疾患詳細

疾患詳細





#272800
Tay-Sachs disease (TSD)
(GM2-gangliosidosis, type I)
(B variant GM2 gangliosidosis)
(Hexosaminidase A deficiency)
(HEXA deficiency)
(Tay-Sachs disease, juvenile, included)
(Hexosaminidase A deficiency, adult type, included)
(GM2-gangliosidosis, adult chronic type, included)
(Tay-Sachs disease, variant B1, included)
(Tay-Sachs disease, pseudo-AB variant, included)

Tay-Sachs 病 (TSD)
(GM2-ガングリオシドーシス I 型)
(B バリアント GM2 ガングリオシドーシス)
(ヘキソサミニダーゼ A 欠損症)
(ヘキソサミニダーゼ A 欠損症, 成人型)
(GM2-ガングリオシドーシス, 成人慢性型)
(Tay-Sachs 病, バリアントB1)
(Tay-Sachs 病, 偽ABバリアント)
(Tay-Sachs 病, 若年性)
(Tay-Sachs 病, 成人型)
指定難病19 ライソゾーム病
小児慢性特定疾病 代86 GM2-ガングリオシドーシス

責任遺伝子:606869 HEXA (hexosaminidase A) <15q23>
遺伝形式:常染色体優性

(症状)
(GARD)
<80%-99%>
 Ataxia (運動失調) [HP:0001251] [028]
 Blindness (盲) [HP:0000618] [06011]
 Cherry red spot of the macula (チェリーレッド斑) [HP:0010729] [0650]
 Developmental regression (発達退行) [HP:0002376] [0125]
 EEG abnormality (脳波異常) [HP:0002353] [01405]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hemiplegia/hemiparesis (片麻痺/片不全麻痺) [HP:0004374] [026131]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Increased muscle lipid content (筋脂質量増加) [HP:0009058]
 Intellectual disability, progressive (進行性知的障害) [HP:0006887] [0120]
 Macrocephaly (大頭) [HP:0000256] [03012]
 Psychomotor deterioration (精神運動発達退行) [HP:0002361] [0125]
 Seizures (けいれん) [HP:0001250] [01405]
<30%-79%>
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Myotonia (筋緊張症, ミオトニア) [HP:0002486] [0279]
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Spasticity (痙縮) [HP:0001257] [0241]
 Splenomegaly (脾腫) [HP:0001744] [01817]

 Apathy (無気力) [HP:0000741] [0403]
 Aspiration (誤嚥) [HP:0002835] [01601]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Dementia (認知症) [HP:0000726] [0123]
 Exaggerated startle response (過剰な驚愕反応) [HP:0002267] [0216]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 GM2-ganglioside accumulation (GM2 ガングリオシド蓄積) [HP:0003495]
 Hypertonia (筋緊張亢進) [HP:0001276] [0241]
 Infantile onset (乳児期発症) [HP:0003593]
 Pallor (蒼白) [HP:0000980] [01406]
 Poor head control (頭部コントロール不全) [HP:0002421] [0242]

(UR-DBMS)
【一般】誤嚥 (肺炎)
 精神運動退行
 けいれん
 認知症
 *早期死亡 ( (5歳までに)
 *発達遅滞 (6か月以内)
【神経】*驚愕反応増加
 *筋緊張低下→後に筋緊張亢進
 頸坐不能
 感情鈍麻
 運動失調
 除皮質強直
 視覚不注意
 外部からの刺激に反応しない
 植物状態
【頭】巨脳
【眼】*黄斑蒼白 + 目立つ中心窩 (チェリー・レッド斑)
 盲 (乳児期後半)
【胸郭】ベル型胸郭
【骨盤】骨盤低形成
【四肢】短肢小人症
【X線】短い肋骨
 橈骨頭脱臼
 長い遠位腓骨
【検査】Gm2-ganglioside の蓄積
 膨れたニューロン
 Hexosaminidase A 欠損 (血清, 組織)
【その他】乳児期発症
 通常は5歳までに致死
 ユダヤ人では1/3,900 出生児
 非ユダヤ人では1/320,000 出生児

(要約) Hexosaminidase A 欠乏症
(HEX A 欠乏症; GM2 ガングリオシドーシス)
●Hexosaminidase A 欠乏症は, 特異的 glycosphingolipid である GM2 ganglioside のリソソーム内蓄積が原因の神経変性疾患のグループを生じる
 表現型は, Tay-Sachs 病 (急性乳児バリアント) である
 Tay-Sachs 病は, 3-6か月令から始まる, 進行性筋力低下, 運動能喪失, 注意力減少, 驚愕反応の増加が特徴で, 神経変性の進行性の証拠を伴う
 →けいれん, 盲, 痙性, 最終的な無力, 死亡 (通常は4歳以前)
○若年 (亜急性), 慢性, および成人発症バリアントは, 後年発症, 緩徐進行性かつより多様な神経学的所見をもつ
 →進行性ジストニア, 脊髄小脳変性, 運動ニューロン病, 一部の成人発症では双極精神病
●診断:血清または白血球でのbeta-hexosaminidase A (HEX A) 酵素活性の欠損またはほぼ欠損を証明すること (beta-hexosaminidase B (HEX B) isoenzyme は正常または上昇)
 HEXA 検査:HEX A の明らかな酵素活性欠乏をもつ健康人で疾患原因変異から偽欠乏アレルを区別するため必要
●遺伝:常染色体劣性
●臨床診断 (Tay-Sachs 病)
 3-6か月令から始まる進行性筋力低下と運動能喪失
 注意力減少 (視覚)
 驚愕反応の増加 (鋭い音へ)
 黄斑の中心窩のチェリーレッド斑
 正常サイズの肝脾
 全身性筋緊張低下と足クローヌスと反射亢進
 →続いて進行性神経変性, 頭囲拡大(水頭症ではない), けいれん, 盲および痙性が続き, 4歳以前に死亡する
(若年性)
 2-10歳に運動失調と協調運動障害で始まる
 発語, 生活能力, 認知能が低下する
 10歳後半までに痙性とけいれんがみられる
 視力喪失は遅く生じ, チェリーレッド斑は一定していない (後半に視神経萎縮と色素性網膜炎がみられる)
 15歳までに除脳拘縮を伴う植物状態となり, 2-3年以内に死亡する
(慢性および成人発症)
 20~30歳代で, 筋力低下~錐体外路症状 (ジストニア, 舞踏病様アテトーゼ, 運動失調)~小脳症状 (構音障害, 運動失調, 協調運動障害, 異常な姿勢) で始まる
 精神運動退行はより目立たない
 発症は早期小児期から10歳代末である
 脊髄小脳変性症, Friedreich 失調または ALSを疑わせる
 40%は精神症状をもつ:うつ, 双極障害, 破瓜病, 扇動, 妄想, 幻覚, パラノイア
●Beta-hexosaminidase A (HEX A) 酵素活性
 TSD: 0%-5%
 若年型または成人型:<15%
※HEX A は1つのαサブユニットと2つのβサブユニットからなる
 HEX B は2つのβサブユニットのホモダイマーである
●保因者検出:HEX A 酵素活性アッセーによる (血清または白血球)
 血清:全ての男性と妊娠していない/経口避妊薬を服用していない女性
 白血球:妊婦, 経口避妊薬を服用している女性, 血清で判定不明の人
●HEXA 遺伝子検査
 3つのヌルアレル(p.Tyr427IlefsTer5, c.1421+1G>C, c.1073+G>A) ホモか複合ヘテロ
 p.Gly269Ser アレル→成人発症型で
 pseudodeficiency アレル (p.Arg247Trp と p.Arg249Trp)→神経疾患とは連関しないが, HEX A活性測定で合成基質の分解が低下
 HEX A酵素活性でヘテロ接合として証明された非ユダヤ人の35%が pseudodeficiency アレル保因者である
 HEX A酵素活性でヘテロ接合として証明されたユダヤ人の2%が pseudodeficiency アレル保因者である
 ケベックではHEXA promoter と exon 1 を含む 7.6kb ゲノム欠失が最も多い TSD 連関アレルである
○シークェンシング解析:130以上の0 HEXA 変異が検出されている
 →90以上はTSDで
・B1バリアント→若年慢性型 p.Arg178Hisが最多→ポルトガル人で
 ヌル+B1バリアント→若年型
 B1バリアントのホモ→軽症慢性型
・成人型
 p.Gly269Ser → Ashkenazi ユダヤ人
 p.Gly250Asp →αサブユニットの exon 7
●頻度:一般集団では1/300が保因者 (アイルランド系米国人 1/50が保因者)
 1:3600 Ashkenazi ユダヤ人生産児 (保因者 1:30)
 最近の調査 Ashkenazi ユダヤ人保因者 1:27.4 (エクソン11の1278insTATC 挿入変異(c.1274_1277dupTATC))→80%を占める
 Sephardic ユダヤ人や非ユダヤ人では疾患頻度は100倍低く, 保因者率は10倍低い 1:250 〜 1:300
・その他の隔離集団
 フランス系カナダ人 (ケベック州東部 St. Lawrence River Valley 地域)→17世紀起源
 ルイジアナの Cajuns (変異はユダヤと同じ;18世紀のフランスに住む創始者夫婦 (ユダヤ人かどうかは不明))
 ペンシルベニアの Old Order Amish
● Ashkenazi ユダヤ人で TSDが多い理由の仮説
1)Heterozygote advantage
 特定の環境に対して選択的有利性をもつ
2)Reproductive compensation
 病気で子供を失った両親は他の子供をもつことで代償しようとする
 →劣性疾患頻度を増加させる
3)Founder effect
 1278insTATC 変異の高頻度はランダム遺伝子浮動の結果である

<小児慢性特定疾病 代86 GM2-ガングリオシドーシス>
概要・定義
GM2-ガングリオシドーシスは、β-ヘキソサミニダーゼAの欠損により発症するテイ・サックス病、β-ヘキソサミニダーゼAとB 両方の欠損により発症するサンドホフ病、GM2活性化蛋白の欠損により発症するGM2ガングリオシド活性化蛋白質欠損症があり、常染色体劣性遺伝形式を示す遺伝病である。脳を中心にGM2ガングリオシドなどの糖脂質が蓄積する。発症頻度はテイ・サックス病、サンドホフ病が1/30万人とされ、GM2ガングリオシド活性化蛋白質欠損症はきわめてまれである。発症時期と臨床経過により、乳児型、若年型、成人型に分類される。乳児型は生後6~7ヶ月までに発達の遅れが見られ、筋緊張低下、音に対する過敏症、眼底のチェリーレッドスポットを認める。肝脾腫、骨異常はほとんどない。若年型は2~10歳頃に発症し、臨床症状は乳児型に類似するが、やや軽度である。成人型は、発達は正常で20~30歳で発症する。歩行障害、構音障害が初期症状として多く、ジストニアなどの錐体外路症状を呈する。
疫学
日本でのテイ・サックス病の罹患率は8万~10万人に1人と考えられている。サンドホフ病は約30万人に1人とされ、GM2ガングリオシド活性化蛋白質欠損症はきわめてまれである。
病因
中枢神経に多いGM2ガングリオシドなどを分解するβ-ヘキソサミニダーゼA、BまたはGM2ガングリオシド活性化蛋白質欠損により発症する。これらに関係する遺伝子はHEXA、HEXB、GM2Aの3種類があり、HEXAの変異によりテイ・サックス病、HEXBの変異によりサンドホフ病、GM2Aの変異によりGM2ガングリオシド活性化蛋白質欠損症が発症する。
症状
テイ・サックス病、サンドホフ病、GM2ガングリオシド活性化蛋白質欠損症を臨床症状で区別するのは困難である。発症年齢により乳児型、若年型、成人遅発型に分類できる。
乳児型は3ヶ月ころまでの発達は正常な場合が多いが、その後精神運動発達遅滞や退行が見られる。眼底のチェリー・レッドスポットは特徴的である。けいれん、視覚や聴覚の障害、嚥下困難などが出現する。
若年型は比較的稀である。2歳~10歳で発症する。進行性の運動失調と協調運動障害の症状が発症し、けいれんも伴い退行が見られる。
成人遅発型は稀で、症状や経過は様々である。チェリー・レッドスポットは認めないことも多い。構音障害、ジストニア、運動失調、アテトーゼなどの錐体外路症状、精神障害など様々な症状を呈する。知的障害は軽度である。
診断
末梢リンパ球、皮膚線維芽細胞のヘキソサミニダーゼAおよびBの活性測定が有用。テイ・サックス病ではヘキソサミニダーゼAのみが、サンドホッフ病ではヘキソサミニダーゼAおよびBが欠損している。症状などから本症が疑われヘキソサミニダーゼAおよびBの活性測定が正常範囲の場合にGM2ガングリオシド活性化蛋白質欠損症を疑い、皮膚線維芽細胞を用いた特殊検査が必要となる。また、遺伝子診断としてはHEXA、HEXB、GM2Aなどの遺伝子変異を検出する。日本人テイ・サックス病では、IVS5,-1G>Tのスプライス異常が多い。
診断方法
1. 乳児型では、音に対する過敏性や眼底のチェリーレッドスポットなどが特徴的な徴候である。成人型はジストニアなどの進行性の錐体外路症状と脊椎変形が主な症状となる。
2. 酵素活性測定と遺伝子診断を行って診断を確定する。
3. 酵素活性測定では、末梢血リンパ球または培養皮膚線維芽細胞を用いてβ-ヘキソサミニダーゼA、Bの活性を測定する。
4. 遺伝カウンセリングなどの情報として、遺伝子診断は有用である。しかし、酵素活性から診断が確実となった患者でも、遺伝子診断では変異が見つからない場合がある。
当該事業における対象基準
全A  疾患名に該当する場合

治療
現段階では対症療法に限られる。マラリア治療薬であるピリメサミンがシャペロンとして有効との報告があるが、臨床応用はなされていない。
予後
乳児型の患者さんは、3歳までに亡くなることが多い。若年型は、10~15歳くらいで植物状態になり亡くなることが多い。
成人型は錐体外路症状、精神障害などで生活が困難となる。
成人期以降
成人型は臨床症状や経過が様々であり、脊髓小脳変性症などとの鑑別に注意する

(責任遺伝子) *606869 HEXA (hexosaminidase A) <15q23>
(1) Tay-Sachs disease (272800); GM2-gangliosidosis, adult onset (272800); GM2-gangliosidosis, juvenile (272800); GM2-gangliosidosis, chronic (272800); GM2-gangliosidosis, late onset (272800)
.0001 Tay-Sachs disease [HEXA, 4-BP INS, 1278TATC [dbSNP:rs387906309] (RCV000224443...) (Myerowitz and Costigan 1988; Triggs-Raine and Gravel 1990; Nishimoto et al. 1991; McDowell et al. 1992; Zlotogora 1993; Thurmon 1993; Frisch et al. 2004)
.0002 Tay-Sachs disease [HEXA, IVS12, G-C, +1 [dbSNP:rs147324677] (ExAC:rs147324677) (RCV000004094...) (Arpaia et al. 1988; Ohno and Suzuki 1988; Myerowitz 1988; McDowell et al. 1989; Strasberg et al. 1997)
.0003 Tay-Sachs disease [HEXA, 7.6-KB DEL, EX1] (RCV000004095) (Myerowitz and Hogikyan 1986; Keats et al. 1987; Myerowitz and Hogikyan 1987; Hechtman et al. 1990; De Braekeleer et al. 1992)
.0004 Tay-Sachs disease [HEXA, GLU482LYS] (dbSNP:rs121907952) (RCV000004096) (Nakano et al.1988; Akalinet al. 1992; Ohno et al. 2008)
.0005 Tay-Sachs disease [HEXA, 1-BP DEL, C1510, FS] (dbSNP:rs797044433) (RCV000004098) (Zokaeem et al. 1987; Lau and Neufeld1989)
.0006 Tay-Sachs disease, B1 variant [HEXA, ARG178HIS] (dbSNP:rs28941770) (HEXA, DN allele) (dbSNP:rs28941770) (ExAC:rs28941770) (RCV000004100...) (Ohno and Suzuki 1988; Tanaka et al. 1988; Goebel et al. 1989; dos Santos et al. 1991; Whitley et al. 1992)
.0007 Tay-Sachs disease, B1 variant [HEXA, ARG178CYS] (dbSNP:rs121907953) (HEXA, Czechoslovakian allele) (dbSNP:rs121907953) (ExAC:rs121907953) (RCV000004102...) (Tanaka et al. 1990)
.0008 GM2-gangliosidosis, adult onset [HEXA, GLY269SER] (dbSNP:rs121907954) (ExAC:rs121907954) (RCV000168285...) (Navon and Proia 1989; Paw et al. 1989; Navon et al. 1990; Kappler et al. 1990; Proia et al. 1990; Brownand Mahuran 1993; Ohno et al. 2008)
.0009 GM2-gangliosidosis, juvenile [HEXA, ARG504HIS] (dbSNP:rs121907955) (RCV000004099...) (Paw etal. 1990; Boustany etal. 1991)
.0010 GM2-gangliosidosis, juvenile [HEXA, ARG499HIS] (dbSNP:rs121907956) (ExAC:rs121907956) (RCV000210735...) (Paw et al. 1990)
.0011 Tay-Sachs disease [HEXA, ARG170GLN] (dbSNP:rs121907957) (RCV000004106...) (Nakano et al. 1990)
.0012 Tay-Sachs disease [HEXA, TRP420CYS] (dbSNP:rs121907958) (ExAC:rs121907958) (RCV000004107) (Tanaka et al. 1990)
.0013 Tay-Sachs disease, juvenile [HEXA, GLY250ASP] (dbSNP:rs121907959) (RCV000004108) (Trop et al. 1990)
.0014 Tay-Sachs disease [HEXA, PHE304DEL] (dbSNP:rs121907960) (ExAC:rs121907960) (RCV000169148) (Navon and Proia 1991)
.0015 GM2-gangliosidosis, chronic [HEXA, ARG504CYS] (dbSNP:rs28942071) (ExAC:rs28942071) (RCV000169084...) (Paw et al. 1991; Akli et al. 1991
.0016 Tay-Sachs disease [HEXA, IVS4AS, G-T, -1] (RCV000004113) (Mules et al. 1991)
.0017 Tay-Sachs disease [HEXA, SER210PHE] (dbSNP:rs121907961) (RCV000004114) (Akli et al. 1991)
.0019 Tay-Sachs disease [HEXA, ARG137TER] (dbSNP:rs121907962) (ExAC:rs121907962) (RCV000255817...) (Akli et al. 1991; Mules et al. 1992)
.0020 Tay-Sachs disease [HEXA, ARG393TER] (dbSNP:rs121907963) (RCV000004111) (Akli et al. 1991)
.0021 Tay-Sachs disease [HEXA, 5-BP DEL, TCTCC, IVS9] (RCV000004115) (Triggs-Raine et al. 1991)
.0022 Tay-Sachs disease [HEXA, 2-BP DEL, TG, EX5] (RCV000004116) (Triggs-Raine et al. 1991)
.0023 Tay-Sachs disease [HEXA, TRP26TER] (dbSNP:rs121907964) (RCV000004117) (Triggs-Raine et al. 1991; Drucker and Navon 1993)
.0024 Tay-Sachs disease [HEXA, ARG178LEU] (dbSNP:rs28941770) (ExAC:rs28941770) (RCV000004118) (Triggs-Raine et al. 1991)
.0025 Tay-Sachs disease [HEXA, IVS2DS, G-C, +1] (RCV000004097) (Triggs-Raine et al. 1991)
.0026 Tay-Sachs disease [HEXA, IVS2DS, G-A, +1] (RCV000004119) (Akli et al. 1991; Mules et al. 1992)
.0027 Tay-Sachs disease, classic [HEXA, MET1VAL] (dbSNP:rs121907965) (ExAC:rs121907965) (RCV000004120) (Mules et al. 1992)
.0028 GM2-gangliosidosis, adult onset [HEXA, ARG499CYS] (dbSNP:rs121907966) (RCV000169417...) (Mules et al. 1992; Akli et al. 1993)
.0029 GM2-gangliosidosis, B1 variant [HEXA, TRP329TER] (dbSNP:rs121907967) (RCV000004122) (Mules et al.1992)
.0030 Tay-Sachs disease [HEXA, TRP485ARG] (dbSNP:rs121907968) (RCV000004123) (Akalin et al. 1992)
.0031 Tay-Sachs disease [HEXA, 1-BP INS] (RCV000004124) (Akalin et al. 1992)
.0032 Tay-Sachs disease [HEXA, TYR180TER] (dbSNP:rs121907969) (RCV000004125) (Drucker et al. 1992)
.0033 Tay-Sachs disease, classic [HEXA, IVS9, G-A, +1 [dbSNP:rs76173977] (RCV000079047...) (Akli et al. 1991; McDowell et al. 1992; Akerman et al. 1992; Triggs-Raine et al. 1992; Akli et al. 1993; Landels et al. 1993)
.0034 Tay-Sachs disease, B1 variant [HEXA, GGA DEL, CODON 320 OR CODON 321] (RCV000004127) (Mules et al. 1992)
.0035 Beta-hexosaminidase A, pseudodeficiency of [HEXA, ARG247TRP] (dbSNP:rs121907970) (ExAC:rs121907970) (RCV000004128...) (Triggs-Raine et al. 1992; Tomczak et al. 1993)
.0036 Tay-Sachs disease, B1 variant [HEXA, VAL192LEU AND VAL200MET] (dbSNP:rs1800429) (ExAC:rs1800429) (RCV000004129) (Ainsworth and Coulter-Mackie 1992; Coulter-Mackie 1994)
.0038 Tay-Sachs disease, B1 variant [HEXA, ASP258HIS] (dbSNP:rs121907971) (RCV000004130) (Fernandes et al. 1992)
.0039 Tay-Sachs disease [HEXA, ARG170TRP] (dbSNP:rs121907972) (ExAC:rs121907972) (RCV000004131) (Fernandes et al. 1992; Akli et al. 1993)
.0040 Tay-Sachs disease [HEXA, 2-BP DEL, CODON 310, FS] (RCV000004132) (Fernandes et al. 1992)
.0041 GM2-gangliosidosis, late onset [HEXA, LYS197THR] (dbSNP:rs121907973) (ExAC:rs121907973) (RCV000004133) (Akli et al. 1993)
.0042 Tay-Sachs disease, juvenile/adult [HEXA, IVS6, +1 [dbSNP:rs387906311] (RCV000432194...) (Akli et al. 1993)
.0043 Tay-Sachs disease [HEXA, PHE211SER] (dbSNP:rs121907974) (RCV000004135) (Akli et al. 1993)
.0044 Tay-Sachs disease [HEXA, LEU127ARG] (dbSNP:rs121907975) (RCV000004136) (Akli et al. 1993)
.0045 Tay-Sachs disease [HEXA, HIS204ARG] (dbSNP:rs121907976) (RCV000004137) (Akli et al. 1993)
.0046 Tay-Sachs disease [HEXA, 2-BP DEL, TT, CODON 142, FS] (RCV000004138) (Akli et al. 1993)
.0047 Tay-Sachs disease [HEXA, MET301ARG] (dbSNP:rs121907977) (ExAC:rs121907977) (RCV000004139) (Akli et al. 1993)
.0048 Tay-Sachs disease [HEXA, GLY454SER] (dbSNP:rs121907978) (RCV000004140) (Fernandes et al. 1992; Akli et al. 1993)
.0049 Tay-Sachs disease [HEXA, LEU39ARG] (dbSNP:rs121907979) (RCV000004141) (Akli et al. 1993)
.0050 Tay-Sachs disease [HEXA, TRP392TER [dbSNP:rs267606862] (RCV000004142) (Shore et al. 1992)
.0051 Tay-Sachs disease [HEXA, IVS7DS, G-A, +1] (RCV000004143) (Hechtman et al. 1992)
.0052 GM2-gangliosidosis, late onset [HEXA, GLY805ALA] (dbSNP:rs121907980) (RCV000004144...) (Hechtman et al. 1992)
.0053 GM2-gangliosidosis, late onset [HEXA, TYR180HIS] (dbSNP:rs28941771) (RCV000004145) (De Gasperi et al. 1996)
.0054 GM2-gangliosidosis, chronic [HEXA, IVS7AS, G-A, -7] (dbSNP:rs770932296) (RCV000004146...) (Fernandes et al. 1997)
.0055 GM2-gangliosidosis, subacute [HEXA, TRP474CYS] (dbSNP:rs121907981) (ExAC:rs121907981) (RCV000004147) (Petroulakis et al. 1998)
.0056 Tay-Sachs disease [HEXA, LEU451VAL] (dbSNP:rs28940871) (RCV000004148) (Karpati et al. 2004)
.0057 GM2-gangliosidosis, subacute (272800) [HEXA, VAL324VAL] (dbSNP:rs28942072) (RCV000004149) (Wicklow et al. 2004)
.0058 Tay-Sachs disease, mild [HEXA, CYS58TYR [dbSNP:rs387906949] (RCV000023580) (Najmabadi et al. 2011)

(ノート)
●(#) は, Tay-Sachs 病は 15q23 の hexosaminidase A 遺伝子 (HEXA; 606869)のαサブユニットのホモ接合または複合ヘテロ接合変異が原因なため

●Tay-Sachs 病は, 常染色体劣性の, 進行性神経変性疾患で, 古典的乳児型では, 通常2,3 歳までに致死的である

臨床症状
●古典的 Tay-Sachs 病は, 発達遅滞の乳児期発症が特徴で, 麻痺, 認知症および盲が続き, 1ないし2歳までに死亡する
 脂質を帯びた神経節細胞による網膜中心窩周囲の灰白色領域は, 中心の 'cherry-red' 斑を残し, 典型的な眼底鏡所見である
 病理的証明は, 中枢神経系の典型的に膨らんだニューロン所見により提供される
 音に対する早期の持続性反応 (驚愕反応) は, 本疾患を認知するのに有用である

●Kolodny (1972)は, Okada ら(1971)が記載した発端者を調べた
 視力は保持され, 視神経萎縮は20か月時に存在しなかったと述べた
 32か月での死亡時, 中枢神経系の光顕所見は, Tay-Sachs 病に類似していた
 患者は, 通常 Tay-Sachs 病のヘテロ接合体を証明する試験が正常であった

Suzuki et al. (1970) and O'Brien (1972) reported non-Jewish patients with the Tay-Sachs variant of juvenile-onset GM2-gangiosidosis. Onset occurred with ataxia between ages 2 and 6 years. Thereafter deterioration to decerebrate rigidity took place. Blindness occurred late in the course in only some patients, unlike the situation in classic Tay-Sachs disease in which blindness is an invariable and early development. Death occurred between ages 5 and 15 years. The defect is a partial deficiency of hexosaminidase A.

●Rapin ら(1976)は, 早期小児期で始まる歩行と姿勢の緩徐進行性悪化, 遠位に始まる筋萎縮, 凹足, 垂足, 軽度の四肢と体幹失調, ジストニア, および構音障害をもつ, Ashkenazi の同胞3例 (男1女2) を記載した
 知能はほとんど以上なく, 視力と視神経は正常で, けいれんは生じなかった
 姉妹1例は, 薬物反応に続いて16歳で死亡した
 剖検は, シマウマ小体を伴うびまん性のニューロン蓄積とGM2-ganglioside の増加を示した
 Hexosaminidase A は2例の生存患者の血清と白血球で減少していた
  彼らの両親は Tay-Sachs 病の保因者の範囲であった
 2例の生存同胞は, 報告時31歳と34歳であった
 この疾患は Tay-Sachs 病のアレリック変種かもしれない
●Kaback ら(1978) は, 似ているが, 別の可能性のある症例を記載した
 Ashkenazi 夫婦の息子は, 16歳までは完全に正常であった
  16歳時軽度の下肢の筋けいれんが始まった
 Hex-A 欠損が, 20歳時スクリーニングで発見された
 両親と姉妹1例はヘテロ接合体であった
 ヘテロカリオン相補試験は, 発端者の細胞が Sandhoff 細胞と癒合された時 Hex-A の発生を示したが, Tay-Sachs 細胞とは相補しなかった
 20-22歳の間で, 患者は劇的に進行性の近位筋消耗, 衰弱, 攣縮, 筋電図異常および CK 上昇を示した
 眼科的, 耳鼻科的および知能機能は, 正常に維持した
 筋生検は, 前角病を示唆した
 直腸神経節細胞は, バルーニングとタマネギ様細胞質小体を示した

●Willner ら(1981) は, バリアント型のHex-A 欠損症をもつ4つの関連のない Ashkenazi ユダヤ人家系9例を報告した
 非典型的 Friedreich 失調症に似ていた
 彼らは, 患者はTay-Sachs アレルと, もう一つの独特のアレルの遺伝的複合かもしれないと提唱した

●Johnson ら(1982) は, 進行性下肢衰弱と攣縮の9年間の既往歴をもつ24歳の Ashkenazi 男性を記載した
 他のデータは, 前角細胞病に一致した
 Hex-A は, 患者で著明に減少し, 両親と兄弟1人で部分的に減少していた
 父方親戚の1人は, 古典的 Tay-Sachs 病をもっていた
 著者らは, Kugelberg-Welander 表現型を示唆する臨床像が, 古典的アレルと軽症アレルの遺伝的複合のため生じたと示唆した

●Griffin (1984) は, hexosaminidase 欠損症と著明な小脳萎縮, 認知症, および脱神経性運動ニューロン病をもつ, 31歳の患者をもった
 両親は部分的欠損症を示した
●Mitsumoto ら(1985) は, 関連のない2家系3例で, hexosaminidase A 欠損症の成人バリアントを記載した
 最初の家系の30歳の非ユダヤ人の発端者は, 16歳で始まった若年性筋萎縮性側索硬化症をもち, 軽度の認知症, 運動失調, および軸索性 (ニューロン性) 運動感覚末梢神経ニューロパチーへ進化した
 健康と思われた32歳の兄弟は, 大学で記憶障害をもっていたが, 8年間で2つの学位をとり, 電気会社で働いた
 彼は, 記憶と理解力の障害のため会社を解雇された
 彼は, 軽度の痙性と運動失調を示したが, 運動ニューロン疾患の証拠はなかった
 2番目の家系では, Ashkenazi の母とシリアのSephardic 父をもつ36歳の男性が, 純粋な脊髄性筋萎縮をもっていた
  彼は, 走れない, または, 投げれないなど, 生涯をとおして身体障害をもっていた
 3例全員が, 著明な小脳萎縮をもっていた
 人工的基質では, Hex-A 活性は Tay-Sachs 病ホモ接合体の範囲内であったが, GM2 基質を使った時は高かった
 患者での Hex-A 活性は, ヘテロ接合体の範囲であった

●Parnes ら(1985)が記載した34歳の英国系カナダ人では, 臨床像は, 若年発症脊髄性筋萎縮のものであった
 非典型的特徴は, 目立つ筋けいれん, 姿勢および動作性振戦, 反復性精神病, 共同運動失調, 皮質脊髄および皮質球病変, および構音障害であった
●Oates ら(1986) は, ジストニア, 認知症, 筋萎縮, 舞踏病様アテトーゼおよび運動失調をもつ24歳の非ユダヤ人男性を報告した
 Hex-A 欠損症のおそらくアレリック型が, 通常でない臨床型をもつと強調した

●Navon ら(1986) は, イスラエルで, 1985年末までに18例の Hex-A-欠損症成人を発見した
 全員が Ashkenazi であった
 臨床像は, 家系間および家系内で差異があった
 脊髄小脳のいろんな運動ニューロンと小脳症状を含んでいた
 患者の多くが, TSD アレルともう一つの希なアレルの複合ヘテロ接合体である可能性がある
 Ashkenazim での非典型的成人疾患の比較的高い頻度は, 遺伝的複合を生じる TSD アレルの比較的高い頻度の結果である

Grebner et al. (1986) studied 3 clinically normal persons, aged 6 to 30 years, with absent serum Hex-A activity against artificial substrates and concluded that they were probably genetic compounds of the usual Tay-Sachs allele and a different mutant allele that in combination with it gave the abnormal phenotype. Karni et al. (1988) described a 39-year-old Israeli woman with proximal lower limb weakness and fasciculations as the only manifestations of Hex-A deficiency.

Bayleran et al. (1987) characterized the defective enzyme in 2 patients with Tay-Sachs disease and a high residual Hex-A activity. Clinical presentation was identical to that found among Ashkenazi patients. Both patients appeared to be heterozygous for the B1 phenotype, having virtually no capacity for hydrolysis of the sulfated HEXA substrate 4-methylumbelliferyl-beta-D-N-acetylglucosamine-6-sulfate (4MUGS).

Barnes et al. (1991) described a 42-year-old man of non-Jewish ancestry who in his 20s and 30s had the onset of slowly progressive gait disturbance, generalized weakness, dysarthria, clumsiness and tremor of his hands, and involuntary jerks. Two previously unreported features were clinically evident sensory neuropathy and internuclear ophthalmoplegia.

Perlman (2002) commented on late-onset Tay-Sachs disease as a Friedreich ataxia phenocopy.

Rucker et al. (2004) evaluated eye movements in 14 patients with late-onset Tay-Sachs disease (average age, 39 years). The main clinical features included childhood clumsiness or incoordination, proximal muscle weakness, ataxia, dysarthria, and tremor. All patients had normal visual function and normal optic fundi without cherry red spots. Saccades were hypometric and multistep with transient decelerations. Peak acceleration values of the saccades were normal, but decelerations occurred sooner and faster than in controls. Smooth pursuit was also impaired. Rucker et al. (2004)postulated a disruption in a 'latch circuit' that normally inhibits pontine 'omnipause' neurons to allow completion of eye movement. Saccade measurements may be a means of evaluating responses to treatment in patients with late-onset Tay-Sachs disease.

Neufeld (1989) provided a review of the disorders related to mutations in the HEXA (606869) and HEXB genes (606873).

Biochemical Features
Balint and Kyriakides (1968) demonstrated accumulation of a glycoprotein in red cells of patients with Tay-Sachs disease. The basic enzyme defect was shown by Okada and O'Brien (1969) to concern one component of hexosaminidase. Total hexosaminidase activity was normal but when components A (HEXA; 606869) and B (HEXB; 606873) were separated, component A was found to be absent. Hultberg (1969) confirmed the findings of Okada and O'Brien (1969). Okada et al. (1971) compared the findings in regard to hexosaminidases A and B in 3 forms of ganglioside GM2 storage disease--Tay-Sachs disease, Sandhoff disease (268800), and juvenile GM2-gangliosidosis.

Galjaard et al. (1974), Thomas et al. (1974), and Rattazzi et al. (1975) showed that Hex-A activity appears after fusion of Tay-Sachs and Sandhoff cells, suggesting genetic (or at least metabolic) complementation.

Beutler et al. (1975) concluded that Hex-A has the structure alpha-beta, whereas Hex-B is beta-beta; Tay-Sachs disease is an alpha-minus mutation, whereas Sandhoff disease is a beta-minus mutation; in the absence of beta subunits there is increased polymerization of alpha units to form Hex-S, which is a normal constituent of plasma and probably has a structure of alpha-6.

O'Brien (1978) made suggestions for nomenclature of the various hexosaminidase A and B mutations. Three loci were postulated: alpha, responsible for the alpha subunit, mapped to chromosome 15; beta, responsible for the beta subunit, mapped to chromosome 5; and an activator locus or loci determining the structure of one or more proteins that stimulate Hex-A to cleave GM2 and GA2 gangliosides.

Conzelmann et al. (1983) used a sensitive assay to demonstrate a correlation between level of residual activity and clinical severity: Tay-Sachs disease, 0.1% of normal; late infantile, 0.5%; adult GM2-gangliosidosis, 2-4%; healthy persons with 'low hexosaminidase,' 11% and 20%.

Several patients with a chronic type of Tay-Sachs disease were found by d'Azzo et al. (1984) to produce alpha-hexosaminidase A.

GM2-Gangliosidosis, B1 Variant

Patients with the GM2-gangliosidosis B1 variant produce hexosaminidase A, which appears catalytically normal when tested with substrates such as 4-methylumbelliferyl N-acetyl-glucosaminidase that are split by an active site of the beta subunit, but is catalytically defective against substrates that are hydrolyzed by the active site on the alpha subunit of normal hexosaminidase A, which is inactivated in patients' enzyme (Kytzia and Sandhoff, 1985).

Li et al. (1981) described a patient described as having a variant of type AB GM2-gangliosidosis but with a probable defect in beta-hexosaminidase A and not in the GM2 activator.

Inui et al. (1983) described a brother and sister from a consanguineous Puerto Rican marriage who had a juvenile-onset lipidosis first evident clinically at age 2.5 years by difficulties in motor function and delay in development. The sibs continued to deteriorate, showing muscle atrophy, spasticity, and loss of speech, and died at ages 7 and 8. Examination of the brains from these patients showed that the disorder was a GM2-gangliosidosis. HEXA and other lysosomal enzymes were normal and the GM2-activator protein was present in high normal concentrations in the liver. The defect in these patients appeared to reside in HEXA, which although normal in heat stability, electrophoretic mobility, and activity toward fluorogenic substrates, was resistant to activation, possibly because of defective binding to the activator. Inui et al. (1983) suggested that this be called the A(M)B variant of juvenile GM2-gangliosidosis to distinguish it from the disorder in patients missing the activator protein. (M = mutant.)

Sonderfeld et al. (1985) showed the expected complementation between the B (Tay-Sachs disease) and 0 (Sandhoff disease) variants and between the AB variant (activator deficiency) and any of the 3 variants: B, 0, and B1. Hex-A was shown to have 2 distinct catalytic sites. Complementation was demonstrated between B1 cells and variant 0 but not with variant B. Thus, the B1 cells must carry a mutation in the gene for the alpha subunit. Confirmation came from studies of the processing of immature enzyme in variant B1 cells showing the presence of alpha precursors and mature alpha chains but at a lower level than normal cells.

Pathogenesis
Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

Mapping
By study of somatic cell hybrids, Gilbert et al. (1975) suggested that a locus determining hexosaminidase A is on chromosome 7. Subsequently, Van Heyningen et al. (1975) found that the MPI (154550) and PK3 (179050) loci are on chromosome 15, and Lalley et al. (1975) concluded that MPI, PK3 and HEXA are syntenic.

Chern et al. (1976) studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X-15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively.

Formiga et al. (1988) reported 2 cases of interstitial deletion of chromosome 15. Assay of hexosaminidase A in 1 enabled them to confirm that the structural gene is located between 15q22 and 15q25 and is included in the deletion. By high resolution in situ hybridization, Takeda et al. (1990) narrowed the assignment to 15q23-q24. Using a cDNA clone for in situ hybridization, Nakai et al. (1991) assigned the HEXA gene to 15q23-q24.

Molecular Genetics
Myerowitz and Costigan (1988) demonstrated that the most frequent DNA lesion in Tay-Sachs disease in Ashkenazi Jews is a 4-bp insertion in exon 11 of the HEXA gene (606869.0001).

The gene responsible for the juvenile form has been shown by molecular analysis of the HEXA gene to be allelic to that responsible for the classic infantile form of Tay-Sachs disease (Paw et al., 1990). Whereas classic Tay-Sachs patients with complete deficiency of hexosaminidase A die before age 5 years, patients with the partial deficiency die by age 15 years.

Tanaka et al. (1990) studied 7 patients with the enzymologic characteristics of the B1 variant. All of the patients, except 1 from Czechoslovakia, carried the same arg178-to-his mutation referred to as DN (see 606869.0006). The Czechoslovakian patient had a mutation in the same codon: a change of nucleotide 532 from C to T resulting in an arg178-to-cys change in the protein (see 606869.0007). Site-directed mutagenesis and expression studies in COS-1 cells demonstrated that either of the point mutations abolished catalytic activity of the alpha subunit. The HEXA gene has 1 intron that is exceptionally large. Is it possible that it contains a sequence that codes for an unrelated protein, with an allelic form in linkage disequilibrium with the Tay-Sachs gene accounting for the high frequency of the gene in Ashkenazim?

Myerowitz (1997) stated that 78 mutations in the HEXA gene had been described, including 65 single-base substitutions, 1 large and 10 small deletions, and 2 small insertions.

Wicklow et al. (2004) described a child with severe subacute GM2-gangliosidosis who presented at age 22 months with classic cherry-red spots of the fundus but did not develop any neurologic deficit until almost age 4. They identified 3 mutations in the HEXA gene: 10T-C (S4P; 606869.0014) and 972T-A (V324V, 606869.0057) on the maternal allele, and 1A-T (M1L; 606869.0027) on the paternal allele. Because the delay in onset of neurologic symptoms indicated the presence of residual HEXA, Wicklow et al. (2004) analyzed the effects of the amino acid substitutions on HEXA expression in COS-7 cells and discovered that the 972T-A mutation created a new exon 8 donor site, causing a 17-bp deletion and destabilization of the resulting abnormal transcript. Wicklow et al. (2004) concluded that the remaining normal mRNA produced from the 972T-A allele must account for the delayed onset of symptoms in this child.

By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the HEXA gene (606869.0058) in a family (M165) in which first-cousin parents had 5 healthy children and 3 children with moderate intellectual disability and seizures.

Diagnosis
Balint et al. (1967) found that both homozygotes and heterozygotes show reduced sphingomyelin in red blood cells and suggested that this reduction is useful in carrier identification.

Triggs-Raine et al. (1990) compared DNA-based and enzyme-based screening tests for carriers of TSD among Ashkenazim. Among 62 Ashkenazi obligate carriers, 3 specific mutations, indicated as 606869.0001, 606869.0002, and606869.0008 among the allelic variants, accounted for all but one of the mutant alleles (98%). In 216 Ashkenazi carriers identified by the enzyme tests, DNA analysis showed that 177 (82%) had 1 of the identified mutations. Of the 177, 79% had the exon 11 insertion mutation (606869.0001), 18% had the intron 12 splice junction mutation (606869.0002), and 3% had the less severe exon 7 mutation associated with adult-onset disease (606869.0008). The results of the enzyme tests in 39 subjects (18%) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remained some possibility of unidentified mutations). Of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i.e., a false-negative enzyme-test result).

Tay-Sachs disease was one of the disorders used as a trial for preamplification DNA diagnosis of multiple disorders bySnabes et al. (1994). They applied single-cell whole-genome preamplification to PCR-based analysis of multiple disease loci from the same diploid cell. The method they described allowed diagnosis of multiple disease genes, analysis of multiple exons/introns within a gene, or corroborative embryo-sex assignment and specific mutation detection at sex-linked loci.

Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spouses of Jewish carriers or as relatives of probands. To define a panel of alleles that might account for most mutations in non-Jewish carriers, Akerman et al. (1997) investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were represented by 12 previously identified mutations, 7 that were newly identified and 1 that remained unidentified. They then investigated 46 enzyme-defined carrier alleles: 19 were pseudodeficiency alleles and 5 mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remained unidentified, despite the testing for 23 alleles. Some may represent false positives for the enzyme test. The results indicated that predominant mutations, other than the 2 pseudodeficiency alleles (739C-T, 606869.0035and 745C-T) and 1 disease allele (IVS9+1G-A; 606869.0033) do not occur in the general population. Thus, Akerman et al. (1997) concluded that determination of carrier status by DNA analysis alone is inefficient because of the large proportion of rare alleles. Notwithstanding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non-Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-A disease allele, and other mutations relevant to the subject's genetic heritage.

Bach et al. (2001) presented results strongly supporting the use of DNA testing alone as the most cost-effective and efficient approach to carrier screening for TSD in individuals of confirmed Ashkenazi Jewish ancestry.

Chamoles et al. (2002) described methods for the assay of hexosaminidase A activity in dried blood spots on filter paper for the screening of newborns.

Vallance et al. (2006) reported 2 clinically unaffected Ashkenazi Jewish brothers who had discrepant results on diagnosis of Tay-Sachs disease carrier status. Both had low-normal serum percent HexA enzyme activity above the cut-off for carrier detection, but leukocyte HexA activity was in the carrier range. DNA analysis showed that both brothers carried the common 4-bp insertion in the HEXA gene (1277_1278insTATC; 606869.0001) gene. Both also had 2 common polymorphisms in the HEXB gene: 619A-G (I207V) and a 2-bp deletion (delTG) in the 3-prime untranslated region. Genotyping of a larger sample of 72 Jewish and 104 non-Jewish alleles samples found that the HEXB variants were in strong linkage disequilibrium with haplotype frequencies of 9.7% and 7.7%, respectively. Three additional TSD carriers with the unusual biochemical phenotype (normal serum HexA activity and decreased leukocyte HexA activity) all carried the same HEXB I207V/delTG haplotype. Finally, analysis of a larger sample of 69 alleles found that the frequency of this HexB haplotype was significantly associated with low serum HexB activity. These findings indicated that this haplotype lowers HexB activity in serum, which has the effect of raising the percent of HexA activity as determined by heat inactivation methods of total Hex activity. This can result in masking of carrier status in carriers of TSD alleles that are measured solely by serum percentage of HexA activity. Vallance et al. (2006) noted that the high prevalence of this HexB haplotype may become clinically relevant in diagnosis of TSD carrier status, and that additional diagnostic methods should be used.

Prenatal Diagnosis

Conzelmann et al. (1985) performed prenatal diagnosis in a family with the pseudo-AB variant (B1 variant) of GM2-gangliosidosis. These patients have a late infantile form with nearly normal beta-hexosaminidase A levels when assayed with the usual synthetic substrate 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide. Since the enzyme is also inactive against another substrate that is thought to be hydrolyzed predominantly by Hex-A, the mutation is in the alpha subunit.

Population Genetics
Many aspects of Tay-Sachs disease and related disorders were discussed in the proceedings of a conference edited byKaback et al. (1977). Tay-Sachs disease is approximately 100 times more common in infants of Ashkenazi Jewish ancestry (central-eastern Europe) than in non-Jewish infants (Kaback et al., 1977). Tay-Sachs disease and Sandhoff disease in French Canadians of Quebec was discussed by Andermann et al. (1977). Whether this represents an infusion of the Tay-Sachs gene from Jewish fur traders or an independent mutation was not known at that time, but was settled when the intragenic lesions were identified; see 606869.0003.

Petersen et al. (1983) concluded that proliferation of the TSD gene occurred among the antecedents of modern Ashkenazi Jewry after the second Diaspora (70 A.D.) and before the major migrations to regions of Poland and Russia (1100 A.D. and later). Among Moroccan Jews, the carriers of a Tay-Sachs mutation were estimated to have a frequency of 1 in 45 (Navon, 1990), a figure not greatly different from that found in North American Jews.

Petersen et al. (1983) found a TSD carrier frequency in 46,304 North American Jews to be 0.0324 (1 in 31). Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a carrier frequency of 0.0327. No carrier was found among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was a 2-fold increase in carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins. Among U.S. Jews originating from Austria, a carrier frequency of 0.1092 was observed.

Yokoyama (1979) concluded that it is unlikely that drift alone was responsible for the high frequency of Tay-Sachs disease in Ashkenazim. Heterozygote advantage was considered a likely additional factor. Spyropoulos et al. (1981) showed that proportionally the grandparents of Tay-Sachs disease carriers died from the same causes as grandparents of noncarriers. They suggested that the finding indirectly supports the notion that the high frequency of the TSD gene in Ashkenazim is 'caused by a combination of founder effect, genetic drift, and differential immigration patterns.'

Diamond (1988) defended selective advantage as the cause of the high frequency of the TS gene in Ashkenazi Jews.

Paw et al. (1990) analyzed the frequency of 3 HEXA mutations among heterozygotes identified in a Tay-Sachs screening program: the 4-nucleotide insertion in exon 11 (606869.0001), the G-to-C transversion at the 5-prime splice site in intron 12 (606869.0002), and the gly269-to-ser mutation in exon 7 (606869.0008). Mutation analysis included PCR amplification of the relevant regions followed by allele-specific oligonucleotide (ASO) hybridization and, in the case of the exon 11 insertion, the formation of heteroduplex PCR fragments of low electrophoretic mobility. The percentage distribution of the exon 11, intron 12, exon 7, and unidentified mutant alleles was 73:15:4:8 among 156 Jewish carriers of HEXA deficiency and 16:0:3:81 among 51 non-Jewish carriers. Regardless of the mutation, the ancestral origin of the Jewish carriers was primarily eastern and (somewhat less often) central Europe, whereas for non-Jewish carriers it was western Europe.

Among 148 Ashkenazi Jews carrying the Tay-Sachs gene, Grebner and Tomczak (1991) found that 108 had the insertion mutation (606869.0001), 26 had the splice junction mutation (606869.0002), 5 had the adult mutation (606869.0008), and 9 had none of the 3. Among 28 non-Jewish carriers tested, most of whom were obligate carriers, 4 had the insertion mutation, 1 had the adult mutation, and the remaining 23 had none of the 3. The 2 patients with the asp258-to-his type of B1 allele (606869.0038) had infantile TSD with serum and fibroblasts containing heterozygote levels of HEXA.

Risch et al. (2003) postulated that geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift, rather than selection, as the mechanism of unusually high frequency of conditions such as TSD.Zlotogora and Bach (2003) provided a rebuttal in support of selection as the determining factor. They stated that the occurrence of several mutations in the same gene or mutations in different genes responsible for the high prevalence of some genetic diseases in relatively small populations is most easily explained by selection, and pointed out that Bardet-Biedl syndrome (209900) has a high frequency among the Bedouins of the Negev, owing to mutations in 3 different genes. They pointed to the occurrence of the high frequency of 4 lysosomal storage diseases among Ashkenazim--TSD, Gaucher disease type I (230800), Niemann-Pick disease (see 257200), and mucolipidosis type IV (252650)--in which the mutations are in genes that encode enzymes from a common biochemical pathway. In all 4, the main storage substances are sphingolipids. A further indication of a nonrandom process is the number of mutations responsible for each disorder. In almost all of the nonlysosomal disorders, 1 mutation is prevalent, and, if more than 1 mutation is found in a given population, its frequency is significantly less than 10% of the first mutation. This is true for almost all the nonlysosomal disorders, except cystic fibrosis (219700), in which a selection process had been suggested, and factor XI deficiency (612416). On the other hand, in all 4 lysosomal disorders among Ashkenazim, the second allele is more than 10% prevalent, when compared with the frequency of the major mutation. Risch and Tang (2003) presented counterarguments.

In Table 4 of their report, Lazarin et al. (2013) noted that among 21,985 ethnically diverse individuals screened for Tay-Sachs disease/HexA deficiency carrier status, they identified 151 carriers. These 151 carriers included 90 carriers of Ashkenazi Jewish ethnicity from a subset of 2,386 Ashkenazi Jewish individuals screened.

History
Fernandes Filho and Shapiro (2004) reviewed the early history of Tay-Sachs disease.

Animal Model
Taniike et al. (1995) produced a mouse model of Tay-Sachs disease by targeted disruption of the HEXA gene. The mice were devoid of beta-hexosaminidase A activity, accumulated GM2 ganglioside in the central nervous system, and displayed neurons with membranous cytoplasmic bodies identical to those of Tay-Sachs disease in humans. Unlike human Tay-Sachs disease in which all neurons store GM2 ganglioside, no storage was evident in the olfactory bulb, cerebellar cortex, or spinal anterior horn cells of these mice. Sango et al. (1995) likewise found that disruption of the Hexa gene in mouse embryonic stem cells resulted in mice that showed no neurologic abnormalities, although they exhibited biochemical and pathologic features of the disease. In contrast, mice in whom the Hexb gene was disrupted as a model of Sandhoff disease were severely affected. The authors suggested that the phenotypic differences between the 2 mouse models was the result of differences in the ganglioside degradation pathway between mice and humans. The authors postulated that alternative ganglioside degradative pathway revealed by the hexosaminidase-deficient mice may be significant in the analysis of other mouse models of the sphingolipidoses, as well as suggest novel therapies for Tay-Sachs disease.

Cohen-Tannoudji et al. (1995) used gene targeting in embryonic stem (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimicked some of the biochemical and histologic features of human Tay-Sachs disease. They displayed, for example, total deficiency of Hexa activity and membranous cytoplasmic inclusions typical of GM2-gangliosidoses found in the cytoplasm of their neurons. However, while the number of storage neurons increased with age, it remained low compared with that found in the human, and no apparent motor or behavioral disorders could be observed. This suggested that beta-hexosaminidase A is not an absolute requirement for ganglioside degradation in mice. Nonetheless, the authors stated that animal models should be useful for the testing of new forms of therapy.

Phaneuf et al. (1996) likewise found that mice with disruption of the Hexa gene suffered no obvious behavioral or neurologic deficit whereas those homozygous for a disruption of the Hexb gene developed a fatal neurodegenerative disease with spasticity, muscle weakness, rigidity, tremor, and ataxia. They proposed that homozygous Hexa-deficient mice escaped disease through particle catabolism of accumulated G(M2) via G(A2) through the combined action of sialidase and beta-hexosaminidase B.

In a mouse model of Tay-Sachs disease, Platt et al. (1997) evaluated a strategy for treatment of the disorder based on N-butyldeoxynojirimycin, an inhibitor of glycosphingolipid (GSL) biosynthesis. When Tay Sachs mice were treated with this agent, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, the authors concluded that limiting the biosynthesis of the substrate for the defective Hexa enzyme prevented GSL accumulation and the neuropathology associated with its storage in lysosomes.

Guidotti et al. (1999) determined the in vivo strategy leading to the highest Hexa activity in the maximum number of tissues in Hexa-deficient knockout mice. They demonstrated that intravenous coadministration of adenoviral vectors coding for both alpha- and beta-subunits, resulting in preferential liver transduction, was essential to obtain the most successful results. Only the supply of both subunits allowed for Hexa overexpression, leading to massive secretion of the enzyme in serum, and full or partial restoration of enzymatic activity in all peripheral tissues tested. These results emphasized the need to overexpress both subunits of heterodimeric proteins in order to obtain a high level of secretion in animals defective in only 1 subunit. Otherwise, the endogenous nondefective subunit is limiting.

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