疾患詳細

疾患詳細





#607616
Niemann-Pick disease, type B
(Acid sphingomyelinase deficiency, visceral type)
(ASMD, visceral type)
(Niemann-Pick disease, type E, indluded)
(Niemann-Pick disease, type F, indluded)
(Niemann-Pick disease, intermediagte, with visceral involvement and rapid progression, included)

Niemann-Pick 病B型
(Acid sphingomyelinase 欠乏症, 内臓型)
(ASMD, 内臓型)
(Niemann-Pick 病E型)
(Niemann-Pick 病F型)
<小児慢性特定疾病 代89 ニーマン・ピック(Niemann-Pick)病>
指定難病19 ライソゾーム病

責任遺伝子:607608 Sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) <11p15.4>
遺伝形式:常染色体劣性

(症状)
(GARD)
 
 Abnormal macular morphology (黄斑形態異常) [HP:0001103] [06523]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Bone-marrow foam cells (骨髄泡沫細胞) [HP:0004333] [2204]
 Decreased HDL cholesterol concentration (HDLコレステロール減少) [HP0003233] [20510]
 Diffuse reticular or finely nodular infiltrations (びまん性網状または微細結節性浸潤) [HP:0002207]
 Dyspnea (呼吸困難) [HP:0002094] [01606]
 Foam cells with lamellar inclusion bodies (層状封入内を伴う泡沫細胞) [HP:0003609]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hypertriglyceridemia (高トリグリセリド血症) [HP:0002155] [20174]
 Increased LDL cholesterol concentration (LDL コレステロール増加) {HP:0003141] [20176]
 Juvenile onset (若年発症) [HP:0003621]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Sea-blue histiocytosis (海青組織球症) [HP:0001982] [2208]
 Short stature (低身長) [HP:0004322] [0130]
 Splenomegaly (脾腫) [HP:0001744] [01817]

(UR-DBMS)
【一般】低身長 (少ない)
 呼吸障害
 反復性呼吸器感染症
 肺胞浸潤にによる肺拡散減少
 *肝脾腫
【神経】神経症状はない
【眼】チェリーレッド斑 (より若い患者で) (少ない)
【胸郭】びまん性網状または繊細な結節状肺浸潤
【血液】*骨髄の大きな泡沫細胞 (NP 細胞)
 "海の青" 組織球
 血小板減少
【検査】acid sphingomyelinase 活性減少
 肺/肝/脾/腎が泡沫細胞と組織球を含む
 泡沫細胞の電顕は層状構造を示す
 LDL コレステロール増加
 中性脂肪増加 (A/B)
 HDL コレステロール減少
【その他】乳児期または小児期発症
 表現型の差異
 Ashkenazi ユダヤ人に多い
 Niemann-Pick disease type A (257200) とアレリック

【一般】精神遅滞 (B型を除く)
 認知症
 けいれん
 腹水
 遷延性黄疸 (1/4)
 肝不全 (B)
【眼】斜視
 垂直の核上性眼筋麻痺
 角膜混濁
 前部水晶体被膜の褐色着色
【心】冠動脈疾患
【皮膚】栄養不全
 (丘疹または結節性皮膚黄色腫)
【検査】apoAI 低値
 細網内皮系と他の細胞型でのsphingomyelin 蓄積→中枢神経節細胞の死亡
【血液】貧血
 *異常な細胞内 sphingomyelin 蓄積
 脾機能高進症
 易出血性

(group A) 急性神経症型 (古典的乳児型), 6か月までに発症し3歳までに死亡
(group B) 中枢神経病変のない慢性型 (内臓型)
(group C) 慢性神経症型 (亜急性または若年型)
(group D) Nova Scotia バリアント
(group E) 成人非神経症型
(group F) Sea-blue 組織球症

(要約) Acid Sphingomyelinase 欠乏症
●Acid sphingomyelinase (ASM) 欠乏症は, 過去には, 早期小児期に死亡するニューロパチー性 (Niemann-Pick 病A型 [NPD-A])または, 非ニューロパチー性 (Niemann-Pick 病B型 [NPD-B])として分類されていた
 中間型が生じるため, 幅広い症状や重症度の範囲に関わらず, NPD-Aではない全てのASM欠乏症を NPD-Bとして取り扱う
○NPD-Aの最初の症状は, 肝脾腫で, 通常は3か月令までに気付かれる
 時間とともに肝と脾は大きくなる
 精神運動発達は12か月レベル以上には発達せず, 12か月以後は神経学的悪化が顕著となる
 古典的な黄斑のチェリーレッド斑 (生後2-3か月はないかも)は, 最終的に全ての患児にみられる
 肺マクロファージへの sphingomyelin 蓄積が原因の間質性肺疾患は, 頻回の肺感染症となり, 呼吸不全となることが多い
 大多数の患児は3歳以前に死亡する
○NPD B型は, 発症が遅く, NPD A型より軽症で, 進行性脾機能亢進を伴う肝脾腫と安定した肝機能障害, 肺機能の緩徐な悪化, 骨減少, 脂質異常が特徴である
 進行性+/-慢性の有意な神経症状は頻度が低い
 成人までの生存が書字売る
●診断:SMPD1 の2アレル性病的バリアントまたは残存 ASM酵素活性 (末梢血リンパ球または培養皮膚線維芽細胞; 10%未満)のいずれかの検出による
●治療
○NPD-A:PT, OT, 経管栄養, 鎮静剤 (被刺激性と睡眠障害)
○NPD-B:出血には輸血, 酸素(肺疾患), 高脂血症の治療, カロリー摂取
●遺伝:常染色体劣性
●臨床診断:示唆する所見
○NPD-A:肝脾腫, 発達遅滞, 間質性肺疾患, チェリーレッド斑
○NPD-B:肝脾腫, 間質性肺疾患, 高脂血症, 血小板減少
●遺伝子検査:SMPD1 酵素診断された患者の95%で病的バリアントあり
○NPD-A:Ashkenazi ユダヤ人では2つのバリアント (p.Arg498Leu, p.Leu304Pro, p.Phe333SerfsTer52) が約90%
○NPD-B:p.Arg610del→北アフリカ・マグレブ地域 (チュニジア, アルジェリア, モロッコ) の90%, 大カナリア島の100%, 米国の20-30%
●酵素診断:対照の10%未満の活性
 p.Gln294Lys は人工基質を使って測定すると正常酵素活性を示すかも
●遺伝子型-表現型相関
 p.Arg610del のホモ接合→軽症, 正常身長体重, 軽い肝脾腫と骨年齢遅延, 正常血清 IGF-I値
 脂質異常は全ての遺伝子型で生じる
 p.Leu139Pro, p.Ala198Pro, p.Arg476Trp →NPD-Bの軽症型
 p.His423Tyr と p.Lys578Asn →サウジアラビアで最も多く, 早期発症重症型である
 p.Gln294Lys →中間表現型でチェコ, スロバキアでみられる
 NPD-Aでみられる病的バリアントとの複合ヘテロ接合はNPD-Aとなる
●頻度:1:250,000
 チリでのp.Ala359Asp→ヘテロ接合頻度 1:105.7, 有病率 1:44,960
 NPD-A→ Ashkenazi ユダヤ人で多い (p.Arg498Leu, p.Leu304Pro, p.Phe333SerfsTer52) の合計ヘテロ接合頻度は 1:80 〜 1:100
 NPD-Bは全世界でみられる
●鑑別診断
○リソソーム蓄積症:Gaucher 病とオーバーラップする
 →肺浸潤と血清HDL低値はNPDの早期にみられる特徴である
○肝脾腫のみられる疾患
 Gaucher 病, hexosaminidase A 欠乏症, Sandhoff 病, Niemann-Pick 病C型 (NPD-C), Wolman 病, ムコ多糖症, オリゴ糖症 (Mucolipidosis II, Mucolipidosis III Alpha/Beta, Mucolipidosis IV)
 →MPSでは粗な顔貌と多発性異骨症
  NPD-Cでは特異的神経所見
  Gaucher 病と Sandhoff 病は酵素検査で鑑別

(Responsible gene) *607608 Sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) <11p15.4>
(1) Niemann-Pick disease, type A (257200)
.0001 Niemann-Pick disease, type A [SMPD1, ARG496LEU] (rs120074117) (gnomAD:rs120074117) (RCV000192227...) (Levran et al. 1990, 1991)
.0003 Niemann-Pick disease, type A [SMPD1, GLY577SER] (rs120074119) (gnomAD:rs120074119) (RCV000003116...) (Ferlinz et al.1991)
.0005 Niemann-Pick disease, type A [SMPD1, LEU261TER] (rs120074120) (gnomAD:rs120074120) (RCV001248867...) (Takahashi et al. 1992)
.0006 Niemann-Pick disease, type A [SMPD1, 2-BP DEL, LEU178FS] (RCV000003119) (Takahashi et al. 1992)
.0007 Niemann-Pick disease, type A [SMPD1, MET382ILE] (rs120074121) (RCV000003120...) (Takahashi et al. 1992)
.0010 Niemann-Pick disease, type A [SMPD1, LEU302PRO] (rs120074124) (gnomAD:rs120074124) (RCV000003123...) (Levran et al. 1992)
.0011 Niemann-Pick disease, type A [SMPD1, 1-BP DEL, PRO330FS] (rs387906289) (RCV000003124...) (Levran et al. 1993)
.0012 Niemann-Pick disease, intermediate form, with macular halo (257200) [SMPD1, TRP391GLY] (rs120074125) (gnomAD:rs120074125) (RCV000003125...) (Sperl et al. 1994; Ferlinz et al. 1995)
.0016 Niemann-Pick disease, type A [SMPD1, ALA482GLU] (rs267607075) (gnomAD:rs267607075) (RCV000780737...) (Rodriguez-Pascau et al. 2009)
.0017 Niemann-Pick disease, type A [SMPD1, TYR467SER] (rs267607074) (RCV000003131) (Rodriguez-Pascau et al. 2009)
(2) Niemann-Pick disease, type B (607616)
.0002 Niemann-Pick disease, type B [SMPD1, ARG608DEL] (rs120074118) (RCV000192229...) (Levran et al. 1991; Vanier et al. 1993; Volders et al., 2002; Fernandez-Burriel et al. 2003; Rodriguez-Pascau et al. 2009)
.0004 Niemann-Pick disease, type B [SMPD1, SER436ARG] (rs267607073) (RCV000003117) Takahashi et al.1992)
.0008 Niemann-Pick disease, type B [SMPD1, GLY242ARG] (rs120074122) (gnomAD:rs120074122) (RCV000003121...) (Takahashi et al. 1992)
.0009 Niemann-Pick disease, type B [SMPD1, ASN383SER] (rs120074123) (gnomAD:rs120074123) (RCV000003122...) (Takahashi et al. 1992)
.0013 Niemann-Pick disease, type B [SMPD1, HIS421TYR] (rs120074126) (RCV000634570...) (Simonaro et al. 2002)
.0014 Niemann-Pick disease, type B [SMPD1, ARG441TER] (rs120074127) (gnomAD:rs120074127) (RCV000003127...) (Lee et al. 2003)
.0015 Niemann-Pick disease, type B (Niemann-Pick disease, intermediate, protracted neurovisceral, included) [SMPD1, GLN292LYS] (rs120074128) (gnomAD:rs120074128) (RCV000169297...) (Pavlu and Elleder 1997; Pavlu-Pereira et al. 2005)

*SMPD1: Sphingomyelin phosphodiesterase 1, acid lysosomal (629 amino acids)
・リソソームacid sphingomyelinase で, sphingomyelin を ceramide に変換する
・1,2-diacylglycerolphosphocholine と 1,2-diacylglycerolphosphoglycerolへのphospholipase C 活性ももつ

(要約)
●Niemann–Pick 病は, 致死性遺伝性代謝性疾患で, リソソーム蓄積症に含まれる
●症状
 症状はSphingomyelinが蓄積する器官に関連する
 肝脾腫:食思不振, 腹部膨満, 腹痛, 血小板減少
 中枢神経:失調歩行, 構音障害, 嚥下障害
 基底核機能障害:ジストニア
 上部脳幹:核上性注視麻痺
 より広範な大脳皮質や皮質下の病変:痴呆, けいれん
 骨髄:腔の拡大, 皮質骨菲薄化
 内反股
 発作性カタプレキシー
 逆睡眠
●原因
 SMPD1 遺伝子変異→ Niemann–Pick 病A型とB型
 NPC1 と NPC2 遺伝子変異→ Niemann-Pick 病 C型 (D型も含む)
●分類 (1961)
 Niemann–Pick disease type A: 古典的乳児
 Niemann–Pick disease type B: 内臓
 Niemann-Pick disease, type C: 亜急性/若年性
 Niemann–Pick disease type D: Nova Scotian 地域
●現在の分類
 Niemann-Pick 病, SMPD1-関連:A型とB型を含む
 Niemann-Pick 病 C型:C1型とC2型 (D型はC1型と同じ遺伝子変異)
●機序
●古典的乳児性A型:ミスセンス変異がsphingomyelinase の完全欠損を生じる
 Sphingomyelin は, 小器官膜を含む細胞膜成分なので, 酵素欠損は脂質分化をブロックし, マクロファージ-単球貪食細胞系のリソソーム内にsphingomyelin の蓄積を生じる
 細胞はsphingomyelin とコレステロールによるリソソーム膨張により拡大する
 組織学的には, 骨髄に脂肪をもつマクロファージと病理検査で, "sea-blue histiocytes" を証明する
 多数の小さな比較的一定したサイズの空胞が形成され, 細胞質は泡沫概観を呈する
●治療:支持療法に限定
 臓器移植の効果は限定的
 骨髄移植の試み
 Zavesca (Miglustat) がNPCに欧州で承認
 CYCLO (2-hydroxypropyl-β-cyclodextrin or HPBCD)のトライアル
●予後
 A型は極めて不良 (18か月までに死亡)
 B型とC型は10歳代〜成人まで生存

<小児慢性特定疾病 代89 ニーマン・ピック(Niemann-Pick)病>
概要・定義
ニーマン・ピック(Niemann-Pick)病は, 酸性スフィンゴミエリナーゼが欠損するA型, B型とNPC1またはNPC2蛋白の異常によって起こるC型に分類される。いずれも常染色体劣性遺伝形式を示す遺伝病である。肝臓, 脾臓, 骨髄の網内系細胞と神経細胞にスフィンゴミエリン, コレステロール, 糖脂質などが蓄積する。発症頻度は12万人に1人とされる。A型は乳児期に発症し, 肝脾腫, 精神運動障害, 垂直方向の眼球運動障害が見られる。B型は小児期に発症し, 肝脾腫が主体であり, 神経症状は伴わない。C型の発症年齢は様々で, 肝脾腫, カタレプキシー, 垂直眼球運動障害, 失調, ジストニア, 痴呆などの神経症状を呈する。成人発症では痴呆, 抑うつ症状などの精神症状を主体とする例もある。
疫学
日本ではA型とB型の罹患率は, 10万人あたり0.5人-1人とされており, B型の患者さんの方が比較的多い。C型の発症頻度は12万人に1人とされる。
病因
A型, B型の原因はSPD1(sphingomylelin phosphodiesterase 1)遺伝子の変異による。点変異, 欠失, スプライス異常など100以上の遺伝子変異が報告されている。C型は, NPC1遺伝子またはNPC2遺伝子の変異による。NPC遺伝子は, 細胞内コレステロール輸送に関係する遺伝子であるが, 細胞内には遊離型コレステロールのみならず, GM1ならびにGM2などのガングリオシドなど蓄積する。
症状
 A型は, 乳児期早期から肝脾腫が著明であり, 筋緊張低下, 哺乳障害, 嘔吐などが出現するし, 成長障害が認められる。6ヶ月以降, 精神運動発達障害が明らかとなり, 急速に神経症状が進行する。症状が進行した患者では, 眼底にチェリー・レッドスポットが見られる。
 B型は, A型よりも症状は軽く小児期以降に発症する。肝脾腫が初発症状であることも多い。肝脾腫の程度は様々であり, 肝障害が進行し, 肝硬変, 門脈圧亢進, 腹水を伴うこともある。また, 血液検査では低HDL血症が特徴的で, 脾機能亢進により血小板減少が認められることがある。胸部X線写真では, 肺浸潤像が認められ, 肺拡散障害が年齢とともに進行する。眼底のチェリー・レッドスポットは約1/3の患者さんに認められるが, 目立った中枢神経症状はほとんどない。
 C型は, 新生児期の死亡から成人期に発症する患者さんまで幅広い発症年齢と症状がある。新生児発症では, 胎児水腫, 胎児腹水で発症する患者さんもおり, 胆汁うっ滞型横断と肝脾腫を示す患者が多い。肝脾腫, 肺症状などの身体症状は神経症状より早期に出現することが多い。脾腫は年齢とともに目立たなくなる。また, 肝脾腫を認めない患者さんもいる。神経症状は, 小脳失調, 構音障害, 燕下障害, 知的障害, 痙れん, ジストニアなどが進行する。核上性垂直性眼球運動障害とカタプレキシー(笑うと力が抜ける)は本症に特徴的である。成人発症例には精神症状も多い。
診断
 A型, B型では, 骨髄中の泡沫細胞(ニーマンピック細胞)が特徴的で診断に有用。確定診断には, 末梢リンパ球や培養皮膚線維芽細胞の酸性スフィンゴミエリナーゼの酵素活性を測定する。酵素活性が低値(10%以下)の時には, 本症と診断できる。B型の残存酵素活性はA型よりやや高い。遺伝子診断としては, SPD1遺伝子変異を検出する。
 C型断では, 骨髓の泡沫細胞の確認と皮膚線維芽細胞のフィリピン染色による遊離型コレステロールの蓄積を確認することが診断に有用である。遺伝子診断としてはNPC1, NPC2の遺伝子変異を検出する。
診断方法
1. 典型例ではカタレプキシー, 垂直方向の眼球運動障害が見られる。
2. 確定診断は, 骨髄の泡沫細胞の確認と, 末梢血リンパ球または培養線維芽細胞のライソゾーム酵素活性測定, および線維芽細胞のフィリピン染色によるコレステロール蓄積の確認により行われる。
3. 遺伝カウンセリングなどの情報として, 遺伝子診断は有用である。しかし, フィリピン染色などで診断が確実となった患者でも, 遺伝子診断では変異が見つからない場合がある。
当該事業における対象基準
全A  疾患名に該当する場合

治療
A型やB型患者さんには, 骨髄移植が試みられているがA型の神経症状には無効であり, 本治療の有効性に関してのエビデンスは乏しい。現在, B型患者さんに対する酵素補充療法が開発されつつあり, 米国で臨床研究が進められている。
C型では, ガングリオシド合成系の酵素を阻害するMilglustat(ブリーザベス)が治療薬として承認されており, 神経症状にある程度の効果が期待できる。また, シクロデキストリンの髄注による臨床研究が日本でも進められている。

予後
A型は予後不良で, ほとんどの患者さんが3歳前後に死亡する。B型は緩徐進行性の経過をとることが多い。C型では, 新生児発症では予後不良が多く, 低年齢での発症は神経症状の進行が早い。
成人期以降
 B型は成人期以降に肝脾腫などの症状で発症することがあり, 成人においても鑑別診断に入れておく必要がある。C型では, 成人期以降に精神症状で発症する例があり注意を要する。

(Responsible gene) *607608 Sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) <11p15.4>
(1) Niemann-Pick disease, type A (257200)
.0001 Niemann-Pick disease, type A [SMPD1, ARG496LEU] (Levran et al. 1990, 1991)
.0003 Niemann-Pick disease, type A [SMPD1, GLY577SER] (Ferlinz et al.1991)
.0005 Niemann-Pick disease, type A [SMPD1, LEU261TER] (Takahashi et al. 1992)
.0006 Niemann-Pick disease, type A [SMPD1, 2-BP DEL, LEU178FS] (Takahashi et al. 1992)
.0007 Niemann-Pick disease, type A [SMPD1, MET382ILE] (Takahashi et al. 1992)
.0010 Niemann-Pick disease, type A [SMPD1, LEU302PRO] (Levran et al. 1992)
.0011 Niemann-Pick disease, type A [SMPD1, 1-BP DEL, PRO330FS] (Levran et al. 1993)
.0012 Niemann-Pick disease, intermediate form, with macular halo (257200) [SMPD1, TRP391GLY] (Sperl et al. 1994; Ferlinz et al. 1995)
.0016 Niemann-Pick disease, type A [SMPD1, ALA482GLU] (Rodriguez-Pascau et al. 2009)
.0017 Niemann-Pick disease, type A [SMPD1, TYR467SER] (Rodriguez-Pascau et al. 2009)
(2) Niemann-Pick disease, type B (607616)
.0002 Niemann-Pick disease, type B [SMPD1, ARG608DEL] (Levran et al. 1991; Vanier et al. 1993; Volders et al., 2002; Fernandez-Burriel et al. 2003)
.0004 Niemann-Pick disease, type B [SMPD1, SER436ARG] (Takahashi et al.1992)
.0008 Niemann-Pick disease, type B [SMPD1, GLY242ARG] (Takahashi et al. 1992)
.0009 Niemann-Pick disease, type B [SMPD1, ASN383SER] (Takahashi et al. 1992)
.0013 Niemann-Pick disease, type B [SMPD1, HIS421TYR] (Simonaro et al. 2002)
.0014 Niemann-Pick disease, type B [SMPD1, ARG441TER] (Lee et al. 2003)
.0015 Niemann-Pick disease, type B [SMPD1, GLN292LYS] (Niemann-Pick disease, intermediate, protracted neurovisceral, included) (Pavlu and Elleder 1997; Pavlu-Pereira et al. 2005)

*SMPD1 (Sphingomyelin Phosphodiesterase 1)
 Genome size 4,559 bp, 631 aa, 69936 Da
 Exons: 6, Coding exons: 6, Transcript length: 2,410 bps, Translation length: 631 residues
● lysosomal acid sphingomyelinase で,sphingomyelin を ceramideへ変換する
 1,2-diacylglycerolphosphocholine や 1,2-diacylglycerolphosphoglycerolへのphospholipase C 活性ももつ
 Isoform 2 と 3 は cofactor Zn(2+) と結合する残基を欠き酵素活性はない
●関係する pathways: Lysosome ; NGF Pathway

(Note)
A number sign (#) is used with this entry because Niemann-Pick disease type B, known as the 'visceral' form, is caused by homozygous or compound heterozygous mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1; 607608), which encodes acid sphingomyelinase (ASM), on chromosome 11p15.

Niemann-Pick disease type A (257200) is an allelic disorder characterized by onset in infancy of a primarily neurodegenerative disorder with death by age 3 years.

See also Niemann-Pick disease types C1 (257220) and C2 (607625).

Niemann-Pick disease types A and B are caused by an inherited deficiency of acid sphingomyelinase activity. The clinical phenotype ranges from a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age (type A) to a later-onset nonneurologic form (type B) that is compatible with survival into adulthood. Since intermediate cases also have been reported, the disease is best regarded a single entity with a clinical spectrum (summary by Schuchman, 2007).

Schuchman (2007) provided a detailed review of Niemann-Pick disease type B, including clinical management.

Clinical Features
In contrast to patients with Niemann-Pick disease type A, patients with type B have involvement of the spleen, liver, and lungs, and remain free of neurologic manifestations despite the massive visceral involvement. Patients with type B often survive into adulthood.

Pfaendler (1953) described non-Jewish Swiss brothers (out of 14 sibs) with Niemann-Pick disease who died at ages 29 and 33 years; they most likely had type B.

Blankenship et al. (1973) reported a family with sea-blue histiocytosis with acid phosphatemia and suggested that it represented a syndrome similar to Gaucher disease (230800). Golde et al. (1975) described a second family with sea-blue histiocytosis, lamellar inclusions, and decreased sphingomyelinase activity. Fried et al. (1978) presented evidence that primary sea-blue histiocyte disease (269600) and Niemann-Pick disease type B are the same. Deficiency of sphingomyelinase could be demonstrated in leukocytes and an intermediate level in heterozygotes. Despite the lack of neurologic symptoms in type B, Wenger et al. (1981) were unable to demonstrate lysosomal sphingomyelinase in brain tissue of a fetus affected with type B.

Landas et al. (1985) reported a 48-year-old woman with debilitating and eventually fatal coronary artery disease and hepatosplenomegaly in whom multiorgan infiltration by sea-blue histiocytes was the consequence of Niemann-Pick disease type B. Strisciuglio et al. (1987) found evidence of involvement of multiple endocrine glands in a patient with type B Niemann-Pick disease and growth failure.

Viana et al. (1990) reported a Brazilian family in which 4 sibs had sea-blue histiocytosis and nonneuropathic Niemann-Pick disease, presumably type B. The kindred was ascertained through a 7-year-old boy who was found to have massive hepatosplenomegaly since infancy. Four of 12 sibs were similarly affected with short stature, bilateral interstitial pulmonary infiltration, and high levels of serum acid phosphatase. Leukocyte acid sphingomyelinase activity ranged from 3.6 to 6.5% of mean control values, and fibroblast activity from 9 to 13% of mean controls. The parents had low-normal levels. The 4 sibs also had very low levels of low density lipoprotein (LDL) cholesterol, very low levels of high density lipoprotein (HDL) cholesterol, and low levels of apoAI. Viana et al. (1990) pointed out that low levels of serum HDL cholesterol have been reported in other patients with Niemann-Pick disease and may be a secondary manifestation of the lysosomal storage disease since low serum HDL cholesterol has been found in at least 2 other diseases in this category, namely, Gaucher disease and cholesteryl ester storage disease.

Volders et al. (2002) reported a unique case of a 55-year-old woman who presented with a clinical picture of Parkinson disease, severe back pain, splenomegaly, and pronounced dyspnea. Radiographic examination of the spine showed multiple vertebral fractures. Niemann-Pick disease type B was diagnosed by the finding of lipid-loaded histiocytes and strongly reduced sphingomyelinase activity. She was found to be homozygous for a mutation in the SMPD1 gene (607608.0002); see MOLECULAR GENETICS. In this patient, Volders et al. (2002) screened for polymorphisms previously described as possibly associated with increased risk for osteoporosis and fractures and found that the patient was heterozygous for polymorphisms of the vitamin D receptor gene (VDR; 601769), the estrogen receptor gene (ESR1; 133430), and the alpha-1 chain of type I collagen (COL1A1; 120150). The dramatic presentation of the patient was thought to be explained by increased physical activity after treatment of Parkinson disease, a genetic predisposition, and worsening of the disease due to interfering medication. She was treated with cholesterol-lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that can inhibit sphingomyelinase, and bisphosphonates. No new fractures occurred, but the interstitial lung disease progressed.

McGovern et al. (2013) performed a systematic evaluation of morbidity and mortality in Niemann-Pick type B disease in a total of 103 patients (49 males, 54 females, age range 1-72 years) studied between 1992 and 2012. Serious morbidities included significant neurologic, hepatic, and cardiac disease. Thirteen patients had some degree of neurologic impairment. Nine had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart disease were present in 9 patients. Of note, only 4 patients were oxygen-dependent, although progressive pulmonary disease is a well-described feature of Niemann-Pick disease. During the follow-up period 18 deaths occurred. Median age of death was 15.5 years (range 1-72). Causes of death included pneumonia, liver failure, and hemorrhage. The majority of deaths (12 of the 18) occurred in patients younger than 21 years, yielding a mortality rate of 19% in the pediatric population.

Cassiman et al. (2016) reviewed the cause of death in 85 patients with Niemann-Pick B and B variant. Of these, 27 were newly reported and 58 were abstracted from the literature. Common disease-related morbidities included splenomegaly (97%), hepatomegaly (91%), liver dysfunction (83%), and pulmonary disease (75%). Among those with symptom onset after 18 years of age, respiratory disease was the primary cause of death in 44%, with bleeding and cardiac disease each accounting for 22%. Among those with symptom onset before 18 years of age, respiratory disease and liver disease each accounted for 28% of deaths and neurodegenerative disease accounted for 15% of deaths. Among those with chronic visceral acid sphingomyelinase deficiency (ASMD), respiratory disease and liver disease accounted for 32% and 29% of deaths, respectively. Among those with chronic neurovisceral ASMD, respiratory and neurodegenerative disease each accounted for 23% of deaths and were followed by liver disease at 19%.

Clinical Variability
Pavlu-Pereira et al. (2005) described 25 Czech and Slovak patients with acid sphingomyelinase deficiency. Five could be clearly classified as having Niemann-Pick disease type A and 4 as having type B. However, 16 (64%) of 25 patients showed variable features, which the authors considered to be an intermediate form of the disease. Twelve of these patients had a combination of visceral storage with a protracted course of neurologic involvement and a general protracted disease course. Three patients had prominent visceral involvement with a rapid course and discrete neuronal storage observed at autopsy. One patient had a rapidly fatal course of visceral involvement without neuronal involvement; he died at age 8 years. The Q292K mutation (607608.0015) was strongly associated with a protracted neurovisceral phenotype in 10 of 12 patients. Pavlu-Pereira et al. (2005) concluded that a phenotypic continuum exists between the basic neurovisceral (type A) and purely visceral (type B) forms of Niemann-Pick disease, and that the intermediate type encompasses a cluster of variants combining clinical features of both types A and B.

Niemann-Pick Disease, Types E and F
Terry et al. (1954) and Lynn and Terry (1964) described an indeterminate adult form of Niemann-Pick disease, type E. Type E patients are adults with moderate hepatosplenomegaly and some increase in sphingomyelin in the liver, spleen, and bone marrow.

Schneider et al. (1978) used the designation type F for a form characterized in 2 patients by childhood onset of splenomegaly, lack of neurologic involvement, diminished sphingomyelinase activity, and thermolabile enzyme. Niemann-Pick disease types E and F have not been well-characterized.

Diagnosis
Simonaro et al. (2002) commented that type B Niemann-Pick disease is a particularly difficult disorder to diagnose clinically. They suggested that it might be useful to screen in heart disease clinics for patients with very low HDL cholesterol levels, since this is a common finding in almost all patients with type B Niemann-Pick disease, or in endocrinology clinics where patients may be seen for growth retardation.

Clinical Management
Following the lead of Adinolfi et al. (1982), who proposed the transplantation of amniotic membrane in the treatment of patients with lysosomal storage disorders, Bembi et al. (1992) treated 5 young patients with Niemann-Pick disease type B with repeated implantations of amniotic epithelial cells as a source of exogenous sphingomyelinase. They concluded that the treatment abolished recurrent infections, mainly of the respiratory tract, and led to other improvements in the general condition of the patients. In 2 cases with increased sphingomyelin in urinary sediments, a single implantation caused a sustained normalization of sphingomyelin and total phospholipids in the urine. Furthermore, a rise in sphingomyelinase activity in peripheral leukocytes to values in the heterozygous range were observed.

Scaggiante et al. (1987) used repeated subcutaneous implantations of amniotic membrane to restore enzyme in a 14-year-old boy with Niemann-Pick disease type B. The patient had massive hepatosplenomegaly and diffuse infiltration of the lungs. Decrease in hepatomegaly was observed.

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

Biochemical Features
Kirkegaard et al. (2010) showed that Hsp70 (140550) stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential cofactor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (trp90 to phe), as well as the pharmacologic and genetic inhibition of ASM, effectively reverted the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease A (257200) and B, severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase-1 gene (SMPD1; 607616) encoding ASM, is also associated with a marked decrease in lysosomal stability, and this phenotype could be effectively corrected by treatment with recombinant Hsp70. Kirkegaard et al. (2010) concluded that, taken together, their data opened exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.

Molecular Genetics
In an Ashkenazi Jewish patient with Niemann-Pick disease type B, Levran et al. (1991) identified a mutation in the acid lysosomal sphingomyelinase phosphodiesterase-1 gene (607608.0002). Takahashi et al. (1992) identified 3 SMPD1 mutations (607608.0008-607608.0009) causing Niemann-Pick disease type B.

Rodriguez-Pascau et al. (2009) identified 17 different mutations in the SMPD1 gene, including 10 novel mutations (see, e.g., A482E; 608607.0016 and Y467S; 608607.0017), in 19 Spanish patients and 2 patients from Maghreb in Northern Africa with Niemann-Pick disease type A (8 patients) or type B (13 patients). The most common mutations were R608del (607608.0002), found in 38% of alleles, and the A482E mutation, found in 9% of alleles. The R608del mutation was always found in patients with type B disease; the A482E and Y467S mutations were found in type A patients. Functional expression studies of the mutant proteins in COS-7 cells showed decreased enzyme activity.

Genotype/Phenotype Correlations
Takahashi et al. (1992) concluded that small deletions or nonsense mutations that result in truncated ASM polypeptide and missense mutations that render the enzyme noncatalytic cause type A Niemann-Pick disease, whereas missense mutations that produce a defective enzyme with residual catalytic activity cause a milder nonneuronopathic type B phenotype.

Population Genetics
Simonaro et al. (2002) collected demographic and/or mutation information on a worldwide sample of 394 patients with type B Niemann-Pick disease. They found that the disorder is panethnic, with the highest incidence occurring in individuals of Turkish, Arabic, and North African descent. Only 5 of the 394 patients were Ashkenazi Jewish, revealing that, unlike the type A form of Niemann-Pick disease, type B does not occur frequently within this population. Mutation analysis of the SMPD1 gene was performed on 228 patients and several novel 'common' mutations were found. The previously reported arg608-to-del mutation (607608.0002) occurred in approximately 12% of the alleles studied. Overall, a total of 45 novel mutations were found, and several new genotype/phenotype correlations were identified.

Animal Model
Using a novel transgenic/knockout strategy to manipulate the intracellular targeting of a hydrolase, Marathe et al. (2000) created a mouse that stably expresses low levels of lysosomal sphingomyelinase (L-SMase) in the complete absence of secretory sphingomyelinase (S-SMase). The brains of these mice exhibited 11.5 to 18.2% of wildtype L-SMase activity, but the cerebellar Purkinje cell layer, which is lost by 4 months of age in mice completely lacking L- and S-SMase, was preserved for at least 8 months. The L-SMase activities in other organs were 1 to 14% of wildtype levels, and by 8 months of age all peripheral organs had accumulated sphingomyelin and demonstrated pathologic intracellular inclusions. Most importantly, L-SMase-expressing mice showed no signs of the severe neurologic disease observed in completely deficient mice, and their life span and general health were essentially normal. The authors concluded that stable, continuous, low level expression of intralysosomal enzyme activity in the brain may preserve CNS function in the absence of secretory enzyme or other confounding factors.

(文献)
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