Copper is an essential trace metal. Proteins exploit the unique redox nature of this metal to undertake a series of facile electron transfer reactions using copper as a cofactor in a select number of critical enzymatic pathway. The signs and symptoms of copper deficiency are the results of impaired function of these cuproenzymes.
Copper homeostasis is maintained entirely by gastrointestinal absorption and biliary excretion. Biliary copper is not absorbed from the gastrointestinal tract, so there is no enterohepatic circulation of this metal.
Wilson disease and Menkes disease are inherited metabolic disorders of copper transport. Each disease results from the absence or dysfunction of homologous copper-transporting ATPase present in the trans-Golgi networt of cells. The Wilson disease ATPase transports copper into the hepatocyte secretary pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, individuals with this autosomal recessive disease present with signs and symptoms arising from impaired biliary copper excretion.
The Menkes disease ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two disease, the respective ATPase function in precisely the same fashion within the cell. The unique clinical features of each disease are the results of the tissue specific expression of these ATPase.
Aceruloplasminemia is an autosomal recessive disease characterized by absent serum ceruloplasmin and progressive neurodegeneration of the basal ganglia in association with specific inherited mutation in the ceruloplasmin gene. Although the basal ganglia symptoms and a lack of serum ceruloplasmin may lead to diagnostic confusion with Wilson disease, magnetic resonance imaging reveals the presence of iron the basal ganglia.

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A case of Lesch-Nyhan's syndrome was presented, This male patient was diagnosed as cerebral palsy at his early infancy and admitted to our Severely Retarded Childrens Center at 9 years and 8 months of age, Not only the typical clinical signs of this syndrome, but also the deficiency of hypoxanthine guanine phosphoribosyl transferase in red cells were recognized. He died, however, at the age of 11 years and 9 months preceded by the unexpected, rapid and extreme elevation of serum uric acid value. The probable direct cause of death is considered to be uric acid nephropathy.

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Wilson病の概念が確立して40年後の1952年にセルロプラスミン欠損が発見された.以来40年間に進展した医療の変遷を日本に重点を置いて回顧した.診断面では, 早期診断が可能となり, GPT上昇が先行する肝病変やKayser-Fleischer輪の進展状況が明らかになるとともに, 多彩な初発症状で診断されるようになった.
治療面ではペニシラミン導入による発症予防の有効性が確立したが, 長期服薬による副作用, 断薬による肝不全や精神症状の発症が問題となり, トリエンの承認に至った.さらに予後を改善するには, マススクリーニングを含む早期診断の普及と, 長期の治療継続を確実なものにするための医師相互の緊密な連絡が不可欠であろう.

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症例は42歳男性．20歳頃より記銘力障害や軽度の人格障害が出現し，30歳頃より暴言，被害妄想を認め，統合失調症と診断され内服加療をされていた．2010年12月に原因不明の肝硬変及び肝機能障害を指摘され，非アルコール性脂肪性肝炎及び薬物性肝障害と診断された．治療を受けていたが2011年1月より歩行障害，転倒，動作緩慢を認め薬剤性パーキンソニズムが疑われ，肝硬変の精査とともに当院を受診した．Kayser-Fleischer角膜輪の存在，血清セルロプラスミン低値，尿中銅排泄量の増加，肝生検での肝硬変の所見と肝組織中銅含量増加ならびに頭部MRIにて大脳基底核の信号異常を認め，一連の精神，神経症状と合わせて肝神経型のウイルソン病と診断した．Trientine hydrochlorideと酢酸亜鉛の内服及びリハビリテーションの開始により，肝機能ならびにパーキンソニズムや精神症状は徐々に改善を認めている．

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症例1は13歳の男性．肝機能障害と溶血性貧血で発症．血清セルロプラスミン値の低下，尿中銅排泄量の増加，Kayser-Fleischer輪からWilson病と診断されD-ぺニシラミンを投与された．しかしビリルビンの上昇と意識障害が出現し，血漿交換療法を施行され改善した．症例2は15歳の女性．黄疸と溶血性貧血で発症．血清セルロプラスミン値の低下，尿中銅排泄量の増加，Kayser-Fleischer輪からWilson病と診断され，D-ぺニシラミンの投与と血漿交換療法を施行され一時改善．しかしD-ぺニシラミンから塩酸トリエンチンへの変更にともない再び溶血性貧血が出現し，再度血漿交換療法を施行され塩酸トリエンチンの増量にて改善が得られた，溶血発作・肝不全症状で発症し内科的治療が奏功したWilson病の2例を報告した．

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We reported a 33-year-old man with a severe neurologic type of Wilson's disease. Neurological examinations revealed apathy, dysphagia, rigidity, bradykinesia and loss of postural reflexes. He was treated with a low copper diet, a combination of trientine and zinc, and rehabilitation. However, no significant change in ADL was observed in the first 11 months of therapy. After that, improvement began and continued for a period of an additional 9 months. Ultimately, neurologic and psychiatric manifestations disappeared and the Barthel Index improved from 30 to 100. A long period was required until substantial improvement began and reached a plateau. The rehabilitation during the period prevented disuse, and then promoted the recovery of functions. On the initiation of therapy, it is difficult to estimate the onset time of recovery or ultimate state of functions. Therefore, it is important to maintain a positive attitude toward the disease during the long-term follow-up.

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1990～1991年に行ったWilson病患者全国実態調査によって集計された成績のうち, 特に神経型・肝神経型Wilson病患者のデータを中心に検討を行った. 発症年齢は, 11歳以降に多く認められたが, 6～10歳にても全症例の約20%を占めていた. 初発症状は, 構音障害が最も高率に認められ, 歩行障害, 羽ばたき振戦, Kayser-Fleischer角膜輪も高頻度にみられた. 6歳以降に構音障害や錐体外路症状を認めた場合には, 本症を疑い精査を行うことが必要であると考えられた. また, ともに生命予後は良好なものの, 療養所, 病院等にて加療中のものが高率に認められた. これは進行した神経障害の不可逆性によると思われ, 本症に対する早期診断・早期治療開始の重要性が認識された.

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新らしく開発されたCephalosporin系薬剤Cefoperazone (CPZ) は, すでに体内への吸収, 移行, 排泄, 安全性などについての基礎的検討を終え, 内科領域では成人に対する臨床効果についての検討がなされ, グラム陽性菌およびグラム陰性菌に対して広い抗菌スペクトラムをもち, 特にグラム陰性菌のPseudomonas aeruginosaなどに対しては, 多くのCephalosporin系薬剤めうちで最も強い抗菌力をもつと報告されている1)。
今回, 小児期感染症の患者に対して, 注射用Cephalosporin剤CPZを使用する機会を得たのでジその結果について報告する。

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　症例は9歳男児。腹痛，発熱と頭痛が出現し，トランスアミナーゼの高値を指摘され，精査目的で入院した。血清銅とセルロプラスミンの低値を認めたため，ウィルソン病を疑い，腹腔鏡下肝生検を施行した。肝表面は平滑で，色調は黄白色調であった。脾の腫大が認められた。肝の組織所見では，肝細胞の脂肪変性と核の空胞化，線維化が観察された。銅染色では陽性所見は認められなかった。本症例は初期ウィルソン病と診断した。

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Recently, deficiency of an enzyme participating in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT), has been demonstrated in children with cerebral dysfunction and hyperuricemia (Lesch-Nyhan syndrome). This study was performed to clarify the biochemical features of the syndrome, effects of allopurinol and benziodaron (Amplivix) on uric acid metabolism in the patients, and changes in activity of HGPRT during pre- and postnatal development.
Material and Methods:
Serum uric acid, urinary uric acid/creatinine ratio, and specific activity of urinary uric acid after intravenous administration of glycine-¹⁴C (U) were determined in 4 Lesch-Nyhan syndrome patients aged 1-6 years. The major symptoms were choreatic and ballistic movement, abnormal postural reflex and mild mental deficiency. Activity of HGPRT in erythrocytes were determined by a modified method of Seegmiller et al. using hypoxanthine-¹⁴C. HGPRT activity in various organs from a fetus, an autopsied infant and an adult control was also determined by the method.
Results:
1) Serum uric acid levels in the patients showed daily fluctuations and ranged from 5.80 to 11.40mg/dl with an average of 8.68±1.20.
2) Uric acid/creatinine ratio in a single urine sample from the patients was higher than 2.80 with an average of 3.35, and daily urinary uric acid excretion was more than 20mg/kg/day.(Fig. 1)
3) Specific activity of urinary uric acid after intravenous administration of glycine-¹⁴C, 2μc/kg, in the patients was ranged 0.64 to 1.69% (control: 0.008%).(Fig. 2)
4) Activity of HGPRT in erythrocytes of the patients was remarkably lower as compared with those of the control.(TABLE I)
5) By administration of allopurinol, 100mg per day, both the serum and urinary uric acid levels were decreased remarkably. Uric acid/creatinine ratio in the patients became lower than those of the control. After administration of Amplivix, 100mg to 150mg per day, the normal serum uric acid levels were obtained invariably in all the patients, while decrease in urinary excretion of uric acid was not remarkable.
By administration of allopurinol, a remarkable increase of xanthine-hypoxanthine fraction in the urine was observed. On the other hand, during the Amplivix treatment, increase of the fraction was not observed, which appeared to indicate that Amplivix showed an uricosuria in during action and inhibition of oxypurine production. In spite of the normal serum uric acid levels for several months during Amplivix treatment, a marked improvement in neurological symptoms was not obtained.(Fig. 3, 4)
6) HGPRT Activity was observed, although low, even in the organs of an embryo of 4 weeks.
In comparison with the activity in the brain and liver of an infant of 2 years, the activity of the organs of a fetus of 8 months as well as of an adult tended to be lower.(TABLE II)
Discussion and Conclusion:
Although the precise mechanism of neurological dysfunction in patients with Lesch-Nyhan syndrome are not known, enzyme deficiency in the brain might play an important role in the development of the extrapyramidal symptoms. Overproduction of uric acid through de novo purine synthesis was comfirmed by detecting hyperuricemia, increased urinary uric acid excretion and increased incorporation of isotopically labeled glycine into uric acid.
As to the cause of cerebral dysfunction, hyperuricemia does not appear to play a predominant role, while the significance of increased hypoxanthine is to be determined. Based on the experience concerning allopurinol and Amplivix treatment, a better effect of the latter on the neurological symptoms has been expected because Amplivix treatment did not result in accumulation of xanthine and hypoxanthine.

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5歳7カ月の男児. 乳幼児期からの頭囲拡大, 精神発達遅延, 肝機能障害を主訴に他院を受診し, 父親がWilson病患者であったことより, 同疾患を疑われたが, 確定診断には至らなかった. 顔貌よりムコ多糖症が疑われ, 当科を受診, 血清セルロプラスミン低値, 尿中銅排泄増加, 頭部MRIなどの諸検査, 尿中ムコ多糖分析, 酵素活性測定, 遺伝子解析を行った. その結果, Sanfilippo症候群B型とWilson病という原因遺伝子が異なる染色体上にある常染色体劣性遺伝の2つの代謝性疾患を合併していると診断した. 両親に血縁関係はないものと判断されたが, このような疾患の合併の報告は現在までになされておらず, 非常に稀な1男児例を経験したので報告する.

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症例は14歳, 女性. 平成13年10月頃より嘔吐, 右季肋部痛が出現. 同年12月3日黄疸, 肝腫大, 肝機能検査異常を認め近医入院. 血清セルロプラスミン低値, 尿中銅高値より Wilson 病と診断. 塩酸 Trientine 2500mg/日投与開始したが, 肝不全が進行するため平成14年1月7日当科紹介入院. 入院後も肝不全の改善みられず, 塩酸 Trientine による鉄芽球性貧血を併発したため生体肝移植を施行した. 術後経過良好であり貧血も改善した. Wilson 病に対する塩酸 Trientine 投与に際し, 鉄芽球性貧血は留意すべき合併症である.

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