactivation [Desai et al 2011]. In theory, unfavorably skewed X-inactivation in some carrier females could be associated with neurologic or other clinical findings related to the disorders. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The clinical spectrum of ATP7A-related copper transport disorders ranges from classic Menkes disease at the severe end to occipital horn syndrome (OHS) to distal motor neuropathy (DMN). Classic Menkes disease is characterized by neurodegeneration and failure to thrive commencing at ages two to three months. The age at diagnosis is usually about eight months. In contrast, OHS presents in early to middle childhood and is characterized predominantly by connective tissue abnormalities. ATP7A-related distal motor neuropathy is adult-in onset, resembles Charcot-Marie-Tooth disease, and shares none of the clinical abnormalities characteristic of Menkes disease or OHS.

Classic Menkes disease. Infants appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. Classic Menkes disease is usually first suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented) and jowly appearance of the face.

Autonomic dysfunction including temperature instability and hypoglycemia may be present in the neonatal period; some infants have syncope and diarrhea.

Vascular tortuosity, bladder diverticulae that can result in bladder outlet obstruction, and gastric polyps are common.

Without early treatment with parenteral copper, and sometimes even with such treatment, classic Menkes disease progresses to severe neurodegeneration and death between ages seven months and 3.5 years. Subdural hematomas and cerebrovascular accidents are common. Respiratory failure, often precipitated by pneumonia, is a common cause of death.

Imaging

  • MRI shows defective myelination, atrophy with ventriculomegaly, and vascular tortuosity.
  • MR angiography reveals a "corkscrew" appearance of cerebral vessels.
  • Radiographs show Wormian bones and metaphyseal spurring and may show rib fractures.

Mild Menkes disease. A few affected individuals in whom motor and cognitive development is better than in classic Menkes disease have been described. Individuals with mild Menkes disease may walk independently and talk. Weakness, ataxia, tremor, and head bobbing are characteristic neurologic findings. Seizures, if present, commence in mid-late childhood; intellectual disability is mild. Connective tissue problems may be more prominent than in classic Menkes disease. Pili torti are present.

Occipital horn syndrome (OHS or X-linked cutis laxa). Intelligence is normal or slightly reduced. The only apparent neurologic abnormalities of OHS are dysautonomia and subtle cognitive deficits. Affected individuals typically live to at least mid-adulthood. Fertility is unknown.

ATP7A-related distal motor neuropathy. The age of onset ranges from five to 60 years, and is typically during the second or thirrd decade of life [Kennerson et al 2010]. Findings include atrophy and weakness of distal muscles in hands and feet, foot drop with steppage gait, sometimes mild proximal weakness in the legs, with normal deep tendon reflexes or absent ankle reflexes. Sensory examination may be normal or show mild loss in the fingers and toes. The index case of the largest family reported had slow progression over 25 years, requiring ankle foot orthotics at age 38 years [Kennerson et al 2009].

Females. Carriers typically do not have symptoms. About one-half of obligate Menkes and OHS carriers show regions of pili torti [Moore & Howell 1985].

Evaluation of obligate female carriers in ATP7A-related distal motor neuropathy families has been limited to date. In the family of Kennerson et al [2009] the clinical neurologic examinations and motor nerve conduction studies of the females proven to be heterozygous were normal.

Genotype-Phenotype Correlations

The amount of residual ATPase enzyme activity correlates with phenotype Menkes disease, OHS, and ATP7A-related distal motor neuropathy and with response to early copper treatment in Menkes disease [Kaler et al 2008].

Tumer et al [2003] observed that with rare exceptions gross gene deletions result in classic Menkes disease with death in early childhood.

Milder variants of Menkes disease and OHS are often associated with splice junction mutations that alter, but do not eliminate, proper RNA splicing (i.e., "leaky" splice junction defects).

This newly discovered allelic variant associated with ATP7A-related distal motor neuropathy involves unique missense mutations within or near the luminal surface of the protein which may be relevant to the abnormal intracellular trafficking shown for these defects and to the mechanism of this form of motor neuron disease [Kennerson et al 2010].

Intrafamilial phenotypic variability is occasionally observed in Menkes disease [Kaler et al 1994, Borm et al 2004, Donsante et al 2007]. Differences noted among affected individuals from two families with ATP7A-related distal motor neuropathy included degree of weakness, atrophy, and sensory loss [Kennerson et al 2010].

Nomenclature

Menkes disease is also known as Menkes kinky hair syndrome or trichopoliodystrophy.

Occipital horn syndrome was formerly known as X-linked cutis laxa.

ATP7A-related distal motor neuropathy is also known as X-linked distal spinal muscular atrophy 3.

Prevalence

The incidence of Menkes disease and its variants is estimated at one in 100,000 births.

Differential Diagnosis

Menkes disease. The differential diagnosis of Menkes disease includes other infantile-onset neurodevelopmental syndromes including:

Occipital horn syndrome (OHS). The differential diagnosis of OHS includes:

The differential diagnosis of ATP7A-related distal motor neuropathy includes other forms of Charcot-Marie-Tooth disease.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in a male diagnosed with Menkes disease, the following evaluations are recommended:

  • Developmental assessment
  • Evaluation of feeding and nutrition
  • Assessment of bladder function

To establish the extent of disease in a male diagnosed with OHS, evaluations for the following are recommended:

  • Bladder diverticula
  • Inguinal herniae
  • Vascular tortuosity
  • Dysautonomia (chronic diarrhea, orthostatic hypotension). Note: Some medical centers have clinical autonomic testing laboratories.
  • Mild cognitive deficits

To establish the extent of disease in a male diagnosed with ATP7A-related distal motor neuropathy (DMN), the following evaluations are recommended:

  • Neurologic examination
  • EMG with nerve conduction studies

Treatment of Manifestations

Menkes disease

  • Gastrostomy tube placement to manage caloric intake and general nutrition in some males with classic Menkes disease
  • Surgery for bladder diverticulae that occur in classic Menkes disease
  • Developmental intervention

ATP7A-related distal motor neuropathy

  • Physical therapy (strength and stretching exercises)
  • Occupational therapy
  • Ankle foot orthotics

Prevention of Primary Manifestations

Menkes disease. In classic Menkes disease, treatment with subcutaneous injections of copper histidine or copper chloride before ten days of age normalizes developmental outcome in some individuals and improves the neurologic outcome in others [Kaler et al 2008, Kaler et al 2010].

Note: Despite very early copper histidine treatment, some infants show no significant improvement relative to the natural history of untreated Menkes disease [Kaler et al 1995, Kaler et al 2008].

To maintain serum copper concentration in the normal range (70-150 µg/dL), the suggested dose of copper chloride is:

  • For children under age one year: 250 µg administered subcutaneously twice a day
  • For children older than age one year: 250 µg administered subcutaneously once a day

Prevention of Secondary Complications

Antibiotic prophylaxis may be necessary to prevent bladder infection.

Surveillance

Monitor serum copper and ceruloplasmin levels to avoid supranormal levels.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Results of a clinical trial of copper histidine for early diagnosed Menkes disease therapy were published [Kaler et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Therapies proven to be ineffective include vitamin C.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy are inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disease or be a carrier of the mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from leukocytes, she has germline mosaicism.
  • Approximately one third of affected males are simplex cases (i.e., they have no known family history of Menkes disease/OHS/DMN). Several possibilities regarding the carrier status of the mothers of simplex male cases need to be considered:
    • The mother is not a carrier and the affected male has a de novo disease-causing mutation. About one third of males have Menkes disease/OHS/DMN as the result of a de novo mutation.
    • The mother is a carrier of a de novo disease-causing mutation that occurred:
      • As a germline mutation that was present at the time of her conception, is present in every cell of her body, and is detectable in DNA extracted from her leukocytes
        OR
      • As a somatic mutation, i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism, in which the mutation is present in only a percentage of cells and may not be detectable in leukocyte DNA
        OR
      • As a mutation that is present only in her ovaries; termed "germline mosaicism," in which not all germ cells have the mutation, and in which the mutation is not detectable in DNA from leukocytes. While germline mosaicism is a theoretical possibility in Menkes disease/OHS/DMN, it has not been unequivocally demonstrated.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother is a carrier, there is a 50% chance of transmitting the ATP7A mutation in each pregnancy. A male who inherits the mutation will be affected with the disorder present in his brother; females who inherit the mutation will be carriers, like the mother, and will not be affected.
  • If the disease-causing mutation cannot be detected in DNA extracted from the leukocytes of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Males with OHS and ATP7A-related DMN pass the disease-causing mutation to all of their daughters and none of their sons.
  • Males with classic Menkes disease have not reproduced to date.

Other family members. The proband's maternal female relatives may be at risk of being carriers, and their offspring, depending on their gender, may be at risk of being carriers or being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family. See Molecular Genetic Testing.

Biochemical testing is generally unreliable for carrier detection because of overlap with normal ranges.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies at increased risk if the ATP7A mutation has been identified in a family member or if biochemical studies have confirmed the diagnosis in a family member. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation). If the karyotype is 46,XY, prenatal testing can be done in one of two ways:

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Corporation for Menkes Disease
    5720 Buckfield Court
    Fort Wayne IN 46804
    Phone: 219-436-0137
    Email: j1@home.com
  • Medline Plus
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. ATP7A-Related Copper Transport Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ATP7AXq21​.1Copper-transporting ATPase 1ATP7A @ LOVDATP7A

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for ATP7A-Related Copper Transport Disorders (View All in OMIM)

300011ATPase, Cu(2+)-TRANSPORTING, ALPHA POLYPEPTIDE; ATP7A
300489SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3; SMAX3
304150OCCIPITAL HORN SYNDROME; OHS
309400MENKES DISEASE

Gene structure. ATP7A contains 23 exons spanning 150 kb genomic DNA. The coding sequence is 4.5 kb. Rarely, alternatively spliced transcripts (of uncertain significance) are discerned in normal tissues. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. There are some known benign variants.

Pathogenic allelic variants. Pathogenic variants tend to be family-specific (unique). A range of mutation types have been identified, including: small insertions and deletions (35%), nonsense mutations (20%), splicing abnormalities (15%), missense mutations (8%), and large deletions or rearrangements (20%) [Culotta & Gitlin 2001].

The ATP7A-related distal motor neuropathy involves unique missense mutations within or near the luminal surface of the protein [Kennerson et al 2010], which may be relevant to the abnormal intracellular trafficking shown for these defects, and the mechanism of this form of motor neuron disease.

Normal gene product. The protein encoded by ATP7A, a P-type ATPase, transports copper across cellular membranes and is critical for copper homeostasis.

Abnormal gene product. ATP7A mutations may result in a gene product with no copper transport capability (associated with a severe phenotype) or reduced quantity of normally functioning gene product (associated with a milder phenotype).

References

Literature Cited

  1. Borm B, Moller LB, Hausser I, Emeis M, Baerlocher K, Horn N, Rossi R. Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/occipital horn syndrome in three affected males in a single family. J Pediatr. 2004;145:119–21. [PubMed: 15238919]
  2. Culotta VC, Gitlin JD. Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. Vol 2. New York, NY: McGraw-Hill; 2001:3105-26.
  3. Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet. 2011;79:176–82. [PMC free article: PMC3099248] [PubMed: 20497190]
  4. Donsante A, Tang JR, Godwin SC, Holmes CS, Goldstein DS, Bassuk A, Kaler SG. Differences in ATP7A gene expression underlie intra-familial variability in Menkes disease/occipital horn syndrome. J Med Genet. 2007;44:492–7. [PMC free article: PMC2597922] [PubMed: 17496194]
  5. Kaler SG, Buist NR, Holmes CS, Goldstein DS, Miller RC, Gahl WA. Early copper therapy in classic Menkes disease patients with a novel splicing mutation. Ann Neurol. 1995;38:921–8. [PubMed: 8526465]
  6. Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA, Goldstein DS, Holmes CS, Gahl WA. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet. 1994;8:195–202. [PubMed: 7842019]
  7. Kaler SG, Holmes CS, Goldstein DS, Tang JR, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358:605–14. [PMC free article: PMC3477514] [PubMed: 18256395]
  8. Kaler SG, Liew CJ, Donsante A, Hicks JD, Sato S, Greenfield JC. Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. J Inher Metab Dis. 2010;33:583–9. [PMC free article: PMC3113468] [PubMed: 20652413]
  9. Kennerson M, Nicholson G, Kowalski B, Krajewski K, El-Khechen D, Feely S, Chu S, Shy M, Garbern J. X-linked distal hereditary motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology. 2009;72:246–52. [PubMed: 19153371]
  10. Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010;86:343–52. [PMC free article: PMC2833394] [PubMed: 20170900]
  11. Moore CM, Howell RR. Ectodermal manifestations in Menkes disease. Clin Genet. 1985;28:532–40. [PubMed: 4075564]
  12. Tumer Z, Birk Moller L, Horn N. Screening of 383 unrelated patients affected with Menkes disease and finding of 57 gross deletions in ATP7A. Hum Mutat. 2003;22:457–64. [PubMed: 14635105]

Suggested Reading

  1. Chelly J, Tumer Z, Tonnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet. 1993;3:14–9. [PubMed: 8490646]
  2. Danks DM, Cartwright E, Stevens BJ, Townley RR. Menkes' kinky hair disease: further definition of the defect in copper transport. Science. 1973;179:1140–2. [PubMed: 4120259]
  3. Donsante A, Johnson P, Jansen LA, Kaler SG. Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain. Am J Med Genet A. 2010;152A:2529–34. [PMC free article: PMC3117432] [PubMed: 20799318]
  4. Ganguly A, Rock MJ, Prockop DJ. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci U S A. 1993;90:10325–9. [PMC free article: PMC47767] [PubMed: 8234293]
  5. Gasch AT, Caruso RC, Kaler SG, Kaiser-Kupfer M. Menkes' syndrome: ophthalmic findings. Ophthalmology. 2002;109:1477–83. [PubMed: 12153799]
  6. Kaler SG. Menkes disease. Adv Pediatr. 1994;41:263–304. [PubMed: 7992686]
  7. Kaler SG, Das S, Levinson B, Goldstein DS, Holmes CS, Patronas NJ, Packman S, Gahl WA. Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small in-frame deletion. Biochem Mol Med. 1996;57:37–46. [PubMed: 8812725]
  8. Kaler SG, Gahl WA, Berry SA, Holmes CS, Goldstein DS. Predictive value of plasma catecholamine levels in neonatal detection of Menkes disease. J Inherit Metab Dis. 1993;16:907–8. [PubMed: 8295415]
  9. Kaler SG, Goldstein DS, Holmes C, Salerno JA, Gahl WA. Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease. Ann Neurol. 1993;33:171–5. [PubMed: 8434878]
  10. Kaler SG, Liew CJ, Donsante A, Hicks JD, Sato S, Greenfield JC. Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. J Inherit Metab Dis. 2010;33:583–9. [PMC free article: PMC3113468] [PubMed: 20652413]
  11. Kaler SG. Genetics of Menkes kinky hair disease. Medscape. 2012.
  12. Levinson B, Conant R, Schnur R, Das S, Packman S, Gitschier J. A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome. Hum Mol Genet. 1996;5:1737–42. [PubMed: 8923001]
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Chapter Notes

Revision History

  • 14 October 2010 (me) Comprehensive update posted live
  • 13 July 2005 (me) Comprehensive update posted to live Web site
  • 9 May 2003 (me) Review posted to live Web site
  • 27 November 2002 (sk) Original submission

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