Homocystinuria

Japanese: ホモシスチン尿症

(2) Homocystinuria (Figure 13-3-11)
Definition/Concept This is an autosomal recessive genetic disease in which the intermediate metabolite homocystine is not converted to cystathionine in the metabolic pathway of methionine, but accumulates in large quantities in the body and is excreted in the urine. The detection rate is 1/176,000. There are no symptoms at birth, but from infancy onwards, it can cause developmental disorders, intellectual disabilities, decreased vision due to ectopia lentis, and glaucoma. Pathophysiology The majority of cases are caused by a deficiency of cystathionine β-synthase (CBS). The CBS gene locus is 21q22.3, with a total length of 30 kb and 23 exons, and more than 100 mutations have been identified to date. The increased homocysteine is converted to homocystine and excreted in the urine, and some is converted to methionine by methionine synthase (MS) and used in protein synthesis. In addition to the typical type caused by a deficiency of CBS, it can also be caused by a deficiency of MS or an abnormality in the metabolism of vitamin _B12 or folate as a coenzyme. Typical CBS deficiency causes lens dislocation, central nervous system disorders (intellectual disability, convulsions), systemic arterial and venous thrombosis, and skeletal abnormalities (Marfan syndrome-like habitus, osteoporosis). High levels of homocysteine in the blood cause vascular endothelial disorders, promoted proliferation of vascular smooth muscle, and increased platelet aggregation, and are attracting attention as a cause of lifestyle-related diseases such as arteriosclerosis. It is also known that serum homocysteine concentrations are high in general healthy people with thrombotic diseases.
Differential diagnosis: Neonatal mass screening reveals elevated blood methionine levels (1-2 mg/dL or more). Hypermethioninemia can be seen in patients with liver disease or when consuming a large amount of protein. To differentiate from other diseases that cause elevated methionine levels, plasma and urinary amino acid analysis is performed. Because homocysteine easily binds to plasma proteins, plasma amino acid analysis may not reveal elevated homocysteine levels even in patients with homostinuria. For a definitive diagnosis, total blood homocysteine, which includes homocysteine bound to protein, is measured. Treatment: A dietary therapy that restricts methionine and adds cystine to make up for the deficiency is continued for the patient's lifetime. To restrict methionine in infants, therapeutic methionine-free milk is used, but because methionine is an essential amino acid necessary for growth, the intake is controlled by switching to low-methionine milk or by using it in combination with regular infant milk. In addition, vitamin therapy may be used to lower blood homocysteine levels by combining vitamin _B6 , vitamin _B12 , and folic acid, which aid in the reduction of homocysteine to methionine. [Yutaka Nakaya]
■ References
Behrman RE eds: Nelson Textbook of Pediatirics, 17th ed, pp. 397-398, 2396-2427, Elsevier, 2006.
Saheki T, Kobayashi K, et al: Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis, 31: 386-394, 2006.

Figure 13-3-11
Sulfur-containing amino acid metabolism and homocystinuria ">

Figure 13-3-11

Homocystinuria (amino acid metabolism disorder)

(3) Homocystinuria
EtiologyHomocystinuria is an autosomal recessive genetic disorder of amino acid metabolism in which homocystine, a methionine metabolic product, accumulates in the blood and is excreted in large amounts in the urine [⇨Figure 13-3-11]. There are three types of homocystinuria: type I, type II, and type III. Type I is caused by a deficiency of cystathionine synthase (gene: long arm of chromosome 21), which converts homocystine to cystathionine. Type II is caused by a deficiency of 5-methyltetrahydrofolate-homocystine-methyltransferase, which remethylates homocystine to methionine. Type III is caused by a deficiency of methylenetetrahydrofolate reductase (gene: short arm of chromosome 1), which produces 5-methyltetrahydrofolate, which is necessary to remethylate homocystine to methionine [⇨13-3-4)].
Neurological type I is also known as the classical type, and is often discovered after the age of three due to lens subluxation. Intellectual disability is progressive and is seen in 70% of cases, psychiatric symptoms in more than 50%, and convulsions in 20%. There are skeletal abnormalities similar to Marfan syndrome, and thrombi and embolism occur in large and small blood vessels. Approximately 40% of cases respond to large doses of vitamin _B6 (vitamin _B6 responsive type).
Type II presents with vomiting, poor feeding, lethargy, hypotonia, developmental delay, megaloblastic anemia, etc. from a few months after birth. Type III presents with different severity of clinical symptoms depending on the level of enzyme deficiency. Patients with complete deficiency often experience apnea attacks and myoclonic convulsions in the neonatal period, leading to coma and death. Patients with partial deficiency progress chronically, and show intellectual disability, convulsions, microcephaly, hypertonia, and limb rigidity. [Tsunetoshi Aoki]
■ References
Behrman RE, Kliegman RM, et al eds: Nelson Textbook of Pediatrics, 19th ed, WB Saunders, Philadelphia, 2011.Scriber CR, Beaudt AL, et al eds: The Metabolic and Molecular Basis of Inherited Disease, 8th ed, McGraw-Hill, New York, 2001.

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

（2）ホモシスチン尿症（homocystinuria）（図13-3-11）
定義・概念
　メチオニンの代謝経路において，中間代謝産物のホモシスチンがシスタチオニンに変換されず，体内に多量に蓄積され尿中へ排出される常染色体劣性遺伝病である．発見率は1/176000である．出生時には無症状であるが，乳児期以降に発育障害，知的障害，水晶体偏位による視力低下・緑内障などを引き起こす．病態生理　シスタチオニンβ-シンターゼ（CBS）の欠損によるものが大部分を占める．CBSの遺伝子座は21q22.3で全長30kb，23エクソンからなり，現在では100種以上の変異が同定されている．増加したホモシステインはホモシスチンに変換され尿中に排泄され，また一部はメチオニン合成酵素（MS）によりメチオニンに変換されて，蛋白合成に用いられる．CBSの欠損による典型的なタイプ以外に，MSの欠損あるいは補酵素としてのビタミンB₁₂代謝異常，葉酸代謝異常によっても生じる．典型的なCBS欠損症は，水晶体脱臼，中枢神経系障害（知能障害，痙攣）全身の動静脈血栓症，骨格異常（Marfan症候群様体型，骨粗鬆症）を起こす．　血中ホモシステイン高値は，血管内皮障害，血管平滑筋増殖促進，血小板凝集亢進を起こし，動脈硬化などの生活習慣病の原因として注目されている．また，一般健常者の血栓性疾患においても，血清ホモシステイン濃度が高値であることが知られている．
鑑別診断
　新生児マススクリーニングでは血中メチオニンの上昇（1～2 mg/dL以上）として把握される．肝疾患や蛋白質を多くとったときに高メチオニン血症がみられる．ほかのメチオニンの上昇する疾患との鑑別には，血漿および尿中アミノ酸分析を行う．ホモシステインは血漿蛋白と容易に結合するため，血漿アミノ酸分析ではホモスチン尿症患者でもホモシステインの上昇を認めないこともある．確定診断のためには，蛋白に結合したホモシステインを含んだ血中総ホモシステインの測定を行う．治療　メチオニンを制限し，不足するシスチンを添加した食事療法を一生継続して行う．乳児ではメチオニンの制限のために治療用メチオニン除去ミルクを使用するが，メチオニンは成長に欠かせない必須アミノ酸であるため低メチオニンミルクに切り替えたり，通常の乳児用ミルクと併用したりして摂取量をコントロールする．また，ホモシステインをメチオニンへ還元する際の補助となるビタミンB₆やビタミンB₁₂，葉酸を併用して血中ホモシステイン濃度を下げるビタミン療法を行うこともある．［中屋　豊］
■文献
Behrman RE eds: Nelson Textbook of Pediatirics, 17th ed, pp. 397-398, 2396-2427, Elsevier, 2006.
Saheki T, Kobayashi K, et al: Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis, 31: 386-394, 2006．

図13-3-11
含硫アミノ酸代謝とホモシスチン尿症">

図13-3-11

ホモシスチン尿症(アミノ酸代謝異常)

（3）ホモシスチン尿症（homocystinuria）
病因
　ホモシスチン尿症は，メチオニン代謝産物であるホモシスチンが血中に蓄積し，尿中に大量に排泄される常染色体劣性遺伝性アミノ酸代謝異常症である【⇨図13-3-11】．本症には，Ⅰ型，Ⅱ型，Ⅲ型が知られ，Ⅰ型はホモシスチンをシスタチオニンに変換するシスタチオニン合成酵素（遺伝子：21番染色体長腕）欠損，Ⅱ型はホモシスチンをメチオニンに再メチル化する5-メチルテトラヒドロ葉酸-ホモシスチン-メチルトランスフェラーゼ欠損，Ⅲ型はホモシスチンをメチオニンに再メチル化するのに必要な5-メチルテトラヒドロ葉酸を生成するメチレンテトラヒドロ葉酸還元酵素（遺伝子：1番染色体短腕）欠損によるホモシスチン尿症がある【⇨13-3-4）】．
神経症状
　Ⅰ型は古典型ともいわれ，多くは3歳以後に，水晶体亜脱臼にて発見される．知的障害は進行性で70％にみられ，精神症状は50％以上，痙攣は20％に観察される．Marfan症候群様の骨格異常があり，大・小血管の血栓・塞栓が発生する．約40％は，ビタミンB₆大量投与が有効（ビタミンB₆反応型）である．
　Ⅱ型は，生後数カ月頃から嘔吐，哺乳不良，嗜眠，筋緊張低下，発達遅滞，巨赤芽球性貧血などを呈する．　Ⅲ型は，酵素欠損の程度により臨床症状の重症度に差がある．完全欠損例は，新生児期に無呼吸発作，ミオクローヌス痙攣があり，昏睡から死に至ることが多い．部分欠損例は，慢性的に経過し，知的障害，痙攣，小頭症，筋緊張亢進，四肢強直などをみる．［青木継稔］
■文献
Behrman RE, Kliegman RM, et al eds: Nelson Textbook of Pediatrics, 19th ed, WB Saunders, Philadelphia, 2011.Scriber CR, Beaudt AL, et al eds: The Metabolic and Molecular Basis of Inherited Disease, 8th ed, McGraw-Hill, New York, 2001.

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