タイトル厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

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厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

Inherited Cu Disorders Current Drug Metabolism, 2012, Vol. 13, No. 3 243Fig. (8). Connective tissue abnormalities in the patient with Menkes diseaseshown in Fig 7. Images on the left and right were taken just before treatmentand at 2 years of age (also during the treatment period), respectively. Bladderdiverticula formation (upper) and osteoporosis (lower) progressed despitetreatment. Arrows show bone fractures.acbdFig. (9). a) Skin laxity in a 18 year-old patient with occipital horn syndrome.b) MRA showing tortuosity of cerebral arteries (arrow). c-d) Occipitalhorns are shown in a skull X-ray (c) and MRI T1 WI (d) (arrows).Clinical features of OHS include mild muscle hypotonia andconnective tissue abnormalities, including exostosis on occipitalbones, bladder diverticula, and skin and joint laxity (Fig. 9). However,neurological abnormalities are milder compared to classicalMD, and include ataxia, dysarthria, mild hypotonia, and mild mentalretardation [40]. Clinical and biochemical heterogeneity hasbeen reported in siblings with the same missense mutation, suggestingthat clinical features depend not only on genetic, but also nongeneticmechanisms [58].4.4. DiagnosisDiagnosis is not difficult once clinical features, such as intractableseizures, connective tissue abnormalities, subdural hemorrhage,and hair abnormalities, appear. However, treatment withcopper-histidine once neurological symptoms appear is too late toprevent neurological disorders. Thus, early diagnosis and treatmentis critical for the neurological prognosis of MD. Hair abnormalitiesand episodes of temporary hypothermia may be clues for an earlydiagnosis, as these are typically observed prior to the appearance ofneurological symptoms. However, diagnosing MD before the age of2 months is difficult because hair abnormalities and temporary hypothermiaare also often observed in normal, premature babies. Incontrast to serum copper and ceruloplasmin levels, which are significantlylower, copper concentrations in cultured fibroblasts frompatients are significantly higher, and can help to provide a definitivediagnosis. Carrier and prenatal diagnosis can be made by mutationanalysis once a mutation has been identified in the patient’s family[41].Male patients with muscle hypotonia and skin laxity should besuspected of OHS. Such patients can be screened by a simple brainX-ray to identify exostoses on occipital bones. Because serum copperand ceruloplasmin can range from normal to low levels in patientswith OHS, diagnosis of OHS cannot be made solely on thebasis of serum levels of copper and ceruloplasmin. Like MD, copperconcentrations are high in cultured fibroblasts from patients,and thus are useful for diagnosing OHS [39,40]. A DNA-baseddiagnosis is also available for OHS [38,40].4.5. Mass ScreeningCopper-histidine therapy prior to neurological manifestationswould be more efficient if patients with MD could be identifiedthrough neonatal mass screening. Because serum copper and ceruloplasminare physiologically low in normal infants, measuringsuch parameters in patients with MD would not be a useful neonatalscreening method. We recently developed a screening method totest for MD based on the ratio of homovanillic acid to vanillylmandelicacid present in urine [59]. However, although a neonatal massscreening using blood samples has been performed worldwide totest for other genetic diseases, the same system using urine sampleshas yet to be implemented. Our method would be easily applicableif mass screening was performed using urine samples. Kaler et al.reported that the ratios of dopamine to norepinephrine and dihydroxphenylaceticacid to dihydroxyphenylglycol in the plasma canhelp with early diagnosis of MD, and that these neurochemicals canbe detected by high-throughput tandem mass spectrometry, a techniquewhich is currently used in neonatal mass screening of otherinherited diseases [60]. This test would need to be adapted for massscreening to apply it as a broad strategy with public health applications.4.6. TreatmentsThe current treatment strategy for MD is parenteral copper administration.Among the available copper components, copperhistidinehas been reported to be the most effective [61]. Copperhistidineinjection improves hair abnormalities (Fig. 5), copperconcentrations in liver, and serum levels of copper and ceruloplasmin.However, neurodegeneration progresses if copper-histidinetherapy is initiated after the onset of neurological symptoms. Onepossible explanation is that the administered copper accumulates atthe blood-brain barrier and is not transported to neurons [46]. Iftreatment is initiated neonatally and while the blood-brain barrier isstill immature, neurodegeneration can be prevented in some patients[61-64]. A recent study conducted on 24 patients with MD showedthat only 12.5% of patients treated with copper during early infancy(?6 weeks of age) retained clinical seizures. Moreover, five patients32