疾患詳細

疾患詳細



軽症型; 重症型; 短い長管骨の軽度の病変; 短い長管骨の重度の短縮と変形と著明な骨端と骨幹端異形成 (Gorlin et al. 1990 より引用)

#253200
Mucopolysaccharidosis VI (MPS6)
(MPS VI)
(Maroteaux-Lamy syndrome)
(Arylsulfatase B deficiency; ARSB deficiency)
(N-acetylgalactosamine-4-sulfatase deficiency)

ムコ多糖症 VI
(Maroteaux-Lamy 症候群)
(アリルスルファターゼB 欠損症)
(N-セチルグルコサミン- 4-スルファターゼ欠損症; ARSB)
指定難病19 ライソゾーム病

責任遺伝子:253200 Arylsulfatase B (ARSB) <5q14.1>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Abnormality of the metaphysis (骨幹端異常) [HP:0000944] [160010]
 Chronic otitis media (慢性中耳炎) [HP:0000389] [014231]
 Coarse facial features (顔貌異常) [HP:0000280] [0408]
 Disproportionate short-trunk short stature (不均衡型短幹性低身長) [HP:0003521] [0130]
 Epiphyseal dysplasia (骨端異形成) [HP:0002656] [160003]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Joint stiffness (関節硬直) [HP:0001387] [15100]
 Mucopolysacchariduria (ムコ多糖症) [HP:0008155] [2066]
 Opacification of the corneal stroma (角膜間質混濁) [HP:0007759] [0620]
 Recurrent upper respiratory tract infections (反復性上気道感染) [HP:0002788] [014230]
 Sinusitis (副鼻腔炎) [HP:0000246] [014232]
 Thick lower lip vermilion (分厚い下口唇) [HP:0000179] [05522]
 Thick nasal alae (分厚い鼻翼) [HP:0009928] [0743]
 
 <30%-79%>
 Broad ribs (幅広い肋骨) [HP:0000885] [16121]
 Genu valgum (外反膝) [HP:0002857] [15112]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hernia (ヘルニア) [HP:0100790] [120]
 Kyphosis (後弯) [HP:0002808] [161502]
 Ovoid vertebral bodies (卵形椎体骨) [HP:0003300] [161511]
 Short neck (短頸) [HP:0000470] [1001]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 
 <5%-29%>
 Abnormal heart valve morphology (心弁形態異常) [HP:0001654] [1120]
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Macroglossia (巨舌) [HP:0000158] [08109]
 Visual impairment (視力障害) [HP:0000505] [06011]
 
 
 Anterior wedging of L1 (L1 前方楔) [HP:0008432] [161505]
 Anterior wedging of L2 (L2 前方楔) [HP:0011941] [161505]
 Aseptic necrosis (無菌性壊死) [HP:0010885] [160018]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Cardiomyopathy (心筋症) [HP:0001638] [0273]
 Cervical myelopathy (頚髄症) [HP:0002318] [0201]
 Constrictive median neuropathy (拘束性正中神経症) [HP:0012185] [0204]
 Depressed nasal bridge (低い鼻梁) [HP:0005280] [0722]
 Dermatan sulfate excretion in urine (尿中デルマタン硫酸排泄) [HP:0008301] [2066]
 Dolichocephaly (長頭) [HP:0000268] [03007]
 Dysostosis multiplex (多発性異骨症) [HP:0000943] [-]
 Flared iliac wings (腸骨翼フレア) [HP:0002869] [1142]
 Glaucoma (緑内障) [HP:0000501] [06606]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hip dysplasia (股関節異形成) [HP:0001385] [1140]
 Hirsutism (多毛) [HP:0001007] [17112]
 Hydrocephalus (水頭症) [HP:0000238] [03010]
 Hypoplasia of the odontoid process (歯状突起低形成) [HP:0003311] [161515]
 Hypoplastic acetabulae (寛骨臼低形成) [HP:0003274] [1143]
 Hypoplastic iliac wing (腸骨翼低形成) [HP:0002866] [1142]
 Inguinal hernia (鼠径ヘルニア) [HP:0000023] [1201]
 Lumbar hyperlordosis (腰部前弯) [HP:0002938] [161501]
 Macrocephaly (大頭) [HP:0000256] [03012]
 Metaphyseal irregularity (不規則な骨幹端) [HP:0003025] [160010]
 Metaphyseal widening (幅広い骨幹端) [HP:0003016] [160010]
 Prominent sternum (目立つ胸骨) [HP:0000884] [11011]
 Split hand (裂手) [HP:0001171] [15203]
 Umbilical hernia (臍ヘルニア) [HP:0001537] [1201]
 
 (UR-DBMS)
【一般】*短幹小人症(2-4歳で成長停止); 成人 身長 110-140 cm
 頻回の上気道感染症
 拘束性肺病
 *肝腫, *脾腫
 *知能正常
【神経】頸髄ミエロパチー
 手根管症候群
【頭】大頭, 大きな長頭, 水頭症
【顔】*軽度の 粗い顔貌
 分厚い口唇
 下顎突出
 幅広い口
【眼】緑内障
 *角膜混濁
 視力喪失
【鼻】低い鼻梁
 大きな鼻, 分厚い鼻孔
【口】巨舌
 歯間解離
 灰色気味のエナメル質
 頻回の齲歯
 小歯, 歯萠出遅延
【耳】難聴
【胸郭】目立つ胸骨
 幅広い肋骨, 肋骨フレア
 鳩胸
【心】弁膜症 (大動脈および僧帽弁)
 乳児心筋症
【体幹】鼠径ヘルニア, 臍ヘルニア
【骨盤】股関節異形成
 寛骨臼r 低形成
 小さなSmall, 腸骨翼フレア
 無菌性壊死 of 大腿骨頭
 外反股
【四肢】*関節拘縮
 外反膝
 鷲手変形
 関節弛緩
 手関節尺側偏位
【X線】多発性異骨症
 大きなΩ型トルコ鞍
 目立つ腰部前弯
 歯状突起低形成
 卵形椎体骨
 L1とL2の前方楔形突出
 骨端異形成
 幅広く不規則な骨幹端
 骨粗鬆症
 扁平脊椎
 頸椎亜脱臼
 後弯
 側弯
 尖った近位第2-4中手骨
 J 型 トルコ鞍
 頭蓋底陥入
【毛髪】軽度の多毛
【皮膚】分厚い皮膚
【検査】ムコ多糖尿 (硫酸ケラタン)
 Arylsulfatase B 欠損 (線維芽細胞, 白血球)
【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
【その他】重症型で20歳まで生存
 軽症型〜重症型がある
 出生前診断が可能
 1/238,095 〜 1/300,000 生産児

(要約)
●Maroteaux–Lamy 症候群 (MPS VI)は arylsulfatase B (ARSB)欠乏によるムコ多糖症である
●Maroteaux–Lamy 症候群の小児は, 通常正常な知能発達をもつが, Hurler 症候群でみられる身体症状の多くをもつ
 重症症状の多様なスペクトラムをもつ
 角膜混濁, 難聴, 硬膜肥厚, 神経および神経根圧迫または外傷による疼痛がある
 最初は成長正常であるが, 8歳あたりで突然停止する
 10歳までに, 短躯, クラウチング肢位, 関節運動制限を生じる
 重症例では, 腹部膨満, 前弯を生じる
 特に骨盤の骨格変化は進行性で, 運動を制限する
 臍ヘルニアまたは鼠径ヘルニアをもつものが多い
 ほぼ全例が心臓弁機能障害をもつ
 高度置換療法:galsulfase (Naglazyme)が成長および関節運動改善に成功している (股関節への酵素注入)
 →$350,000/年 (最も高い薬の1つ)

<小児慢性特定疾病 代79 ムコ多糖症Ⅵ型>
概要・定義
N-アセチルガラクトサミン―4-スルファターゼ(アリルスルファターゼB)が先天的に欠損することに起因する常染色体劣性遺伝病である。本症の臨床所見は、成長障害、骨関節症状、心臓弁膜症、角膜混濁などを呈し,ムコ多糖症I型(ハーラー症候群)と類似しているが、知的障害は伴わない。身体所見、発症時期、症状の進行速度により重症型・中間型・軽症型に分類されるが、病型の境界は不鮮明で幅広いスペクトラムを示す。
疫学
きわめてまれな疾患で現在確認されている日本人生存症例は10例以下である。
病因
ライソゾーム内でデルマタン硫酸(DS)を分解するために必要なN-アセチルガラクトサミン―4-スルファターゼ(アリルスルファターゼB)の欠損が原因で、DSが過剰蓄積する。
症状
身体所見は、ハーラー症候群と共通する症状・経過を示すが、知的障害はみられない。
① 骨・関節障害:頸椎軸不安定・亜脱臼による頸髄圧迫、手指の屈曲拘縮(鷲手)、脊椎後弯、股・膝・肘・肩関節の拘縮が認められる。
② 気道障害:胸郭変形による拘束性肺障害、閉塞性肺障害、気管変形・狭小化、巨舌、アデノイド・扁桃肥大、声帯肥厚などが認められ、睡眠時無呼吸、いびき、日中の傾眠傾向、呼吸音の増強、肺胞低換気などをきたす。
③ 眼科的異常:進行性の角膜混濁、緑内障、網膜色素変性を認める。
④ 耳鼻科的異常:反復性の中耳炎を認め、軽度から中等度の混合性難聴を呈する。
⑤ 循環器障害:僧帽弁・大動脈弁を主とした閉鎖不全症、狭窄症などの心弁膜症を認める。
⑥ 神経症状:頭蓋骨底や椎骨変形による脊髄圧迫、水頭症、手根管症候群などを認める。知能は正常である。
⑦ その他:乳児期からの広範な異所性蒙古斑、臍・鼠径ヘルニアを認める。腹部膨隆(肝脾腫大)、特徴的顔貌(頭囲拡大、側頭・前頭の膨隆、鞍鼻、大きく硬い鼻翼、厚い口唇、歯肉肥厚、歯列不整、厚く硬い耳介)が見られる。
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同胞の出生前診断には有用である。
① 画像検査:レントゲン画像において、弾丸様指骨、中手骨の先細り、椎体前面の楔状変形、椎体の扁平化、第2頸椎歯突起低形成、肋骨のオール上変形、大腿骨頭形成不全などの多発性異骨症(Dysostosis Multiplex)が認められる。頭部MRIでは、cribriform(ふるい状)あるいはhoneycomb-like(蜂の巣様)と呼ばれる血管周囲腔の拡大による陰影像が見られる。
② 尿中ウロン酸(グリコサミノグリカン):各年齢における総排泄量の基準値に対して、増加を認める。分画上はDSの異常排泄を認める。
③ 酵素活性:白血球、培養線維芽細胞などでARSB活性低下が認められる。
④ 遺伝子解析:
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
対症療法と原因療法がある。後者としては、造血細胞移植と酵素補充療法がある。
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かなり重症化する。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ので、適宜対症療法を実施する。

(Original) Maroteaux et al. (1963)
(Responsible gene) *611542 Arylsulfatase B (ARSB) <5q14.1>
(1) Mucopolysaccharidosis type VI (253200)
.0001 Mucopolysaccharidosis type VI intermediate [ARSB, GLY137VAL] (rs118203938) (gnomAD:rs118203938) (RCV000677557...) (Wicker et al. 1991)
.0002 Mucopolysaccharidosis type VI severe [ARSB, CYS117ARG] (rs118203939) (gnomAD:rs118203939) (RCV000000926...) (Jin et al. 1992)
.0003 Mucopolysaccharidosis type VI mild [ARSB, LEU236PRO] (rs118203940) (RCV000000927...) (Jin et al. 1992)
.0004 Mucopolysaccharidosis type VI severe [ARSB, CYS405TYR] (rs118203941) (gnomAD:rs118203941) (RCV000723435...) (Jin et al. 1992)
.0005 Mucopolysaccharidosis type VI severe [ARSB, 1-BP DEL, 238G] (rs431905493) (RCV000000929...) (Litjens et al. 1992)
.0006 Mucopolysaccharidosis type VI severe [ARSB, 1-BP DEL, 743C] (rs431905494) (RCV000000930...) (Isbrandt et al. 1996)
.0007 Mucopolysaccharidosis type VI severe [ARSB, 11-BP DEL AND LEU72GLN] (rs397514441) (gnomAD:rs397514441) (RCV000677514...) (Isbrandt et al. 1996)
.0008 Mucopolysaccharidosis type VI [ARSB, ARG95GLN] (rs118203942) (gnomAD:rs118203942) (RCV000078002...) (Litjens et al. 1996)
.0009 Mucopolysaccharidosis type VI [ARSB, TYR210CYS] (rs118203943) (gnomAD:rs118203943) (RCV000078003...) (Litjens et al. 1996)
.0010 Mucopolysaccharidosis type VI [ARSB, HIS393PRO] (rs118203944) (gnomAD:rs118203944) (RCV000424623...) (Litjens et al. 1996)
.0011 Mucopolysaccharidosis type VI [ARSB, IVS5AS, G-C,-1] (rs431905495) (gnomAD:rs431905495) (RCV000000935) (Garrido et al. 2007)
.0012 Mucopolysaccharidosis type VI [ARSB, IVS5AS, T-G, -8] (rs431905496) (gnomAD:rs431905496) (RCV000000936) (Garrido et al. 2007)

*ARSB (Arylsulfatase B)
 Genome size 208,879 bp, Minus strand: 533 aa, 59687 Da
 Exons: 8, Coding exons: 8, Transcript length: 4,852 bps, Translation length: 533
●Arylsulfatase B は sulfatase family に属する
 arylsulfatase B homodimer は,N-Acetyl-D-galactosamine, chondriotin sulfate, および dermatan sulfate の硫酸基を水解する
 タンパクはリゾチームを標的とする
 chondroitin-4-sulfate (C4S) から硫酸基を除去し,その分解を調節する
 細胞接着,細胞移動および結腸上皮での侵入に関与する
 中枢神経では,神経突起の外方正常とニューロン可塑性のレギュレーターである
 →硫酸グリコサミノグリカンとニューロカンのレベルをコントロールすることで作用する
●関係する pathways: Lysosome; Chondroitin sulfate/dermatan sulfate metabolism

(Note)
A number sign (#) is used with this entry because mucopolysaccharidosis type VI (MPS6) is caused by homozygous or compound heterozygous mutation in the ARSB gene (611542) on chromosome 5q14.

Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal (Azevedo et al., 2004).

Clinical Features
Maroteaux et al. (1963) first described this disorder as a novel dysostosis associated with increased urinary excretion of chondroitin sulfate.

Alder (1939) reported a brother and sister who developed changes in the hip joints at puberty. The sibs also had azurophilic cytoplasmic inclusions in polymorphonuclear leukocytes. The boy developed a waddling gait, and both sibs were found to have bony destruction in the shoulders, hips, and skull, and later in the knees and spine. The sister died of an unknown cause. The boy had herniotomy at the age of 36 years, a decompressive laminectomy C1 to C7 at age 50, hip replacement at age 51, and operation for aortic stenosis at age 60. He was very intelligent and a dedicated violin maker.Gitzelmann et al. (1987) determined that fibroblasts from the brother had only 2 to 3% residual arylsulfatase B deficiency, consistent with MPS VI. The leukocyte inclusions, referred to as 'Alder granules' (Alder, 1939) or 'Reilly granules' (Reilly, 1941), were a striking finding. Levy et al. (1980) showed that platelets as well as leukocytes show Reilly granules in MPS VI.

Peterson et al. (1975) reported a pregnant woman with MPS VI who had myelopathy due to compression of the cervical spinal cord by thickened dura. During the last trimester, she had severe neurologic deterioration with spastic quadriparesis and impairment of sphincter function. There was no improvement 2 months after delivery, so a cervical laminectomy and longitudinal splitting of the dura from C-5 to the foramen magnum was done. She experienced good return of function. Young et al. (1980) and Poser et al. (1983) described a mild form of MPS VI in a 41-year-old woman with spastic tetraplegia due to compressive myelopathy secondary to dural thickening. She had normal intelligence, was a college graduate, and mother of 2 children.

Wilson et al. (1980) described a 43-year-old man with MPS VI and aortic stenosis who had successful aortic valve replacement. He had short stature (150 cm tall). Two brothers were similarly affected with MPS VI and aortic stenosis.

Saul et al. (1984) described a 15-year-old boy with enzymatically confirmed MPS VI and stature at the 75th percentile (174 cm). He had corneal clouding and joint stiffness.

Vestermark et al. (1987) reported a case of enzymatically proven Maroteaux-Lamy syndrome in which there was severe mental retardation at age 8 years. Since mental retardation is highly unusual in MPS VI, it may have had another cause in this patient.

Cantor et al. (1989) described glaucoma in 4 adult women with MPS VI, 3 of whom were sisters. The authors suggested that the initial mechanism was secondary angle closure due to thickening of the cornea. An alternative mechanism could be obstruction of the trabecular meshwork by mucopolysaccharides, causing secondary open-angle glaucoma.

Tonnesen et al. (1991) described a mildly affected Maroteaux-Lamy patient who had normal total excretion of MPS but elevated excretion of dermatan sulfate in the urine. The level of arylsulfatase B was as low as that in severe MPS VI. The patient was a 33-year-old man who presented to an orthopedic surgery department at age 6, and again at age 27, for hip abnormalities. His height was 160 cm. Dysplasia in both hips and slightly increased thoracic kyphosis were found. Cardiologic and ophthalmologic examinations were normal.

Litjens et al. (1992) reported an 11-year-old boy with severe MPS VI. He presented at 1 day of age with edema of the hands and feet and respiratory distress. He already had coarse dysmorphic features and skeletal survey showed advanced bone age. Dysostosis multiplex was evident on skeletal survey at 2 days of age. A blood film showed inclusion bodies in myeloid cells and in some monocytes and lymphocytes. Levels of dermatan sulfate in the urine were grossly elevated. He had corneal clouding at 3 months of age, which became so dense as to make him blind by 7 years, when a left corneal transplant was done. Hydrocephalus required shunting at 4 years, and cervical cord compression resulting from upper cervical instability required surgical stabilization at 6 years of age. Genetic analysis identified a homozygous mutation in the ARSB gene (611542.0005).

Tan et al. (1992) described a brother and 2 sisters and a fourth unrelated patient with a mild form of MPS VI complicated by stenosis of the aortic and mitral valves. Double-valve replacement was successfully performed in a 30-year-old architect and his 34-year-old school teacher sister and in the unrelated patient, a 21-year-old college freshman. Respiratory problems were indicated by difficult intubation and problems with sleep apnea.

Neufeld and Muenzer (1995) classified patients with MPS VI into severe, intermediate, or mild forms. The severe form was characterized by very early onset and severe progression of symptoms: facial dysmorphism, skeletal abnormalities, compression of the spinal cord, corneal clouding, hepatosplenomegaly, and mental retardation. The mild form was characterized by very late onset and absence of mental retardation. The intermediate form showed the middle of the spectrum of phenotypes.

Schwartz and Cohen (1998) described the development of hydrocephalus in a patient with Maroteaux-Lamy syndrome who had had bilateral corneal transplantation at the age of 7 years.

Azevedo et al. (2004) reported clinical and biochemical studies of 28 MPS VI patients evaluated at a Brazilian center. Age at symptom onset varied from before 6 months (48%), 6 to 30 months (40%), to 36 months or older (12%). Seven families (27%) were consanguineous. The most common clinical features included short stature, coarse facial features, corneal clouding, joint contracture, claw hands, thickened skin, hirsutism, umbilical hernia, and splenomegaly. EKG abnormalities were found in 74%; most had valvular abnormalities. Only 1 child had poor school performance, which was attributed to poor economic conditions.

Swiedler et al. (2005) conducted a cross-sectional survey of individuals with MPS VI to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 individuals affected with MPS VI over the age of 4 years from 15 countries, representing more than 10% of the estimated world prevalence of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-minute walk, could be demonstrated across all age groups. High urinary GAG values (greater than 200 microg/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values less than 100 microg/mg creatinine for those participants over the age of 20 years. In the absence of longitudinal data, Swiedler et al. (2005) concluded that urinary GAG levels could predict clinical morbidity and that longer-term survival may be associated with urinary GAG levels below a threshold of 100 microg/mg creatinine.

Mut et al. (2005) reported a boy with MPS VI who presented at age 18 years with spastic quadriparesis. MRI showed spinal canal stenosis at multiple levels of the cervical, thoracic, and lumbar regions. Ligamentum flavum hypertrophy caused by excessive deposition of mucopolysaccharides was found to be the principal pathology responsible for the cord compression and myelopathy. Decompression surgery resulted in clinical improvement.

Huang et al. (2015) studied 5 patients with MPS VI. Two (aged 10 and 15 years) had multifocal depigmented retinopathy, 1 (28 years old) had parafoveal retinal folds and a blurred disc margin in the right eye, and 2 (both aged 28 years) showed no definite eye anomaly. Spectral-domain optical coherence tomography (SD-OCT) showed focal choroidal thinning in areas of depigmented retinopathy in the first 2 patients, and irregular retinal pigment epithelium, ellipsoid zone, and external limiting membrane in the patient with parafoveal retinal folds.

Tomanin et al. (2018) reviewed all variants in the ARSB gene in patients with MPS6 reported in the literature and in public databases. Clinical characteristics of the patients were highly variable. Age at diagnosis (reported in 172 patients) ranged from less than 1 year to 45 years of age, with a mean of 7.8 years and a median of 5.0 years. Two patients, both with an older affected sib, were diagnosed at birth.

Biochemical Features
Brooks et al. (1990) described a monoclonal-based system using an immunochemical technique coupled with enzyme kinetic analysis for immunoquantification of the ARSB enzyme, which normally is present at low levels. Studies of cultured skin fibroblasts derived from MPS VI patients suggested a range of mutants, with either no quantifiable protein or protein lacking enzyme activity. Brooks et al. (1991) characterized the residual N-acetylgalactosamine 4-sulfatase in fibroblasts from 16 MPS VI patients. Fibroblasts from the most severely affected patients contained the lowest levels of 4-sulfatase protein, usually with few epitopes detected, whereas fibroblasts from mildly affected patients had higher levels of 4-sulfatase protein, with all 7 epitopes detected. A 44-year-old patient, with no clinical signs of MPS VI and reduced 4-sulfatase activity and protein (both 5% of normal) and dermatansulfaturia, had 5% of normal catalytic capacity. Except for slight photophobia and hearing loss, clinical and radiologic examination failed to reveal any of the signs expected for MPS VI patients (Hopwood, 1991). The other 15 MPS VI patients had 0 to 1.4% of the catalytic capacity of fibroblasts from normal controls. Brooks et al. (1991) proposed that enzyme replacement therapy achieving a correction of more than 5% of normal catalytic capacity would be required to avoid the onset of the MPS VI clinical phenotype.

Inheritance
Black et al. (1986) reported a large, consanguineous, German Acadian ('Cajun') family from rural Louisiana in which 11 persons, including monozygotic twins, had MPS VI. Inheritance was clearly autosomal recessive. Although distributed in 6 sibships over 2 generations, all had the same surname, derived from an immigrant who came from the same area in Germany as did the consanguineous family reported by Spranger et al. (1970).

Clinical Management
Krivit et al. (1984) reported successful bone marrow transplantation in a 13-year-old girl with MPS VI. Full engraftment was present for 24 months. She showed normal arylsulfatase B activity in peripheral lymphocytes and granulocytes, with lesser increases in liver biopsy specimens. Urinary excretion of acid mucopolysaccharide decreased, and ultrastructural evidence of accumulated dermatan sulfate was no longer detectable in bone marrow cells, in peripheral-blood cells, or in Ito cells of liver. Twenty-four months after engraftment, hepatosplenomegaly was substantially decreased and cardiopulmonary function was normal. Visual acuity and joint mobility were also improved. The patient returned to school and continued to perform well in academic studies.

Herskhovitz et al. (1999) described the results of bone marrow transplantation (BMT) in 4 patients with MPS VI, 3 of whom underwent BMT due to cardiomyopathy and 1 for severe obstructive sleep apnea. During a follow-up period ranging between 1 and 9 years, the facial features became less coarse in all patients and cardiac manifestations improved or remained stable. However, skeletal changes persisted or progressed, although posture and joint mobility improved, and all patients remained ambulatory. The authors concluded that BMT may prolong survival and improve quality of life in MPS VI patients.

Giugliani et al. (2007) provided detailed management guidelines for MPS VI. They reviewed enzyme replacement therapy and bone marrow transplantation. Also included were guidelines for specific management of affected organ systems, such as respiratory, cardiac, skeletal, ophthalmologic, and central nervous system.

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.

Molecular Genetics
In a patient with mucopolysaccharidosis type VI, born of consanguineous parents, Wicker et al. (1991) identified a homozygous mutation in the ARSB gene (611542.0001).

In patients with MPS VI, Jin et al. (1992) identified homozygous or compound heterozygous mutations in the ARSB gene (611532.0002-611542.0004).

In 9 patients with MPS VI, Litjens et al. (1996) identified several mutations in the ARSB gene (see, e.g.,611542.0008-611542.0010). All patients were compound heterozygotes and showed variable phenotypes ranging from mild to severe. For each patient, the combined biochemical phenotypes of the 2 mutant sulfatase alleles demonstrated a good correspondence with the observed clinical phenotype.

Litjens and Hopwood (2001) stated that a total of 45 clinically relevant mutations had been identified in the ARSB gene in patients with mucopolysaccharidosis type VI. Missense mutations represented the largest group, with 31 identified. No common mutations had been described, making screening of the general population difficult.

Villani et al. (1999) found 5 novel mutations of the ARSB gene in Italian patients with MPS VI. Each defect was confirmed by restriction enzyme or amplification refractory mutation system (ARMS) analysis.

Among 12 Spanish and 4 Argentinian patients with MPS VI, Garrido et al. (2007) identified 19 different mutations, including 9 novel mutations, in the ARSB gene. The most common mutant alleles were splice site mutations, 611542.0011and 611542.0012, which accounted for 21.9% and 12.5% of mutant alleles, respectively.

Tomanin et al. (2018) reviewed all variants in the ARSB gene in patients with MPS6 reported in the literature and in public databases and identified 908 alleles with 198 distinct nonpolymorphic variants from 478 patients. They also identified 3 benign variants that had previously been incorrectly reported as pathogenic. Most (59.5%) unique variants were missense mutations, followed by small deletions (13.5%), nonsense (12.0%), splice site or intronic variants (5.0%), small duplications (3.0%), and large deletions (3.0%). Of the unique alleles, 31.7% appeared only once with an additional 28.5% appearing twice. Of the identified patients, 54.8% were homozygous for pathogenic ARSB variants, 35.6% were heterozygous, 9.2% had only one allele reported, and 0.4% had both alleles unidentified. Pathogenic variants in ARSB do not appear to be concentrated in any particular region of the ASB protein. Analysis of the genotype-phenotype correlation based on homozygotes was poorly informative for most variants, although some variants did appear to be associated with a more rapidly progressive phenotype. The authors emphasized the importance of submitting variants to public databases.

Population Genetics
Using multiple ascertainment sources, Nelson et al. (2003) obtained an incidence rate of MPS VI in western Australia for the period 1969 to 1996 of approximately 1 in 320,000 live births.

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 (see 253000) accounted for 15%, 16%, and 10%, respectively. MPS VI 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
Jordans (1947) reported a Dutch family in which 9 individuals in 3 generations had granulation anomalies of the leukocytes, similar to Alder or Reilly granulations. The inclusions were apparently indistinguishable from those observed in mucopolysaccharidoses, but the pattern of inheritance was autosomal dominant.

(Note 2)
In 1963, Maroteaux et al described a patient with a moderately severe Hurler-like phenotype but normal intelligence and high urinary excretion of DS.

Three forms of mucopolysaccharidosis VI (MPS VI) exist: mild type (Paterson DE et al 1982, Poser C et al 1983), intermediate type, and severe type (Rampini S et al 1986, Spranger 1972, Spranger J et al 1970). There may even be a very mild form (Saul RA et al 1984). Mutational studies in variable phenotypes have been performed (Isbrandt D et al 1994). Children with the mild type develop reasonably well until about 6 years of age when short stature, corneal clouding and spinal deformities are noted. Legg-Perthes-like disease of the hips and aortic stenosis become apparent. The patients usually survive to adulthood (Paterson DE et al 1982). In patients with severe type, morphologic changes are noted in early childhood and the disease progresses more rapidly to a state of severe disability with strikingly short stature, coarse facial appearance, hyperextended head, musculoskeletal abnormalities, severe corneal clouding, markedly reduced hearing, and prominent cardiac defects that frequently lead to death in adolescence.

MPS VI has autosomal recessive inheritance, the three types being the results of allelic mutations in the structural gene encoding arylsulfatase B. The gene has been mapped to chromosome 5q13-q14 (Litjens T et al 1989) by in situ hybridization. The Maroteaux-Lamy syndrome was found to occur in 1/216, 000 births in British Columbia (Lowry RB et al 1990). An animal model of MPS VI in Siamese and other cats has been extensively described and characterized (Crawley AC et al 1997, Jezyk PF et al 1977, McGovern MM et al 1985). The clinical and biochemical features are caused by abnormal intracellular accumulation of DS in mesenchymal cells and, secondarily, in parenchymal cells of internal organs, such as the liver. Although N-acetylgalactosamine-4-sulfate residues are also present in chondroitin-4-sulfate, there is no evidence for the accumulation of this GAG in MPS VI individuals.

Facies.
A prominent forehead may be noted at birth. The facies, similar to that in Hurler syndrome, with apparent hypertelorism, depressed nasal bridge, full cheek and lips, relatively broad jaws, large cranium, and abundant eyebrows and scalp hair, becomes evident at the sixth year of life, occasionally earlier (Spranger J et al 1970, Biervliet JP et al 1977). Marked corneal opacity is present in some patients (Neufeld EF, Muenzer J 1995) as well as glaucoma (Cantor LB et al 1989).

Musculoskeletal system.
Adult height is usually 110-140 cm but those having the mild form may near 168 cm (Pilz H et al 1979). The chest is deformed, with a prominent sternum. Multiple joint contractures and clawhand deformity secondary to flexion contractures of the fingers begin after the first year of life.

Genua valga, lumbar kyphosis, and sternal protrusion are common. The radiographic changes in the severe type are similar to those of MPS I-H and are striking examples of dysostosis multiplex (Neufeld EF, Muenzer J 1995). Ossification of the superior portion of the femoral capital epiphysis may be markedly defective. In the mild type, there are cranial changes, wide ribs, and pelvic dysplasia but few changes in spine and tubular bones (Spranger J et al 1970). Hernias are common in the severe form.

Other findings.
Hepatomegaly is almost invariably present in the severe form. The spleen is enlarged in about half of the cases. Cardiovascular involvement is common, with aortic stenosis, mitral valve regurgitation, cardiomyopathy (as a presenting feature), endocardial fibroelastosis, and narrowing of the coronary and other arteries (Fong LV et al 1987, Hayflick S et al 1992, Marwick TH et al 1992, Schieken RN et al 1975, Tan CTT et al 1992).

Hearing defects, both conductive and sensorineural, may be detected audiometrically. Mentation is nearly always normal, with rare exception (Taylor HR et al 1978, Vestermark S et al 1987); when there is mental retardation, it is not always clear that it was caused by the MPS. However, impaired vision and hearing, restricted mobility, and secondary psychologic reaction may impede intellectual performance (Spranger 1972, Spranger J et al 1970). Neurologic deficits most frequently include hydrocephalus, peripheral nerve compression (e.g., carpal tunnel syndrome), or hypoplasia of the odontoid process associated with atlantoaxial subluxation. Myelopathy and radiculopathy have also been reported (Goldberg MF et al 1970, Peterson DI et al 1975, Rampini S et al 1987). Marked tracheal stenosis has been documented (Rampini S et al 1987).

Oral manifestations.
The tongue becomes large with the full development of all clinical features. The teeth are frequently widely spaced. Eruption of primary and permanent dentition is retarded (Nakamura T et al 1992, Smith KS et al 1995). Some are deeply buried, being angulated in the mandible, and are surrounded by radiolucent bony defects that presumably represent the accumulation of dermatan sulfate in hyperplastic follicles as seen in MPS I-H, MPS I-H/S, and in MPS II-B. The follicular fluid in MPS VI is composed of hyaluronic acid (Roberts MW et al 1984). The mandibular condyle is hypoplastic.

Laboratory findings.
There is an abundance of coarse, dense inclusions in granulocytes and monocytes and in a large proportion of lymphocytes in peripheral blood smears. Bone marrow preparations exhibit coarse inclusions in reticulohistiocytes, granulocytes, and their precursors (Markesbery WR et al 1980). Biopsy may be easily done on the conjunctiva (Libert 1980). Electron microscopic studies have shown numerous electrolucent vacuoles in cells from brain, liver, lung, and skin (Levy LA et al 1980, Libert 1980). Large quantities of DS are excreted in the urine, but the level decreases with age. Heterozygote testing has been difficult through enzymatic methods, but a method has been reported in which ratios of arylsulfatase B to another lysosomal sulfatase, arylsulfatase A, are used to minimize the overlap between normal and heterozygote populations.

The condition has been diagnosed prenatally (Van Dyke DL et al 1981). Diagnosis from chorionic villi through enzyme determination may not be accurate (Sanguinetti N et al 1986). Through molecular genetic studies, progress has been made toward determining various mutations in the arylsulfatase B gene, providing molecular evidence for genetic heterogeneity (Isbrandt D et al 1996, Jin W-D et al 1992). Attempts to relate molecular findings and clinical phenotype have been made (Litjens T et al 1996). In several patients with an intermediate form of MPS VI, novel mutant alleles have been found (Voskoboeva E et al 1994, Wicker G et al 1991).

(Note 2)
In 1963, Maroteaux et al described a patient with a moderately severe Hurler-like phenotype but normal intelligence and high urinary excretion of DS.

Three forms of mucopolysaccharidosis VI (MPS VI) exist: mild type (Paterson DE et al 1982, Poser C et al 1983), intermediate type, and severe type (Rampini S et al 1986, Spranger 1972, Spranger J et al 1970). There may even be a very mild form (Saul RA et al 1984). Mutational studies in variable phenotypes have been performed (Isbrandt D et al 1994). Children with the mild type develop reasonably well until about 6 years of age when short stature, corneal clouding and spinal deformities are noted. Legg-Perthes-like disease of the hips and aortic stenosis become apparent. The patients usually survive to adulthood (Paterson DE et al 1982). In patients with severe type, morphologic changes are noted in early childhood and the disease progresses more rapidly to a state of severe disability with strikingly short stature, coarse facial appearance, hyperextended head, musculoskeletal abnormalities, severe corneal clouding, markedly reduced hearing, and prominent cardiac defects that frequently lead to death in adolescence.

MPS VI has autosomal recessive inheritance, the three types being the results of allelic mutations in the structural gene encoding arylsulfatase B. The gene has been mapped to chromosome 5q13-q14 (Litjens T et al 1989) by in situ hybridization. The Maroteaux-Lamy syndrome was found to occur in 1/216, 000 births in British Columbia (Lowry RB et al 1990). An animal model of MPS VI in Siamese and other cats has been extensively described and characterized (Crawley AC et al 1997, Jezyk PF et al 1977, McGovern MM et al 1985). The clinical and biochemical features are caused by abnormal intracellular accumulation of DS in mesenchymal cells and, secondarily, in parenchymal cells of internal organs, such as the liver. Although N-acetylgalactosamine-4-sulfate residues are also present in chondroitin-4-sulfate, there is no evidence for the accumulation of this GAG in MPS VI individuals.

Facies.
A prominent forehead may be noted at birth. The facies, similar to that in Hurler syndrome, with apparent hypertelorism, depressed nasal bridge, full cheek and lips, relatively broad jaws, large cranium, and abundant eyebrows and scalp hair, becomes evident at the sixth year of life, occasionally earlier (Spranger J et al 1970, Biervliet JP et al 1977). Marked corneal opacity is present in some patients (Neufeld EF, Muenzer J 1995) as well as glaucoma (Cantor LB et al 1989).

Musculoskeletal system.
Adult height is usually 110-140 cm but those having the mild form may near 168 cm (Pilz H et al 1979). The chest is deformed, with a prominent sternum. Multiple joint contractures and clawhand deformity secondary to flexion contractures of the fingers begin after the first year of life.

Genua valga, lumbar kyphosis, and sternal protrusion are common. The radiographic changes in the severe type are similar to those of MPS I-H and are striking examples of dysostosis multiplex (Neufeld EF, Muenzer J 1995). Ossification of the superior portion of the femoral capital epiphysis may be markedly defective. In the mild type, there are cranial changes, wide ribs, and pelvic dysplasia but few changes in spine and tubular bones (Spranger J et al 1970). Hernias are common in the severe form.

Other findings.
Hepatomegaly is almost invariably present in the severe form. The spleen is enlarged in about half of the cases. Cardiovascular involvement is common, with aortic stenosis, mitral valve regurgitation, cardiomyopathy (as a presenting feature), endocardial fibroelastosis, and narrowing of the coronary and other arteries (Fong LV et al 1987, Hayflick S et al 1992, Marwick TH et al 1992, Schieken RN et al 1975, Tan CTT et al 1992).

Hearing defects, both conductive and sensorineural, may be detected audiometrically. Mentation is nearly always normal, with rare exception (Taylor HR et al 1978, Vestermark S et al 1987); when there is mental retardation, it is not always clear that it was caused by the MPS. However, impaired vision and hearing, restricted mobility, and secondary psychologic reaction may impede intellectual performance (Spranger 1972, Spranger J et al 1970). Neurologic deficits most frequently include hydrocephalus, peripheral nerve compression (e.g., carpal tunnel syndrome), or hypoplasia of the odontoid process associated with atlantoaxial subluxation. Myelopathy and radiculopathy have also been reported (Goldberg MF et al 1970, Peterson DI et al 1975, Rampini S et al 1987). Marked tracheal stenosis has been documented (Rampini S et al 1987).

Oral manifestations.
The tongue becomes large with the full development of all clinical features. The teeth are frequently widely spaced. Eruption of primary and permanent dentition is retarded (Nakamura T et al 1992, Smith KS et al 1995). Some are deeply buried, being angulated in the mandible, and are surrounded by radiolucent bony defects that presumably represent the accumulation of dermatan sulfate in hyperplastic follicles as seen in MPS I-H, MPS I-H/S, and in MPS II-B. The follicular fluid in MPS VI is composed of hyaluronic acid (Roberts MW et al 1984). The mandibular condyle is hypoplastic.

Laboratory findings.
There is an abundance of coarse, dense inclusions in granulocytes and monocytes and in a large proportion of lymphocytes in peripheral blood smears. Bone marrow preparations exhibit coarse inclusions in reticulohistiocytes, granulocytes, and their precursors (Markesbery WR et al 1980). Biopsy may be easily done on the conjunctiva (Libert 1980). Electron microscopic studies have shown numerous electrolucent vacuoles in cells from brain, liver, lung, and skin (Levy LA et al 1980, Libert 1980). Large quantities of DS are excreted in the urine, but the level decreases with age. Heterozygote testing has been difficult through enzymatic methods, but a method has been reported in which ratios of arylsulfatase B to another lysosomal sulfatase, arylsulfatase A, are used to minimize the overlap between normal and heterozygote populations.

The condition has been diagnosed prenatally (Van Dyke DL et al 1981). Diagnosis from chorionic villi through enzyme determination may not be accurate (Sanguinetti N et al 1986). Through molecular genetic studies, progress has been made toward determining various mutations in the arylsulfatase B gene, providing molecular evidence for genetic heterogeneity (Isbrandt D et al 1996, Jin W-D et al 1992). Attempts to relate molecular findings and clinical phenotype have been made (Litjens T et al 1996). In several patients with an intermediate form of MPS VI, novel mutant alleles have been found (Voskoboeva E et al 1994, Wicker G et al 1991).

(文献)
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