疾患詳細

疾患詳細





#257200
Niemann-Pick disease, type A
(Sphingomyelin lipidosis)
(Sphingomyelinase deficiency)
(Acid sphingomyelinase deficiency, neurovisceral type; ASMD)
(Niemann-Pick disease, intermediate, protracted neurovisceral, included)

Niemann- Pick 病 (NPD)
(スフィンゴミエリンリピドーシス)
(スフィンゴミエリナーゼ欠損症)
(酸性スフィンゴミエリナーゼ, 神経内臓型)
(Niemann- Pick 病, A および B 型)
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-p15.1>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <30%-79%>
 Cherry red spot of the macula (チェリーレッド斑) [HP:0010729] [0650]
 
 
 Athetosis (アテトーゼ) [Hp:0002305] [02600]
 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]
 Constipation (便秘) [HP:0002019] [01803]
 Diffuse reticular or finely nodular infiltrations (びまん性網状または微細結節性浸潤) [HP:0002207]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Feeding difficulties in infancy (哺乳障害, 乳児期) [HP:0008872] [01411]
 Foam cells with lamellar inclusion bodies (層状封入内を伴う泡沫細胞) [HP:0003609]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Infantile onset (乳児期発症) [HP:0003593]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Lymphadenopathy (リンパ節腫大) [HP:0002716] [2228]
 Microcytic anemia (小球性貧血) [HP:0001935] [2201]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Osteoporosis (骨粗鬆症) [HP:0000939] [160015]
 Protuberant abdomen (腹部膨満) [HP:0001538] [01801]
 Psychomotor retardation (精神運動発達遅滞) [HP:0025356] [0120]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Rigidity (固縮) [HP:0002063] [0240]
 Sea-blue histiocytosis (海青組織球症) [HP:0001982] [2208]
 Short stature (低身長) [HP:0004322] [0130]
 Spasticity (痙縮) [HP:0001257] [0241]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Vomiting (嘔吐) [HP:0002013] [01425]
 Xanthomatosis (黄色腫症) [HP:0000991] [2330] [0804]

(UR-DBMS)
【一般】低身長
 低出生体重, 成長障害, 食餌摂取障害
 頻回の呼吸器感染症
 腹部膨満
 *肝脾腫
 新生児黄疸 (1/4)
 嘔吐
 便秘
 精神運動発達遅滞
 精神遅滞 (B型以外で)
 認知症
 けいれん
 呼吸障害
 腹水
 肝不全 (B型)
【神経】筋緊張低下
 筋力低下
 反射低下
 痙性 (後に)
 硬直 (後に)
 アテトーゼ (後に)
 運動失調
 ミオクローヌス
【眼】チェリー・レッド斑 (若年者で)
 灰色の顆粒状黄斑
 斜視
 垂直の核上性眼球運動障害
 角膜混濁
 前水晶体被殻の褐色変色
【胸郭】びまん性網状または微細結節性肺浸潤
【心】冠動脈疾患
【X線】骨粗鬆症
【皮膚】丘疹状または結節性皮膚黄色腫
 栄養失調
【検査】sphingomyelinase 低下 (5%未満)
 多くの器官 (肺, 肝, 脾,腎, 脳) が泡沫残存細胞と組織球を含む
 (電顕) 泡沫細胞は層状封入体を示す
 高脂血症 (A/B型)
 HDL コレステロール低値
 LDL コレステロール低値
 apoAI 低値
 細網内皮系およびその他の細胞へのスフィンゴミエリン蓄積→中枢神経節細胞の死亡
【血液】小球性貧血
 *大きな空胞化泡沫細胞 ('NP 細胞') (骨髄 / 肝/ 脾)
 リンパ球空胞
 'Sea blue' 組織球
 リンパ節腫大
 脾臓機能亢進
 易出血性
【その他】乳児期発症
 3歳までに死亡
 Ashkenazi ユダヤ人に多い
 Nieman-Pick disease type B (607616)とアレリック
 Allelic 疾患 to Nieman-Pick 病 B型(607616)

(A 型) 急性ニューロパチー型
(B 型) 慢性型
 神経病変なし
(C 型) 慢性ニューロパチー型
(D 型) Nova Scotia 亜型
(E 型) 成人非ニューロパチー型
(F 型) 海青組織球型

(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

(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

<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] (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)
 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 A 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 B (607616) is an allelic disorder characterized by visceral involvement only and survival into adulthood.

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).

Knudson and Kaplan (1962) suggested that 3 types of the disorder can be distinguished: infantile cerebral, juvenile cerebral, and noncerebral. Later, 5 forms of Niemann-Pick disease were distinguished. Four were delineated by Crocker (1961): the classical infantile form (type A), the visceral form (type B), the subacute or juvenile form (type C; 257220), and the Nova Scotian variant (type D; see 257220). The fifth, the adult form (type E; see 607616), was described by Terry et al. (1954) and Lynn and Terry (1964).Schneider et al. (1978) used the designation type F (see 607616) for a form characterized in 2 patients by a thermolabile enzyme. Most patients fall into Crocker's group A, with death before age 3 years.

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

Clinical Features
In Niemann-Pick disease, lipid, mainly sphingomyelin, accumulates in reticuloendothelial and other cell types throughout the body. The accumulation in ganglion cells of the central nervous system leads to cell death. Crocker and Farber (1958) presented a detailed clinical and pathologic account of 18 patients with Niemann-Pick disease. Persistent early jaundice, enlarging abdomen, and poor nutritional and developmental progress were the most common initial complaints. Hepatosplenomegaly, retarded physical and mental growth and severe neurologic disturbances, including hypotonia, rigidity, and mental retardation, were features. Symptoms usually developed by 6 months and death occurred by 3 years of age. Crocker and Farber (1958), Forsythe et al. (1959), and others suggested that the biologic behavior can be widely variable.

Wiedemann et al. (1965) found large storage cells in the bone marrow of both clinically normal parents of a sibship with several affected children. The parents were first cousins. The authors noted that about 40% of cases were Jewish. Heterogeneity was emphasized by Lowden et al. (1967) who described non-Jewish sibs with both clinical and chemical differences from the usual disease.

In addition to a cherry red spot, Walton et al. (1978) found corneal opacification and brown discoloration of the anterior lens capsule in all of 4 infants with type A Niemann-Pick disease who were studied in their first year.

Barness et al. (1987) presented a well-studied case of Niemann-Pick disease type A at a clinicopathologic conference.

McGovern et al. (2006) reported the natural history of 10 unrelated patients with type A Niemann-Pick disease. All affected infants had a normal neonatal course and early development. The presenting symptom in all patients was hepatosplenomegaly, and the median age at diagnosis was 6 months. Median developmental age for all 10 did not progress beyond 12 months for developmental milestones. None achieved independent sitting, crawling, or walking; most had progressive hypotonia with loss of deep tendon reflexes. All patients had cherry red spots by age 12 months. Nonneurologic symptoms included vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbances. The median time from diagnosis to death was 21 months.McGovern et al. (2006) concluded that type A Niemann-Pick disease shows a homogeneous, relentless, neurodegenerative clinical course with death within 3 years of onset.

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.

Pathogenesis
In the classic infantile type (type A), Brady et al. (1966) demonstrated that the biochemical defect is deficient activity of the enzyme that catalyzes cleavage of sphingomyelin to phosphorylcholine and ceramide. Uhlendorf et al. (1967) found the metabolic defect in cell culture. Increased sphingomyelin was demonstrated in cells from bone marrow, skin, and amnion; the last makes prenatal diagnosis possible.

Schneider and Kennedy (1967) found that sphingomyelinase is deficient only in the infantile and visceral forms (type B).

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 and B (607616), 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.

Clinical Management
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
Levran et al. (1991) identified a point mutation in the SMPD1 gene (607608.0001) in an Ashkenazi Jewish patient with type A Niemann-Pick disease. Takahashi et al. (1992) characterized 3 SMPD1 mutations (607608.0005-607608.0007) causing Niemann-Pick disease type A. Ida et al. (1996) identified 3 novel mutations in the SMPD1 gene in Japanese patients with type A and B Niemann-Pick disease.

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
Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, Slatkin (2004) considered available genetic data to be consistent with a founder effect resulting from a severe bottleneck in population size between 1100 A.D. and 1400 A.D. and an earlier bottleneck in 75 A.D., at the beginning of the Jewish Diaspora. He concluded that a founder effect can account for the relatively high frequency of alleles causing 4 different lysosomal storage disorders, including Niemann-Pick disease, Tay-Sachs disease (TSD; 272800), and Gaucher disease (230800), if the disease-associated alleles are recessive in their effects on reproductive fitness.

Animal Model
By homologous recombination in embryonic stem cells, Otterbach and Stoffel (1995) achieved targeted disruption of the SMPD1 gene in transgenic mice. Homozygous mice accumulated sphingomyelin extensively in the reticuloendothelial system of liver, spleen, bone marrow, and lung, as well as in the brain. Most strikingly, the ganglionic cell layer of Purkinje cells of the cerebellum degenerated completely, leading to severe impairment of neuromotor coordination. The picture resembled that of the neurovisceral form of Niemann-Pick disease (type A). Horinouchi et al. (1995) obtained similar results in Asm knockout mice.

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