疾患詳細

疾患詳細



小人症, 後弯, 外反膝, 屈曲した膝, 短頸, 胸骨突出, 大きな関節; 胸腰部脊椎の扁平化; 臼蓋骨化欠乏, 大腿骨頭異形成, 外反股; 上肢の長管骨が下肢より重度, 上腕骨, 橈骨, 尺骨および中手骨が短く粗で湾曲し不規則な骨端板を伴い不規則な管状構造をもつ, 手根骨骨化中心欠損; エナメル質低形成; エナメル質の厚さが減少 (Gorlin et al. 1990 より引用)

#253000
Mucopolysaccharidosis type IVA (MPS4A)
(Morquio syndrome A)
(MPS IVA; MPS4A)
(Morquio A disease)
(Galactosamine-6-sulfate sulfatase, deficiency)
(GALNS deficiency)

ムコ多糖症 IVA
(Morquio 症候群 A)
(ガラクトサミン-6-スルファターゼ欠損症)
指定難病19 ライソゾーム病
小児慢性特定疾病 代78 ムコ多糖症Ⅳ型

責任遺伝子:612222 Galactosamine-6-sulfate sulfatase (GALNS) <16q24.3>
遺伝形式:常染色体劣性

((症状)
(GARD)
 Abnormal heart valve morphology (心弁奇形) [HP:0001654] [1120]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Carious teeth (齲歯) [HP:0000670] [08314]
 Cervical myelopathy (頚髄症) [HP:0002318] [0201]
 Cervical subluxation (頚椎亜脱臼) [HP:0003308] [161515]
 Chondroitin sulfate excretion in urine (尿中コンドロイチン硫酸排泄) [HP:0012070] [2066]
 Coarse facial features (粗な顔貌) [HP:0000280] [0408]
 Constricted iliac wings (腸骨翼収縮) [HP:0003277] [1142]
 Coxa valga (外反股) [HP:0002673] [15110]
 Disproportionate short-trunk short stature (不均衡型短幹性低身長) [HP:0003521] [0130]
 Epiphyseal deformities of tubular bones (長管骨骨端変形) [HP:0003053] [160003]
 Flaring of rib cage (肋骨胸郭フレア) [HP:0000904] [16122]
 Genu valgum (外反膝) [HP:0002857] [15112]
 Grayish enamel (灰色のエナメル質) [HP:0000683] [08313]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hyperlordosis (前弯) [HP:0003307] [161501]
 Hypoplasia of the odontoid process (歯状突起低形成) [HP:0003311] [161515]
 Inguinal hernia (鼠径ヘルニア) [HP:0000023] [1201]
 Joint laxity (関節弛緩) [HP:0001388] [15102]
 Juvenile onset (若年発症) [HP:0003621]
 Keratan sulfate excretion in urine (尿中ケラタン硫酸排泄) [HP:0012069] [2066]
 Kyphosis (後弯) [HP:0002808] [161500]
 Large elbow (大きな肘) [HP:0030865] [15103]
 Mandibular prognathia (下顎突出) [HP:0000303] [0541]
 Metaphyseal widening (骨幹端拡大) [HP:0003016] [160010]
 Opacification of the corneal stroma (角膜間質混濁) [HP:0007759] [0620]
 Osteoporosis (骨粗鬆症) [HP:0000939] [160015]
 Ovoid vertebral bodies (卵形椎体骨) [HP:0003300] [161511]
 Platyspondyly (扁平脊椎) [HP:0000926] [161505]
 Pointed proximal second through fifth metacarpals (尖った近位第2-5中手骨) [HP:0001223]  「16041」
 Prominent sternum (目立つ胸骨) [HP:0000884] [11011]
 Recurrent upper respiratory tract infections (反復性上気道kansenn) [HP:0002788] [014230]
 Restrictive ventilatory defect (拘束性換気障害) [HP:0002091] [01606]
 Scoliosis (側弯) [HP:0002650] [161502]
 Ulnar deviation of the wrist (手の尺側偏位) [HP:0003049] [15208]
 Wide mouth (幅広い口) [HP:0000154] [0802]
 Widely spaced teeth (弛緩隔離) [HP:0000687] [08300]

(UR-DBMS)
【一般】短幹小人症
 成人身長 82 〜 115 cm
 頻回の上気道感染症
 拘束性肺病
 軽度の肝腫
 *知能正常
【神経】頸髄ミエロパチー
【顔】軽度の粗い顔貌
 下顎突出
【眼】*角膜混濁
【口】幅広い口
 歯間解離
 灰色がかったエナメル質
 頻回の齲歯
【耳】難聴
【心】弁膜症
【胸郭】*肋骨胸郭フレア
 目立つ胸骨
【体幹】鼠径ヘルニア
【骨盤】外反股
 腸骨翼狭窄
【四肢】*関節弛緩
 外反膝
 手関節尺側偏位
【X線】骨粗鬆症
 扁平脊椎
 歯状突起低形成
 頸椎亜脱臼
 後弯
 卵形椎体骨
 高度前弯
 側弯
 管骨骨端変形
 拡大した骨幹端
 尖った第2-5近位手根骨
【検査】N-acetylgalactosamine-6-sulfatase 欠損 (線維芽細胞, 白血球)
 *ムコ多糖尿 (硫酸ケラタン, 年令とともに低下)
 尿中 Chondroitin 6-sulfate 排泄
【その他】出生時は正常にみえる
 1-3歳発症
 出生前診断が可能

【一般】過呼吸
【神経】対麻痺
 下腿虚弱
【胸郭】鳩胸
【骨盤】股関節異形成
【X線】脊髄圧迫
 軽度の多発性異骨症
 頭蓋底陥入
【治療】酵素置換療法が有効との報告はない
【出生前診断】羊水穿刺で可能

(要約) ムコ多糖症 IVA型
(MPS IVA, Morquio A 病, Morquio 症候群A型)
●ムコ多糖症IVA (MPS IVA) は, 重症で急速進行性早期発症型〜緩徐進行性遅発型までの連続である
 MPS IVAの小児は, 出生時に独特の臨床所見はもっていない
・重症型は, 通常1〜3歳で明らかとなり, 最初は後側弯, 外反膝および漏斗胸を示す
・緩徐進行型は, 後期小児期または思春期まで明らかにならないかもしれない
 →最初に股関節障害 (疼痛, 拘縮, Legg Perthes病) を示す
 進行性骨および関節病変は, 低身長や, 疼痛と関節炎を生じ, 肢体不自由となる
 他の器官の病変は, 呼吸障害, 閉塞性睡眠時無呼吸, 心弁疾患, 難聴, 角膜混濁による視力障害, 歯異常および肝腫を生じうる
 脊髄圧迫は, 神経障害を生じる多くみられる合併症である
 患児は初期は知能正常である
●診断:既往歴, 身体所見, 骨X線, 眼科所見, 尿glycosaminoglycans (GAG) 解析で示唆され, N-acetylgalactosamine 6-sulfatase (GALNS) 酵素活性測定か GALNS 遺伝子検査で確定される→変異検出率86%
・遺伝:常染色体劣性
・既往歴:出生時正常, アデノイド/扁桃切除術, ヘルニア修復, 耳チューブ, 頸椎減圧+/-癒合, 呼吸器障害, 心弁異常, 歯異常
・身体所見 (重症型): 低身長, 短躯, 正常四肢, 手の尺側偏位, 鳩胸, 下部肋骨フレア, 突背, 側彎, 外反膝, 関節過伸展, よたよた歩行, 転倒
・X線:歯状核低形成, 頸椎不安定, 後弯, 突背, 側弯, 鳩胸(漏斗胸), 腸骨翼フレア, 平坦な大腿骨骨端, 外反股
・眼科:角膜混濁による視力障害, 乱視, 網膜症 +/-
・ GAGスクリーニング (量的GAG解析, 質的GAG解析)
 尿中 keratan sulfate (KS)上昇→ N-acetylgalactosamine 6-sulfatase (MPS IVA) または B-galactosidase (MPS IVB)欠乏による
 尿中 chondroitin 6-sulfate (C6S)上昇→ N-acetylglactosamine 6-sulfatase (MPS IVA)欠乏による
●頻度: 1:76,000 〜 1:640,000
 MPS IVA 1:270,000; MPS IVB <1:1,000,000 (ドイツ)

<小児慢性特定疾病 代78 ムコ多糖症Ⅳ型>
概要・定義
Morquio 症候群(ムコ多糖症IV型)は, 短胴性低身長, X脚, 手関節弛緩, 角膜混濁, 弁膜症, 尿中ケラタン硫酸(KS)・コンドロイチン硫酸(CS)の排泄増加を特徴とする常染色体劣性遺伝病である。本症はN-アセチルガラクトサミン-6-硫酸サルファターゼ(GALNS)の欠損を原因とするA型と, βガラクトシダーゼの欠損を原因とするB型に分類されるが, A型が大半を占める。GALNSの欠損によりKSとCSの分解が阻害され, 骨や角膜などのライソゾームに蓄積する
疫学
発症率は出生約50万人(日本)に1人と報告されている。

病因
ライソゾーム内でケラタン硫酸を分解するために必要なN-アセチルガラクトサミン-6-硫酸サルファターゼ(GALNS)またはβガラクトシダーゼの欠損が原因で, KSが過剰蓄積するために, 全身骨が変形する。
症状
以下の症状を認める。
① 骨・関節障害:出生時には明らかな異常を認めないが, 2~3歳までに短胴型小人症, 鳩胸, 下部肋骨の拡張, 脊椎後弯(突背), 脊椎側弯, 外反膝(X脚), 関節過伸展などが認められるようになる。レントゲンでは椎体扁平化, 第2頸椎歯突起低形成, 肋骨扁平化, 股関節異常などが認められる。靱帯弛緩のために手首の力や握力が非常に弱く, 着衣・整容・書字などに困難をきたす。動揺性歩行も特徴的である。歯突起低形成のために環軸椎脱臼・亜脱臼, 頸髄圧迫を生じやすく, 四肢麻痺にいたる例も多い。転倒や頸部の無理な伸展を契機に突然死する可能性もある。重症例では7~8歳頃に成長が停止し, 平均最終身長は110~120cmである。
② 気道障害:胸郭変形による拘束性肺障害, ムコ多糖の蓄積による閉塞性肺障害, 気管軟化, 巨舌, アデノイド・扁桃肥大, 声帯肥厚などが認められる。睡眠時無呼吸, いびき, 日中の傾眠傾向, 呼吸音の増強, 肺胞低換気, 発声障害などをきたす。
③ 歯科的異常:歯は小さく, 歯間が広く, エナメル質は菲薄で齲蝕を生じやすい。
④ 眼科的異常:角膜に微細な混濁を認める。
⑤ 聴力障害:軽度から中等度の混合性難聴を認める。
⑥ 循環器障害:心弁膜症を認める。
⑦ 知能:正常である。
診断
ムコ多糖の過剰蓄積は, 尿中ムコ多糖の定量で判定する。尿中ムコ多糖の分画から, 病型をある程度予測できるが, 最終的には, 血液あるいは培養皮膚線維芽細胞などで酵素活性の低下を証明し確定診断とする。遺伝子診断は, 診断を確定するのに必須ではないが重症度の予後判定や家族内の保因者診断や発端者の同胞の出生前診断には有用である。
① 画像診断:椎体の扁平化, 第2頸椎歯突起低形成
② 尿中ウロン酸(グリコサミノグリカン):総量の増加は軽微なので, KSの増加を確認する。
③ GALNS活性:白血球, 線維芽細胞などにおけるGALNS活性の低下を証明する。
④ 遺伝子解析:GALNS遺伝子変異
診断方法
(1) 下記の症状・臨床検査からムコ多糖症を疑う。
症状:特有の顔貌, 関節拘縮, 関節変形, 骨の変形, 精神運動発達障害, 神経学的退行, 角膜混濁, 難聴, 繰り返す滲出性中耳炎, アデノイド, 扁桃肥大, 臍ヘルニア, そけいヘルニア, 肝脾腫大, 閉塞性呼吸障害, 騒音性呼吸, 異所性の蒙古斑など。それぞれの症状は, 治療を行わないと加齢に伴い進行する。
臨床検査:全身骨X線で多発性の骨形態変化を認める。その他, 尿中ウロン酸排泄量の上昇があり, 病型により, デルマタン硫酸, ヘパラン硫酸, ケラタン硫酸などの過剰排泄を認める。
(2) 確定診断は酵素診断によりなされる。白血球, 培養線維芽細胞などの検体から, 以下の酵素の活性低下を示すことにより, 診断が確定する。なお, 遺伝子診断は, 補助的検査であり, 原則として, 確定診断には用いない。
ムコ多糖症I型: α-L-iduronidase
ムコ多糖症II型: Iduronate sulfarase
ムコ多糖症III型:  heparan N-sylfatase
 α-N-acetylglucosaminidase
 acetylCoA:α-glucosaminide acetyltransferase
 N-acetylglucosamine 6-sulfatase
ムコ多糖症IV型: N-acetylgalactosamine 6-sulfatase欠損症
 β-galactosidase欠損症
ムコ多糖症VI型: N-Acetylgalactosamine 4-sulfatase(別名arylsulfatase B)
ムコ多糖症VII型: β-Glucuronidase
※  なお, 2014年2月現在, 検査センターエスアールエルで, 尿中ウロン酸, ムコ多糖分画および血液検体を用いたムコ多糖症 I型, II型, III型, IV型, VI型, VII型の酵素診断が可能である。

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
IV型に対する酵素補充療法が2014年にわが国で承認された。
予後
進行性で致死性の重篤な疾患である。
成人期以降
進行性疾患のため成人期には特に重症化する。酵素補充療法も病態の進行を完全に阻止することはできない。

(オリジナル) Morquio (1929), Brailsford (1929)
(責任遺伝子) *612222 Galactosamine-6-sulfate sulfatase (GALNS) <16q24.3>
.0001 Morquio syndrome A (253000) [GALNS, ASN204LYS] (dbSNP:rs118204435) (RCV000000733) (Fukuda et al. 1992; Tomatsu et al. 1992)
.0002 Morquio syndrome A [GALNS, ALA138VAL] (dbSNP:rs118204436) (RCV000000734) (Tomatsu et al. 1992)
.0003 Morquio syndrome A [GALNS, ARG386CYS] (dbSNP:rs118204437) (ExAC:rs118204437) (RCV000079019...) (Tomatsu et al. 1992; Tomatsu et al. 2004)
.0004 Morquio syndrome A [GALNS, 2BP DEL] (RCV000000737) (Fukuda et al. 1992; Tomatsu et al. 1992)
.0005 Morquio syndrome A [GALNS, ILE113PHE] (dbSNP:rs118204438) (RCV000000738...) (Tomatsu et al. 1995; Yamada et al. 1998)
.0006 Morquio syndrome A [GALNS, GLN473TER] (dbSNP:rs118204439) (RCV000000739) (Tomatsu et al. 1995)
.0007 Morquio syndrome A [GALNS, ASN487SER] (dbSNP:rs118204440) (RCV000000736) (Tomatsu et al. 1995)
.0008 Morquio syndrome A [GALNS, ARG94GLY] (dbSNP:rs118204441) (RCV000000740) (Bunge et al. 1997)
.0009 Morquio syndrome A [GALNS, ARG259GLN] (dbSNP:rs118204442) (RCV000000741) (Bunge et al. 1997; Tylki-Szymanska et al. 1998)
.0010 Morquio syndrome A [GALNS, GLY301CYS] (dbSNP:rs118204443) (RCV000000743) (Kato et al. 1997)
.0011 Morquio syndrome A [GALNS, SER162PHE] (dbSNP:rs118204444) (RCV000000744) (Kato et al. 1997)
.0012 Morquio syndrome A [GALNS, PHE69VAL] (dbSNP:rs118204445) (RCV000000745) (Kato et al. 1997)
.0013 Morquio syndrome A, mild [GALNS, THR312SER] (dbSNP:rs118204446) (RCV000000748) (Yamada et al. 1998)
.0014 Morquio syndrome A, mild [GALNS, ASP60ASN] (dbSNP:rs118204447) (RCV000000749) (Montano et al. 2003)
.0015 Morquio syndrome A, mild [GALNS, ALA291THR] (dbSNP:rs118204448) (RCV000000742) (Montano et al. 2003)
.0016 Morquio syndrome A, mild [GALNS, TRP230TER] (dbSNP:rs118204449) (RCV000000746) (Montano et al. 2003)
.0017 Morquio syndrome A, mild [GALNS, 1374T DEL] (RCV000000747) (Montano et al. 2003)
.0018 Morquio syndrome A [GALNS, GLY340ASP [dbSNP:rs267606838] (RCV000000750) (Wang et al. 2010)

*GALNS: Galactosamine-6-sulfate sulfatase (522 amino acids)
・リソソーム exohydrolase である N-acetylgalactosamine-6-sulfatase をコードする
 → glycosaminoglycans, keratan sulfate, および chondroitin 6-sulfate の分解に必要である

(ノート)
●(#) は, Morquio 症候群 A としても知られるムコ多糖症 IVA 型 (MPS IVA) は, galactosamine-6-sulfate sulfatase をコードする遺伝子 (GALNS; 612222) の変異が原因であるため

●Morquio 症候群 B (253010)は, 遺伝的に別疾患で, beta-galactosidase 遺伝子 (GLB1; 611458) の変異が原因であるオーバーラップする臨床症状をもつ

●ムコ多糖症 IVA 型は, keratan sulfate と chondroitin-6-sulfate の細胞内蓄積が特徴の常染色体劣性リソソーム蓄積病である
 鍵となる臨床症状には, 低身長, 骨格異型性, 歯奇形および角膜混濁がある
 知能は正常で, 直接的中枢神経病変はない
 骨格変化は神経学的合併症となりうる
 多様な重症度があるが, 重症表現型をもつ患者は, 通常は10〜20歳代を越えて生存しない (Montano et al., 2008)

●McKusick (1972) は, 1929〜1959年の間に骨格疾患の寄せ集めが Morquio のカテゴリーに含まれたと述べた
 →いろんな型の脊椎骨端異形成や多発性骨端異形成を含む

●Nelson et al. (1988) は,3つのサブグループへ MPS IVA を分けることを提唱した
 重症の古典型,中間型および軽症型
 →12例の酵素学的に証明された症例で観察された臨床的多様性を反映する
 軽症の患者は,比較的高い残存酵素活性を示した

臨床症状
● Morquio 症候群の第1例はOsler (1897) により軟骨異形成としてフランス人カナダ人の男女同胞2例で報告されたようだ (→ McKusick, 1972, p 583, 図 11-23).

●ウルグァイのモンテビデオの Morquio (1929)と, 英国バーミンガムの Brailsford (1929) により, 同時に別々に記載された疾患は, 我々が現在, 角膜混濁, 大動脈弁疾患および尿中ケラタン硫酸排泄の発症として認知する疾患であった
●Morquio (1929)は, スウェーデン人集団の1家系同胞4例で本疾患を観察した
 目立つ特徴には,骨ジストロフィー,角膜混濁,大動脈弁疾患および尿中 keratosulfate 排泄があった

●Greenberg (1968) は,歯状突起低形成による環軸椎脱臼の危険な合併症が,Morquio 病といろんな型の脊椎骨端異形成で生じうると述べた

●Gadbois ら(1973) は, ケベック州で48例の Morquio 症候群を証明した
 彼らは27家系に分布していた
 ムコ多糖類の全尿中排泄は正常範囲内であったが, 硫酸ケラタンの排泄が正常より2-3倍増加していた

●Hussels (1974) は, 正常な子供2人をもつ患者女性1例を記載した

●Guiney and Stevenson (1982)は, N-acetylgalactosamine-6-sulfate sulfatase欠乏による記載された Morquio 症候群の女性1例を記載した
 67歳まで生存した
 原因不明でエピソード性の無呼吸に数日かかった後, 彼女はベッドで死亡した

●Hecht et al. (1984) は,非常に軽症型の Morquio 症候群の14歳男児を報告した
 難治性両側性 Legg-Perthes 病として受診した
 彼は,低身長 (15パーセンタイル) と短躯をもっていたが,鳩胸,外反膝,過剰な関節弛緩,角膜混濁,または顔貌異常はなかった
 X線検査は,軽度の扁平脊椎,第1腰椎の前方楔,最小の歯状突起低形成,異常な大腿骨頭骨端を示した
 N-acetylgalactosamine-6-sulfate sulfatase 活性は,白血球で検出不能,線維芽細胞で低値であった
 尿中 keratan sulfate は,22.9 mg/全量 (正常値は < 2 mg/全量)であった
 Fujimoto and Horwitz (1983)の症例とHolzgreve et al. (1981)の2例を一緒に,この経験は軽症型の MPS IVA が存在することを示唆した

●Beck et al. (1986) は,N-acetylgalactosamine-6-sulfate (GalNAc-6-S) sulfatase 欠乏症の重症型,中間型および軽症型があると示唆した
 彼らは,身長 156 cm の30歳男性を報告した
 重度の股関節疾患, 微細な角膜沈着物 (スリットランプで), 楔状の第1腰椎をもっていた
 尿中 keratan sulfate または chondroitin sulfate の増加はなかったが, GALNS 活性は線維芽細胞で著明に減少していた
 著者らは,Morquio A のバリアントかもしれない,いわゆる 'nonkeratosulfate-excreting Morquio syndrome' (252300)と類似性に気づいた

● Nelson and Thomas (1988) は,MPS IVA 12例の全例で,環軸椎不安定がない,またはある,歯状突起異形成を発見した
 一般的に,この所見は,本疾患の全体的臨床重症度によく相関した
 著者らは,頸椎圧迫の症状や症候のあるこれらの患者の注意深い経過観察の重要性を強調した
 後部頸髄の証明された障害は,上部頸椎の後部癒合の適応となるであろう

●Montano et al. (2008) は,Morquio A 病の患者354例のデータを基に,成長曲線をつくった
 男女の平均出生時体長はそれぞれ 52.6 と 52.1 cmであった
 18歳以上の男女の平均最終身長は,それぞれ 122.4 と 113.1 cmであった
 →男で -7.4 SD, 女で -7.7 SD に相当した
 18歳以上の男女の平均 BMI は,それぞれ 24.7 と 25.6 kg/m(2)であった
 Morquio A 患者の成長パターンは,1歳以後の成長速度の障害が特徴であった

Harmatz et al. (2015) performed a longitudinal analysis of endurance and respiratory function from a natural history study of patients with Morquio A syndrome. The authors used a 6-minute walk test and a 3-minute stair climb test as well as measuring respiratory evaluation by forced vital capacity (FVC) and maximum voluntary ventilation (MVV). At year 0 (baseline), 353 subjects were assessed; at year 1, 184; and at year 2, 78. The overall annualized estimate of change in the 6-minute walk test distance was -4.86 +/- 3.25 m. In contrast, little change (-0.14 +/- 0.60 stairs/min) was observed in the 3-minute stair climb test. Annualized changes in FVC and MVV were 2.44 +/- 0.68% and 1.01 +/- 2.38%, respectively. FVC and MVV increased in patients less than 14 years of age, but decreased in older patients.

Caciotti et al. (2015) reported the clinical data, biochemical assays, molecular analyses, and in silico structural analyses of mutations in 37 MPS IVA patients. Thirty-one patients had the severe phenotype, 3 were intermediate, and 3 were mild. The phenotypic features of the patients were reported in the supplemental material for this paper.

生化学的特徴
●Matalon et al. (1974) は,Morquio 病の酵素欠乏には,6-sulfatase が関与すると結論した
 → keratan sulfate と chondroitin sulfate の両方を触媒する
●DiFerrante et al. (1978) は,さらに,障害が galactosamine-6-sulfate sulfatase に影響すると示唆した

●Glossl et al. (1984)は,MPS IVA の一部の症例の線維芽細胞は,acetylgalactosamine-6-sulfate sulfatase の予測された欠乏に加え,neuraminidase (NEU1; 608272)の欠乏を示すことを発見した
 残存neuraminidase活性は対照の約5%であったが,GalNAc-6-S sulfatase 活性は1%未満であった
 neuraminidase は末梢白血球では正常であった
 患者線維芽細胞とMPS IVAのもう一人の患者の線維芽細胞との体細胞融合は,sulfatase 欠乏を是正しなかったが,sialidosis 線維芽細胞との癒合は neuraminidase レベルの増加を生じた
 異なる MPS IVA 細胞10株の再研究は,2株でneuraminidase低値を,6株で正常下限を示した

その他の特徴
●Levin et al. (1975) は,Morquio A 症候群患者12例で見られた古典的口異常を記載した
 上顎前方歯は幅広く離解し張り出し,後方歯は先細りし尖った歯冠先端をもっていた
 エナメル質は正常な固さであったが,一部の患者は厚さが減少した小孔のあるエナメル質をもっていた
 硬口蓋は幅広く平坦であった

●Nelson and Kinirons (1988) は,本疾患の12例全例に典型的歯変化を発見したが,変化はいろんな程度であった
 歯変化はMPS IVA でのみみられ,MPS IVB にはなかった

●Cahane et al. (1990) は,Morquio 症候群の30歳代の男女同胞2例を報告した
 →他の型のムコ多糖症やムコリピドーシスで見られる合併症である緑内障を生じた

Borlot et al. (2014) specifically assessed the CNS involvement in 9 Brazilian patients with MPS IVA confirmed by biochemical analysis. The patients ranged in age from 5 to 26 years. All had motor weakness, and 6 had impaired deep sensation. Cognition was normal in all but 1, who had delayed development at age 5. In 7 patients, brain and spinal cord imaging showed variable abnormalities, including clival hypoplasia, basilar invagination, and arachnoid cysts. All patients had odontoid hypoplasia and degenerative features of the neuroaxis, and 8 had spinal cord compression. Borlot et al. (2014) recommended thorough neurologic examination and imaging of all patients with MPS IVA.

診断
● Danes and Bearn (1967)は,Morquio 症候群の6家系の患者の線維芽細胞で,異染性 (metachromasia) の証拠を発見できなかった
 反対に,他の型のムコ多糖症患者からの線維芽細胞は,metachromasia を示した
 Danes and Bearn (1967) noted that classic Morquio syndrome involves only the skeletal system and postulated that had tissue from the cornea, cartilage, or growing bone been examined, metachromasia may have been present. Based on the findings, the authors suggested that Morquio syndrome should not be classified as a generalized mucopolysaccharidosis.

Nelson et al. (1988) found that examination of urinary glycosaminoglycans by a 2-dimensional electrophoresis technique was a reliable and efficient diagnostic assay with no false-negative results.

Prenatal Diagnosis
Beck et al. (1992) made the diagnosis of MPS IVA in a fetus at 23 weeks of gestation. A previously born child was affected. Ultrasound showed moderate ascites, and keratan sulfate was found in the amniotic fluid. The diagnosis was confirmed after pregnancy termination.

Clinical Management
Hendriksz et al. (2014) reported the outcome of a phase 3 randomized placebo-controlled study of elosulfase alfa administered to 176 patients over the age of 5 years with Morquio A syndrome. These patients were randomized (1:1:1) to receive elosulfase alfa 2.0 mg/kg every other week, elosulfase alfa 2.0 mg/kg/week, or placebo for 24 weeks. The primary efficacy measure was a 6-minute walk test distance. Secondary efficacy measures were a 3-minute stair climb test, followed by changes in urine keratan sulfate. Hendriksz et al. (2014) found that elosulfase alfa improved endurance as measured by the 6-minute walk test in the weekly, but not in the every-other-week, dose group; it did not improve endurance on the 3-minute stair climb test, but it did reduce urine keratan sulfate and had an acceptable safety profile.

Charrow et al. (2015) reviewed consensus recommendations for diagnostic evaluation, monitoring, and perioperative management of spinal cord compression that were developed by a multinational, multidisciplinary panel of experts to assess patients with Morquio syndrome.

Hendriksz et al. (2018) reported the outcome of 2 sequential open label studies on treatment with elosulfase alfa in patients with Morquio A syndrome. The first study involved escalating doses of elosulfase alfa of 0.1, 1.0, and 2.0 mg/kg/week in 20 patients, followed by a long-term extension study of 2.0 mg/kg/week in 17 of the first-study participants. Hendriksz et al. (2018) found that urinary keratin sulfate decreased concurrently with increasing doses of elosulfase alfa. Disease stabilization was suggested, as study participants did not seem to have the progressive clinical deterioration that would be expected in an untreated natural history population. Antidrug antibodies were identified in all patients, but this was not associated with changes in clinical parameters, urine keratin sulfate content, or adverse events. There was a favorable safety profile over the 5 years of the studies.

Molecular Genetics
In patients with MPS IVA, Tomatsu et al. (1992) identified 4 different mutations in the GALNS gene (612222.0001-612222.0004).

In 5 unrelated Japanese patients with MPS IVA, Hori et al. (1995) found, in heteroallelic state, 2 separate deletions of nearly 8.0 and 6.0 kb in the GALNS gene. There were Alu repetitive elements near the breakpoints of the 8.0-kb deletion; this deletion had clearly resulted from an Alu-Alu recombination. The 6.0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at the deletion breakpoints. This was the first documentation of a frequently occurring double deletion in a gene that is not a member of a gene cluster. One of the patients was homozygous for the double deletion, and the others were heterozygous. In the 4 heterozygous patients, Tomatsu et al. (1996)identified novel mutations in the GALNS gene on the other allele: 1 nonsense and 3 missense.

Bunge et al. (1997) performed mutation analysis of the GALNS gene in 35 patients with MPS IVA from 33 families, mainly of European origin. By nonradioactive SSCP screening, they identified 35 different gene mutations, 31 of them novel. Together they accounted for 88.6% of the disease alleles of the patients investigated. The great majority of the gene alterations proved to be point mutations, 23 missense, 2 nonsense, and 3 affecting splicing. Six small deletions (1 to 27 bp) and 1 insertion were also characterized. In a Polish family, 2 mildly affected sibs were compound heterozygous for 2 mutations in the GALNS gene: R94G (612222.0008) and R259Q (612222.0009). Their mother, who was homozygous for the R259Q mutation, was found to have greatly reduced enzymatic activity, but only limited manifestations of MPS IVA: short trunk with slight prominence of sternum, and hoarse voice. She had no corneal clouding and was 1.60 m tall.

Analyzing DNA from 21 patients of diverse ethnic and geographic origins by SSCP and sequencing,Tomatsu et al. (1997) detected 16 mutations in the GALNS gene, including 14 new mutations (11 missense, 1 premature termination, 1 splice site alteration, and 1 cryptic site alteration). All 12 missense and nonsense mutations were shown by transient expression to abolish or greatly reduce GALNS activity, thereby providing an explanation as to why they produce MPS IVA. All mutations were readily confirmed by restriction enzyme or allele-specific oligonucleotide analysis. These findings, coupled with previously reported mutations, brought the total of different mutations to 41 among independent families with Morquio syndrome.

Tomatsu et al. (2005) summarized information on 148 unique mutations in the GALNS gene, including 26 novel mutations. Heterogeneity in GALNS mutations accounted for an extensive clinical variability within MPS IVA. They noted that 7 nonsynonymous SNPs and 9 synonymous SNPs had been described. Of the analyzed mutant alleles, missense mutations accounted for 78.4%; small deletions, 9.2%; nonsense mutations, 5.0%; large deletions, 2.4%; and insertions, 1.6%. Transitional mutations at CpG dinucleotides accounted for 26.4% of all the described mutations. Three missense mutations accounted for over 5% of all mutations: R386C (612222.0003), G301C (612222.0010), and I113F (612222.0005).

Caciotti et al. (2015) studied 37 Italian MPS IVA patients and found that standard sequencing procedures failed to characterize the second disease-causing mutation in 16% of patients. Searching for large rearrangements and mRNA defects in this 16% identified splicing defects or large deletions on the other allele in 67% of these. Caciotti et al. (2015) reported 14 novel mutations in GALNS among the 37 patients.

Morquio Syndrome and APRT Deficiency
Wang et al. (1999) described a Czech patient with Morquio syndrome and adenine phosphoribosyltransferase (APRT; 102600) deficiency with subsequent 2,8-dihydroxyadenine urolithiasis, both of which were caused by a 100-kb deletion on chromosome 16q24.3 with breakpoints in intron 2 of the GALNS gene and intron 2 of the APRT gene. Fukuda et al. (1996) described a Japanese patient with a submicroscopic deletion involving GALNS and APRT in one chromosome and a point mutation in the other GALNS allele (R386C; 612222.0003). Wang et al. (1999) concluded that APRT is located telomeric to GALNS on 16q24.3, that GALNS and APRT are transcribed in the same orientation (centromeric to telomeric), and that combined APRT/GALNS deficiency may be more common than hitherto realized.

Genotype/Phenotype Correlations
Sukegawa et al. (2000) studied 15 missense mutations and 2 newly engineered active site mutations (C79S, C79T) in the GALNS gene by transient expression analysis. Mutant proteins, except for C79S and C79T, were destabilized and detected as insoluble precursor forms, while the C79S and C79T mutants were of a soluble mature size. Mutations identified in patients with the severe phenotype had no activity, whereas mutations identified in patients with the mild phenotype had a considerable residual activity (1.3-13.3% of wildtype GALNS activity). Sukegawa et al. (2000) also constructed a tertiary structural model of human GALNS from the x-ray crystal structure of homologous sulfatases and investigated 32 missense mutations. The authors proposed 3 different biochemical models for the severe phenotype: (i) destruction of the hydrophobic core or modification of the packing; (ii) removal of a salt bridge to destabilize the entire conformation; (iii) modification of the active site. In contrast, mild mutations were mostly located on the surface of the GALNS protein.

Population Genetics
In British Columbia, between 1952 and 1986, 6 cases of MPS IVA were observed, yielding a frequency of 1 in 216,412 live births (Lowry et al., 1990).

Using multiple ascertainment sources, Nelson et al. (2003) obtained an incidence rate for MPS IVA in western Australia for the period 1969 to 1996 of approximately 1 in 640,000 live births.

Wang et al. (2010) identified 27 GALNS mutations, including 16 novel mutations, among 24 Chinese patients with MPS IVA. Approximately 63% of the mutations found in the Chinese patients were not observed in other countries, suggesting that a different mutational spectrum may exist in the Chinese population. The most common mutation G340D (612222.0018) was present in 8 (16.7%) of 48 mutant alleles and was found only in 5 patients from central eastern China. Haplotype analysis indicated a founder effect.

Khan et al. (2017) analyzed the epidemiology of the mucopolysaccharidoses in Japan and Switzerland and compared them to similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II (309900), accounting for 55% of all MPS. MPS I (see 607014), III (see 252900), and IV accounted for 15%, 16%, and 10%, respectively. MPS VI (253200) and VII (253220) were more rare and accounted for 1.7% and 1.3%, respectively. A retrospective epidemiologic data collection was performed in Switzerland between 1975 and 2008 (34 years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12%, 24%, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3% and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS was also reported to be higher in these countries.

History
Wiedemann (1992) provided a biographic sketch of Luis Morquio (1867-1935) of Montevideo. Chudley and Chakravorty (2002) published illustrations of 2 Uruguayan postal stamps honoring Morquio, one issued in 1969 and the other in 2001.

Bernal and Briceno (2006) examined pottery artifacts from the Tumaco-La Tolita culture, which existed on the border of present-day Colombia and Ecuador approximately 2,500 years ago, and described multiple figurines of an adult with apparent short stature, coarse facies, short nose, short neck, small thorax, and the left shoulder set higher than the right, findings suggestive of mucopolysaccharidosis IV.Bernal and Briceno (2006) believed these artifacts to be among the earliest artistic representations of disease.

Animal Model
Tomatsu et al. (2003) generated transgenic mice homozygous for a disruption in exon 2 of the Galns gene. These mice had no detectable GALNS enzyme activity, showed increased urinary glycosaminoglycan levels, and accumulated glycosaminoglycans in multiple tissues including liver, kidney, spleen, heart, brain, and bone marrow. At 2 months old, lysosomal storage was present primarily within reticuloendothelial cells. By 12 months old, vacuolar change was observed in glomeruli and heart valves. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage, and keratan sulfate and chondroitin-6-sulfate were more abundant in corneal epithelial cells of Galns -/- mice. Surprisingly, radiographs revealed no change in the skeletal bones of mice up to 12 months old.

Tomatsu et al. (2008) found that weekly treatment of MPS IVA mice for 12 weeks with enzyme replacement using native GALNS or SUMF1-modified GALNS resulted in clinical improvement, manifest by a marked reduction of storage material in visceral organs, bone marrow, heart valves, ligaments, and connective tissue. Pharmacokinetics and biodistribution were assessed and found to be similar for the 2 GALNS enzymes used. There was a dose-dependent clearance of storage material observed in brain, and blood keratan sulfate was reduced to nearly normal levels. The study provided proof of concept for enzyme replacement therapy in MPS IVA.

Tomatsu et al. (2008) had noted lack of improvement in bone pathology in MPS IVA mice treated with long-term enzyme replacement therapy (ERT). Tomatsu et al. (2015) administered recombinant enzymes to newborn mice: the first injection was administered intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from the fifth to fourteenth weeks were intravenous into the tail vein. MPS4A mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was better organized than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to treatment. Levels of serum keratan sulfate were kept normal in newborn ERT-treated mice. Tomatsu et al. (2015) concluded that the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice.

(ノート 2)
●1929年, Morquio と Brailsford は, 別々に短躯小人症, 進行性脊椎変形, 短形, 鳩胸, 外反膝, 扁平足, 歯状突起低形成および正常智能が特徴の疾患をもつ症例を報告した
 臨床的および, 後に生化学的および分子遺伝学的異質性が 早いもので1931年 Dale により, 後にその他により証明された (Guiney WB Jr, Stevenson RE 1982, Hecht JT et al 1984, Nelson J et al 1988)
 1960年頃, 本疾患は, glycosaminoglycan KS のリソソーム蓄積と尿中排泄が原因のMPSとして認知された
●Matalon et al (1974) は, KS を分解する酵素である galactosamine-6-sulfate sulfatase 欠乏が原因のより多い重症型 (MPS IVA)を発見した (Singh J et al 1976)
●Arbisser et al (1977) は, N-acetylgalactosamine-6-sulfate sulfatase 正常だがリソソーム B-galactosidase が欠乏の患者1例を記載した
 この一般的に軽症な疾患は MPS IVB として知られ, 数例で報告されている (Arbisser et al 1977, Glossl J et al 1981, Groebe H et al 1980, Holzgreve W et al 1981, Ishii N et al 1995, Van der Horst GTJ et al 1983)
 しかし, 全例が軽症とは限らない (Holzgreve W et al 1981, Von Noorden GK et al 1983)
 beta-galactosidase は事実原発性障害であり, 内在性インヒビターの欠損と両親での中間酵素レベルにより示された (Groebe H et al 1980, Spranger 1977)
●Maroteaux et al (1982) は, Morquio 症候群に一致する臨床像をもつが, N-acetylgalactosamine-6-sulfate sulfatase および beta-galactosidase 活性が正常な2例を記載した
●FISH により, galactosamine-6-sulfate sulfatase は16q24.3 にマップされた (Baker 1993, Tomatsu S et al 1996)

●MPS IVA は, その後, 重症, 中間および軽症型さえもつことが示された (Cole DE et al 1996, Hecht JT et al 1984, Nelson J, Kinirons M 1988, Nelson J, Thomas PS 1988, Nelson J et al 1988, Van der Horst GTJ et al 1983)
 →異なるアレルが関与する
 重症度の違いは, 数例での neuraminidase 活性の合併によっても説明されるかもしれない (Glossl J et al 1981)
 分子遺伝学では, アレル異質性が証明されており, 顕著のようにみえる (Bunge S et al 1997, Sukegawa K et al 2000, Tomatsu S et al 1997)
 非常に多くの変異が異なる集団で報告されている
 →例, ミスセンス変異, ナンセンス変異, 埋没部位変化, 早期終止
(Hori T et al 1995, Kato Z et al 1997, Hori T et al)
 Morquio 症候群の全型が常染色体劣性遺伝である
 MPS IVA の頻度は約1/76, 000 (Nelson 1997) 〜 1/216, 400 (Lowry RB et al 1990) と推定されている
 MPS IVB の頻度は不明であるが, MPS IVA よりまれである

MPS IVA
●IVA 型は3つの重症度をもつ
 歯所見は全ての型に存在する (Gardner 1975, Nelson J, Kinirons M 1988, Nelson J, Thomas PS 1988, Nelson J et al 1988)

顔貌
●顔貌は特異的ではないが, 顔の下半分は頸部短縮と過伸展のため顕著であることが多い

筋骨格系
●短頸と短躯, および少しだが短い四肢のため身長が減少する
 成人身長は 100 cm を越えることはまれである (80-120 cm)
 頭は本質的に正常であるが, 軽度の舟状頭が頭蓋縫合早期癒合のため存在するかんもしれない
 頭は肩に直接のっているようにみえる
 頸部は非常に短縮し, 頸椎湾曲の誇張と運動制限を伴う (Dale 1931, Ransford A et al 1996, Stevens JM et al 1991)

●頸髄症が重要な合併症である (Mikles M, Stanton RP 1997, Northover H et al 1996)
 頸部 MRI は頸椎圧迫が症状や兆候により示唆されるより顕著かもしれないことを示している (Hughes DG et al 1997)
 2年目以後, 胸部は著明な後弯または後側弯, 脊椎全般の平坦化, 特徴的鳩胸, 鎖骨接合部からほぼ水平に伸び中央部が下に曲がる胸骨を示す
 腰椎部は, 突背様後弯を示すことが多い
 →よりまれに第1腰椎領域の前腕を示す
 脊髄圧迫は, 環軸椎脱臼の合併症として上部頸部に, または胸腰部突背に生じうる (Blaw ME, Langer LO 1969)
 →死亡となるかもしれない

●四肢は不均衡に長いようにみえる
 関節過動性があるかもしれない
 手関節は通常拡大している
 外反膝, 肥厚した膝関節, 扁平足がほぼ一定した所見である
 肢位は凖クラウチングである
 通常, 著明な太鼓腹である
 X線学的には, 全般性扁平脊椎と, 第12胸椎と第1腰椎低形成, 外反股, 腸骨フレア, 進行性大腿骨頭平坦化と断片化がみられる
 若年症候群にでは, 椎体骨は卵型で上部寛骨臼は骨化欠乏がある
 歯状突起は低形成または欠損している
 第2〜第5中手骨基部は円錐形であるが, 軸は正常に狭窄している (Langer LO, Carey LS 1966)
 橈骨と尺骨の遠位端は, 互いに傾斜している
 全骨は著明に骨粗鬆症である

他の所見
●角膜は緩徐であるがびまん性に混濁している
 →霞んでいる形
 this is rarely obvious to the unaided eye before the tenth year of life. Glaucoma may develop (Cahane M et al 1990, Von Noorden GK et al 1983), as well as cataracts (Olsen H et al 1993). Progressive hearing loss usually begins in adolescence. Intelligence is nearly always normal. Mitral and aortic regurgitation have been reported (Wippermann C-F et al 1995).

MPS IVB.
● MPS IVA の患者と反対に,MPS IVB の患者は有意に軽症表現型をもつ
 彼らは,正常知能,軽度の多発性異骨症,軽度の鳩胸,角膜混濁,歯状突起低形成,中等度の腰椎後弯および最小の外反膝をもつ
 X線は,腰椎の扁平脊椎と舌様突出を示す
 C2-C3 亜脱臼が知られている
 典型的には,患者は正常な聴覚をもち,心雑音はもっていない
 角膜混濁は明らか,またはスリットランプ検査が繊細な角膜沈着を観察するのに必要かもしれない
 疾患の臨床発症は不安定なよたよた歩行が特徴であることが多い

口症状
● MPS IVA の患者では,乳歯と永久歯の両方が鈍い,灰色の歯冠と小孔のあるエナメル質をもつ
 →エナメル質は非常に薄く,はげ落ちる傾向があり,歯の間に小さな間隙を生じる (Nelson J, Kinirons M 1988, Rolling I et al 1999)
 咬頭は小さく平坦で形成不全があり,齲歯が多い (Gardner 1975, Sela M et al 1975)
 下顎関節頭は平坦または凹かもしれない
 反対に,MPS IVB ではエナメル質は正常にみえ,2つのタイプの臨床的区別する手段となる
 MPS IVB 患者は幅広い口蓋と歯間隔離をもつ傾向がある

鑑別診断.
●Practically all types of short-spine dwarfism have been confused with Morquio syndrome. In contrast to Morquio syndrome, achondroplasia is usually apparent at birth, with skeletal changes entirely different from those in MPS IVA. MPS l-H has radiographic similarities to Morquio syndrome during the first few years of life, but mentality is reduced and the gross physical appearance is strikingly characteristic. Although corneal clouding and hearing loss were thought to be the distinguishing factors, they are also features of Morquio syndrome (Von Noorden GK et al 1983). Multiple epiphyseal dysplasia, a dominantly inherited disorder, may also simulate Morquio syndrome, but spinal involvement, if present, is of a lesser degree.

Diastrophic dysplasia is characterized by progressive kyphoscoliosis, but normal vertebral body height, micromelia, clubfoot, widening of metaphyses and epiphyses of long bones, some limitation of joint motion, and thickened pinnae easily distinguish Morquio syndrome. Children with metatropic dysplasia at first exhibit a long-trunked and later a short-trunked dwarfism. The disorder is characterized by progressive kyphoscoliosis and anisospondyly without hypoplasia of the last thoracic and first lumbar vertebral bodies.

Spondyloepiphyseal dysplasia congenita, a type II collagen defect, inherited as a dominant trait, is a short-trunk dwarfism. There is platyspondyly but little or no involvement of the hands and feet, no corneal clouding, and no keratansulfaturia. Myopia is often severe. Rickets and hypophosphatasia should also be considered.

Individuals with Dyggve-Melchior-Clausen syndrome somewhat resemble those with Morquio disease in skeletal alterations but do not have corneal clouding, do not excrete KS in the urine, and are usually mentally retarded. They do not have enamel deficiency. Pointing of the proximal metacarpals does not occur. There is neither hypoplasia of the odontoid process nor of the inferior thoracic and lumbar vertebrae. The iliac crest has a lacy border. The disorder has autosomal recessive inheritance. Since several patients have had normal intelligence (Smith-McCort dysplasia), this disorder has genetic heterogeneity (Nakamura K et al 1997).

Congenital dysplasia of the odontoid process with atlantoaxial dislocation can be seen in a number of disorders: Morquio syndrome, Aarskog syndrome, Dyggve-Melchior-Clausen syndrome, pseudoachondroplasia, cartilage-hair hypoplasia, spondyloepiphyseal dysplasia congenita, and spondylometaphyseal dysplasia.

Laboratory findings.
Marked excretion of KS in the urine in childhood is a constant feature but excretion diminishes markedly by the teenage years in MPS IVA. Some younger patients with MPS IVB do not excrete KS (Fujimoto A, Horwitz AL 1983, Jenkins P et al 1973, Norman 1974). N-acetylgalactosamine-6-sulfatase may be determined in cultured fibroblasts, isolated leukocytes, cultured amniotic cells, and chorionic villi (Yuen M, Fensom AH 1985). The same applies to mutational analyses (Hopwood JJ, Morris CP 1990, Ogawa T et al 1995, Van Diggelen OP et al 1990), postnatally as well as prenatally., beta-Galactosidase may be assayed using a p-nitrophenyl or 4-methylumbelliferyl beta-galactoside (Arbisser AI et al 1977). Marked excretion of KS in the urine, in childhood, is a constant feature of MPS type IVA (Glossl J et al 1981). It slowly decreases, reaching normal levels in adults. Usually coarse granular inclusions may be found in peripheral neutrophilic granulocytes and fibroblasts exhibit metachromasia. Ultrastructural studies of epiphyseal plates (Jenkins P et al 1973) and brain (Kato Z et al 1997) have been described. Prenatal diagnosis has been carried out (Kleijer WJ et al 2000, Zhao H et al 1990).


(文献)
(1) Brailsford JF: Chondro-osteo-dystrophy: roentgenographic and clinical features of child with dislocation of vertebrae. Am J Surg 7: 404-410, 1929
(2) Morquio L. Sur une forme de dystrophie osseuse familiale. Bull Soc Pediat Paris 27: 145-152, 1929
(3) Morquio L: Sur une forme de dystrophie osseuse familiale. Arch Med Enf 32:129-140, 1929
(4) Dale F: Unusual forms of familial osteochondrodystrophie. Acta Radiol 12:337-358, 1931
(5) Von Noorden GK et al. Ocular findings in Morquio-Ullrich's disease. Arch Ophthal 64: 585-591, 1960
(6) Maroteaux P, Lamy M. Opacites corneennes et troubles metaboliques dans la maladie de Morquio. Rev Franc Etud. Clin Biol 6: 481-483, 1961
(7) Zellweger H et al. Morquio-Ullrich's disease: report of 2 cases. J Pediat 59: 549-561, 1961
(8) Pedrini V et al. Isolation and identification of keratosulphate in urine of patients affected by Morquio-Ullrich disease. Proc Soc Exp Biol Med 110: 847-849, 1962
(9) Robins MM et al. Morquio's disease: an abnormality of mucopolysaccharide metabolism. J Pediat 62: 881-889, 1963
(10) Langer LOJr, Carey LS: The roentgenographic features of the KS mucopolysaccharidosis of Morquio (Morquio-Brailsford's disease). Am J Roentgen 97: 1-20, 1966
(11) Greenberg AD: Atlantoaxial dislocations. Brain 91: 655-684, 1968
(12) Blaw ME, Langer LOJr: Spinal cord compression in Morquio-Brailsford's disease. J Pediat 74: 593-600, 1969
(13) Linker A et al. Morquio's disease and mucopolysaccharide excretion. J Pediat 77: 1039-1047, 1970
(14) McKusick VA: Non-keratan-sulfate-excreting Morquio syndrome. In (eds.): Heritable Disorders of Connective Tissue. St. Louis: C. V. Mosby, Pp. 600-604, 1972
(15) Gadbois P et al. La maladie de Morquio dans la province de Quebec. Un. Med Canada 102: 602-607, 1973
(16) Jenkins P et al: Morquio-Brailsford disease. A report of four affeeted sisters with absenee of exeessive keratan sulfate in the urine. Br J Radiol 46:668-675, 1973
(17) Hussels I: Morquio syndrome in a woman with two normal children. In Bergsma D. (eds.): Skeletal Dysplasias. Amsterdam: Excerpta Medica, Pp. 465-466, 1974
(18) Matalon R et al. Morquio's syndrome: a deficiency of chondroitin sulfate N-acetylhexosamine sulfate sulfatase. Pediat Res 8: 436, 1974
(19) Matalon R et al: Morquio's syndrome: Deficiency of a chondroitin sulfate N-acetylhexosamine sulfate sulfatase. Biochem Biophys Res Commun 61:759-765, 1974
(20) Norman ME: Two brothers with nonkeratan sulfate-excreting Morquio syndrome. Birth Defects 10(12):467 469, 1974
(21) Gardner DG: The dental manifestations of the Morquio syndrome (MPS type IV): A diagnostic aid. Am J Dis Child 129:1445-1448, 1975
(22) Levin LS et al. Oral findings in the Morquio syndrome (mucopolysaccharidosis IV). Oral Surg Oral Med Oral Path 39: 390-395, 1975
(23) Sela M et al: Oral manifestations of Morquio's syndrome. Oral Surg 39:583-589, 1975
(24) McKusick VA: Osler as a medical geneticist. Johns Hopkins Med J 139: 163-174, 1976
(25) Singh J et al. N-acetylgalactosamine-6-sulfate sulfatase in man: absence of the enzyme in Morquio disease. J Clin Invest 57: 1036-1040, 1976
(26) Arbisser AI et al: Morquio-like syndrome with beta-galactosidase deficiency and normal hexosamine sulfatase activity: Mucopolysaccharidosis IVB . Am J Med Genet 1:195-205, 1977
(27) Riedner ED, Levin LS: Hearing patterns in Morquio's syndrome (mucopolysaccharidosis IV). Arch Otolaryng. 103: 518-520, 1977
(28) Spranger JW: Beta-galactosidase and the Morquio syndrome. Am J Med Genet 1:207-209, 1977
(29) DiFerrante NM et al. Deficiencies of glucosamine-6-sulfate or galactosamine-6-sulfate sulfatases are responsible for different mucopolysaccharidoses. Science 199: 79-81, 1978
(30) Glossl J et al. Morquio's disease type A: absence of material cross reacting with antibodies against N-acetylgalactosamine-6-sulfate sulfatase. Hum Genet 54: 87-91, 1980
(31) Groebe H et al: Morquio syndrome (mucopolysaccharidosis IVB) associated with beta-galactosidase deficiency. Report of two cases. Am J Hum Genet 32:258-272, 1980
(32) Glossl J et al: Different properties of residual N-acetylgalactosamine-6-sulfate sulfatase in fibroblasts form mild and severe forms of Morquio disease type A. Pediatr Res 15:976-978, 1981
(33) Holzgreve W et al. Morquio syndrome: clinical findings in 11 patients with MPS IVA and 2 patients with MPS IVB. Hum Genet 57: 360-365, 1981
(34) Edwards MK et al: CT metrizamide myelography of the cervical spine in Morquio syndrome. AJNR Am J Neuroradiol 3:666 669, 1982
(35) Guiney WBJr, Stevenson RE: Morquio disease (MPS IV) with survival to age 67 years. Proc Greenwood Genet Center 1: 84-87, 1982
(36) Maroteaux P et al. Heterogeneite des formes frustes de la maladie de Morquio. Arch Franc Pediat 39: 761-765, 1982
(37) Fujimoto A, Horwitz AL: Biochemical defect of non-keratan-sulfate excreting Morquio syndrome. Am J Med Genet 15:265-273, 1983
(38) Guibaud P et al: Morquio syndrome moderated by beta galactosidase deficiency. Mucopolysaccharidosis (type IV B) or oligosaccharidosis. Ann Pediatr 30:681-686, 1983
(39) Van Der Horst GTJ et al. Morquio B syndrome: a primary defect in beta galactosidase. Am J Med Genet 16: 261-275, 1983
(40) Van Gemund JJ et al. Morquio-B disease, spondyloepiphyseal dysplasia associated with acid beta-galactosidase deficiency. Report of three cases in one family. Hum Genet 64: 50-54, 1983
(41) Von Noorden GK et al: Ocular findings in the Morquio-Ullrich's disease. Arch Ophthalmol 64:581-591, 1983
(42) Glossl J et al. Partial deficiency of glycoprotein neuraminidase in some patients with Morquio disease type A. Pediat Res 18: 302-305, 1984
(43) Hecht JT et al. Mild manifestations of the Morquio syndrome. Am J Med Genet 18: 369-371, 1984
() Lowry RB et al. Morquio syndrome (MPS IVA) and hypophosphatasia in a Hutterite kindred. Am J Med Genet 22: 463-475, 1985
(44) Yuen M, Fensom AH: Diagnosis of classical Morquio's disease: N-acetylgalactosamine 6-sulphate sulphatase activity in cultured fibroblasts, leukocytes, amniotic cells and chorionic villi. J Inherit Metab Dis 8: 80-86, 1985
(45) Beck M et al. Heterogeneity of Morquio disease. Clin Genet 29: 325-331, 1986
(46) Beck M et al. Morquio's disease type B (B-galactosidase deficiency) in three siblings. S Afr Med J 72: 704-708, 1987
(47) Gibson GJ et al. Human N-acetylgalactosamine-4-sulphate sulphatase: purification, monoclonal antibody production and native and subunit M(r) values. Biochem J 248: 755-764, 1987
(48) Giugliani R et al. Progressive mental regression in siblings with Morquio diusease type B (mucopoysaccharidosis IVB). Clin Genet 32: 313-325, 1987
(49) Wraith JE et al. The mucopolysaccharidoses. Aust Paediat J 23: 329-334, 1987
(50) Nelson J et al. Clinical findings in 12 patients with MPS IV A (Morquio's disease): further evidence for heterogeneity. Part I: clinical and biochemical findings. Clin Genet 33: 111-120, 1988
(51) Nelson J et al. Clinical findings in 12 patients with MPS IV A (Morquio's disease): further evidence for heterogeneity. Part II: dental findings. Clin Genet 33: 121-125, 1988
(52) Nelson J et al. Clinical findings in 12 patients with MPS IV A (Morquio's disease): further evidence for heterogeneity. Part III: odontoid dysplasia. Clin Genet 33: 126-130, 1988
(53) Cahane M et al. Glaucoma in siblings with Morquio syndrome. Brit J Ophthal 74: 382-383, 1990
(54) Hopwood JJ, Morris CP: The mueopolysaeeharidoses. Diagnosis, moleeular geneties and treatment. Mol Biol Med 7:381-404, 1990
(55) Lowry RB et al. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet 85: 389-390, 1990
(56) Van Diggelen OP et al: A fluorimetric enzyme assay for the diagnosis of Morquio disease type A (MPS IVA). Clin Chim Acta 187:131-140, 1990
(57) Zhao H et al. Prenatal diagnosis of Morquio disease type A using a simple fluorometric enzyme assay. Prenatal Diagn 10: 85-92, 1990
(58) Stevens JM et al: The odontoid proeess in Morquio-Brailsford's disease: The effeets of oeeipitoeervieal fusion. J Bone Joint Surg Br 73:851-858, 1991
(59) Tomatsu S et al. Morquio disease: isolation, characterization and expression of full-length cDNA for human N-acetylgalactosamine-6-sulfate sulfatase. Biochem Biophys Res Commun 181: 677-683, 1991
(60) Beck M et al. Fetal presentation of Morquio disease type A. Prenatal Diag. 12: 1019-1029, 1992
(61) Fukuda S et al. Mucopolysaccharidosis type IVA: N-acetylgalactosamine-6-sulfate sulfatase exonic point mutations in classical Morquio and mild cases. J Clin Invest 90: 1049-1053, 1992
(62) Tomatsu S et al. Mucopolysaccharidosis type IVA: characterization and chromosomal localization of N-acetylgalactosamine-6-sulfate sulfatase gene and genetic heterogeneity. Am J Hum Genet 51 (suppl.): A178, 1992
(63) Wiedemann H-R. The pioneers of pediatric medicine: Luis Morquio (1867-1935). Europ J Pediat 151: 549, 1992
(64) Baker E et al. The Morquio A syndrome (mucopolysaccharidosis IVA) gene maps to 16q24.3. Am J Hum Genet 52: 96-98, 1993
(65) Masuno M et al. Mucopolysaccharidosis IV A: assignment of the human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene to chromosome 16q24. Genomics 16: 777-778, 1993
(66) Olsen H et al: Cataracts in Morquio syndrome (mucopolysaccharidosis IVA). Ophthalmol Paediatr Genet 14:87-89, 1993
(67) Nakashima Y et al. Mucopolysaccharidosis IV A: molecular cloning of the human N-acetylgalactosamine-6-sulfatase gene (GALNS) and analysis of the 5-prime-flanking region. Genomics 20: 99-104, 1994
(68) Tomatsu S et al. A novel splice site mutation in intron 1 of the GALNS gene in a Japanese patient with mucopolysaccharidosis IVA. Hum Mol Genet 3 (8): 1427-8, 1994
(69) Hori T et al. Mucopolysaccharidosis type IVA: common double deletion in the N-acetylgalactosamine-6-sulfatase gene (GALNS). Genomics 26: 535-542, 1995
(70) Ishii N et al: Clinieal and moleeular analysis of a Japanese boy with Morquio B disease. Clin Genet 48:103-108, 1995
(71) Iwata H et al. Mucopolysaccharidosis IVA: polymorphic haplotypes and informative RFLPs in the Japanese population. Hum Genet 95 (3): 257-64, 1995
(72) Ogawa T et al. Mucopolysaccharidosis IVA: screening and identification of mutations of the N-acetylgalactosamine-6-sulfate sulfatase gene. Hum Mol Genet 4 (3): 341-9, 1995
(73) Tomatsu S et al. Mucopolysaccharidosis IVA: identification of a common missense mutation I113F in the N-Acetylgalactosamine-6-sulfate sulfatase gene. Am J Hum Genet 57 (3): 556-63, 1995
(74) Tomatsu S et al. Mucopolysaccharidosis IVA: structural gene alterations identified by Southern blot analysis and identification of racial differences. Hum Genet 95 (4): 376-81, 1995
(75) Tomatsu S et al. Two new mutations, Q473X and N487S, in a Caucasian patient with mucopolysaccharidosis IVA (Morquio disease). Hum Mutat 6: 195-196, 1995
(76) Wippermann C-F et al: Mitral and aortic regurgitation in 84 patients with mucopolysaccharidoses. Eur J Pediatr 154:98-101, 1995
(77) Cole DE et al: Heteroallelic missense mutations of me galactosamine-6-sulfate sulfatase (GALNS) gene in a mild form of Morquio disease (MPS IVA). Am J Med Genet 63:558-565, 1996
(78) Northover H et al: Mucopolysaceharidosis type IVA (Morquio syndrome): A elinieal review. J Inherit Metab Dis 19:357-365, 1996
(79) Ransford A et al: Oeeipito-atlanto-axial ffision in Morquio-Brailsford syndrome. J Bone Joint Surg Br 78:307-313, 1996
(80) Tomatsu S et al. Mucopolysaccharidosis IVA: four new exonic mutations in patients with N-acetylgalactosamine-6-sulfate sulfatase deficiency. Am J Hum Genet 58: 950-962, 1996
(81) Bunge S et al. Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio A syndrome. Hum. Mutat. 10: 223-232, 1997
(82) Hughes DG et al: MRI of the brain and craniocervical junetion in Morquio's disease. Neuroradiology 39:381-385, 1997
(83) Kato Z et al. A novel common missense mutation G301C in the N-acetylgalactosamine-6-sulfate sulfatase gene in mucopolysaccharidosis IVA. Hum. Genet. 101: 97-101, 1997
(84) Mikles M, Stanton RP: A review of Morquio syndrome. Am J Orthop 26:533-540, 1997
(85) Nakamura K et al: Dyggve-Melchior-Clausen syndrome without mental retardation (Smith-McCort dysplasia): Morphologic findings in the growth plate oftheiliaccrest. AmJMedGenet72:11-17, 1997
(86) Nelson J: Incidence of the mucopolysaccharidoses in Normern Ireland. Hum Genet 101:355-358, 1997
(87) Tomatsu S et al. Fourteen novel mucopolysaccharidosis IVA producing mutations in GALNS gene. Hum. Mutat. 10: 368-375, 1997
(88) Tylki-Szymanska A et al. Clinical, biochemical and molecular findings in a two-generation Morquio A family. Clin. Genet. 53: 369-374, 1998
(89) Yamada N et al. Molecular heterogeneity in mucopolysaccharidosis IVA in Australia and Northern Ireland: nine novel mutations including T312S, a common allele that confers a mild phenotype. Hum. Mutat. 11: 202-208, 1998
(90) Rolling I et al: Dental findings in three siblings with Morquio syndrome. Int J Paediatr Dent 9:219-224, 1999
(91) Wang L et al. Combined adenine phosphoribosyltransferase and N-acetylgalactosamine-6-sulfate sulfatase deficiency. Molec. Genet. Metab. 68: 78-85, 1999
(92) Kleijer WJ et al: First-trimester diagnosis of Morquio disease type A. Prenat Diagn 20:183-185, 2000
(93) Sukegawa K et al. Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes. Hum. Molec. Genet. 9: 1283-1290, 2000
(94) Chudley, A. E.; Chakravorty, C. : Genetic landmarks through philately: Luis Morquio 1867-1935. Clin. Genet. 62: 438-439, 2002
(95) Montano, A. M.; Kaitila, I.; Sukegawa, K.; Tomatsu, S.; Kato, Z.; Nakamura, H.; Fukuda, S.; Orii, T.; Kondo, N. : Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype. Hum. Genet. 113: 162-169, 2003
(96) Nelson, J.; Crowhurst, J.; Carey, B.; Greed, L. : Incidence of the mucopolysaccharidoses in western Australia. Am J Med Genet 123A: 310-313, 2003
(97) Tomatsu, S.; Dieter, T.; Schwartz, I. V.; Sarmient, P.; Giugliani, R.; Barrera, L. A.; Guelbert, N.; Kremer, R.; Repetto, G. M.; Gutierrez, M. A.; Nishioka, T.; Serrato, O. P.; Montano, A. M.; Yamaguchi, S.; Noguchi, A. : Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate. J. Hum. Genet. 49: 490-494, 2004
(98) Tomatsu, S.; Montano, A. M.; Nishioka, T.; Gutierrez, M. A.; Pena, O. M.; Trandafirescu, G. G.; Lopez, P.; Yamaguchi, S.; Noguchi, A.; Orii, T. : Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum. Mutat. 26: 500-512, 2005
(99) Bernal, J. E.; Briceno, I. : Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador. Clin. Genet. 70: 188-191, 2006
(100) Montano, A. M.; Tomatsu, S.; Brusius, A.; Smith, M.; Orii, T. : Growth charts for patients affected with Morquio A disease. Am. J. Med. Genet. 146A: 1286-1295, 2008
(101) Wang, Z., Zhang, W., Wang, Y., Meng, Y., Su, L., Shi, H., Huang, S. Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations. J. Hum. Genet. 55: 534-540, 2010
(102) Borlot, F., Arantes, P. R., Quaio, C. R., Franco, J. F. S., Lourenco, C. M., Gomy, I., Bertola, D. R., Kim, C. A. Mucopolysaccharidosis type IVA: evidence of primary and secondary central nervous system involvement. Am. J. Med. Genet. 164A: 1162-1169, 2014
(103) Hendriksz, C. J., Burton, B., Fleming, T. R., Harmatz, P., Hughes, D., Jones, S. A., Lin, S.-P., Mengel, E., Scarpa, M., Valayannopoulos, V., Giugliani, R., STRIVE Investigators, Slasor, P., Lounsbury, D., Dummer, W. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J. Inherit. Metab. Dis. 37: 979-990, 2014
(104) Caciotti, A., Tonin, R., Rigoldi, M., Ferri, L., Catarzi, S., Cavicchi, C., Procopio, E., Donati, M. A., Ficcadenti, A., Fiumara, A., Barone, R., Garavelli, L., and 16 others. Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio--A syndrome-associated mutations. Hum. Mutat. 36: 357-368, 2015
(105) Charrow, J., Alden, T. D., Breathnach, C. A. R., Frawley, G. P., Hendriksz, C. J., Link, B., Mackenzie, W. G., Manara, R., Offiah, A. C., Solano, M. L., Theroux, M. Diagnostic evaluation, monitoring, and perioperative management of spinal cord compression in patients with Morquio syndrome. Molec. Genet. Metab. 114: 11-18, 2015
(106) Harmatz, P. R., Mengel, K. E., Giugliani, R., Valayannopoulos, V., Lin, S.-P., Parini, R., Guffon, N., Burton, B. K., Hendriksz, C. J., Mitchell, J. J., Martins, A. M., Jones, S. A., Guelbert, N., Vellodi, A., Wijburg, F. A., Yang, K., Slasor, P., Decker, C. Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome. Molec. Genet. Metab. 114: 186-194, 2015
(107) Tomatsu, S., Montano, A. M., Oikawa, H., Dung, V. C., Hashimoto, A., Oguma, T., Gutierrez, M. L., Takahashi, T., Shimada, T., Orii, T., Sly, W. S. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions? Molec. Genet. Metab. 114: 195-202, 2015
(108) Khan, S. A., Peracha, H., Ballhausen, D., Wiesbauer, A., Rohrbach, M., Gautschi, M., Mason, R. W., Giugliani, R., Suzuki, Y., Orii, K. E., Orii, T., Tomatsu, S. Epidemiology of mucopolysaccharidoses. Molec. Genet. Metab. 121: 227-240, 2017
(109) Hendriksz, C., Santra, S., Jones, S. A., Geberhiwot, T., Jesaitis, L., Long, B., Qi, Y., Hawley, S. M., Decker, C. Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment. Molec. Genet. Metab. 123: 479-487, 2018

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