疾患詳細

疾患詳細





#204200
Ceroid lipofuscinosis, neuronal, 3 (CLN3)
(Neuronal ceroid lipofuscinosis, juvenile type; JNCL)
(Batten disease; BTS)
(Vogt-Spielmeyer disease)
(Spielmeyer-Sjogren disease)

セロイドリポフスチン症, 神経性, 3
(神経性セロイドリポフスチン症, 若年型)
(Batten 病)
(Vogt-Spielmeyer 病)
(Spielmeyer-Sjogren 病)
指定難病19 ライソゾーム病
代101 神経セロイドリポフスチン症

責任遺伝子:607042 CLN3 gene <16p11.2>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Abnormal electroretinogram (ERG 異常) [HP:0000512] [0690]
 Abnormal pyramidal sign (錐体路サイン異常) [HP:0007256] [02140][01405][0213][0241][0242][02613][0274]
 Abnormality of extrapyramidal motor function (錐体外路運動機能異常) [HP:0002071] [02141]
 Abnormality of visual evoked potentials (視覚誘発電位異常) [HP:0000649] [0690]
 Ataxia (運動失調) [HP:0001251] [028]
 Behavioral abnormality (行動異常) [HP:0000708] [022]
 Blindness (盲) [HP:0000618] [06011]
 Dementia (認知症) [HP:0000726] [0123]
 EEG abnormality (脳波異常) [HP:0002353] [01405]
 Focal-onset seizure (焦点発症けいれん) [HP:0007359] [01405]
 Generalized tonic-clonic seizures (全身性強直間代性発作) [HP:0002069] [01405]
 Iris hypopigmentation (虹彩低色素) [HP:0007730] [06100]
 Motor deterioration (運動悪化) [HP:0002333] [0125]
 Neurological speech impairment (神経学的発語障害) [HP:0002167] [023]
 Retinopathy (網膜症) [HP:0000488] [0652]
 
 
 Abnormal cerebellum morphology (小脳形態異常) [HP:0001317] [16013]
 Anxiety (不安) [HP:0000739] [02201]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Cataract (白内障) [HP:0000518] [0640]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Concentric hypertrophic cardiomyopathy (同心性[求心性]肥大型心筋症) [HP:0005157] [0273]
 Curvilinear intracellular accumulation of autofluorescent lipopigment storage material (自己蛍光脂肪色素沈着物質の曲線的細胞内沈着) [HP:0003205]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Fingerprint intracellular accumulation of autofluorescent lipopigment storage material (自己蛍光脂肪色素沈着物質の指紋性細胞内沈着) [HP:0003208]
 Glaucoma (緑内障) [HP:0000501] [06606]
 Increased extraneuronal autofluorescent lipopigment  (神経外自己蛍光脂肪色素増加) [HP:0003463]
 Increased neuronal autofluorescent lipopigment (ニューロンの自己蛍光性脂肪色素増加) [HP:0002074]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Macular degeneration (黄斑変性) [HP:0000608] [06523]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Parkinsonism (パーキンソニズム) [HP:0001300] [028]
 Progressive inability to walk (進行性歩行不能) [HP:0002505] [028]
 Progressive visual loss (進行性視力喪失) [HP:0000529] [06011]
 Psychomotor deterioration (精神運動発達退行) [HP:0002361] [0125]
 Psychosis (精神病) [HP:0000709] [0206]
 Rod-cone dystrophy (杆体-錐体ジストロフィー) [HP:0000510] [06524]
 Seizures (けいれん) [HP:0001250] [01405]
 Undetectable electroretinogram (ERG検出不能) [HP:0000550] [0690]
 Vacuolated lymphocytes (空胞性リンパ球) [HP:0001922] [2212]

(UR-DBMS)
【一般】黒内障性家族性白痴
 精神遅滞
 認知症
 *認知低下 / ミオクロニー性けいれん (5 - 10 歳発症)
 進行性歩行不能
 学習障害
【神経】錐体外路サイン
 小脳サイン
 運動失調
 構音障害
 ニューロンリソソームでの自己蛍光脂肪色素の蓄積
 ニューロン変性
 脳重量減少
 行動異常
 精神病
 生検での自己貪食能性空胞 (一部の患者で)
 電子濃度の高い物質の筋原線維間と筋鞘下への蓄積 (一部の患者で)
【眼】*急速な視力喪失 (4 - 10 歳)
 盲 (6- 14歳)
 *網膜色素変性症 (4 - 10 歳)
 黄斑変性
 視神経萎縮
 網膜萎縮
 非角膜エレクトロレチノグラム (ERG) の廃絶
 緑内障, 水晶体誘発性
 白内障, 若年発症性成熟
【心】同心性肥大型心筋症, 重症 (長期例での遅い発症)
【X線】大脳皮質 / 白質萎縮
 後弯
 側弯
【検査】リソソーム内の指紋様封入体と曲線小体 (結膜, 皮膚, 筋, 直腸, 骨髄, 脳, バッフィーコート)
 尿沈渣 didohols 増加
 リンパ球空胞化
 ニューロン外細胞への脂肪色素の沈着
 電顕で細胞の'指紋プロフィール'
 電顕で細胞の'曲線プロフィール'
【その他】4-10歳で発症
 20-40歳で死亡
 多様な重症度, 一部の患者はほとんど神経障害のない遷延経過をもつ
 全世界の Batten 病アレルの85%は 1.02 kb のゲノム欠失

(要約) 神経性セロイドリポフスチン症
●神経性セロイドリポフスチン症 (NCL) は, 遺伝性神経変性リソソーム蓄積病で, 進行性知能および運動悪化.けいれんおよび早期死亡が特徴である
 視力喪失が大多数の型での特徴である
 臨床表現型は, 伝統的に発症年齢と臨床症状の出現順により, 乳児型, 後期乳児型, 若年型, 成人型および北部てんかん (進行性てんかん-精神遅滞 [EPMR]) に特徴付けられる
 しかし, 遺伝的およびアレル異質性があり, 新しい命名と分類が, 責任遺伝子と発症年齢を加味して提唱された
 例) CLN1 病, 乳児期発症と CLN1 病, 若年発症は, 両方とも PPT1 変異が原因であるが, 異なる発症年齢をもつ
 最も多いNCLs は CLN3 病, 古典的若年型と CLN2 病, 古典的後期乳児型である (有病率は人種と国により異なる)
●CLN2 病, 古典的後期乳児型
 初発症状は典型的には2-4歳で出現し, 通常はてんかんで始まり, 発達退行, ミオクローヌス失調, 錐体路症状が続く
 視力障害は典型的には4-6歳で出現し, 急速に光覚のみへと進行する
 寿命は6-10代早期の範囲である
●CLN3 病, 古典的若年型
 発症は通常は4-10歳である
 急速に進行する視力喪失が1-2年内に重度の視力障害となり, これが初発症状のことが多い
 全身性強直性間代性けいれん+/-複雑部分けいれんが典型的には10歳あたりで出現する
 寿命は10代後半~30歳代である
●他の型の NCL は, 行動変化, てんかん, 視力障害, または発達遅滞と発達喪失をもつかもしれない
 経過は非常に多様である
 いくつかの遺伝子型-表現型相関が有用である
●診断:酵素活性アッセーと分子遺伝学的検査による
 まれな症例では, 診断は生検組織の電顕による
 責任遺伝子は13ある→PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, KCTD7
●治療:対症保存療法 (けいれん, 栄養障害, 胃食道逆流, 肺炎, 流涎.うつと不安, 痙性, パーキンソン症状, ジストニア)
 Benzodiazepines →けいれん, 不安, 痙性
 Trihexyphenydate →ジストニア, 流涎
 嚥下障害→胃チューブ
 抗うつ剤, 抗精神病薬→ CLN3で
●注意: Carbamazepine や phenytoin はけいれん発作やミオクローヌスを増加させ, 症状の悪化を来すことあり
 lamotrigine →けいれん発作やミオクローヌスを悪化させることあり (特にCLN2 で).
●遺伝:常染色体劣性 (成人発症は常染色体劣性または常染色体優性)
●臨床診断
・けいれん
・進行性認知機能悪化
・運動機能障害 (不随意運動, 若年小児でのミオクローヌス, 運動失調, 痙性)
・視力喪失
1) 先天性 少数 CTSD 出生前または周生期 けいれん, 小頭
2) 乳児型 主要 PPT1 6-24か月 認知/運動悪化, 視力喪失, けいれん
     まれ KCTD7
3) 後期乳児型 古典的 多数 TPP1 2-4歳 けいれん, 運動/認知悪化, 視力喪失
     バリアント フィンランド CLN5 4-7歳 認知/運動角化, けいれん, 視力喪失
           少数 CLN6 18か月-8歳 けいれん, 視力喪失
           少数 MFSD8       認知/運動悪化, けいれん, 視力喪失
           少数 CLN8 3-7.5 歳 運動悪化, けいれん, 視力喪失
           まれ CTSD
           少数 PPT1
3) 若年型 古典的 多数 CLN3 4-10 歳 視力喪失, けいれん, 認知/運動悪化, 神経精神病
     バリアント 少数 PPT1 4-10 歳 視力喪失, けいれん, 認知/運動悪化, 神経精神病
           まれ TPP1 4-10 歳 視力喪失, けいれん, 認知/運動悪化, 神経精神病
           まれ CLN9 2 4-10 歳 視力喪失, けいれん, 認知/運動悪化, 神経精神病
           まれ ATP13A2 4-10 歳 視力喪失, けいれん, 認知/運動悪化, 神経精神病
4) 北部てんかん (NE) フィンランド CLN8 5-10 歳 けいれん, 認知悪化, 時々視力喪失
5) 成人型(Kufs 病) まれ CTSD, PPT1, CLN3, CLN5, CLN6, CTSF, GRN 15-50 歳 認知/運動悪化, けいれん(A型), 行動異常 (B型)
6) 成人(Parry 病); 常染色体優性 DNAJC5
●組織学的検査:白血球または組織での電顕→非古典的NCLではいまだ必須である
 電顕 (皮膚, 筋, 結膜, 直腸など)
 タイプにより特徴ある沈着物
・顆粒状オスミウム好性沈着物 (GROD) → CLN1 と CLN10/CTSD で
・曲線状プロフィール優位→ CLN2
・指紋プロフィール→ CLN3
・混合型封入体→ CLN5, CLN6, MFSD8, CLN8, その他の後期乳児型とよび成人バリアント型
●酵素活性: 白血球, 線維芽細胞, 胎盤絨毛で3つのリソソーム酵素が欠乏している
・Palmitoyl-protein thioesterase 1 (PPT-1)→ fluorimetric assay
・Tripeptidyl-peptidase 1 (TPP-1)
・Cathepsin D (CTSD)
<臨床症状>
●CLN1 病, 古典的乳児型 256730 (以前の古典的乳児型 NCL, INCL, Santavuori-Haltia 型)
 CLN1 病は, 通常6-24か月で発症するが, 6か月以前や2歳以後発症も生じうる
 初発症状:発達遅滞, ミオクローヌス発作 +/- けいれん
 その他, 頭囲成長の悪化, 特異的脳波変化 (13か月からの), Rett 症候群に似た手の常同運動, 軽度~中等度知能障害もみられうる
 言語障害やおもちゃへの興味の喪失があるが, 周囲への興味は持続する
 中等度の運動機能障害をもつ
 網膜盲とけいれんが2歳までに明らかとなる (ERGは4歳までに記録できなくなる)
 精神運動発達は急速に悪化し, 寿命は2~9歳である
 MRI 所見は, 多様な大脳萎縮, 視床および基底核のシグナルの変化, 薄い輝度の強い脳室周囲縁がみられる
 進行性のびまん性大脳萎縮が生後4歳内にみられその後安定する
●CLN2 病, 古典的後期乳児期型 204500 (以前の後期乳児期 NCL, LINCL, Jansky-Bielschowsky 病)
 初発症状は, 典型的には2-4歳で出現し, 通常てんかんから始まる
 全身性強直性間代性けいれん, アブサン, 部分けいれんがみられうる
 ミオクローヌスはけいれん発症後に明らかとなる
 時に発達遅滞がけいれん発症以前にあきらかとなる
 けいれん発症後, 以前に獲得した運動/言語および認知能は喪失する
 視力障害は4-6歳で出現し, 急速に盲へと進行する
 通常6歳までに寝たきりとなり, 障害は重度で介護が中期小児期までに必要となる
 寿命は6歳~思春期であるが, より長い可能性がある
 早期の脳波は光刺激で後頭領域に棘波を示しうる
 ERGは通常受診時以上であるが, その後すぐ記録できなくなる
 VEPsは長期にわたり亢進し, 最終段階で減弱する
 MRI は, 進行性小脳および大脳萎縮を示し, 基底核や視床は正常である
●後期乳児期NCLバリアント
・CLN5 病, バリアント後期乳児期型:発症はフィンランドでは通常4.5~7歳である
 寿命は13~35歳
・CLN6 病:視力喪失とけいれんが初発症状.4歳以後発症の場合はてんかん, 運動失調, ミオクローヌスが初発症状
・MFSD8/CLN7 病:視力喪失とけいれんが初発症状, 4歳以後発症の場合はてんかん, 運動失調, ミオクローヌスが初発症状
・CLN8 病:発症は2-6歳
●CLN3 病 204200 (以前の古典的若年型 NCL, JNCL, Batten 病, Spielmeyer-Vogt 病) →CLN3
 発症は通常4-8歳 (平均約5歳)
 急速な視力喪失がほぼ常に初発症状で, 2-5年間は唯一の症状かもしれない
 視力喪失発症ご2-4年以内に重度視力障害となる
 JNCL早期での検査は, 黄斑の変化のみを示すかもしれない
 →次第に典型的な汎網膜変性が生じる (網膜末梢の色素変化, 血管減弱, 視神経蒼白)
 ERGは早期から光受容体機能の喪失を示す
 全身性強直性間代性けいれん+/-巣状けいてんが9-18歳の間に出現する
 運動および知能悪化の進行は多様である
 発語障害 (早口どもり, 反響言語と間違われることが多い)と緩徐な認知低下がけいれん発症あたりで出現する
 行動異常, 錐体外路症状, 睡眠障害は10歳代で出現する
 一部で, 精神症状 (思考障害, 注意力障害, 身体症状, 攻撃的行動) がみられる
 うつはまれである
 後半に心症状 (再分極障害, 心室肥大, 洞性調律障害) がみられる
 大多数の患者は10歳代後半〜20歳代前半まで生存する
 CT/MRI は15歳以上で大脳萎縮と軽度の小脳萎縮を示す
○非典型的 JNCL
 CLN3 の複合ヘテロ接合変異のことが多い (c.461-280_677+382del +もう一つ)
○JNCL バリアント
 CLN1 の軽症変異
 CLN9 責任遺伝子不明
●成人型 NCL (ANCL)
 初発症状は30歳あたりで出現し約10年後に死亡する
 眼科所見は正常である
○A型:進行性ミオクロニー発作 (難治性が多い), 痴呆症, 運動失調, 後半の錐体路および錐体外路症状
 CLN6 変異をもつ
○B型:行動異常と痴呆症が特徴で, 運動障害, 運動失調, 錐体外路症状, 球上 (脳幹)症状を伴うことがある
 CTSF 変異あり
●Northern Epilepsy (NE, Progressive Epilepsy with Mental Retardation, EPMR)
 特殊な表現型で, CLN8の変異が原因である
 強直性間代性または複雑部分発作, 緩徐な知能低下, 運動機能障害が特徴である
 視覚障害はまれ

<代101 神経セロイドリポフスチン症>
概要・定義
神経セロイドリポフスチン症は病理学的に規定される神経変性を特徴とする疾患群であり, 神経細胞, 心筋, 骨格筋に電子密度が高く, 自家蛍光を発するリポフスチン顆粒の蓄積を認める。常染色体劣性遺伝形式で遺伝する。
疫学
欧米では1万に1人と頻度が高いが, 2001年の我が国での全国調査では27例との報告があった。
病因
CLN1,2,3,5,6,7,8,10が本症の責任遺伝子として報告されている。病気の表現型と責任遺伝子は1対1の対応はしておらず, 同じ遺伝子の変異が別の病型を示す事もある。神経細胞などのライソゾーム内に自家蛍光を発する褐色のリポフスチン顆粒の蓄積が認められることが特徴。
症状
乳幼児期から小児期にかけて神経系の障害として発症する進行性の遺伝性神経変性疾患であり, 視力障害, 運動失調やけいれん等を呈し, 最終的には寝たきりとなる。その一部は進行性ミオクロニー発作の症状を呈する。発症年齢,臨床経過より一般に乳児型, 遅発性乳児型, 小児型, 成人型の4型に分けられる。
治療
対象療法
予後
予後は不良で平均余命は先天型で生後数時間から数週間, 乳児型で8~11年, 遅発乳児型と若年型で6~30年とされる。
成人期以降
神経症状が進行すると寝たきり, 人工呼吸器, 胃瘻などとなるので全身の管理が重要である。
診断方法
(1) 神経症状や退行, 視力障害などからNCLが疑われ他の病気が見いだせない場合はNCLを疑う。
(2) 確定診断は酵素診断もしくは遺伝子診断よりなされる。リンパ球, 培養線維芽細胞などの検体でPPT-1,TPP-1,Cathepsin Dの活性低下を証明するか, もしくは, 一連の責任遺伝子の変異を同定する。変異の報告はhttp://www.ucl.ac.uk/nclに記載されている。NCLの責任遺伝子, 対応する蛋白質を<<表>>にしめす。
CLN1 PPT1 (Palmitoyl-protein thioesterase 1)
CLN2 TPP1 (Tripeptidyl peptide 1)
CLN3 Cln3p
CLN5 Cln5p
CLN6 Cln6p
CLN7 MFSD8/Cln7p (Major facilitator superfamily domain-containing protein 8)
CLN8 Cln8p
CLN10 Cathepsin D
診断へのアプローチはドイツハンブルグ大学の小児科より発表されているフローチャートが役立つ
(図 http://www.ncl-netz.de/en/diagnostic.htm)。
当該事業における対象基準
全A
疾患名に該当する場合

(機序) タンパクの誤ったグリコシル化 (dolichol oligosaccharides の大量蓄積)
(責任遺伝子) *607042 CLN3 gene <16p12.1>
.0001 Ceroid lipofuscinosis, neuronal, 3 (204200) [CLN3, 1-KB DEL, FS181TER] (rs1555468634) (RCV000003731...) (The International Batten disease Consortium 1995; Jarvela et al. 1996; Kitzmuller et al. 2008)
.0002 Ceroid lipofuscinosis, neuronal, 3 [CLN3, 3-KB DEL, FS291TER] (RCV000003732) (The International Batten disease Consortium 1995)
.0003 Ceroid lipofuscinosis, neuronal, 3 [CLN3, 6-KB DEL] (RCV000003733) (Taschner et al. 1995; The International Batten disease Consortium 1995)
.0004 Ceroid lipofuscinosis, neuronal, 3 [CLN3, IVSDS, G-C, +1; 76-BP DEL; EXON DEL] (RCV000003734) (The International Batten disease Consortium 1995)
.0005 Ceroid lipofuscinosis, neuronal, 3, protracted [CLN3, GLU295LYS] (rs121434286) (gnomAD:rs121434286) (RCV000811923...) (Wisniewski et al. 1998)
.0006 Ceroid lipofuscinosis, neuronal, 3, protracted [CLN3, TYR199TER] (rs267606737) (gnomAD:rs267606737) (RCV000823290...) (Sarpong et al. 2009)
.0007 Ceroid lipofuscinosis, neuronal, 3, protracted [CLN3, GLY165GLU] (rs786201028) (RCV000162326) (Cortese et al. 2014)

*CLN3 (CLN3 Lysosomal/Endosomal Transmembrane Protein, Battenin)
 Genome size 28,923 bp, Minus strand; 438 aa, 47623 Da
 Exons: 17, Coding exons: 15, Transcript length: 3,867 bps, Translation length: 438 residues
●リソソーム機能に関与する
●ゴルジネットワーク, エンドソーム, autophagosomes, リソソームおよび細胞膜を結ぶ微小管依存性 anterograde 輸送を調節する
 リソソーム pH, リソソーム蛋白分解, 受容体仲介性エンドサイトーシス, 自己貪食, TGN からのタンパクや脂質の輸送, アポトーシスおよびシナプス伝達などの細胞プロセスに参加する
 trans-Golgi network (TGN)から microdomain 関連タンパクの細胞膜への輸送, リソソーム (CTSD遊離のCTSD成熟への調整し, APP の細胞内プロセッシングを生じる)へのIGF2R輸送などの他の膜成分へのタンパク輸送を促進する
 浸透圧ストレスに反応してCTSDを調節する
 galactosylceramide と結合し, trans Golgiからraftsへ輸送し, ceramide 合成を調停することで細胞生存への瞬時の下流効果をもつかも
 細胞膜では, アクチン依存性イベントを調節する
 → filopodia 形成, 細胞移動, ARF1-CDC42 pathwayを介してのパイノサイトーシス, MYH10 と fodrinとの相互作用を通しての細胞骨格構築→a+, K+ ATPase complexの細胞膜との連関の調節
 扁桃核, 海馬, 小脳でのシナプス伝達をsynaptic vesicles 濃度の調節を通して調節する
 →短期可塑性と年齢依存性不安行動, 学習および記憶を調停する
 輸送と合成の調節を通して, 水, イオン, アミノ酸, タンパクおよび脂質などの複合体の細胞ホメオスターシスに参加する (主に脳と腎)
●関係する pathways: Lysosome

(ノート)
●(#) は,神経セロイドリポフスチン症3 (CLN3) は,16p12のCLN3 遺伝子 (607042) のホモ接合または複合ヘテロ接合変異が原因であるため

●神経セロイドリポフスチン症 (NCL; CLN) は,臨床的および遺伝的異質性のある神経変性疾患で.電顕的に異なるパターンで自己蛍光発色性脂肪色素貯留物質の細胞内蓄積が特徴である
 臨床経過には,進行性認知症,けいれん,および進行性視力障害 (Mole et al., 2005) が含まれる

● CLN3のホールマークは,'指紋' プロフィールをもつ脂肪色素の電顕的パターンである
 →3つの異なる出現をもつ
  リソソーム残存小体内の純粋パターン,曲線状または四角いパターンを伴う,大きな膜結合性リソソーム小胞内の小さな成分パターン
 リソソーム小胞内の指紋プロフィールの組み合わせは,CLN3 患者のリンパ球の通常みられる特徴である

●CLNの表現型記載と遺伝的異質性は CLN1 (256730)を参照すること

命名
●CLNs は,最初は発症年齢にしたがって分類された
  CLN3 は,若年発症型 (JNCL)で,発症は4〜10歳である
 しかし,分子異常の証明とともに,CLNs は,現在は,基盤となる遺伝子異常にしたがって数字的に分類されている
 CLN3 は,発症年齢に関わらず CLN3 遺伝子変異が原因の CLN である

●JNCL は,Batten 病, Vogt-Spielmeyer 病, および Spielmeyer-Sjogren 病とも呼ばれている
●Mole et al. (1999) は,NCLs の包括的命名として 'Batten 病' を使用した
 彼らは,多くの細胞型での自己蛍光正脂肪色素の蓄積が特徴の神経変性疾患のグループとして定義した

臨床症状
●Batten (1903, 1914) は,家族型黄斑変化を伴う大脳変性症の若年発症を記載した

●Spalton et al. (1980) は,Batten 病の26例をレビューした
 小児は6〜7歳時,急激な進行性視力喪失,早期知的退行およびけいれんを生じた
 黄斑反省は早期症状に一致した
 末梢網膜変化は疾患の進行とともにより著明となった

●Wisniewski et al. (1992) は,若年発症 CLN の163例の臨床と病理学的特徴をレビューした
 疾患は,黄斑変性,視神経萎縮+/-色素性網膜炎を伴う緩徐な視力喪失の4〜10歳発症が特徴であった
 その他の特徴には,痙攣と緩徐な精神および運動機能障害があった
 ニューロンおよび非ニューロン組織の電顕検査は,指紋封入体を示した
 死亡の最も早い年r婦負は16歳で,最年長の生存患者は40歳であったが,21年間植物状態であった

In a review of 57 patients with CLN3, Boustany (1992) concluded that the first symptom was insidious onset of retinitis pigmentosa between ages 4 and 6 years, which was often not identified before age 7 or 8 years. Visual decline was followed by progressive cognitive decline, and most patients developed seizures by age 10 years. Other motor symptoms included myoclonus, parkinsonism, and a severe dysarthria resulting in mutism in their twenties. Most patients developed behavioral problems with angry outbursts, physical violence, and features of depression.

Taschner et al. (1995) reported a Moroccan child, born of consanguineous parents, with Batten disease. He had a typical clinical history of failing vision at the age of 9 years, leading to a diagnosis of tapetoretinal degeneration with normal neurologic examinations and scanning studies at that time. He became forgetful shortly after the start of visual deterioration and had, from the age of 11 years, generalized seizures that were well controlled by valproic acid. More than 1% of lymphocytes were vacuolated, most of which contained storage material in a 'fingerprint' pattern. At the age of 19 years, he developed parkinsonism without tremor. Molecular genetic studies identified a small homozygous deletion in the CLN3 gene (607042.0003).

The International Batten Disease Consortium (1995) reported a Finnish patient with Batten disease confirmed by identification of compound heterozygosity for 2 deletions in the CLN3 gene (607042.0001; 607042.0002). After a normal birth and early childhood, he developed failing vision at age 6.5 years. Electroretinogram was abolished, and visual evoked potential was abnormal with delayed latency. Slight motor clumsiness and muscular hypotonia were found. Vacuolated lymphocytes were positive on repeated examinations. From age 11, he had generalized epileptic seizures that were well controlled by sodium valproate-clonazepam. An MRI at age 16 showed slight central, cortical, and cerebellar atrophy. The patient was still able to walk independently, but jumping had become difficult.

Wisniewski et al. (1998) reported 2 sibs with a protracted form of juvenile-onset CLN3: the sister died at age 51 of aspiration pneumonia and the brother was living at age 39. The sister developed progressive visual loss at 5 years of age and became totally blind at age 13. From 45 years of age, she had progressive impairment of coordination, memory loss, problems with naming and calculation, and episodes of confusion. A general examination at age 48 was normal. Neurologic examination showed disorientation for time and space, impairment of short- and long-term memory, dysarthria, oromandibular dystonia, and naming deficit. A pendular nystagmus was present. The optic fundi showed optic nerve atrophy, pigmentary retinal degeneration, and spicules. The brother began to lose vision at age 5 years, leading to blindness at the age of 12. The main finding on examination was blindness secondary to optic atrophy and pigmentary retinal degeneration. Both were compound heterozygous for 2 mutations in the CLN3 gene (607042.0001; 607042.0005).

Cortese et al. (2014) reported 2 adult Italian brothers, born in a consanguineous family, with a protracted form of CLN3 confirmed by genetic analysis (G165E; 607042.0007). Both sibs presented at age 7 years with visual loss, which rapidly progressed to total blindness due to retinitis pigmentosa. Psychomotor development was normal. At ages 36 and 29 years, respectively, both developed well-controlled generalized seizures and severe concentric hypertrophic cardiomyopathy requiring pacemakers. Brain imaging showed mild cerebral and cerebellar vermian atrophy. Both sibs later showed mild cognitive impairment, but there was no evidence of muscle impairment except for mildly increased serum creatine kinase. Muscle biopsy showed autophagic vacuoles with glycogen and myelin-like debris, as well as autofluorescence. Electron-dense material formed structures similar to curvilinear bodies. Lymphocytes showed cytoplasmic vacuolization.

Nielsen et al. (2015) studied the ophthalmologic features in all 35 patients with JNCL born in Denmark between 1971 and 2003. During the study period (1996-2012), cataracts were detected in 5 patients at the average age of 20.1 + 1.6 years (mean, +2 SD). All 5 patients had the common 1.02-kb deletion in the CLN3 gene (607042.0001). Two of the 5 patients developed acute glaucoma, and 1 patient had prophylactic cataract surgery. Nielsen et al. (2015) concluded that presenile cataract formation and secondary acute glaucoma are complications of JNCL for which patients over the age of 16 years should be screened routinely.

Pathologic Features
The major pathologic features of Batten disease are (1) severe widespread neuronal degeneration resulting in retinal atrophy and in massive loss of brain substance, the average brain weight being about 600 gm, and (2) accumulation of lipofuscin in neuronal perikaryon (Zeman and Donahue, 1963; Gonatas et al., 1963).

Vacuolation of the lymphocytes is a well-established feature in the homozygote (McKusick, 1963). Although Rayner (1963) claimed that about 1% of lymphocytes are vacuolated in heterozygotes, Burrig et al. (1982) concluded that cytoplasmic vacuoles and inclusions occur only in homozygotes. Strouth et al. (1966) reported characteristic leukocyte abnormalities in juvenile-onset CLN.

Armstrong et al. (1974) reported deficiency of leukocyte peroxidase in patients with the CLN2 (204500) and CLN3; however, Farrell and Sumi (1977) were unable to confirm the reported deficiency of leukocyte peroxidase.

Dayan and Trickey (1970) found large amounts of lipofuscin in the thyroid of patients with Batten disease. Farrell and Sumi (1977) identified fingerprint profiles, curvilinear bodies, and rectilinear bodies in skin biopsies from patients with CLN3. Baumann and Markesbery (1978)identified numerous fingerprint profiles ultrastructurally within vacuolated lymphocytes from 4 patients with Batten disease.

In a 7-year-old child with juvenile-onset CLN3, Brod et al. (1987) detected vacuolated peripheral blood lymphocytes and characteristic ultrastructural fingerprint profiles. The patient's mother, who was presumably heterozygous, also demonstrated vacuolated lymphocytes with membranous formations and osmiophilic granular bodies. Kimura and Goebel (1988) examined lymphocytes from 10 patients with juvenile-onset CLN3 and found that vacuolated lymphocytes varied from 34 to 67% in specimens. In addition, the percentage of vacuolated lymphocytes increased with duration of illness up to age 11.

Dawson et al. (1989) reported decreased levels of cathepsin H (116820) and phospholipase A1 in a subset of patients with juvenile-onset CLN.

Subunit C of the Fo region of the ATP synthase complex of the inner mitochondrial membrane is found in high concentrations in lysosomes in late infantile CLN2 and juvenile CLN3. Kominami et al. (1995) found marked delay of degradation of subunit C in patient fibroblasts with no significant differences between control and patient cells with regard to degradation of cytochrome oxidase subunit IV. Furthermore, accumulation of labeled subunit C in the mitochondrial fraction was detected before lysosomal appearance of the radiolabeled subunit, suggesting to the authors a specific failure in the degradation of subunit C after its normal inclusion in mitochondria and its consequent accumulation in lysosomes. Jolly (1995) reported that subunit C represents more than 50% of the accumulated metabolites in the ovine form of CLN and also accumulates significantly in late infantile and juvenile forms of human CLN and several other animal forms. The author suggested that the extreme hydrophobicity and lipophilicity of subunit C may be partially responsible.

Ramirez-Montealegre and Pearce (2005) reported that lysosomes from juvenile Batten disease lymphoblast cell lines demonstrated defective transport of arginine. Furthermore, a depletion of arginine in these cells was noted. Lysosomal arginine transport in normal lysosomes is ATP-, vacuolar ATPase (see 606939)-, and cationic-dependent. Both arginine and lysine are transported by the same transport system, designated system c. However, lysosomes from juvenile Batten disease lymphoblasts were only defective for arginine transport. An antibody to CLN3 was able to block lysosomal arginine transport, and transient expression of CLN3 in JNCL cells restored lysosomal arginine transport. Ramirez-Montealegre and Pearce (2005) suggested that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell.

診断
●Bessman and Baldwin (1962) は, 関連のない3家系からの5例とごく近い親類の一部でイミダゾール酸尿を発見した
 彼らは, この所見はヘテロ接合体の発見と, この疾患カテゴリーでのヘテロ接合の証明に有用かもしれないと示唆した
●Danes and Bearn (1968) は, ホモ接合体とヘテロ接合体の両方が細胞培養で皮膚線維芽細胞の異染性をもとに証明できることを示した

● LaBadie and Pullarkat (1990) は, polyacrylamide gel electrophoresis (PAGE)により, Batten 病患者の尿で低分子ペプチドを証明し, これらは本疾患の特異的生化学的マーカーかもれいないと示唆した

●Goebel (1996) は, 神経セロイドリポフスチン症をレビューし, 疾患型の正しい診断には患者細胞の電顕検査を必要とすることに気付いた
 CLN3 は, 指紋プロフィール +/- 曲線プロフィールが特徴である

●Jarvela et al. (1996) は, CLN3 遺伝子の多く見られる 1.02 kb 欠失 (607042.0001) を検出するための rapid diagnostic solid-phase minisequencing test 開発した
●Taschner et al. (1997) は, Batten 病に伴う CLN3 遺伝子の欠失を検出するアレル特異的PCR法を記載した

●Marshall et al. (2005) は, 若年発症性 CLN3 患者の運動, 行動および機能を評価するための.多モード臨床評価法であるthe Unified Batten Disease Rating Scale (UBDRS)を開発した

Prenatal Diagnosis

Munroe et al. (1996) used PCR to identify the intragenic microsatellite marker D16S298 to make the prenatal diagnosis of Batten disease on the basis of a chorionic villus sample. The Finnish woman sought counseling because of a son with Batten disease. Allele 6 at the D16S298 marker is present in 96% of Finnish Batten disease patients. Both the fetus and the affected son carried the same high-risk genotype, 6/6, and both were homozygous for the 1-kb deletion. The pregnancy was terminated, and the diagnosis was confirmed by electron microscopy of fetal cells.

Clinical Management
To study the efficacy of dopaminergic medication for extrapyramidal symptoms in juvenile-onset CLN3, Aberg et al. (2001) treated 10 patients with levodopa and 6 patients with selegiline and found a favorable response to levodopa, as measured by scoring on the motor part of the Unified Parkinson Disease Rating Scale. Six of 10 patients treated with levodopa showed decreased symptoms at 1 year, and 4 showed increased symptoms, although 3 of these showed decreased symptoms at 6 months. Patients treated with selegiline and those untreated showed no significant difference at 1 year.

Mapping
Eiberg et al. (1989) found linkage between haptoglobin (HP; 140100) and Batten disease on chromosome 16q22 (maximum lod score of 3.00).Gardiner et al. (1990) confirmed the mapping of Batten disease to chromosome 16 (maximum lod score of 6.05 at marker D16S148).

By linkage studies in a larger group of families, Callen et al. (1991) concluded that the most likely location for CLN3 is the interval between D16S67 and D16S148. Physical mapping of these markers by mouse/human hybrid cell analysis and fluorescence in situ hybridization positioned them at 16p12.3-p12.1 and 16p12.1-p11.2, respectively. Callen et al. (1991) concluded that CLN3 is in a 2-cM interval on 16p12. Mitchison et al. (1993) reported the findings in 70 CLN3 families. Crossovers in 3 maternal meioses allowed localization of CLN3 to the interval between D16S297 and D16S57. Haplotype analysis suggested that most CLN3 chromosomes arose from a single founder mutation.

Using highly informative dinucleotide repeat markers, Lerner et al. (1994) refined the localization of CLN3 to 16p12.1. They found that one haplotype, D16S298/D16S299, was highly overrepresented, accounting for 54% of CLN3 chromosomes as compared with 8% of control chromosomes. They conclusively excluded the CLN2 (204500) locus from this region.

By haplotype and linkage disequilibrium mapping in 111 affected families, including 27 Finnish families, Mitchison et al. (1995) predicted that the CLN3 gene lies 8.8 kb (range 6.3 to 13.8 kb) from D16S298 and 165.4 kb (range 132.4 to 218.1 kb) from D16S299. Enrichment of certain alleles indicated that the same major mutation is responsible for Batten disease in Finland as in most other European countries.

Molecular Genetics
The International Batten Disease Consortium (1995) demonstrated that the mutation responsible for 73% of Batten disease chromosomes was a 1.02-kb deletion in the CLN3 gene (607042.0001). In Finland, 90% of patients with Batten disease carry the 1.02-kb deletion (Jarvela et al., 1996).

In a Moroccan child with Batten disease, Taschner et al. (1995) found homozygosity for a small deletion in the CLN3 gene (607042.0003).

Munroe et al. (1997) identified homozygosity for the common 1.02-kb CLN3 deletion in 139 (74%) of 188 unrelated patients with Batten disease; 41 were compound heterozygous for the deletion and another CLN3 mutation. By SSCP analysis and direct sequencing, Munroe et al. (1997) found 19 novel mutations in the CLN3 gene, bringing the total number of known disease-associated mutations in CLN3 to 23.

Mole et al. (1999) tabulated the mutations that had been identified in the various CLNs; they reported 25 mutations and 2 polymorphisms associated with CLN3.

Genotype/Phenotype Correlations
Kitzmuller et al. (2008) demonstrated that the common 1.02-kb deletion retains residual function. Overexpression of the mutant CLN3 transcripts consistently caused lysosomes to decrease in size. Studies in mouse cell models and yeast confirmed that the corresponding mutant transcripts retained significant function. The majority of the mutant 1.02-kb deletion CLN3 protein was retained within the endoplasmic reticulum. Kitzmuller et al. (2008) concluded that the common mutant CLN3 protein retains significant function and that JNCL is a mutation-specific disease phenotype. The residual function likely explains why this form of CLN shows later onset and less severe clinical manifestations compared to other forms of CLN.

Population Genetics
In West Germany, Claussen et al. (1992) estimated the frequency of juvenile-onset CLN3 to be 0.71 per 100,000 live births and of CLN2 to be 0.46 per 100,000 live births. The estimates were based on a novel method applicable to other autosomal recessive disorders. For 10 years, 1968 through 1977, the slope of registration of new cases was a steep, nearly straight line. The authors presumed that this represented a period of efficient registration of new cases.

CLN3 is especially enriched in Finland with an incidence of 1:21,000 live births and a carrier frequency of 1 in 70 (Mitchison et al., 1995).

History
Tuck-Muller et al. (1995) observed a balanced translocation between chromosomes 10 and 18, t(10;18)(q22.1;q21.1), in a girl with typical Batten disease beginning at 5 years of age. The intracellular cytosomes were predominantly fingerprint in type. Translocation was not observed in the patient's mother or sister. The father was unavailable for analysis. Although Tuck-Muller et al. (1995) stated that the translocation may be unrelated to the disease, the findings raised the possibility of genetic heterogeneity in this form of CLN.

Animal Model
A model of Batten disease in sheep was discussed by Jolly et al. (1992) and a model in the dog by Koppang (1992) and Taylor and Farrow (1992).

A yeast model for the study of Batten disease was created by Pearce and Sherman (1998). They had previously cloned the Saccharomyces cerevisiae homolog of the CLN3 gene, designated BTN1. The amino acid structure of the yeast and human proteins had been shown to be 39% identical and 59% similar. They reported that BTN1-delta deletion yeast strains were more resistant to a chemical denoted ANP, a phenotype that could be complemented in yeast by the human CLN3 gene. Furthermore, the severity of Batten disease in humans and the degree of ANP resistance in yeast were related when the equivalent amino acid replacements in the CLN3 and the BTN1 proteins were compared. These results indicated that yeast can be used as a model for the study of Batten disease.

Chattopadhyay et al. (2002) reported neutralizing autoantibodies to glutamic acid decarboxylase (GAD2; 138275) in Cln3-knockout mice serum that associates with brain tissue but is not present in sera or brain of normal mice. A concomitant elevation of glutamate in the brain of Cln3-knockout mice colocalized with presynaptic markers. An autoantibody to GAD2 was present in sera of all 20 individuals tested with Batten disease, and postmortem brain tissue from 1 patient showed decreased reactivity to an anti-GAD antibody. The authors proposed that an autoimmune response to GAD2 may contribute to a preferential loss of GABAergic neurons associated with Batten disease.

(文献)
(1) Sjogren T: Die juvenile amaurotische Idiotie. Klinische und erblichkeitsmedizinische Untersuchungen. Hereditas 14: 197-426, 1931
(2) Harlem OK: Juvenile cerebroretinal degeneration (Spielmeyer-Vogt). Am J Dis Child 100: 918-923, 1960
(3) Bessman SP, Baldwin R: Imidazole aminoaciduria in cerebromacular degeneration. Science 135: 789-791, 1962
(4) Rayner S: Juvenile amaurotic idiocy in Sweden with particular reference to the occurrence of vacuoles in the lymphocytes of homo- and heterozygotes. Uppsala: Univ. of Uppsala, 1962
(5) Gonatas NK et al. A case of juvenile lipidosis: the significance of electron microscopic and biochemical observations of a cerebral biopsy. J NeuroPath Exp. Neurol 22: 557-580, 1963
(6) McKusick VA: Medical genetics 1962. J Chronic Dis 16: 457-634, 1963
(7) Rayner S: Juvenile amaurotic idiocy in Sweden. Proc 11th Int. Cong. Genet, The Hague 0: 283, 1963
(8) Zeman W, Donahue S: Fine structure of the lipid bodies in juvenile amaurotic idiocy. Acta NeuroPath 3: 144-149, 1963
(9) Levenson J et al. Carnosine excretion in juvenile amaurotic idiocy. Lancet II: 756-757, 1964
(10) Strouth JC et al. Leukocyte abnormalities in familial amaurotic idiocy. New Eng J Med 274: 36-38, 1966
(11) Seitelberger F et al. The myoclonic variant of cerebral lipidosis. In Aronson S, Volk BW (eds.): Inborn Disorders of Sphingolipid Metabolism. Oxford: Pergamon Press, Pp. 43-74, 1967
(12) Zeman W, Strouth JC: Leukocytic hypergranulation versus lymphocytic vacuolization as markers for heterozygotes and with Batten-Spielmeyer-Vogt disease. In Aronson SM, Volk BW (eds.): Inborn Disorders of Sphingolipid Metabolism. Oxford: Pergamon Press, Pp., 1967
(13) Danes BS, Bearn AG: Metachromasia and skin-fibroblast cultures in juvenile familial amaurotic idiocy. Lancet II: 855-856, 1968
(14) Dayan AD, Trickey RJ: Thyroid involvement in juvenile amaurotic idiocy (Batten's disease). Lancet II: 296-297, 1970
(15) Dolman CL, Chang E: Visceral lesions in amaurotic familial idiocy with curvilinear bodies. Arch Path 94: 425-430, 1972
(16) Gordon NS et al. Neuronal ceroid lipofuscinosis (Batten's disease). Arch Dis Child 47: 285-291, 1972
(17) Smith H: Sea-blue histiocytes in marrow in Batten-Spielmeyer-Vogt disease. Pathology 6: 323-327, 1974
(18) Hittner HM, Zeller RS: Ceroid-lipofuscinosis (Batten disease). Arch Ophthal 93: 178-183, 1975
(19) Markesbery WR et al. Late-infantile neuronal ceroid-lipofuscinosis: an ultrastructural study of lymphocyte inclusions. Arch Neurol 33: 630-635, 1976
(20) Farrell DF, Sumi SM: Skin punch biopsy in the diagnosis of juvenile neuronal ceroid-lipofuscinosis: a comparison with leukocyte peroxidase assay. Arch Neurol 34: 39-44, 1977
(21) Baumann RJ, Markesbery WR: Juvenile amaurotic idiocy (neuronal ceroid lipofuscinosis) and lymphocyte fingerprint profiles. Ann Neurol 4: 531-536, 1978
(22) Gadoth N: Neuronal ceroid-lipofuscinosis (Batten's disease): diagnostic approach and results of therapeutic trial. Metab Ophthal 2: 193-196, 1978
(23) Lake BD, Cavanagh NPC: Early-juvenile Batten's disease--a recognisable sub-group distinct from other forms of Batten's disease: analysis of 5 patients. J Neurol Sci 36: 265-271, 1978
(24) Spalton DJ et al. Juvenile Batten's disease: an ophthalmological assessment of 26 patients. Brit J Ophthal 64: 726-732, 1980
(25) Burrig K-F et al. Lack of structural abnormalities in lymphocytes from heterozygotes of juvenile type of generalized ceroid-lipofuscinosis: a light and electron microscopic study. Neuropediatrics 13: 216-218, 1982
(26) Kimura S, Goebel HH: Electron microscopic studies on skin and lymphocytes in early juvenile neuronal ceroid-lipofuscinosis. Brain Dev 9: 576-580, 1987
(27) Eiberg H et al. Batten disease (Spielmeyer-Sjogren disease) and haptoglobins (HP): indication of linkage and assignment to chromosome 16. Clin Genet 36: 217-218, 1989
(28) Eiberg H et al. Batten disease (Spielmeyer-Sjogren disease) and haptoglobins (HP): indication of linkage and assignment to chromosome 16. Cytogenet Cell Genet 51: 994, 1989
(29) Gardiner M et al. Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) gene (CLN) maps to human chromosome 16. Genomics 8: 387-390, 1990
(30) LaBadie GU, Pullarkat RK: Low molecular weight urinary peptides in ceroid-lipofuscinoses: potential biochemical markers for the juvenile subtype. Am J Med Genet 37: 592-599, 1990
(31) Callen DF et al. Batten disease (ceroid-lipofuscinosis neuronal, juvenile type) locus (CLN) maps to human chromosome 16p12. Cytogenet Cell Genet 58: 1999, 1991
(32) Callen DF et al. Regional mapping of the Batten disease locus (CLN) to human chromosome 16p12. Am J Hum Genet 49: 1372-1377, 1991
(33) Claussen M et al. Incidence of neuronal ceroid-lipofuscinoses in West Germany: variation of a method for studying autosomal recessive disorders. Am J Med Genet 42: 536-538, 1992
(34) Jolly RD et al. Sheep and other animals with ceroid-lipofuscinoses: their relevance to Batten disease. Am J Med Genet 42: 609-614, 1992
(35) Koppang N: English setter model and juvenile ceroid-lipofuscinosis in man. Am J Med Genet 42: 599-604, 1992
(36) Riis RC et al. Tibetan terrier model of canine ceroid lipofuscinosis. Am J Med Genet 42: 615-621, 1992
(37) Taylor RM, Farrow BRH: Ceroid lipofuscinosis in the border collie dog: retinal lesions in an animal model of juvenile Batten disease. Am J Med Genet 42: 622-627, 1992
(38) Wisniewski KE et al. Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: review of data and observations. Am J Med Genet 42: 525-532, 1992
(39) Mitchison HM et al. Fine genetic mapping of the Batten disease locus (CLN) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci. Genomics 16: 455-460, 1993
(40) Lerner TJ et al. Linkage disequilibrium between the juvenile neuronal ceroid lipofuscinosis gene and marker loci on chromosome 16p12.1. Am J Hum Genet 54: 88-94, 1994
(41) Bennett MJ, Boriack RL: Erythrocyte membrane reacylation in juvenile neuronal ceroid-lipofuscinosis: measurement of membrane-bound carnitine palmitoyl transferase, acyl-CoA synthetase, and lysophospholipid: acyl-CoA acyltransferase activities. Am J Med Genet 57 (2): 304-6, 1995
(42) Boriack RL et al. Mitochondrial damage results in a reversible increase in lysosomal storage material in lymphoblasts from patients with juvenile neuronal ceroid-lipofuscinosis (Batten Disease). Am J Med Genet 57 (2): 301-3, 1995
(43) Cardona F, Rosati E: Neuronal ceroid-lipofuscinoses in Italy: an epidemiological study. Am J Med Genet 57 (2): 142-3, 1995
(44) Chronister R et al. Cellular distribution of lesions in Batten disease. Am J Med Genet 57 (2): 191-5, 1995
(45) Dooley TP et al. Phenol sulfotransferases: candidate genes for Batten disease. Am J Med Genet 57 (2): 327-32, 1995
(46) Dyken P, Wisniewski K: Classification of the neuronal ceroid-lipofuscinoses: expansion of the atypical forms. Am J Med Genet 57 (2): 150-4, 1995
(47) Elleder M et al. Tissue culture loading test with storage granules from animal models of neuronal ceroid-lipofuscinosis (Batten disease): testing their lysosomal degradability by normal and Batten cells. Am J Med Genet Jun 5 1995 57 (2): 213-21, 1995
(48) Ezaki J et al. Abnormal degradative pathway of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid-lipofuscinosis (Batten disease). Am J Med Genet 57 (2): 254-9, 1995
(49) Goebel HH et al. Significance of lipopigments with fingerprint profiles in eccrine sweat gland epithelial cells. Am J Med Genet 57 (2): 187-90, 1995
(50) Goebel HH et al. Pigment variant of neuronal ceroid-lipofuscinosis. Am J Med Genet 57 (2): 155-9, 1995
(51) Heikkila E et al. Circadian rhythm studies in neuronal ceroid-lipofuscinosis (NCL). Am J Med Genet 57 (2): 229-34, 1995
(52) Heim P, Kohlschutter A: Avoid diagnostic delay of late infantile and juvenile neuronal ceroid-lipofuscinosis (LINCL, JNCL): a word to pediatricians, neurologists, and ophthalmologists. Am J Med Genet 57 (2): 238, 1995
(53) Hofman IL, Taschner PE: Late onset juvenile neuronal ceroid-lipofuscinosis with granular osmiophilic deposits (GROD). Am J Med Genet 57 (2): 165-7, 1995
(54) Hosain S et al. Diagnoses of neuronal ceroid-lipofuscinosis by immunochemical methods. Am J Med Genet 57 (2): 239-45, 1995
(55) International Batten Disease Consortium: Isolation of a novel gene underlying Batten disease, CLN3. Cell 82: 949-957, 1995
(56) Jarvela IE et al. Physical map of the region containing the gene for Batten disease (CLN3). Am J Med Genet 57 (2): 316-9, 1995
(57) Kieseier BC, Goebel HH: Immunelectronmicroscopic characterization of T4 and T8 lymphocytes and natural killer cells in neuronal ceroid-lipofuscinosis. Am J Med Genet 57 (2): 222-4, 1995
(58) Lake BD et al. Bone marrow transplantation in Batten disease (neuronal ceroid-lipofuscinosis). Will it work? Preliminary studies on coculture experiments and on bone marrow transplant in late infantile Batten disease. Am J Med Genet 57 (2): 369-73, 1995
(59) Jolly RD: Comparative biology of the neuronal ceroid-lipofuscinoses (NCL): an overview. Am J Med Genet 57 (2): 307-11, 1995
(60) Johnson DW et al. Role of subunit-9 of mitochondrial ATP synthase in Batten disease. Am J Med Genet 57 (2): 350-60, 1995
(61) Katz M, Siakotos AN: Canine hereditary ceroid-lipofuscinosis: evidence for a defect in the carnitine biosynthetic pathway. Am J Med Genet 57 (2): 266-71, 1995
(62) Khan KM et al. Abnormal acid phosphatases in neuronal ceroid-lipofuscinoses. Am J Med Genet 57 (2): 285-9, 1995
(63) Kominami E et al. New insight into lysosomal protein storage disease: delayed catabolism of ATP synthase subunit c in Batten disease. Neurochem Res.20: 1305-1309, 1995
(64) Lerner TJ et al. Isolation of genes from the Batten candidate region using exon amplification. Batten Disease Consortium. Am J Med Genet 57 (2): 320-3, 1995
(65) Maertens P et al. Free radicals, anticonvulsants, and the neuronal ceroid-lipofuscinoses. Am J Med Genet 57 (2): 225-8, 1995
(66) Majander A et al. Palmitate oxidation in muscle mitochondria of patients with the juvenile form of neuronal ceroid-lipofuscinosis. Am J Med Genet 57 (2): 298-300, 1995
(67) March PA et al. Morphological alterations in neocortical and cerebellar GABAergic neurons in a canine model of juvenile Batten disease. Am J Med Genet 57 (2): 204-12, 1995
(68) Messer A et al. Genetics of primary and timing effects in the mnd mouse. Am J Med Genet 57 (2): 361-4, 1995
(69) Mitchison HM et al. Refined localization of the Batten disease gene (CLN) by haplotype and linkage disequilibrium mapping to D16S288-D16S383 and exclusion from this region of a variant form of Batten disease with granular osmiophilic deposits. Am J Med Genet 57 (2): 312-5, 1995
(70) Mitchison HM et al. Batten disease gene, CLN3: linkage disequilibrium mapping in the Finnish population, and analysis of European haplotypes. Am J Hum Genet 56 (3): 654-62, 1995
(71) Moroni-Rawson P et al. Variant proteins in ovine ceroid-lipofuscinosis. Am J Med Genet 57 (2): 279-84, 1995
(72) Munroe PB et al. Analysis of Batten disease candidate genes STP and STM. Am J Med Genet 57 (2): 324-6, 1995
(73) Nardocci N et al. Neuronal ceroid-lipofuscinosis: a clinical and morphological study of 19 patients. Am J Med Genet 57 (2): 137-41, 1995
(74) Palmer DN et al. Batten disease and the ATP synthase subunit c turnover pathway: raising antibodies to subunit c. Am J Med Genet 57 (2): 260-5, 1995
(75) Philippart M et al. New Spielmeyer-Vogt variant with granular inclusions and early brain atrophy. Am J Med Genet 57 (2): 160-4, 1995
(76) Prasad VV, Pullarkat RK: Report on the Fifth International Conference on Neuronal Ceroid-Lipofuscinoses. Am J Med Genet 57 (2): 125-7, 1995
(77) Rider JA: Batten disease--an overview of research and funding. Am J Med Genet 57 (2): 128-9, 1995
(78) Rowan SA, Lake BD: Tissue and cellular distribution of subunit c of ATP synthase in Batten disease (neuronal ceroid-lipofuscinosis). Am J Med Genet 57 (2): 172-6, 1995
(79) Siakotos AN et al. Biosynthesis and metabolism of 4-hydroxynonenal in canine ceroid-lipofuscinosis. Am J Med Genet 57 (2): 290-3, 1995
(80) Savill J et al. Early detection of canine ceroid-lipofuscinosis (CCL): an ultrastructural study. Am J Med Genet 57 (2): 250-3, 1995
(81) Taschner PE et al. Carrier detection of Batten disease (juvenile neuronal ceroid-lipofuscinosis). Am J Med Genet 57 (2): 333-7, 1995
(82) Taschner PE et al. Application of chromosome 16 markers in the differential diagnosis of neuronal ceroid-lipofuscinosis. Am J Med Genet 57 (2): 338-43, 1995
(83) Taschner PE; et al. Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease). Am J Hum Genet 56 (3): 663-8, 1995
(84) Tuck-Muller CM et al. Translocation 10;18 in a patient with juvenile neuronal ceroid-lipofuscinosis (Batten disease). Am J Med Genet 57 (2): 168-71, 1995
(85) Starita C et al. Decreasing hydraulic conductivity of Bruch's membrane: relevance to photoreceptor survival and lipofuscinoses. Am J Med Genet 57 (2): 235-7, 1995
(86) Walkley SU et al. Pathogenesis of brain dysfunction in Batten disease. Am J Med Genet 57 (2): 196-203, 1995
(87) Westlake VJ et al. Immunocytochemical studies in the ceroid-lipofuscinoses (Batten disease) using antibodies to subunit c of mitochondrial ATP synthase. Am J Med Genet 57 (2): 177-81, 1995
(88) Wisniewski KE et al. Rapid detection of subunit c of mitochondrial ATP synthase in urine as a diagnostic screening method for neuronal ceroid-lipofuscinoses. Am J Med Genet 57 (2): 246-9, 1995
(89) Janes RW et al. A model for Batten disease protein CLN3: functional implications from homology and mutations. FEBS Lett. 399: 75-77, 1996
(90) Jarvela I et al. Rapid diagnostic test for the major mutation underlying Batten disease. J. Med. Genet. 33: 1041-1042, 1996
(91) Lee RL et al. Isolation and chromosomal mapping of a mouse homolog of the Batten disease gene CLN3. Genomics 35: 617-619, 1996
(92) Munroe PB et al. Prenatal diagnosis of Batten's disease. Lancet 347: 1014-1015, 1996
(93) Mitchison HM et al. Genomic structure and complete nucleotide sequence of the Batten disease gene, CLN3. Genomics 40: 346-350, 1997
(94) Munroe PB et al. Spectrum of mutations in the Batten disease gene, CLN3. Am. J. Hum. Genet. 61: 310-316, 1997
(95) Taschner PEM et al. Rapid detection of the major deletion in the Batten disease gene CLN3 by allele specific PCR. J. Med. Genet. 34: 955-956, 1997
(96) Pearce DA, Sherman F: A yeast model for the study of Batten disease. Proc. Nat. Acad. Sci. 95: 6915-6918, 1998
(97) Wisniewski KE et al. Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis. Ann. Neurol. 43: 106-110, 1998
(98) Jarvela I et al. Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). Hum. Molec. Genet. 8: 1091-1098, 1999
(99) Kremmidiotis G et al. The Batten disease gene product (CLN3p) is a Golgi integral membrane protein. Hum. Molec. Genet. 8: 523-531, 1999
(100) Lauronen L et al. Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis. Neurology 52: 360-365, 1999
(101) Mole SE et al. Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Hum. Mutat. 14: 199-215, 1999
(102) Haskell RE et al. Batten disease: evaluation of CLN3 mutations on protein localization and function. Hum. Molec. Genet. 9: 735-744, 2000
(103) Aberg, L. E., Rinne, J. O., Rajantie, I., Santavuori, P. A favorable response to antiparkinsonian treatment in juvenile neuronal ceroid lipofuscinosis. Neurology 56: 1236-1239, 2001
(104) Luiro K et al. CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. Hum. Molec. Genet. 10: 2123-2131, 2001
(105) Chattopadhyay, S.; Ito, M.; Cooper, J. D.; Brooks, A. I.; Curran, T. M.; Powers, J. M.; Pearce, D. A. : An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum. Molec. Genet. 11: 1421-1431, 2002
(106) Marshall, F. J.; de Blieck, E. A.; Mink, J. W.; Dure, L.; Adams, H.; Messing, S.; Rothberg, P. G.; Levy, E.; McDonough, T.; DeYoung, J.; Wang, M.; Ramirez-Montealegre, D.; Kwon, J. M.; Pearce, D. A. : A clinical rating scale for Batten disease: reliable and relevant for clinical trials. Neurology 65: 275-279, 2005
(107) Mole, S. E.; Williams, R. E.; Goebel, H. H. : Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6: 107-126, 2005
(108) Ramirez-Montealegre, D.; Pearce, D. A. : Defective lysosomal arginine transport in juvenile Batten disease. Hum. Molec. Genet. 14: 3759-3773, 2005
(109) Kitzmuller, C.; Haines, R. L.; Codlin, S.; Cutler, D. F.; Mole, S. E. : A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis. Hum. Molec. Genet. 17: 303-312, 2008
(110) Cortese, A., Tucci, A., Piccolo, G., Galimberti, C. A., Fratta, P., Marchioni, E., Grampa, G., Cereda, C., Grieco, G., Ricca, I., Pittman, A., Ciscato, P., and 9 others. Novel CLN3 mutation causing autophagic vacuolar myopathy. Neurology 82: 2072-2076, 2014
(111) Nielsen, A. K., Drack, A. V., Ostergaard, J. R. Cataract and glaucoma development in juvenile neuronal ceroid lipofuscinosis (Batten disease). Ophthalmic Genet. 36: 39-42, 2015

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