Info

36+38

34+13

29+11

1 wk

38+19

40+21

64+31

1 mo

56+25

46+16

71+24

2 mo

58+27

77+25

92+42

3 mo

70+32

83+15

Diagnosing patients with MNK who are older than 3 mo is not difficult; their diagnosis is based on their symptoms, low serum levels of copper and ceruloplasmin, and characteristic radiological changes. The diagnosis can be confirmed by further biochemical findings, such as lack of improvement in serum copper and ceruloplasmin levels after oral administration of copper and high levels of copper in cultured fibroblasts. However, early diagnosis is very difficult. During the neonatal period, the clinical features of patients with MNK and their serum copper and ceruloplasmin levels cannot be distinguished from those of unaffected infants. The retention of 64Cu in uptake studies with cultured fibroblasts and an elevated ratio of dihydroxyphenylalanine (DOPA) to dihydroxyphenylglycol (DHPG) in the serum have been reported to be useful indicators for early diagnosis (48). However, these assays cannot be easily and quickly performed in the case of most infants suspected of having MNK. A much simpler test for early diagnosis is to ascertain whether serum copper and ceruloplas-min levels fail to increase after oral administration of copper.

A DNA-based diagnostic test is now available. However, a large number of different mutations in the ATP7A gene have been documented. Moreover, a few patients with MNK or OHS have been found to have no mutations in exons of the ATP7A gene (unpublished data). Therefore, even if a mutation is not found, MNK or OHS can not be excluded as a potential diagnosis.

Heterozygote females can be diagnosed based on pili torti in their hair and/or an elevated copper concentration in cultured fibroblasts. DNA-based diagnosis is very useful for carrier detection when the mutant ATP7A has been identified in the index patient.

DNA-based diagnosis is also very useful for prenatal diagnosis when the mutation in the family has been identified. If the mutation cannot be identified, prenatal diagnosis is still possible by analyzing the copper concentration or by measuring 64Cu uptake in cultured chorionic villi or amniotic cells (49,50).

7. TREATMENT

The currently accepted treatment for patients with MNK is parenteral administration of copper. Among the different forms of copper used in such cases (i.e., copper-histidine, copper-acetate, and copper-ethylenediaminetetraacetic acid (EDTA), copper-histidine has been reported to be taken up by the brain most effectively (51). Treatment by parenteral administration of copper-histidine immediately improves the serum copper and ceruloplasmin levels as well as the hair abnormalities in patients with MNK. Christodoulou et al. have reported that neurological degeneration can also be prevented when treatment is initiated before the age of 2 mo (52). In some patients with MNK, however, early treatment does not normalize the neurological outcome (53). Such different responses to early treatment may arise from differences in the residual levels of ATP7A activity or differences in the processing of copper-histidine (51). When treatment is initiated in patients older than 2 mo, the neurological disturbances cannot be improved. These findings indicate that the newborn period is critical for normal neurodevelopment and that a certain level of copper is essential. This period is

Fig. 6. Two siblings with classical Menkes disease. (a) Photograph of the 2-yr-old elder brother who has been treated since the age of 8 mo. His hair has become normal, but his neurological disturbances could not be improved. (b) Photograph of the 2-yr-old younger brother who has been treated with copper-histidine injections since the age of 22 d.

Fig. 6. Two siblings with classical Menkes disease. (a) Photograph of the 2-yr-old elder brother who has been treated since the age of 8 mo. His hair has become normal, but his neurological disturbances could not be improved. (b) Photograph of the 2-yr-old younger brother who has been treated with copper-histidine injections since the age of 22 d.

Fig. 7. X-ray films of the elder brother. Left and right films were taken at the age of 8 mo when the treatment was started, and at the age of 2 yr, respectively. The elongation and tortuousness of the brain vessels are shown (upper, magnetic resonance angiograms); the development of bladder diverticula (lower, cystograms) are progressive.

Fig. 7. X-ray films of the elder brother. Left and right films were taken at the age of 8 mo when the treatment was started, and at the age of 2 yr, respectively. The elongation and tortuousness of the brain vessels are shown (upper, magnetic resonance angiograms); the development of bladder diverticula (lower, cystograms) are progressive.

also associated with prematurity of the blood-brain barrier. In the mouse model of MNK, copper accumulates in the blood-brain barrier (54,55). Thus, parenterally administered copper is probably trapped in the blood-brain barrier of patients and is not transported to the neurons after the barrier matures. Therefore, early treatment is very important to prevent the neurological disturbances in patients with MNK.

Two siblings with MNK who were treated with subcutaneous injections of copper-histidine and who exhibited typical clinical courses of MNK are described here. The elder patient was diagnosed as having MNK at the age of 8 mo based on the characteristic clinical features and biochemical findings of MNK. Treatment with copper-histidine was initiated at the age of 8 mo. The serum copper and ceruloplasmin levels have been maintained within the normal range since the initiation of treatment. The hair abnormalities have also improved (Fig. 6a). However, the neurological disturbances have not improved at all. Moreover, the connective tissue abnormalities have progressed in spite of ongoing treatment (Fig. 7). At the time of the elder brother's diagnosis, the younger brother was in his 28th gestational week and was prenatally diagnosed as having MNK on the basis of high copper levels in the amniocytes (30.7 ng/mg protein; normal: 12.3 ± 4.4). A planned cesarean section was performed in the 36th gestational week, and subcutaneous copper-histidine therapy was initiated at the age of 22 d. His neurological development has been completely normal (Fig. 6b). At his present age of 3 yr, he can run and he speaks a lot. However, radiological examination has revealed a small diverticulum of the bladder and spurs on the metaphyses of the long bones. The elder brother seems to have followed the typical clinical course of MNK when treatment is started late, whereas the younger patient seems to have followed the course of patients with MNK who receive early treatment.

As shown by these two patients, a serious problem that remains unsolved is that parenteral administration of copper cannot completely improve the connective tissue disorder, even when treatment is started at an early age. Patients who receive early treatment and develop well neurologically often display the clinical characteristics of patients with OHS. Because copper transport from the cytosol to the Golgi apparatus is disturbed in the affected cells, the parenterally administered copper may not reach the organelles (probably the trans-Golgi network), where copper is incorporated into lysyl oxidase. More effective means of treatment must be found to prevent the connective tissue abnormalities. A more effective means of treatment would also be beneficial for patients with OHS, for whom there is presently no available treatment.

0 0

Post a comment