Menkes disease is an X-linked recessive disorder characterized by generalized copper deficiency. The clinical features result from the dysfunction of several copper-dependent enzymes.
De Bie et al. (2007) provided a detailed review of the molecular pathogenesis ... Menkes disease is an X-linked recessive disorder characterized by generalized copper deficiency. The clinical features result from the dysfunction of several copper-dependent enzymes. De Bie et al. (2007) provided a detailed review of the molecular pathogenesis of Menkes disease.
Carrier status for the Menkes disease gene can usually be determined by examination of multiple hairs from scattered scalp sites for pili torti. Carrier status can, of course, never be completely excluded by negative findings of such scrutiny. ... Carrier status for the Menkes disease gene can usually be determined by examination of multiple hairs from scattered scalp sites for pili torti. Carrier status can, of course, never be completely excluded by negative findings of such scrutiny. Moore and Howell (1985) found pili torti in all affected males and in 43% of 28 obligate carriers or females at risk. When present, pili torti can be considered, in their opinion, a reliable indicator of heterozygosity. Changes in the metaphyses of the long bones resemble scurvy. Ascorbic acid oxidase is copper-dependent. Tumer et al. (1994) described first trimester prenatal diagnosis of Menkes disease using a specific DNA probe.
In a family of English-Irish descent living in New York, Menkes et al. (1962) described an X-linked recessive disorder characterized by early retardation in growth, peculiar hair, and focal cerebral and cerebellar degeneration. Severe neurologic impairment began within ... In a family of English-Irish descent living in New York, Menkes et al. (1962) described an X-linked recessive disorder characterized by early retardation in growth, peculiar hair, and focal cerebral and cerebellar degeneration. Severe neurologic impairment began within a month or two of birth and progressed rapidly to decerebration. Five males were affected but the gene could by inference be identified in 4 generations. The failure to grow brought the affected infants to medical attention at the age of a few weeks and death occurred in the first or second year of life. The hair was stubby and white. Microscopically it showed twisting, varying diameter along the length of the shaft, and often fractures of the shaft at regular intervals. Rather extensive biochemical investigations showed elevated plasma glutamic acid as the only consistent abnormality. The anatomic change in the central nervous system was described on the basis of 2 autopsies. Bray (1965) observed 2 brothers who died as infants with spastic dementia, seizures, and defective hair. Blood and urine amino acids were normal. Whether this is the same disorder as that in Menkes' family was unclear. The condition described by Yoshida et al. (1964) may have been the same. French and Sherard (1967) presented evidence that they interpreted as indicating that this disorder may represent an abnormality of lipid metabolism. Their 16-month-old patient showed: (1) scant, whitish, lackluster, kinky hair that microscopically showed pili torti, monilethrix and trichorrhexis nodosa; (2) retarded growth; (3) micrognathia and highly arched palate; (4) decline in mental development; (5) onset of focal and generalized seizures; and (6) spastic quadriparesis with clenched fists, opisthotonos, and scissoring. Biochemical studies showed depressed serum tocopherol and normal amino acid content of hair serum and urine. An abnormal autofluorescence is displayed by hair and by Purkinje cells' axons. 'Kinky hair disease' proved a designation useful in detection of new cases, since the hair change is an easily remembered feature by which physicians can be alerted to the condition (O'Brien, 1968). Changes in the metaphyses of the long bones and tortuosity of cerebral arteries have been described. Hypothermia and acute illness with septicemia were modes of presentation. Patchy abnormality of systemic arteries with stenosis or obliteration was observed by Danks et al. (1971). They also observed toluidine-blue-metachromasia of fibroblasts. Wesenberg et al. (1969) pointed out that the fetal hair does not show pili torti. Goka et al. (1976) found that cultured fibroblasts have a concentration of copper over 5 times that of normal fibroblasts. Williams et al. (1978) described the cellular pathology of Menkes disease. Osaka et al. (1977) reported 2 Japanese families. They pointed out that the hair may not be abnormal, that serum copper determination is a simple and reliable diagnostic test, and that 'congenital hypocupraemia' may be a preferred designation. An abnormality in egress of copper from Menkes disease fibroblasts was suggested by studies of Chan et al. (1978). Defective metallothionein (see 156530) was suggested. Haas et al. (1981) reported an X-linked disorder of copper metabolism which, by my interpretation, may be an allelic variant of Menkes syndrome. The disorder affected 4 males in 3 sibships connected through females. Similarities to Menkes disease were X-linked recessive inheritance, marked psychomotor retardation with seizures, low serum copper and ceruloplasmin (117700) levels, and a block in gut copper absorption. Differences from Menkes disease included normal birth weight, no hypothermia, grossly and microscopically normal hair, and radiographically normal bones. Survivorship was much longer than in Menkes disease. The neurologic disorder was static and characterized by hypotonia and choreoathetosis. Tonnesen et al. (1991) reviewed the cases of atypical Menkes reported by Haas et al. (1981). No pili torti were found in one case and very few (2 in 1,000) in a second. In addition, low levels of copper and ceruloplasmin in the serum were puzzling findings. However, (64)Cu uptake and retention was significantly increased in the range seen for classic Menkes patients, and copper uptake in female relatives gave the same uptake pattern as in heterozygotes in other families with the classic disorder. Godwin-Austen et al. (1978) described a disorder clinically reminiscent of Wilson disease but without Kayser-Fleischer rings. Symptoms began at age 12 years and defective copper absorption from the distal intestine, with high copper levels in rectal mucosa, was demonstrated. X-linked inheritance was suggested. Proud et al. (1996) reported on the clinical features of 4 affected persons in 3 generations of a family that manifested an unusual variant of the Menkes syndrome. These patients had normal head circumference, moderate to severe mental retardation, onset at age of 3 to 4 years, dysarthria, laxity of skin, bladder diverticula, tortuous vessels, chronic diarrhea, and occipital exostoses (evident in 3 persons aged 18 to 38 years). Study of the MNK gene showed an A-to-T change at the +3 position of the splice donor site near the 3-prime end of the MNK coding sequence resulting in abnormal splicing (Kaler et al., 1994). The authors proposed that maintenance of 20% of normal splicing could explain unique phenotypic manifestations in affected persons. Proud et al. (1996) suggested that these patients, as well as a patient with occipital horn syndrome reported by Wakai et al. (1993), represent a new variant of Menkes syndrome. Phenotypic overlap between Menkes syndrome and the occipital horn syndrome (304150) is to be expected since both are caused by mutations in the ATP7A gene (300011). Gerard-Blanluet et al. (2004) described occipital horns in a classic case of Menkes disease caused by an 8-bp deletion in the ATP7A gene (300011.0011). They pointed out that 'occipital horn' refers to a wedge-shaped calcification that forms within the tendinous insertions of the trapezius and sternocleidomastoid muscles at their attachment to the occipital bone. They suggested that presence of voluntary traction on these hyperlax tendons attached to the skull could then have provoked calcification of the occipital tendons as an aberrant way of reparation. Gerard-Blanluet et al. (2004) suggested that voluntary traction of the relevant muscles persisting after 2 years of age, needing both sustained voluntary head control and long survival, is required for the development of occipital horns in patients with Menkes disease caused by a deleterious mutation in the ATP7A gene. Jankov et al. (1998) described a newborn male who presented with acute onset of severe intraabdominal bleeding, hemorrhagic shock, and multiple fractures leading to death on day 27. Menkes disease was diagnosed at autopsy and confirmed by copper accumulation studies on cultured fibroblasts. Such an early onset of fatal complications in Menkes disease had not previously been reported. The mutation in this case was said to have been identical to that found in an unrelated male with Menkes disease who died at the age of 4 years without severe connective tissue disease. Horn (1999) reported that the mutation in ATP7A was arg980 to ter (300011.0005). Tumer and Horn (1997) reviewed the clinical and genetic aspects of Menkes syndrome, including phenotypic expression in females, mutation spectrum, diagnosis, and treatment. They also discussed the mottled mouse as a model for Menkes syndrome and new insights into normal and defective copper metabolism provided by biochemical and genetic studies of Menkes syndrome and Wilson disease (277900).
Three independent groups, in San Francisco (Vulpe et al., 1993), Oxford (Chelly et al., 1993), and Michigan (Mercer et al., 1993), cloned a candidate gene for Menkes disease. Vulpe et al. (1993), who proceeded directly from the translocation ... Three independent groups, in San Francisco (Vulpe et al., 1993), Oxford (Chelly et al., 1993), and Michigan (Mercer et al., 1993), cloned a candidate gene for Menkes disease. Vulpe et al. (1993), who proceeded directly from the translocation breakpoints at Xq13.3 to the gene by cDNA library screening with a YAC fragment and exon trapping experiments, succeeded in obtaining a complete set of clones corresponding to an 8.5-kb transcript that encodes a 1,500 amino acid protein. The 5-prime region of the same locus was also obtained by Chelly et al. (1993) who took the more cumbersome but genetically rigorous step of first identifying genomic fragments that were deleted in cytogenetically normal patients with Menkes disease, and by Mercer et al. (1993) who employed a strategy involving long range restriction mapping and fluorescence in situ hybridization (FISH) analysis. Two lines of evidence strongly implicated the cloned MNK locus in the etiogenesis of Menkes disease: nonoverlapping portions of the gene were deleted in 16 of 100 unrelated patients (Chelly et al., 1993), and the expression of the transcript was reduced or altered in 23 of 32 patients (Vulpe et al., 1993; Mercer et al., 1993). By a database search of the predicted sequence, Vulpe et al. (1993) found strong homology to P-type ATPases, a family of integral membrane proteins that use an aspartyl phosphate intermediate to transport cations across membranes. The protein has the characteristics of a copper binding protein. Northern blot experiments showed that MNK mRNA is present in a variety of cell types and tissues except liver, in which expression is reduced or absent. This is consistent with the clinical observation that the liver is largely unaffected in Menkes disease and fails to accumulate excess copper. The MNK protein is localized to the trans-Golgi network (TGN) (Petris et al., 1996). Studies with copper-resistant Chinese hamster ovary cells (CHO) by Petris et al. (1996) suggested that the MNK protein cycles between the TGN and the plasma membrane, depending on the concentration of copper within the cell. TGN38 (603062) is another protein that cycles between the TGN and the plasma membrane (Ladinsky and Howell, 1992; Reaves et al., 1993). A number of Golgi-resident proteins contain specific localization signals, and Francis et al. (1998) showed that this is true also of MNK. By immunofluorescence, they showed that the full-length recombinant Menkes protein, the isoform that is not expressed in the occipital horn syndrome, localizes to the Golgi apparatus, whereas the alternatively spliced form, which lacks sequences for transmembrane domains 3 and 4 encoded by exon 10 and is expressed in the occipital horn syndrome, localizes to the endoplasmic reticulum. Using sequences from exon 10 fused to a non-Golgi reporter molecule, Francis et al. (1998) showed that a 38-amino acid sequence containing transmembrane domain 3 of the MNK protein was sufficient for localization to the Golgi complex. Therefore, the protein sequence encoded by exon 10 may be responsible for this differential localization and both isoforms may be required for comprehensive transport of copper within the cell. By immunogold electron microscopic analyses, La Fontaine et al. (1998) mapped the MNK protein to the TGN. When the extracellular copper concentration was increased, MNK in the CHO cells was redistributed to the cytoplasm and plasma membrane, but returned to the TGN under basal, low copper conditions. The MNK protein is normally localized predominantly in the TGN; however, when cells are exposed to excessive copper it is rapidly relocalized to the plasma membrane where it functions in copper efflux. Petris and Mercer (1999) found that in cells stably expressing tagged MNK protein, extracellular antibodies were internalized to the perinuclear region, indicating that the tagged MNK at the TGN constitutively cycles via the plasma membrane in basal copper conditions. Under elevated copper conditions, the tagged MNK was recruited to the plasma membrane; however, internalization of the tagged protein was not inhibited, and the protein continued to recycle through cytoplasmic membrane compartments. These findings suggested that copper stimulates exocytic movement of MNK to the plasma membrane rather than reducing MNK retrieval and indicated that MNK may remove copper from the cytoplasm by transporting copper into the vesicles through which it cycles. Screening 383 unrelated patients affected with Menkes syndrome, Tumer et al. (2003) found 57 with gross deletions in the ATP7A gene (14.9%). Except for a few cases, gross gene deletions resulted in a classic form of Menkes disease with death in early childhood. Moller et al. (2005) identified 21 novel missense mutations in the ATP7A gene in patients with Menkes disease. The mutations were located within the conserved part of ATP7A between residues val842 and ser1404. Molecular 3-dimensional modeling based on the structure of ATP2A1 (108730) showed that the mutations were more spatially clustered than expected from the primary sequence. The authors suggested that some of the mutations may interfere with copper binding.
Danks et al. (1971) suggested that the frequency may be 1 in 40,000 live births in Melbourne and higher than previously thought because some patients may die undiagnosed.
Tonnesen et al. (1991) estimated that the combined ... Danks et al. (1971) suggested that the frequency may be 1 in 40,000 live births in Melbourne and higher than previously thought because some patients may die undiagnosed. Tonnesen et al. (1991) estimated that the combined frequency of live-born Menkes disease patients in Denmark, France, the Netherlands, the United Kingdom, and West Germany was 1 per 298,000 live-born babies in the period 1976 to 1987. They estimated the mutation rate for Menkes disease to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during that period.
Menkes disease is suspected in males who develop hypotonia, failure to thrive, and seizures between age six and ten weeks....
DiagnosisClinical DiagnosisMenkes 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 trunkUmbilical or inguinal herniaeHypotonia, neurodevelopmental delays, and failure to thrive, typically manifest by age three to six monthsOccipital 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 jointsBladder diverticulaInguinal herniaeVascular tortuosityDysautonomia (chronic diarrhea, orthostatic hypotension)Mild cognitive deficitsATP7A-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 symptomsDistal muscle weakness and atrophy in feet and hands with occasional pes cavus foot deformitiesDeep tendon reflexes vary from normal to diminished, with frequently absent ankle reflexesNerve conduction tests: reduced compound motor amplitudes with generally normal conduction velocities with positive waves and fibrillations on EMGTestingSerum 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 NeuropathyView in own windowSerum ConcentrationMenkes Disease 1 Occipital Horn SyndromeATP7A-Related Distal Motor NeuropathyNormalCopper 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 OHSPlasma 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 biosynthesisCarrier females. Biochemical testing is generally unreliable for carrier detection because of overlap with normal ranges.Molecular Genetic TestingGene. ATP7A is the only gene known to be associated with Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy.Clinical testingSequence analysis or mutation scanning. Direct sequence analysis of the ATP7A coding region and flanking intron sequences detects:In males: point mutations and small intra-exonic deletions and insertions (~80% of mutations) [Tumer et al 2003];In females: point mutations and small intra-exonic deletions and insertions. Note: Deletion of an exon, multiple exons, or an entire ATP7A allele in a female could be masked in sequence analysis or mutation scanning by her normal allele.Deletion/duplication analysis. Testing by a variety of methods can be used to detect deletion of an ATP7A exon, multiple exons, or the whole gene in about 15% of males and females [Tumer et al 2003].Table 2. Summary of Molecular Genetic Testing Used in Menkes Disease and Occipital Horn SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected Males Carrier Females ATP7ASequence analysis or mutation scanning 2,3Sequence variants 4 ~80%~80% ClinicalSmall intra-exonic deletions and insertionsDeletion / duplication analysis 5Exonic, multiexonic, or whole-gene deletions~15% 6~15% 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.3. Sequence analysis of genomic DNA cannot detect deletion of an exon(s) or a whole gene on the X chromosome in carrier females.4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 5. Testing that identifies 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.6. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm the diagnosis in a probandSerum concentration of copper and ceruloplasmin for Menkes disease and OHS only.Plasma and CSF catecholamine analysis for Menkes disease and OHS onlyMolecular genetic testing for all three phenotypesCopper 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.Genetically Related (Allelic) DisordersMenkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy are the only phenotypes currently known to be associated with mutations in ATP7A.
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....
Natural HistoryThe 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.ImagingMRI 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.
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]....
Genotype-Phenotype CorrelationsThe 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].
Menkes disease. The differential diagnosis of Menkes disease includes other infantile-onset neurodevelopmental syndromes including:...
Differential DiagnosisMenkes disease. The differential diagnosis of Menkes disease includes other infantile-onset neurodevelopmental syndromes including:Biotinidase deficiencyOrganic aciduriasAminoaciduriasMitochondrial myopathies (see Mitochondrial Diseases Overview)Occipital horn syndrome (OHS). The differential diagnosis of OHS includes:FBLN5-related cutis laxa, inherited in an autosomal recessive manner and caused by mutations in the gene encoding fibulin-5ELN-related cutis laxa, inherited in an autosomal dominant manner and caused by mutations in the gene encoding elastin.The differential diagnosis of ATP7A-related distal motor neuropathy includes other forms of Charcot-Marie-Tooth disease.
To establish the extent of disease in a male diagnosed with Menkes disease, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in a male diagnosed with Menkes disease, the following evaluations are recommended:Developmental assessmentEvaluation of feeding and nutritionAssessment of bladder functionTo establish the extent of disease in a male diagnosed with OHS, evaluations for the following are recommended:Bladder diverticulaInguinal herniaeVascular tortuosityDysautonomia (chronic diarrhea, orthostatic hypotension). Note: Some medical centers have clinical autonomic testing laboratories.Mild cognitive deficitsTo establish the extent of disease in a male diagnosed with ATP7A-related distal motor neuropathy (DMN), the following evaluations are recommended:Neurologic examinationEMG with nerve conduction studiesTreatment of ManifestationsMenkes diseaseGastrostomy tube placement to manage caloric intake and general nutrition in some males with classic Menkes diseaseSurgery for bladder diverticulae that occur in classic Menkes diseaseDevelopmental interventionATP7A-related distal motor neuropathyPhysical therapy (strength and stretching exercises)Occupational therapyAnkle foot orthoticsPrevention of Primary ManifestationsMenkes 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 dayFor children older than age one year: 250 µg administered subcutaneously once a dayPrevention of Secondary ComplicationsAntibiotic prophylaxis may be necessary to prevent bladder infection.SurveillanceMonitor serum copper and ceruloplasmin levels to avoid supranormal levels.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationResults 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.OtherTherapies proven to be ineffective include vitamin C.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATP7AXq21.1Copper-transporting ATPase 1ATP7A @ LOVDATP7AData 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) View in own window 300011ATPase, Cu(2+)-TRANSPORTING, ALPHA POLYPEPTIDE; ATP7A 300489SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3; SMAX3 304150OCCIPITAL HORN SYNDROME; OHS 309400MENKES DISEASENormal allelic variants. 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. There are some known normal allelic variants.Pathologic allelic variants. Pathologic allelic 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).