Wikipedia. Instance of, disease, Designated intractable/rare diseases. Subclass of, hair disease, metal metabolism disorder. Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport . A number sign (#) is used with this entry because of evidence that Menkes disease is caused by mutation in the gene encoding Cu(2+)-transporting ATPase .
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CC HPO: The occipital horn syndrome is caused by mutation in the same gene. 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. 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 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. French and Sherard presented evidence that they interpreted as indicating that this disorder may represent an abnormality of lipid metabolism.
Their month-old patient showed: 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. 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.
They also observed toluidine-blue-metachromasia of fibroblasts. 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.
Defective metallothionein ennfermedad was suggested. 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 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.
Orphanet: Diagn stico molecular de la enfermedad de Menkes gen ATP7A
The neurologic disorder was static and characterized by hypotonia and choreoathetosis. No pili torti were found in one case and very few 2 in 1, 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 menkds.
Symptoms began menkds age 12 years and defective copper absorption from the distal intestine, with high copper levels in rectal mucosa, was demonstrated.
OMIM Entry – # – MENKES DISEASE
X-linked inheritance was suggested. 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. Phenotypic overlap between Menkes syndrome and the occipital horn syndrome is to be expected since both are caused by mutations in the ATP7A gene dnfermedad 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. Menkes disease was diagnosed at autopsy and confirmed by copper accumulation studies on df 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 reported that the mutation in ATP7A was arg to ter Tumer and Horn 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 menkrs metabolism provided by biochemical and genetic studies of Menkes syndrome and Wilson disease Features were somewhat variable, but included hypotonia, myopathic facies, coarse hair, silvery hair, skin and joint laxity, and severe global developmental delay.
All had cerebrovascular tortuosity and brain or cerebellar atrophy.
Two patients had seizures. Serum copper levels were decreased in 2 patients and low-normal in the third patient.
Two patients were treated with copper without a clear benefit to cognitive development, although 1 of the patients who received treatment did not develop seizures. The report indicated that females with Menkes disease can have significant manifestations of the disorder. Copper deficiency in animals leads to connective tissue changes because formation of lysine-derived cross-links in elastin and collagen enfsrmedad interfered with, the amine oxidase responsible for the initial modification of lysine being copper-dependent.
This may explain the arterial abnormalities. The striking hair changes are probably the result enfermedac defective formation of disulfide bonds in keratin since this process is copper-dependent, jenkes copper deficiency in sheep leads to the formation of wool with defective cross-linking Collie et al. Menkes had sent hair from his original patients to the Australian Wool Commission, but at that early date the Commission could not identify the problem Menkes, In both disorders, fibroblasts had markedly increased copper content and rate of incorporation of 64 Cu, and accumulation was in metallothionein see or a metallothionein-like protein as previously established for Menkes cells.
Histochemical staining showed that copper was distributed uniformly throughout the cytoplasm in both cell types, this location being consistent with accumulation in metallothionein. Both fibroblast types showed very low lysyl oxidase activity and increased extractability of newly synthesized collagen, but no abnormality in cell viability, duplication enfermdad, prolyl 4-hydroxylase activity, or collagen synthesis rate.
Skin biopsy specimens from one E-D IX patient showed the same abnormalities in lysyl oxidase activity nefermedad collagen extractability. Envermedad similarities in biochemical findings between type IX Ehlers-Danlos syndrome and Menkes syndrome may indicate allelism. In studies of cultured cells from both conditions, Kuivaniemi et al.
Although the rapid degradation of a mutant protein could not be excluded, the authors favored the idea that synthesis of the lysyl oxidase protein is impaired. Scheinberg and Collins suggested that the primary defect resides in zinc, i. When ionic zinc is present in the liver or intestine it induces the synthesis of metallothionein to which the zinc is bound. Since the affinity of metallothionein for copper istimes greater than that for zinc, copper in either organ displaces zinc and binds to metallothionein.
In the liver such bound copper is probably unavailable for incorporation into specific copper ‘apo’ proteins. In the intestine copper does not enter the circulation; advantage has been taken of this fact to decrease the intestinal absorption of copper by administering zinc in Wilson disease Deficiency of ZBP in Menkes disease would presumably result in an increased concentration of nonprotein-bound, ionic zinc–the only form of the element that has been shown to induce synthesis of metallothionein.
Menkes gave a useful review in which he listed 6 cuproenzymes, 5 enfrrmedad which may account for features of the disorder: Dopamine-beta-hydroxylase is also a cuproenzyme; dde role its deficiency may have in the phenotype of kinky hair disease is unclear. During a systematic chromosomal survey of unrelated boys with Menkes enfefmedad, Tumer et al. The same rearranged X chromosome was present de novo in the boy’s phenotypically normal mother, where it was preferentially inactivated.
This finding supported localization of the MNK locus to Xq13 and suggested fine mapping to subband Xq The chromosomal band associated with the X-inactivation center XIC; was present, in this patient, on the proximal long arm of the rearranged X chromosome, in line with the location of XIC proximal to MNK.
Comparative mapping suggested to Horn et al. Linkage studies in 5 Dutch families suggested close situation of the Menkes locus and the centromere recombination fraction 0. Centromeric heteromorphism was used as the ‘marker trait. From a 3-point analysis, Tonnesen et al. In studies of 4 families in which a characteristic X-centromeric marker was segregating with Menkes disease, Friedrich et al.
The breakpoint in the X chromosome was at Xq They established a enfer,edad cell line from the patient of Kapur et al. Southern blot analyses using a number of probes specific for chromosomes X and 2 showed that the enfermeddad in this patient–and, therefore, probably the Menkes gene–mapped to a small subregion of band Xq They concluded that the most likely location of MNK is Xqq Working with DNA from the cells from the patient with the translocation t 2;X reported by Kapur et al.
They demonstrated that the normal X chromosome was late replicating, whereas the derivative X chromosome was selectively early replicating.
The diagnosis was menkrs by findings of low levels of serum copper and ceruloplasmin with increased copper uptake in cultured fibroblasts. The authors hypothesized that function of the ATP7A gene had been disrupted by the translocation, either by a structural disruption or by ‘silencing’ as a result of inappropriate localized inactivation in an otherwise active X;13 derivative chromosome. Three independent groups, in San Francisco Vulpe et al.
The 5-prime region of the same locus was also obtained by Chelly et al. Two lines of evidence strongly implicated the cloned MNK locus in the etiogenesis of Menkes disease: By a database search of the predicted sequence, Vulpe et al. 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 menoes unaffected in Menkes disease and fails to accumulate excess copper. A number of Golgi-resident proteins contain specific localization signals, and Francis et al. 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.