疾患詳細

疾患詳細



粗な顔貌, 聾 (Autio) (Gorlin et al. 1990 より引用)

#248500
Mannosidosis, alpha B, lysosomal (MANSA)
(Alpha-mannosidosis)
(Lysosomal alpha-D-mannosidase deficiency)
(Alpha-mannosidase B deficiency)

マンノース症, αB, リソソーム
(α-マンノース症)
(リソソーム α-D-マンノシダーゼ欠損症)
(α-マンノシダーゼ B 欠損症)
指定難病19 ライソゾーム病
小児慢性特定疾病 代82 マンノシドーシス

責任遺伝子:609458 Mannosidase, alpha, class 2B, member 1 (MAN2B1) <19p13.2>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Cataract (白内障) [HP:0000518] [0640]
 Coarse facial features (粗な顔貌) [HP:0000280] [0408]
 Corneal opacity (角膜混濁) [HP:0007957] [0620]
 Craniofacial hyperostosis (頭蓋顔面過骨症) [HP:0004493] [160016]
 Delayed skeletal maturation (骨成熟遅滞) [HP:0002750] [160001]
 Depressed nasal bridge (低い鼻梁) [HP:0005280] [0722]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hypoplastic inferior ilia (下部腸骨低形成) [HP:0008821] [1142]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Macroglossia (巨舌) [HP:0000158] [08109]
 Skeletal dysplasia (骨格異形成) [HP:0002652] [16]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Type II diabetes mellitus (II 型糖尿病) [HP:0005978] [2013]
 
 <30%-79%>
 Abnormality of the helix (耳介異常) [HP:0011039] [09008]
 Bowing of the long bones (長管骨湾曲) [HP:0006487] [1505]
 Chronic otitis media (慢性中耳炎) [HP:0000389] [014231]
 Generalized abnormality of skin (全体的皮膚異常) [HP:0011354] [18]
 Gingival overgrowth (歯肉過成長) [HP:0000212] [0808]
 Hip dysplasia (股関節異形成) [HP:0001385] [1140]
 Hypertelorism (両眼開離) [HP:0000316] [06607]
 Inguinal hernia (鼠径ヘルニア) [HP:0000023] [1201]
 Kyphosis (後弯) [HP:0002808] [161500]
 Macrotia (大耳) [HP:0000400] [09019]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Narrow palate (狭口蓋) [HP:0000189] [0822]
 Open bite (開放咬合) [HP:0010807] [08305]
 Prominent supraorbital ridges (目立つ眼窩上縁) [HP:0000336] [0511]
 Scoliosis (側弯) [HP:0002650] [161502]
 Short neck (短頸) [HP:0000470] [1001]
 
 <5%-29%>
 Arthritis (関節炎) [HP:0001369] [15115]
 Avascular necrosis (無血管性壊死) [HP:0010885] [160018]
 Dental malocclusion (不正咬合) [HP:0000689] [08300]
 Hallucinations (幻覚) [HP:0000738] [0206]
 Increased intracranial pressure (頭蓋内圧増加) [HP:0002516] [03010]
 Macrocephaly (大頭) [HP:0000256] [03012]
 Mandibular prognathia (下顎突出) [HP:0000303] [0541]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Synostosis of joints (関節骨癒合) [HP:0100240] [160021]
 Widely spaced teeth (歯間開離) [HP:0000687] [08300]
 
 
 Abnormality of the rib cage (肋骨胸郭異常) [HP:0001547] [1612]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 Broad forehead (幅広い額) [HP:0000337] [0501]
 Cerebellar atrophy (小脳萎縮) [HP:0001272] [16013]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Decreased antibody level in blood (血中抗体減少) [HP:0004313] [22092]
 Delayed myelination (髄鞘化遅延) [HP:0012448] [160127]
 Depressed nasal ridge (低い鼻堤) [HP:0000457] [0722]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysostosis multiplex (多発性異骨症) [HP:0000943] [-]
 Epicanthus (内眼角贅皮) [HP:0000286] [06811]
 Femoral bowing (大腿骨湾曲) [HP:0002980] [16092]
 Flat occiput (平坦な後頭部) [HP:0005469] [03014]
 Frontal bossing (前頭突出) [HP:0002007] [0501]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Gliosis (グリオーシス) [HP:0002171]  [160127]
 Growth delay (成長遅滞) [HP:0001510] [0130]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Hypertrichosis (多毛) [HP:0000998] [17112]
 Impaired smooth pursuit (円滑な追視障害) [HP:0007772] [0695]
 Increased vertebral height (脊椎骨の高さの増加) [HP:0004570] [161518]
 Limb ataxia (四肢運動失調) [HP:0002070] [028]
 Low anterior hairline (低い前頭部毛髪線) [HP:0000294] [17107]
 Malar flattening (平坦な頬部) [HP:0000272] [05200]
 Midface retrusion (顔面中部後退) [HP:0011800] [05200]
 Nystagmus (眼振) [HP:0000639] [06609]
 Pectus carinatum (鳩胸) [HP:0000768] [1105]
 Recurrent bacterial infections (反復性細菌感染症) [HP:0002718] [01423]
 Retinal degeneration (網膜変性) [HP:0000546] [0652]
 Sensorineural hearing impairment (感音難聴) [HP:0000407] [0910]
 Spasticity (痙縮) [HP:0001257] [0241]
 Spinocerebellar tract disease in lower limbs (下肢の脊髄小脳路病) [HP:0007232]
 Spondylolisthesis (脊椎辷り症) [HP:0003302] [161507]
 Thick eyebrow (眉毛叢生) [HP:0000574] [1721]
 Thickened calvaria (頭蓋冠肥厚) [HP:0002684] [160113]
 Thoracolumbar kyphosis (胸腰部後弯) [HP:0005619] [161500]
 Vacuolated lymphocytes (空胞性リンパ球) [HP:0001922] [2212]

(UR-DBMS)
【一般】成長遅滞 (数例)
 肝腫
 脾腫
 精神運動発達遅滞
 急速な知能退行による精神遅滞
 発語障害
 反復性細菌感染
 高身長, 嘔吐, 腹部膨満
【神経】筋緊張低下
 失調歩行
 四肢失調
 痙縮
 開扇反射
 構音障害
 反射亢進
 神経細胞は網状顆粒状パターンを伴う膜結合性水疱を伴うバルーニングを示す
 不器用な運動機能
 下肢の皮質脊髄路疾患 (成人で)
 下肢の皮質小脳路疾患 (成人で)
 大脳萎縮 (成人で)
 髄鞘化遅延
 グリオーシス
【頭】大頭
 平坦な後頭部
 脳室拡大
【顔】粗な顔貌
 幅広い額
 額突出
 顔面中部低形成
 下顎突出
 目立つ眼窩上縁
 副鼻腔低形成〜欠損 (60%)
【眼】内眼角贅皮
 水晶体の 'スポーク様' 混濁
 成人患者では網膜変性, 進行性
 成人患者ではスムースな追跡眼球運動障害
 成人患者での眼振
 角膜混濁
 両眼開離
 チェリーレッド斑
【鼻】平坦な鼻
 幅広い鼻
【口】巨舌
 歯肉肥大
 幅広い歯間
【耳】感音難聴
 大きな耳介
 耳介聳立
【頸部】短頸
【胸】鳩胸
 分厚い骨梁不全の肋骨
【体幹】鼠径ヘルニア (一部の患者で)
 臍ヘルニア (60%)
【骨盤】軽度の変形
【四肢】大きな手足
 関節過動 (多様)
【X線】多発性異骨症
 頭蓋骨肥厚
 異常な椎体骨 (卵形, 平坦, くちばし状)
 脊椎高増加
 胸腰部突背
 脊椎すべり症
 大腿骨湾曲
 小脳萎縮 (成人で)
 白質変化が生じうる (成人で)
 骨粗鬆症
 中手骨異常
 視神経交叉溝の垂直化
 幅広く湾曲した橈骨/尺骨
【毛髪】眉毛叢生
 前頭部毛髪線低位
 多毛
 全部毛髪渦
【検査】尿中 mannose-containing oligosaccharides 増加
 血漿と白血球で lysosomal alpha-mannosidase 活性減少
【免疫】低ガンマグロブリン血症
 抗血小板抗体
 抗好中球抗体
 haptoglobin 低値
【血液】空胞化リンパ球 (細胞の90%)
 好中球機能障害 (化学遊走能, 貪食能)
 幼若化反応障害
 泡沫マクロファージ (蓄積細胞) (骨髄)
 汎血球減少
【その他】幅広い表現型多様性と重症度
 神経症状は進行性
 大多数の患者は正常発達ののち早期小児期発症を示す
 一部の患者は乳児期発症を示す
 一部の患者は小児期以後の発症を示す

(要約) Alpha-Mannosidosis
●αマンノース症は軽症から重症までの臨床像の連続である
 3つの臨床サブタイプがあるThree clinical subtypes include:
(1) 軽症型 (1型):10歳以後に認められ骨格異常やミオパチーがなく緩徐進行性である
(2) 中等症型 (2型):10歳以前に認められ骨格異常とミオパチーがあり緩徐進行性である→大多数はこの型
(3) 重症型 (3型):出生前喪失または進行性中枢神経病変による早期死亡
 軽症型の患者は軽度〜中等度知能障害, 難聴, 特異な顔貌, 臨床またはX線学的骨異常, 免疫不全, 原発性中枢神経疾患 (主に運動失調を生じる小脳病変)をもつ
 精神症状の期間が多い
 合併症状には, 角膜混濁, 肝脾腫, 無菌性破壊性関節炎, 代謝性ミオパチーがみられうる
 αマンノース症は潜行的に進行性である
 一部の患者は50歳代まで生存する
●診断
 末梢血白血球または線維芽細胞などの他の有核細胞での acid alpha-mannosidase 酵素活性欠乏による (fluorometric assay)
 →患者では正常活性の5-10% (残存活性は他の小器官由来である)
 →この方法での保因者検査は, 保因者と非保因者間の酵素活性のオーバーラップがあるため信頼できない (正常の40-60%)
 尿中mannose-rich oligosaccharides排泄の増加 (thin-layer chromatography)→診断的ではない
 末梢血光顕:リンパ球の90%に空胞
●MAN2B1 が唯一の知られている原因遺伝子である
 配列バリアントは98.5%で, 部分的または全体的欠失は<2%
 全部で125以上の原因変異が報告されている
 3つの変異 (p.Arg750Trp, p.Leu809Pro, c.1830+1G>C) が35.4%を占める
 ミスセンス変異c.2248C>T (p.Arg750Trp) が最も多い変異である
 欠失/重複はquantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray (CMA) による
●治療
 抗生剤, 補聴器, 耳管チューブ, 眼鏡, 理学療法, 車椅子, 整形外科的介入, VPシャント
 手話, 特殊教育
 予防接種
 骨髄移植, 末梢血幹細胞移植
●自然歴
 以前は2つの明瞭な表現型をもつと記載されたが, 現在では周生期致死型 (出生前喪失)〜無症状型または成人で初めて診断される型までの臨床症状の連続として認知される
 少なくとも2つの主要な型が存在すると示唆されている
 重症型:肝腫と早期死亡となる重症感染を伴う
 軽症型:知能障害, 難聴, 成人まで生存する
●運動機能:運動発達遅滞, 不器用, 運動失調, 関節異常, 代謝性ミオパチー, 筋緊張低下, 一般的には痙性, 強直, ジスキネジアはみられない
●知能:初期正常→知能障害, 成人発症型は IQ 60-80
●精神症状:25%以上で, 思春期後半〜早期青春期で
●脳画像:部分的からのトルコ鞍, 小脳萎縮, 白質シグナル異常
●難聴:大多数は早期小児期発症, 非進行性, 混合性
●顔貌:Hurler 様顔貌, 粗な顔貌 (大頭と目立つ額, 低い鼻梁, 丸い眉毛, 下顎突出, 歯間隔離, 巨舌)
●骨:無症状性骨減少〜巣状融解性または硬化性病変〜骨壊死
 軽度〜中等度の多発性異骨症は90%にみられる
(X線) 分厚い頭蓋骨, 脊椎骨異常 (卵形, 平坦, 鉤型), 腸骨低形成, 手の短管骨の軽度の拡大, X脚 (多い)

<小児慢性特定疾病 代82 マンノシドーシス>
概要・定義
糖蛋白質の糖鎖を加水分解するリソソ-ム酵素の中で,アルファ結合した終末mannoseを加水分解するのはα-mannosidase(LAMAN, EC3.2.1.24),ベータ結合した終末mannoseを加水分解するのはβ-mannosidase(MANBA, EC3.2.1.25)と呼ばれる。それぞれの酵素欠損による疾患をα-mannosidosis(OMIM #248500), β-mannosidosis(OMIM #248510)と呼んでいる.α-mannosidase遺伝子(MAN2B1)は19p13.2-q12に,β-mannosidosis遺伝子(MANBA)は4q21-25にマップされ,いずれも常染色体劣性遺伝形式をとる.大変稀な疾患であり, 国内報告は殆どない。
症状
共通した臨床症状としては, 粗野な顔貌,多発性骨異形成,高身長,精神発達遅延,退行,肝脾腫, 角膜混濁,白内障(特徴的な棘状白濁),難聴などを乳児期から幼児期にかけて認める.
1)α-mannosidosisには臨床的に乳児型(type I)と若年成人型(type II)に分類されるが,その中間型もある。乳児型は生後3カ月から1歳までに精神運動発達遅延,筋力低下,肝脾腫,易感染性,粗野な顔貌,dysostosis multiplex(多発性骨異形成)などに気付かれる.その他に突背,関節拘縮,角膜混濁,白内障(棘状白濁),難聴,巨舌などを認める.若年成人型は1-4歳頃までに精神運動発達遅延,難聴などで発症する軽症型であり,進行も乳児型に比し緩徐である。 
2)β-mannosidosisにも重症度に差があるが,典型的には1-6歳までに精神運動発達遅延を認めるが,粗野な顔貌, dysostosis multiplexは軽度であり,他に易感染性,難聴,被角血管腫などを伴う。
診断
リンパ球の空胞化(ただしβ-mannosidosisにおいては認めない), 尿中mannose含有物質の薄層クロマトグラフィー分析, 汎血球減少症,低ガンマグロブリン血症などが診断に有用な臨床症状である。確定診断は白血球, 皮膚線維芽細胞におけるα/β-mannosidase活性の測定で可能である。またそれぞれの遺伝子検査が可能である。
診断方法
臨床所見 (上記), 生化学分析, および遺伝子解析に基づいて行う。
・臨床検査;リンパ球の空胞化(ただしβ-mannosidosisにおいては認めない), 尿中mannose含有物質の薄層クロマトグラフィー分析, 汎血球減少症,低ガンマグロブリン血症
・確定診断;白血球, 皮膚線維芽細胞におけるα-mannosidase活性の測定が確定診断となる.
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
支持療法などが主たる治療法である。造血幹細胞移植の報告がある。
成人期以降
重症度にもよるが, 支持療法が中心であり, 進行したあとは経管栄養, 気管切開, 人工呼吸器の適応について検討を要する。


(解説) Mannosidosis マンノシドーシス
 α‐マンノシダーゼの先天的欠損.精神遅滞,脊柱後弯,舌肥大,リンパ球空胞化を伴い,マンノースが組織中に蓄積する.
(頻度) 75 例以上
(コメント) acidic alpha-mannosidase A & B (血漿, 白血球, 線維芽細胞)
(サブタイプ)
Type I (重症乳児型) 肝脾腫, 重度の反復性感染症, 早期死亡 (3-10 歳)
Type II (軽症若年成人型) 難聴, 精神遅滞, 軽度の多発性異骨症
(責任遺伝子) *609458 Mannosidase, alpha, class 2B, member 1 (MAN2B1) <19p13.2>
.0001 Alpha-mannosidosis (248500) [MANB, HIS71LEU] (dbSNP:rs28934600) (dbSNP:rs387906261) (RCV000001752) (Nilssen et al. 1997; Gotoda et al. 1998)
.0002 Alpha-mannosidosis [MANB, ARG760TER] (dbSNP:rs121434331) (ExAC:rs121434331) (RCV000001753) (Gotoda et al. 1998)
.0003 Alpha-mannosidosis [MANB, GLN639TER] (dbSNP:rs121434332) (RCV000001754) (Gotoda et al. 1998)
.0004 Alpha-mannosidosis [MANB, ARG750TRP] (dbSNP:rs80338680) (ExAC:rs80338680) (RCV000001755) (Gotoda et al. 1998; Berg et al. 1999)
.0005 Alpha-mannosidosis [MANB, PRO356ARG] (dbSNP:rs121434333) (RCV000001756) (Gotoda et al. 1998)
.0006 Alpha-mannosidosis [MAN2B1, IVS14DS, G-C, +1] (dbSNP:rs80338677) (ExAC:rs80338677) (RCV000020364) (Riise Stensland et al. 2012)
.0007 Alpha-mannosidosis [MAN2B1, LEU809PRO [dbSNP:rs80338681] (ExAC:rs80338681) (RCV000020367) (Riise Stensland et al. 2012)

*MAN2B1: Mannosidase, alpha, class 2B, member 1 (1011 amino acids)
・alpha-D-mannosides の末端の非還元型alpha-D-mannose残基を加水分解する酵素である
 その活性は糖タンパク回転中に遊離されたN連結炭水化物の異化に必要である
・glycosyl hydrolases のファミリー38のメンバーである
・全てのタイプのalpha-mannosidic連結を分割する
・mannosidases は2つのサブタイプに分けられる; I と I
 mannosidase I は oligo-mannose oligosaccharide Man9(GlcNAc)2 の (1,2)-linked alpha-D-mannose残基を加水分解する
 mannosidase II は Man5(GlcNAc)3の (1,3)- and (1,6)-linked alpha-D-mannose 残基を加水分解する
 両サブタイプは二価陽イオン cofactor を必要とする

(ノート)
A number sign (#) is used with this entry because alpha-mannosidosis (MANSA) is caused by homozygous or compound heterozygous mutation in the MAN2B1 gene (609458) on chromosome 19p13.

Alpha-mannosidosis is an autosomal recessive lysosomal storage disease characterized by mental retardation, coarse facial features, skeletal abnormalities, hearing impairment, neurologic motor problems, and immune deficiency. Expression of the disease varies considerably, and there is a wide spectrum of clinical findings and severity. Affected children are often normal at birth and during early development. They present in early childhood with delayed psychomotor development, delayed speech, and hearing loss. Additional features include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, dysostosis multiplex, and motor impairment (summary by Malm and Nilssen, 2008).

Classification Systems
Two classification systems have been used to describe the clinical presentation of alpha-mannosidosis. The earlier system delineated a more severe 'type I,' which shows infantile onset, rapid mental deterioration, hypotonia, splenomegaly, severe dysostosis multiplex, and severe recurrent infections, often resulting in death by age 8 years. Individuals with the less severe 'type II' show normal early development with later childhood development of mental retardation, hearing loss, coarse facies, neurologic deterioration, and survival well into adulthood (summary by Desnick et al., 1976and Gotoda et al., 1998). A later classification system delineated 3 clinical types. Type 1 is the mildest form, with onset after age 10 years, without skeletal abnormalities and very slow progression. Type 2 is a moderate form, with onset before age 10 years, presence of skeletal abnormalities, and slow progression with development of ataxia by age 20 to 30 years. Type 3 is the severe form, with onset in early infancy, skeletal abnormalities, and obvious progression leading to early death from primary central nervous system involvement or myopathy. Most patients belong to clinical type 2 (summary by Malm and Nilssen, 2008). Despite the clinical heterogeneity of the disorder, there are no apparent genotype/phenotype correlations (Berg et al., 1999; Riise Stensland et al., 2012).

CLINICAL FEATURES
●Ockerman (1967) は, 明らかに新しい疾患の孤発例, 男児1例を記載した
 易感染性, 嘔吐, 粗な顔貌, 巨舌, 平坦な鼻, 大きな耳介, 歯間解離, 大頭, 大きな手足, 高身長, 軽度の肝脾腫, 筋緊張低下, 腰部突背, 骨格異常, 脳室拡大, 白内障, 低ガンマグロブリン血症, 骨髄の蓄積細胞, 骨髄と末梢血のリンパ球空胞化が特徴であった
 組織学的研究は, 大脳皮質, 脳幹, 脊髄, 下垂体後葉, 網膜, 腸筋神経叢に蓄積物質 (酸性ムコ多糖ではない) を示した
 肝の全マンノースが著明に増加していた
 全組織の Alpha-mannosidase 活性が異常に低値であったが, 他の acid hydrolases は正常活性より高かった
 患者は, 頭蓋内圧亢進発作中に4.5歳で死亡した
 粗な顔貌と多発性異骨症を含む症状は, Hurler 症候群 (607014)を示唆する
 ムコリピドーシス I 型 (256550) と分類された患者の数例は, マンノシドーシスであることが証明された

Ockerman et al. (1973) referred to the identification of mannosidosis in 2 Hungarian sisters and 3 Finnish boys, including 2 brothers. A procedure for the study of low molecular weight urinary compounds containing mannose was useful in the study of these cases.

Bach et al. (1978) reported 2 sibs, born of consanguineous Palestinian parents, with mild mental retardation, delayed speech, coarse facies, and limited mobility of the large joints. Cultured fibroblasts showed partial alpha-mannosidase deficiency (20% of normal), and the sibs were considered to be mildly affected. However, both patients had vacuolated leukocytes and fibroblasts consistent with the disease phenotype.

In cultured cell from patients with mannosidosis, Desnick et al. (1976) found defects of neutrophil function, including depressed chemotactic responsiveness and impaired phagocytosis of bacteria. They suggested that recurrent respiratory tract infections resulted from immunoglobulin deficiencies.

●Montgomery ら(1982)は, 約50例の報告を発見した
 臨床表現型は, ごく少数の症状から, 小児期死亡まで差異がある
 大多数の患者は, 生後1年ないし2年でみられた
 幅広い重症度は, アレリック型を反映するのかもしれない
 Montgomery ら(1982) は32歳男性1例を記載した
  18か月時, 肝脾腫, 多発性異骨症および粗な顔貌のため, おそらく Hurler 症候群の脂肪軟骨ジストロフィーをもつと診断され, 聾, 精神遅滞, 鳩胸, 胸腰部突背, 分厚い頭蓋骨および水晶体混濁の比較的軽症の非進行性経過をたどった

●Press ら(1983) は, 1981年に汎血球減少で受診した時33歳のマンノシドーシスの男性1例を報告した
 彼は26歳で初診し, 高度の歯肉肥大, 重度精神遅滞, および大腿骨湾曲をもっていた
 歯肉にマンノースを帯びた組織球が証明された
 汎結集減少の自己免疫基盤は, 抗血小板抗体と抗好中球抗体およびハプトグロビン低値により証明された
 著者らは, 赤血球膜でのマンノース豊富な糖タンパクとオリゴ糖の異常な蓄積が, 新しい抗原決定因子の発生に責任があると推測した

●Michelakakis ら(1992) は, II 型マンノシドーシスの13歳男児と彼の24歳の姉を記載した
 両者とも, 血漿および白血球の酵素の大きな減少があった
 男児は, 2歳までは, 正常な身体および精神運動発達をもったが, 進行性精神退行が2歳時生じた
 頻回の呼吸器感染症が生じた
 粗い顔貌がり, 分厚い眉毛, 解離した切歯, 下顎突出, 前方毛髪線低位があった
 両側性軽症感音性聾があった
 骨格には, S1 にL5の脊椎すべりを伴う脊椎分離を示した
 姉は, 同様に遅延し, 分厚い眉毛と下顎突出, 感音性聾をもっていた

●Bennet ら(1995) は, マンノシドーシスの異なる症状をもつ関連のない2例を報告した
 1例は, 早期小児期に, I 型マンノシドーシスに特徴的な重症表現型をもっていた
 1例は, II 型マンノシドーシスの診断が, 後期成人期での進行性神経退行の発症後でつけられた
 両者は, オリゴ糖の非進行性尿スクリーニングで検出された
Lysosomal alpha-mannosidase activity was markedly reduced in lymphoblasts transformed from both patients' blood cells. Kinetic analyses showed that the enzyme from the type I patient had a 400-fold reduction in affinity, while that from the type II patient was reduced 40-fold. All 4 parents had reduced alpha-mannosidase activity in lymphoblasts. The type I patient had a large hydrocele and bilateral inguinal hernias at birth. 'Coarse' facial appearance and delays in speech development prompted referral at age 13 months. At that time, hepatosplenomegaly and cataracts were noted, together with a broad forehead, frontal bossing, flat occiput, midfacial hypoplasia, epicanthal folds, hypertrichosis, and an anterior hair whorl. Brain scans showed increased ventricular size and macrocephaly. Foamy cytoplasm within vacuolated lymphocytes were demonstrated by bone marrow studies. The woman with type II mannosidosis was said to have a normal phenotype during early childhood but required special education from the second grade onward. She learned to read and write and was independent until age 25 years when she developed bowel incontinence. Evidence of corticospinal and spinocerebellar tract disease progressed over the ensuing 15 years and was more pronounced in the lower limbs. Cerebrocortical atrophy was first documented at age 35. The diagnosis of mannosidosis was made at the age of 40.

Gotoda et al. (1998) reported a Japanese woman with alpha-mannosidosis confirmed by genetic analysis (609458.0002). From the age of 1 year she had suffered from recurrent infections, such as bronchitis and otitis media. Hearing loss and delayed psychomotor development were noted at age 2 years. At the age of 9 years she entered a school for the deaf, where she did poorly. She gradually developed gait disturbance. Physical examination at the age of 36 years showed an IQ of 19, coarse facies, retinal degeneration, sensorineural hearing loss, increased deep tendon reflexes, spastic gait, and mild limb ataxia. There were vacuolated lymphocytes in her peripheral blood. Similar vacuoles were also found in biopsied muscle cells and fibroblasts. Lysosomal alpha-mannosidase activity of peripheral leukocytes was decreased to less than 1% of normal controls, whereas other lysosomal enzyme activities were all within the normal range. Thin-layer chromatography showed increased urinary excretion of oligosaccharides. A younger sister, aged 42, had a clinical history and features similar to those of the patient; pathologic examination of muscle from this sister had been reported by Kawai et al. (1985).

In a patient with alpha-mannosidosis originally reported by Autio et al. (1973), Gotoda et al. (1998) identified compound heterozygosity for 2 mutations in the MAN2B1 gene (609458.0003; 609458.0004). The patient was the only child of healthy, nonconsanguineous parents. He had recurring infections during the first year of life. By age 17 months he was speaking only a few words and impaired hearing was suspected. He had coarse facial features, delayed psychomotor functions, and brisk tendon reflexes. Approximately 80% of his peripheral blood leukocytes were vacuolated, and his alpha-mannosidase activity was reduced to approximately 2% of normal.

Gutschalk et al. (2004) reported 3 adult sibs, aged 38 to 47 years, with alpha-mannosidosis. In late adolescence, all 3 developed progressive cerebellar ataxia characterized by gait ataxia, impaired smooth pursuit, nystagmus, dysarthria, and extensor plantar responses. All also had sensorineural deafness from early childhood and developed progressive retinal degeneration during late adolescence. One patient reported delusions and hallucinations. MRI showed cerebellar atrophy and periventricular white matter changes. MR spectroscopy showed no evidence of demyelination, and Gutschalk et al. (2004) concluded that the neurodegeneration in adult mannosidosis results from lysosomal accumulation of storage material.

Courtney and Pennesi (2011) described the ocular findings in 2 brothers with alpha-mannosidosis. In addition to corneal and lenticular changes, the brothers had fundus changes including slightly pale optic discs (mild optic atrophy), retinal vascular attenuation, and mottled retinal pigment epithelium (RPE), most notable in the macula and surrounding the fovea. Additionally, there were numerous nummular yellow-white deposits evident at the level of the RPE. No foveal light reflex, peripapillary sparing, or bone spicule pigmentary change was found in either eye. Spectral-domain optical coherence tomography revealed retinal thinning. Fundus autofluorescence showed granular areas of hypoautofluorescence in the macula as well as in the posterior pole surrounding the optic nerve where speckled hyperautofluorescence was intermixed with hypoautofluorescent areas.

Lehalle et al. (2019) reported 7 patients, aged 5 to 25 years, from 5 families with MANSA. All 7 patients had biallelic mutations in MAN2B1, reduced leukocyte alpha-mannosidase activity, and elevated mannose-rich oligosaccharides in the urine. All 7 were diagnosed with bilateral hearing loss, either sensorineural or mixed, in the first 8 years of life. Of the 6 patients in whom cognitive features were reported, all had mildly impaired intellectual development or learning disabilities. Skeletal abnormalities were identified in 2 patients: one had dysostosis with thickening of the cranial vault, bilateral coxa vara, irregularity of the glenoidal and acetabular cups and rib thickness, and the other had thickening and modeling anomalies of the long bone metaphyses and irregularity of the vertebral endplates. None of the patients had cognitive regression or early motor delays, and coarsened facial features were only recognized retrospectively in some of the patients. Lehalle et al. (2019) recommended that hearing loss, especially when associated with learning or cognitive abnormalities, should raise a possible diagnosis of alpha-mannosidosis or another lysosomal storage disorder.

Central Nervous System Abnormalities
Borgwardt et al. (2016) studied central nervous system abnormalities in 34 MANSA patients ranging in age from 6 to 35 years. Ten patients underwent brain MRI and magnetic resonance spectroscopy (MRS). Brain imaging showed occipital white matter signal abnormalities in 5 of the 10 patients, and age-inappropriate myelination in 6. MRS demonstrated significantly elevated mannose complex in gray and white matter, consistent with gliosis. All 34 patients were analyzed for cerebrospinal fluid (CSF) markers: there were elevated concentrations of tau (MAPT; 157140), GFAP (137780), and NEFL (162280) in 97%, 74%, and 41% of CSF samples, respectively. There was a negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function. The data indicated that the disorder is associated with early neuropathologic changes.

▼ Diagnosis
Guffon et al. (2019) proposed diagnostic algorithms for alpha-mannosidosis based on the consensus opinion of an expert panel. They suggested that the most prominent signs that should prompt investigation for this disease in patients 10 years of age and younger include speech delay, hearing loss, developmental delay, and facial dysmorphism. In patients older than 10 years, the most prominent signs include hearing loss, ataxia, psychiatric disturbances, and skeletal abnormalities. Guffon et al. (2019) suggested that enzyme screening in dried blood spot or leukocytes should be the first screening method, followed by confirmatory molecular testing.

Prenatal Diagnosis
Poenaru et al. (1979) reported successful prenatal diagnosis of mannosidosis in 2 at-risk families by analyzing enzyme activity of amniotic cells from the fetus.

▼ Clinical Management
Enzyme Replacement Therapy
Harmatz et al. (2018) reported the effect of enzyme replacement therapy with velmanase alfa in treating alpha-mannosidase across several clinical trials. Using a multiple variable analysis model that takes into account pharmacodynamic, functional, and quality of life domains, Harmatz et al. (2018) showed a clinically meaningful treatment effect and a continued long-term treatment effect. Within the pharmacodynamic domain, it was found that velmanase alfa showed effectiveness in reducing serum oligosaccharide load in most treated patients. There was a greater response to treatment in participants under 18 years of age compared to those greater than 18 years of age.

Negative Reports
Investigators have demonstrated that zinc can stimulate residual alpha-mannosidase activity in cultured cells from patients with mannosidosis (Kistler et al., 1977). Wong et al. (1993) reported a trial of oral zinc therapy for 3 years in a 4-year-old boy with alpha-mannosidosis. However, after almost 10 years of follow-up of the patient on and off zinc therapy, they concluded that there was no substantial clinical improvement.

Biochemical Features
Ockerman et al. (1973) found that normal liver alpha-mannosidase exists in at least 3 forms, separable by DEAE cellulose chromatography. The lysosomal A and B forms were most active at pH 4.4, whereas form C was most active at pH 6.0. In 2 cases of mannosidosis, Carroll et al. (1972) found that forms A and B were missing. Cheng et al. (1986) found that although mannosidase A and B differed in their subunit compositions, they were immunologically identical. The authors suggested that the differences in A and B were due to differences in processing, and that both forms arise from a single locus.

Ben-Yoseph et al. (1982) found that mannosidase activity was normal in the medium of cultured fibroblasts from patients with mannosidosis. However, incubation of the mannosidosis extracellular enzyme with either normal or patient cell lysates resulted in a partial loss of activity, whereas an additive value was observed with the normal extracellular enzyme. Ben-Yoseph et al. (1982) suggested that the enzymatic defect in mannosidosis is expressed only after the enzyme has been delivered to lysosomes and presumably has undergone some form of processing there. However, Cheng et al. (1986) provided evidence that the enzyme secreted by mannosidosis fibroblasts was not related immunologically to lysosomal mannosidase.

Molecular Genetics
In 2 Palestinian sibs with alpha-mannosidosis (248500) originally reported by Bach et al. (1978), Nilssen et al. (1997) identified a homozygous mutation in the MAN2B1 gene (609458.0001).

In 4 unrelated patients with alpha-mannosidosis, Gotoda et al. (1998) identified mutations in the MAN2B1 gene (609458.0001-609458.0005). All mutations were in either homozygous or heterozygous state.

Riise Stensland et al. (2012) identified 96 different pathogenic mutations in the MAN2B1 gene, including 83 novel mutations, in 130 unrelated patients with alpha-mannosidosis from 30 countries. Most of the mutations were private, but R750W (609458.0004) was found in 50 patients from 16 countries and accounted for 27.3% of disease alleles. Other recurrent mutations included a splice site mutation in intron 14 (609458.0006), found in 13 disease alleles, and L809P (609458.0007), found in 8 disease alleles. Twenty-nine novel missense mutations were identified. Most did not show any residual enzyme activity when expressed in COS-7 cells, but 10 showed some activity, including 5 with 30% or more residual activity. There were no apparent genotype/phenotype correlations.

Population Genetics
Harmatz et al. (2018) stated that the prevalence of alpha-mannosidase is estimated to be as low as 1:1 million live births.

Riise Stensland et al. (2012) found that the R750W mutation in the MAN2B1 gene (609458.0004) was the most common mutation among 130 unrelated patients with alpha-mannosidosis from 30 countries. It was found in 50 patients from 16 countries and accounted for 27.3% of disease alleles. Haplotype analysis indicated at least 4 independent events causing R750W, with 1 haplotype accounting for 95% of the alleles. Population-based analysis suggested that the mutant allele arose in eastern Europe.

Animal Model
Hocking et al. (1972) described recessive inheritance of mannosidosis in cattle. The disease is manifest by head tremor, aggressive tendency, ataxia, failure to thrive, and early death.

Berg et al. (1997) identified a 4-bp deletion in the feline Man2b1 gene in a Persian cat with mannosidosis; the deletion resulted in a frameshift from codon 583 and premature termination at codon 645. No enzyme activity could be detected in the liver of the cat. A domestic long-haired cat expressing a milder phenotype had enzyme activity of 2% of normal; this cat did not possess the 4-bp deletion.

In the Man2b1 cDNA of alpha-mannosidosis-affected Angus cattle, Tollersrud et al. (1997) found a 961T-C transition, resulting in a phe321-to-leu amino acid substitution. In affected Galloway cattle, they found a 662G-A transition that caused an arg221-to-his substitution. Phe321 and arg221 are conserved among the alpha-mannosidase class-2 family.

Crawley et al. (1999) identified alpha-mannosidosis in the guinea pig.

Therapeutic Strategies
Walkley et al. (1994) studied the effects of bone marrow transplantation (BMT) in alpha-mannosidosis in cats where the disease shows clinical, morphologic, and biochemical features closely resembling those in the human disease. BMT-treated animals showed little or no progression of neurologic signs 1 to 2 years after transplant, whereas untreated cats became severely impaired and reached end-stage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy demonstrated no evidence of lysosomal storage within most neurons. Histochemical localization of acidic alpha-D-mannosidase showed that functional enzyme was present in neurons, glial cells, and cells associated with blood vessels. This study provided direct evidence that bone marrow transplantation can lead to significant replacement of lysosomal hydrolase within neurons of the central nervous system and can compensate for the genetic metabolic defect.

Roces et al. (2004) reported correction of storage of neutral oligosaccharides in a mouse model of alpha-mannosidosis after intravenous administration of Man2b1 from bovine kidney and human and mouse recombinant MAN2B1. The bovine and human enzymes were barely phosphorylated, whereas the bulk of the mouse Man2b1 contained mannose 6-phosphate recognition markers. Clearance and apparent half-life of the internalized enzyme was dependent on the enzyme source as well as tissue type. The corrective effect was time-, tissue- and dose-dependent, and the effects were observed to be transient. After a single dose injection of MAN2B1, the maximum corrective effect was observed between 2 and 6 days. Injection of 250 microU of human MAN2B1 per gram of body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney, and heart of neutral oligosaccharides. A decrease in mannose-containing oligosaccharides was also observed in the brain, with storage levels in treated mice less than 30% of levels found in control mice.

Blanz et al. (2008) demonstrated that the neuropathology of a mouse model for alpha-mannosidosis could be efficiently treated using recombinant human alpha-mannosidase (rhLAMAN). After intravenous administration of various doses (25-500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a greater than 70% clearance of stored substrates in visceral tissues and doses of 250 U/kg were sufficient for clearance in peripheral neurons of the trigeminal ganglion, repeated high-dose injections (500 U/kg) were required to achieve a greater than 50% reduction of brain storage. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to nearly complete disappearance of storage vacuoles. In addition, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated alpha-mannosidosis mice. Uptake of rhLAMAN seemed to be independent of mannose-6-phosphate receptors, consistent with the low phosphorylation profile of the enzyme.

(ノート2)
●αマンノシドーシスは, ムコ多糖症の1つのタイプで, Ockermann (1967)により最初に特徴づけられた
●少なくとも60例が今日まで報告されている (Autio S et al 1973, Autio S et al 1982)
●遺伝は, 常染色体劣性で, 両親の血縁が25%にみられる (Vidgoff J et al 1977)
 遺伝的異質性がある
 より重症の乳児型 (I 型)
 より軽症の若年-成人型 (II 型)
  (Desnick RJ et al 1976)
 家系の間で相当な差異がある (Michelakakis H et al 1992, Mitchell ML et al 1985)
●acid alpha-mannosidase をコードする遺伝子は 19p13.2-q12 にある (Kaneda Y et al 1987)
 リソソーム alpha-mannosidase cDNA はクローニングされ, 多くの変異が報告されている
(Berg T et al 1999, Gotoda Y et al 1998, Nilssen O et al 1997)
●患者は生後数か月から1歳までは本質的に正常であるが, 約60%が反復性呼吸器感染症にかかりやすい
(Desnick RJ et al 1976, Malm D et al 2000)
 表現度は, 小児期死亡から, 少数の臨床症状まで差異がある
(Autio S et al 1982, Bemnet JK et al 1995)
 成人は低身長をもつ (Autio S et al 1982)

顔貌
●粗な顔貌 (眼窩上縁突出, 両眼開離, 幅広い鼻基部, 下顎突出), が生後2-3か月から気付かれ, 進行性である
 しかし, MPS I-H の程度ではなく, I-cell 病ほど早期ではない (Mitchell ML et al 1986)
 鼻梁は平坦な傾向がある
 額や下顎と突出している
 頸部はいくらか短い

中枢神経
●早期の運動発達遅滞がある
 不器用な運動機能と失調としてみられる
 精神遅滞は I 型と II 型の両方に存在するが, I 型では急速な知能悪化がある
 言語遅滞がある
 腱反射は短い
 3例での MRI では, 骨変化, 視神経交差溝の垂直化, 小脳萎縮, 白質のシグナル変化がある (Dietemann JL et al 1990).

眼と耳
●車軸様後部水晶体または表面角膜の混濁が症例の25%にみられる
(Arbisser AE et al 1976, Letson RD, Desnick RJ 1978)
 チェリー・レッド斑も報告されている
 重度の高音感音難聴が多い II 型の特徴である (一定してではない) (Nilssen O et al 1997)

筋骨格
●全身性の軽度の筋緊張低下がある
 腹部膨満がある
 臍ヘルニアは60%でみられる
 患者全員が軽度の多発性異骨症をもつ
  数例ではより重症となり, 他では改善する
(DeFriend DE et al 2000, Eckhoff DG, Garlock JS 1992, Spranger J et al 1976, Weiss SW et al 1983)
 頭蓋骨は分厚く, 少なくとも60%で副鼻腔は低形成ないし欠損している
 長管骨は骨粗鬆症性である
 尺骨と橈骨は幅広く, 湾曲した骨幹と薄い皮質がある
 関節の動きの重症度に著明な差異がある (Vidgoff J et al 1977)
 脊椎は卵形, 平坦で, 数例ではくちばし状である
  突背形成を伴う (Mitchell ML et al 1985, Yunis JJ et al 1976)
 軽度の骨変形が股関節に多い

その他
●肝脾腫が50%にみられる (Vidgoff J et al 1977)
 しかし, 小児期に消失しうる

口腔
●巨舌と歯間解離が知られている (Ockermann 1967)
●歯肉と口腔内歯肉過形成の走査電顕は, 繊細な網状顆粒状物質の蓄積性空胞を含む組織球を明らかにした (Ishigami T et al 1995)

検査
●末梢血および骨髄リンパ球は, 細胞の90%空胞化している (Autio S et al 1982)
 粗い暗い色の顆粒が好中球にみられる
 好中球化学遊走能に障害がある
 汎血球減少が知られている (Press OW et al 1983)
 IgG 減少が知られている
 本疾患は, 白血球と培養線維芽細胞での acid alpha-D-mannosidase 減少所見により診断される
(Thomas GH, Beaudet AL 1995)
 マンノース豊富なオリゴ糖が, 患者の尿中にすぐ検出できる
 ヘテロ接合体検出は可能である
 出生前診断は, 胎盤絨毛での acid alpha-D-mannosidase 欠損の所見により成し遂げられる (Petushkova 1991)
 しかし, alpha-Mannosidase 活性は, 培養羊水細胞の1/3以下であることがわかっている (Fukuda M et al 1990)
 この所見は, よい対照データが必要なことを強調する
 ネコでの alpha-mannosidosis による骨髄移植 (BMT) が報告されている (Walkley SU et al 1994)
 ネコでの疾患の, 臨床, 形態学および生化学的特徴は, ヒトによく似ている
 BMT-で治療された動物は, BMT 後1-2年神経症状の進行は, ほとんど, または全くないが, 未治療のネコは重度に障害された

(文献)
(1) Ockerman PA: A generalized storage disorder resembling Hurler's syndrome. Lancet II: 239-241, 1967
(2) Kjellman B et al. Mannosidosis: a clinical and histopathologic study. J Pediat 75: 366-373, 1969
(3) Ockerman PA: Mannosidosis: isolation of oligosaccharide storage material from brain. J Pediat 75: 360-365, 1969
(4) Hultberg B. Properties of alpha-mannosidase in mannosidosis. Scand J Clin Lab Invest 26: 155-160, 1970
(5) Carrol M et al. Human mannosidosis--the enzymic defect. Biochem Biophys Res Commun 49: 579-583, 1972
(6) Hocking JD et al. Deficiency of alpha-mannosidase in Angus cattle. An inherited lysosomal storage disease. Biochem J 128: 69-78, 1972
(7) Autio S et al. Mannosidosis: clinical, fine-structural and biochemical findings in three cases. Acta Paediat Scand 62: 555-565, 1973
(8) Ockerman PA et al. Diagnosis of mannosidosis. Lancet I: 207-208, 1973
(9) Masson PK et al. Biochem Biophys Res Commun 56:296-303, 1974
(10) Gehler J et al. Mannosidosis: clinical and biochemical findings. BDOAS 11(6):269-272, 1975
(11) Tsay GC et al. Glycopeptide storage in skin fibroblasts cultured from a patient with alpha-mannosidase deficiency. J Clin Invest 56: 711-718, 1975
(12) Arbisser AI et al. Ocular findings in mannosidosis. Am J Ophthal 82: 465-471, 1976
(13) Aylsworth AS et al. Mannosidosis: phenotype of a severely affected child and characterization of alpha-mannosidase activity in cultured fibroblasts from the patient and his parents. J Pediat 88: 814-818, 1976
(14) Desnick RJ et al. Mannosidosis: clinical, morphologic, immunologic, and biochemical studies. Pediat Res 10: 985-996, 1976
(15) Mali JWH et al. A lysosomal storage disorder of the epidermis characterized by a deficiency of alpha-mannosidase and an accumulation of mannose-rich materials. Brit J Derm 95:627-630, 1976
(16) Murphree AL et al. Cataract in mannosidosis. BDOAS 12(3):319-326, 1976
(17) Spranger J et al. Radiologic features of mannosidosis. Radiology 119:401-407, 1976
(18) Yunis JJ et al. Clinical manifestations of mannosidosis--a longitudinal study. Am J Med 61: 841-848, 1976
(19) Champion MJ, Shows TB: Mannosidosis: assignment of the lysosomal alpha-mannosidase B gene to chromosome 19 in man. Proc Nat Acad Sci 74: 2968-2972, 1977
(20) Ingram PH et al. Expression of alpha-D-mannosidase in man-hamster somatic cell hybrids. Biochem Genet 15: 455-476, 1977
(21) Milla PJ et al. Mannosidosis - clinical and biochemical study. Arch Dis Child 52:937-942, 1977
(22) Vidgoff J et al. Mannosidosis in three brothers--a review of the literature. Medicine 56: 335-348, 1977
(23) Bach G et al. A new variant of mannosidosis with increased residual enzymatic activity and mild clinical manifestation. Pediat Res 12: 1010-1015, 1978
(24) Champion MJ et al. Studies on the alpha-mannosidase (MAN-B), peptidase D (PEP D) and glucose on chromosome 19 in man. Cytogenet Cell Genet 22: 186-189, 1978
(25) Letson RD, Desnick RJ: Punctate lenticular opacities in type 1I mannosidosis. Am J Ophthalmol 85:218-224, 1978
(26) Poenaru L et al. Antenatal diagnosis in three pregnancies at risk for mannosidosis. Clin Genet 16: 428-432, 1979
(27) Gordon BA et al. Unusual clinical and ultrastructural features in a boy with biochemically typical mannosidosis. Acta Paediat Scand 69: 787-792, 1980
(28) Jolly RD et al. Mannosidosis: patterns of storage and urinary excretion of oligosaccharides in the bovine model. Aust J Exp Biol Med Sci 58: 421-428, 1980
(29) Poenaru L et al. Residual mannosidase activity in human mannosidosis: characterization of the mutant enzyme. Am J Hum Genet 32: 354-363, 1980
(30) Mitchell ML et al. Mannosidosis: two brothers with different degrees of disease severity. Clin Genet 20: 191-202, 1981
(31) Autio S et al. The clinical course of mannosidosis. Ann Clin Res 14: 93-97, 1982
(32) Ben-Yoseph Y et al. Apparently normal extracellular acidic alpha-mannosidase in fibroblast cultures from patients with mannosidosis. Am J Hum Genet 34: 100-111, 1982
(33) Montgomery TR et al. Mannosidosis in an adult. Johns Hopkins Med J 151: 113-117, 1982
(34) Vandevelde M et al. Hereditary neurovisceral mannosidosis associated with alpha-mannosidase deficiency in a family of Persian cats. Acta Neuropath 58: 64-68, 1982
(35) Press OW et al. Pancytopenia in mannosidosis. Arch Intern Med 143: 1266-1268, 1983
(36) Weiss SW et al: Bilateral destructive synovitis associated with alpha-mannosidase deficiency. Am J Surg Pathol 7:487 494, 1983
(37) Warner TG et al. Alpha-mannosidosis: analysis of urinary oligosaccharides with high performance liquid chromatography and diagnosis of a case with unusually mild presentation. Clin Genet 25: 248-255, 1984
(38) Mitchell ML et al: Mannosidosis: Two brothers with different degrees of disease severity. Clin Genet 20:191-202, 1985
(39) Jansen PHP et al. Mannosidosis: a study of two patients, presenting clinical heterogeneity. Clin Neurol 89:185-192, 1987
(40) Kaneda Y et al. Regional assignment of five genes on human chromosome 19. Chromosoma 95: 8-12, 1987
(41) Nebert DW et al. The P450 gene superfamily: recommended nomenclature. DNA 6: 1-11, 1987
(42) Dietemann JL et al: MR findings in mannosidosis. Neuroradiology 32:485-487, 1990
(43) Fukuda M et al: Variation of lysosomal enzyme activity with gestational age in chorionic villi. J Inherit Metab Dis 13:862-866, 1990
(44) Petushkova NA: First-trimester diagnosis of an unusual case of a-mannosidosis. Prenat Diagn 11:279-283, 1991
(45) Eckhoff DG, Garlock JS: Severe destructive polyarthropathy in association with a metabolic storage disease. A case report. J Bone Joint Surg Am 74:1257-1261, 1992
(46) Michelakakis H et al. Phenotypic variability of mannosidosis type II: report of two Greek siblings. Genetic Counseling 3: 195-199, 1992
(47) Wong LTK et al Oral zinc therapy in the treatment. of alpha-mannosidosis. Am J Med Genet 46: 410-414, 1993
(48) Nebes VL, Schmidt MC: Human lysosomal alpha-mannosidase: isolation and nucleotide sequence of the full-length cDNA. Biochem Biophys Res Commun 200: 239-245, 1994
(49) Walkley SU et al: Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease. Proc Natl Acad Sci U S A 91:2970 2974, 1994
(50) Bennet JK et al. Clinical and biochemical analysis of two families with type I and type II mannosidosis. Am J Med Genet 55 (1): 21-6, 1995
(51) Ishigami T et al: Oral manifestations of alpha-mannosidosis: Report of a case with ultrastructural findings. J Oral Pathol Med 24:85-88, 1995
(52) Thomas GH, Beaudet AL: Disorders of glycoprotein degradation and structure: alpha-mannosidosis, beta-mannosidosis, fucosidosis, sialidosis, aspartyl-glucosaminuria, and carbohydrate-deficient glycoprotein syndrome. In: The Metabolic Basis of Inherited Disease, 7th ed, Scriver CR et al (eds), McGrawHill, New York, pp 2533-2537., 1995
(53) Beccari T et al. Assignment of lysosomal alpha-D-mannosidase to mouse chromosome 8. Mammalian Genome 7: 707-708, 1996
(54) Liao Y-F et al. Cloning, expression, purification, and characterization of the human broad specificity lysosomal acid alpha-mannosidase. J. Biol. Chem. 271: 28348-28358, 1996
(55) Berg T et al. Purification of feline lysosomal alpha-mannosidase, determination of its cDNA sequence and identification of a mutation causing alpha-mannosidosis in Persian cats. Biochem. J. 328: 863-870, 1997
(56) Nilssen O et al. Alpha-mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum. Molec. Genet. 6: 717-726, 1997
(57) Riise HMF et al. Genomic structure of the human lysosomal alpha-mannosidase gene (MANB). Genomics 42: 200-207, 1997
(58) Tollersrud OK et al. Purification of bovine lysosomal alpha-mannosidase, characterization of its gene and determination of two mutations that cause alpha-mannosidosis. Europ. J. Biochem. 246: 410-419, 1997
(59) Gotoda Y et al. Missense and nonsense mutations in the lysosomal alpha-mannosidase gene (MANB) in severe and mild forms of alpha-mannosidosis. Am. J. Hum. Genet. 63: 1015-1024, 1998
(60) Berg T et al. Spectrum of mutations in alpha-mannosidosis. Am. J. Hum. Genet. 64: 77-88, 1999
(61) Crawley AC et al. Alpha-mannosidosis in the guinea pig: a new animal model for lysosomal storage disorders. Pediat. Res. 46: 501-509, 1999
(62) Gutschalk, A.; Harting, I.; Cantz, M.; Springer, C.; Rohrschneider, K.; Meinck, H.-M. : Adult alpha-mannosidosis: clinical progression in the absence of demyelination. Neurology 63: 1744-1746, 2004
(63) Roces, D. P.; Lullmann-Rauch, R.; Peng, J.; Balducci, C.; Andersson, C.; Tollersrud, O.; Fogh, J.; Orlacchio, A.; Beccari, T.; Saftig, P.; von Figura, K. : Efficacy of enzyme replacement therapy in alpha-mannosidosis mice: a preclinical animal study. Hum. Molec. Genet. 13: 1979-1988, 2004
(64) Blanz, J.; Stroobants, S.; Lullmann-Rauch, R.; Morelle, W.; Ludemann, M.; D'Hooge, R.; Reuterwall, H.; Michalski, J. C.; Fogh, J.; Andersson, C.; Saftig, P. : Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in alpha-mannosidosis mice. Hum. Molec. Genet. 17: 3437-3445, 2008
(65) Courtney, R. J., Pennesi, M. E. Retinal dystrophy in 2 brothers with alpha-mannosidosis. Arch. Ophthal. 129: 799-802, 2011
(66) Riise Stensland, H. M. F., Klenow, H. B., Van Nguyen, L., Hansen, G. M., Malm, D., Nilssen, O. Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. Hum. Mutat. 33: 511-520, 2012 (Note: Erratum: Hum. Mutat. 37: 827 only, 2016)
(67) Borgwardt, L., Danielsen, E. R., Thomsen, C., Mansson, J. E., Taouatas, N., Thuesen, A. M., Olsen, K. J., Fogh, J., Dali, C. I., Lund, A. M. Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function. Clin. Genet. 89: 489-494, 2016
(68) Harmatz, P., Cattaneo, F., Ardigo, D., Geraci, S., Hennermann, J. B., Guffon, N., Lund, A., Hendriksz, C. J. Borgwardt, L. Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): novel global treatment response model and outcomes in patients with alpha-mannosidosis. Molec. Genet. Metab. 124: 152-160, 2018
(69) Guffon, N., Tylki-Szymanska, A., Borgwardt, L., Lund, A. M., Gil-Campos, M., Parini, R., Hennermann, J. B. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Molec. Genet. Metab. 126: 470-474, 2019
(70) Lehalle, D., Colombo, R., O'Grady, M., Heron, B., Houcinat, N., Kuentz, P., Moutton, S., Sorlin, A., Thevenon, J., Delanne, J., Gay, S., Racine, C., and 11 others. Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: report of seven new cases. Am. J. Med. Genet. 179A: 1756-1763, 2019

2009/11/10
2011/08/18
2012/06/06
2012/07/19
2012/12/01
2015/03/04 SNP
2016/05/26 ノート/文献追加
2016/06/16 症状改訂
2017/08/24 RCV
2020/04/28 ノート/文献追加
2020/05/14