疾患詳細

疾患詳細





#300257
Danon disease
(Vacuolar cardomyopathy and myopathy, X-linked)
(Pseudoglycogenosis II)
(Antopol disease)
(Lysosomal glydogen storage disease without acid maltase deficiency, formerly)
(Glycogen storage disease IIb; GSD2B, formerly)
(GSD IIb, formerly)

Danlon 病
(空胞性心筋症およびミオパチー, X連鎖性)
(偽グリコーゲン蓄積症 II)
(Antopol 病)
(リソソームグリコーゲン蓄積病, 酸性マルターゼ欠損なし, 以前の)
(グリコーゲン蓄積病 IIb; GSD2B, 以前の)
指定難病32 自己貪食空胞性ミオパチー
指定難病19 ライソゾーム病

責任遺伝子:309060 Lysosome-associated membrane protein 2 (LAMP2)
遺伝形式:X連鎖優性

(症状)
(GARD)
 <80%-99%>
 Cardiorespiratory arrest (心肺停止) [HP:0006543] [0171]
 Dilated cardiomyopathy (拡張型心筋症) [HP:0001644 [0273]
 Gait disturbance (歩行障害) [HP:0001288] [028]
 Hypertrophic cardiomyopathy (肥大型心筋症) [HP:0001639] [0273]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Muscle flaccidity (筋弛緩) [HP:0010547] [-]
 
 
 Arrhythmia (不整脈) [HP:0011675] [01700]
 Cardiomegaly (心拡大) [HP:0001640] [1121]
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Elevated serum creatine kinase (血清クレアチニンキナーゼ上昇) [HP:0003236] [2045]
 EMG: myopathic abnormalities (筋電図: ミオパチー変化) [HP:0003458]
 Exercise intolerance (運動不耐症) [HP:0003546] [0278]
 Exercise-induced muscle cramps (運動誘発性筋けいれん) [HP:0003710] [0274]
 Generalized amyotrophy (全身性筋萎縮) [HP:0003700] [0270]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hypokinesia (寡動) [HP:0002375] [02608]
 Myocardial fibrosis (心筋線維症) [HP:0001685]
 Myocardial necrosis (心筋壊死) [HP:0001700]
 Pes cavus (凹足) [HP:0001761] [15602]
 Proximal muscle weakness (近位筋筋力低下) [HP:0003701] [0270]
 Visual impairment (視力障害) [HP:0000505] [06011]
 Wolff-Parkinson-White syndrome (Wolff-Parkinson-White 症候群) [HP:0001716] [01700]
 X-linked dominant inheritance (X連鎖優性遺伝) [HP:0001423]

(UR-DBMS)
【一般】不整脈
 Wolff-Parkinson-White 症候群
 精神遅滞 (70%)
 認知障害, 軽度
 発達遅滞
 沈下性肺炎
 軽度の虚弱
 心不全
 心停止
 房室結節ブロック
【神経】動作緩慢
 近位筋力低下 (85% )
 びまん性筋萎縮
 運動不耐症
 運動での筋けいれん
 EMG はミオパチー変化を示す
 筋生検は筋質 PAS 陽性空胞を示す
 筋生検は筋線維とリソソームにグリコーゲン蓄積を示す
 筋鞘の陥凹またはヒダは空胞を囲む膜につながる
 空胞は自己貪食性である
 空胞膜は筋鞘タンパクで免疫染色される
  LAMP2 タンパクは重度減少または欠損
 補体C5b-9 膜攻撃複合タンパクが空胞内に染色されるが筋線維膜は染色されない
 alpha-glucosidase または acid maltase活性は正常
 *ミオパチー (緩徐進行性) (小児期発症または遅発)
【眼】男性で中等度の中心視力喪失 (20/60)
 保因者女性の視力は正常~ほぼ正常 (20/30-20/20)
 保因者女性のスリットランプ検査で繊細な層状白濁
 男性で抹消網膜色素のほぼ完全な喪失
 保因者女性で抹消網膜色素のごま塩斑
 保因者女性の ERG は非特異的変化
【心】肥大型心筋症
 拡張型心筋症
 心拡大
 収縮減少
 生検は肥大した心筋細胞を示す
 心筋細胞は不規則な核をもつ
 心筋細胞は筋線維とリソソームでのグリコーゲン蓄積を示す
 心筋細胞は変性ミトコンドリア, グリコーゲン, 顆粒状デブリをもつ空胞化細胞質をもつ
 心筋線維症
 心筋壊死
 LAMP2 タンパクの重度減少または欠損
【足】凹足 (まれ)
【検査】リソソーム alpha-1,4-glucosidase 減少(横紋筋)
 acid maltase 活性正常
 血清 CK 増加
【その他】表現型の差異
 全ての患者が骨格筋症状または精神遅滞 をもつわけではない
 患者男性で突然死が10歳代で生じる
 患者女性で突然死が40歳代で生じる
 女性は心症状が遅発性の軽度の表現型をもつことが多い

<指定難病32 自己貪食空胞性ミオパチー>
概要
 骨格筋の筋線維内に特徴的な自己貪食空胞が出現する極めて稀少な遺伝性の筋疾患で, 原因不明で治療も未確立である。致死性心筋症と進行性のミオパチー(筋力低下・筋萎縮)を来す予後不良な進行性疾患である。
原因
自己貪食空胞性ミオパチーの代表疾患:
 Danon 病(ダノン病)と過剰自己貪食を伴うX連鎖性ミオパチー(XMEA)では, 原因遺伝子が発見されたが, その他の臨床病型は原因不明である。
 Danon 病 → Lysosome-associated membrane protein 2 (LAMP2)
 過剰自己貪食を伴うX連鎖性ミオパチー (XMEA) → VMA21, S. erevisiae, homolog of (VMA21) 
 また病気の発症のメカニズムは依然未解明である。特徴的な自己貪食空胞が共通して出現することから, 筋変性過程に自己貪食(オートファジー)が関与することが疑われ, 何らかの共通の分子病態との関連が推測される。
症状
(1)骨格筋障害による緩徐進行性の四肢筋力低下と筋萎縮や筋痛
(2)心筋障害による進行性の心筋症(肥大型, 拡張型), 不整脈
(3)精神遅滞
但し, 臨床病型によっては, (2), (3)を伴わないことがある。
発症年齢は様々で, 生下時から 50 歳代まで報告がある。 男女ともに発症するが, 男性の方が早い場合が多い。
治療法
 治療法は確立していない。心筋障害は予後決定因子で致死性であり, 心臓移植のみが根治療法である。 他の症状や合併症については, 対症療法が主体である。
予後
 男女ともに発症年齢を問わず, 心臓移植を行わない場合, 心不全症状の出現から平均2年で急速に死 に至る(Sugie et al. Neurology 2002)。けいれんなどの中枢神経障害や肝障害, 腎障害, 肺水腫, 網膜症など多臓器障害を来すことがある。また, 自閉症や脳血管障害, 末梢神経障害を有する症例の報告もある。筋障害が進行すると, 呼吸困難や嚥下困難, 筋緊張低下をきたす。生下時より発症した場合は, 運動発育 遅延を呈する。

<指定難病診断基準>
Definite, Probableを対象とする。

(1)ダノン病診断基準
(MIM# 300257, Danon disease, LAMP-2 deficiency)
 Definite
●診断に有用な特徴
A. 臨床的特徴 (男性は a,b 必須, 女性は a 必須, c-g は参考所見)
 a. 肥大型または拡張型心筋症
 b. 進行性の筋力低下および筋萎縮
(以下は参考所見)
 c. X連鎖性優性遺伝または孤発性
 d. 発症年齢は, 男性は 10 歳代から, 女性は 30 歳代からが多い
 e. 知的遅滞を伴うことが多い。
 f. 血清 CK 値は, 正常から軽度高値(1,000IU/L 以下)
 g. 針筋電図で筋原性変化(fibrillation potential や高振幅 MUP)が認められることがある
B. 筋生検所見 (a,b は必須, c,d は参考所見)
 a. 自己貪食空胞を伴う筋線維
 b. 空胞膜上でのアセチルコリンエステラーゼ活性(骨格筋での組織化学染色)
(以下は参考所見)
 c. 空胞膜上での筋鞘膜蛋白(ジストロフィン, サルコグリカン, ラミニンα2, カベオリン-3 など)発現
(骨格筋での免疫組織化学染色)
 d. (電子顕微鏡にて) 自己貪食空胞周囲の基底膜の存在
C. LAMP-2 の評価 (a または b)
 a. LAMP-2 欠損 (免疫組織化学染色またはウェスタンブロット解析)
 b. LAMP-2 遺伝子変異

●除外すべき疾患
 臨床的鑑別
 ・他のミオパチーや筋ジストロフィーなどの筋疾患
 ・神経原性疾患
 ・他の原因の確定している心筋症
 病理学的鑑別
 ・自己貪食空胞を来す他のミオパチー

●診断カテゴリー
 Definite:A又はBの少なくとも一方を満たし, かつCを満たすもの
 Probable:A+Bを満たすもの

(責任遺伝子) *309060 Lysosome-associated membrane protein 2 (LAMP2)
.0001 Danon disease (300257) [LAMP2, 2-BP DEL, 1097AA] (RCV000010654) (Nishino et al. 2000)
.0002 Danon disease [LAMP2, LEU113TER] (rs137852527) (RCV000010655) (Nishino et al. 2000)
.0003 Danon disease [LAMP2, IVS6, G-C, +5] (rs1352584474) (RCV000010656) (Nishino et al. 2000)
.0004 Danon disease [LAMP2, 1-BP INS, 974A] (RCV000010657) (Nishino et al. 2000)
.0005 Danon disease [LAMP2, IVS5, G-A, +1] (rs1251075016) (RCV000010658) (Nishino et al. 2000)
.0006 Danon disease [LAMP2, 1-BP DEL, 14G] (rs1183994410) (RCV000010659) (Nishino et al. 2000)
.0007 Danon disease [LAMP2, 1-BP INS, 883T] (rs1327363415) (RCV000010660) (Takahashi et al. 2002)
.0008 Danon disease [LAMP2, 7-BP DEL] (rs1436181133) (RCV000010661) (Charron et al. 2004)
.0009 Danon disease [LAMP2, GLN174TER] (rs104894857) (RCV000010662) (Charron et al. 2004)
.0010 Danon disease [LAMP2, VAL310ILE] (rs104894858) (RCV000157981...) (Arad et al. 2005)
.0011 Danon disease [LAMP2, TRP321ARG] (rs104894859) (RCV000010664) (Musumeci et al. 2005)
.0012 Danon disease [LAMP2, 1-BP DEL, 1219A] (RCV000010665) (Taylor et al. 2007)

(ノート)
A number sign (#) is used with this entry because of evidence that Danon disease, also known as X-linked vacuolar cardiomyopathy and myopathy, is caused by mutation in the LAMP2 gene (309060), which encodes lysosome-associated membrane protein-2, on chromosome Xq24.

●Danon 病は, 主に心筋を侵すX連鎖優性疾患である
 骨格筋と精神遅滞が, 差異のある特徴である
 筋とリソソームでのグリコーゲンの蓄積のため, 最初, Danon 病は '正常な acid maltase' または alpha-glucosidase (GAA; 606800) を伴うグリコーゲン蓄積症 II 型 (Pompe 病; 232300) のバリアントとして分類された (Danon et al., 1981)
 しかし, Nishino et al. (2000) は, Danon 病は, グリコーゲンは常に増加しているわけではないので, グリコーゲン蓄積症ではないと述べた

●Sugie et al. (2005) は, Danon 病を, 自己貪食性空胞性ミオパチーの1つの型と分類した
 筋鞘の特徴を伴う, 細胞質内自己貪食性空胞が特徴である
 特徴的空胞は, 筋鞘タンパク, 基底層および acetylcholinesterase 活性を含む二次的につくられた膜により囲まれた自己リソソームであると信じられている

●過剰な自己貪食能を伴うX連鎖性ミオパチー (XMEA; 310440) は, 類似した病理的特徴をもつ別疾患である

臨床症状
●Antopol et al. (1940) は, 心不全で10歳代で死亡した兄弟2例を記載した
 1例の剖検は, 心筋に限定したグリコーゲン蓄積症を示した
●Mehrizi and Oppenheimer (1960) は, 心筋にグリコーゲンが異常蓄積した心不全をもつ関連した患者2例を報告した

●Danon et al. (1981) は, 精神遅滞, 肥大型心筋症および近位筋力低下をもつ関連のない男性2例を報告した
 1例は肝腫をもっていた
 骨格筋生検は, リソソーム性グリコーゲン蓄積症を示唆する特徴を示した
 しかし, acid alpha-glucosidase 活性は正常で, Pompe 病, または GSD II を除外した
 両患者は, 17歳時死亡した
●Riggs et al. (1983) は, 兄弟2例で, 正常acid maltase をもつリソソーム蓄積症を記載した
 兄弟の1例は3歳時筋力低下を示した
 両者は, Wolff-Parkinson-White 心電図所見をもっていた

●Bergia ら(1986) は, 姉妹2例がこの組合わせをもつ3人の息子を産んだ1家系を記載した
 知能悪化は5歳くらいに始まった
 肥大性心筋症は10歳代で症状が出始め1例では17歳, 2例目では21歳で死亡した
 彼らの10歳代の評価では, 患児は遠位筋群の衰弱, Gower 手技陽性, 筋力低下の主な上腕筋腓骨筋分布を示した
 CK は lactate dehydrogenase, aspartate aminotransferase, および alanine aminotransferase と同様に上昇していた
 高度近視もあった
 患者2例の母は, 変異遺伝子の保因者と思われ, 血清筋酵素の上昇のない心筋症の証拠をもっていた

●Tripathy et al. (1988) は, 完全房室結節ブロックの症状を生じた18歳黒人男性を記載した
 心内膜心筋生検は, GSD II の所見に類似した膜結合性グリコーゲン示した
 糖原病は, 身体の残りの検査, 組織学および筋と皮膚線維芽細胞の酵素研究が正常だったので, 心筋に限定されているようであった

●Dworzak et al. (1994) は, 3世代以上の男性3例と女性2例が, 正常 acid maltase 活性をもつリソソーム性グリコーゲン蓄積性ミオパチーをもつシシリア人家系を記載した
 心疾患は, 第1世代の女性1例と, 彼女の息子の1例で死亡を生じた
 発端者, 彼の妹, 彼女の息子が生存し, 詳細に研究された
 発端者は, 心臓移植を受けた
 彼の32歳の妹は, 心房細動と心エコーで収縮機能障害を伴う軽度の左室拡大をもっていた
 彼女は, あmた軽度の知能障害, 四肢虚弱, および筋生検で軽度の筋病変をもっていた
 Dworzak et al. (1994) は, これは多臓器病変をもつ女性の最初の症例であると述べた

●Murakami et al. (1995) は, Danon 病3例の骨格筋生検で, 筋鞘の, まれにヒダまたは陥凹を伴う細胞質内空胞を発見した
 空胞を閉じこめる膜に結合していた
 免疫組織化学的研究は, 空胞膜は, acetylcholinesterase と筋鞘および基底層タンパクを含むことを示した

●Sugie et al. (2002) は, 遺伝子解析で確認された Danon 病の13家系の男性患者20例と女性患者18例で, 臨床病理学的特徴を記載した
 全患者が心筋症をもっていた
 男性は30歳以前に罹患したが, 大多数の女性患者は, 成人になって心筋症を生じた
 男性患者20例中18例 (90%) と, 女性患者18例中6例 (33%) は, 骨格筋ミオパチーをもっていた
 男性患者20例中14例 (70%) と, 女性患者18例中1例 (6%) は, 精神遅滞をもっていた
 筋組織学は, LAMP2 を欠く膜内にacid phosphatase 陽性物質を含む塩基性空胞明らかにした
 心移植が, この致死的心筋症の最も効果的治療であった

●Laforet et al. (2004) は, 軸索性 Charcot-Marie-Tooth 病 (例, CMT2A1; 118210)の特徴をもつ Danon 病の1例を報告した
 凹足, 下肢遠位筋萎縮および遠位感覚喪失を含む
 彼はまた, 若年成人で網膜症による進行性視力喪失も生じた

●Lobrinus et al. (2005) は, 遺伝子解析で確認された Danon 病のスイス人家系を報告した
 男性患者4例と女性患者2例があった
 発端者は, 思春期に心室性不整脈を伴う重度の左室心筋症を生じた
 彼は, 軽度の近位および軸虚弱を伴うびまん性筋力低下と著明な血清 CK 増加をもっていた
 IQ は 76 であった
 いとこ2例が, 軽度の筋病変, 正常知能, および思春期に発症した心症状を伴う心病変をもっていた
 いとこ2例の母は, 40歳時心筋症のため突然死した
 Cardiac muscle biopsy from the proband and 1 cousin showed hypertrophic cardiomyocytes with enlarged and irregular nuclei and vacuolated cytoplasm, as well as absence of LAMP2 protein. Electron microscopy showed that the vacuoles contained degenerating mitochondria, glycogen, small vesicles, and granular debris. Although skeletal muscle biopsies from all 3 patients showed normal morphology and normal glycogen content, all had complete absence of the LAMP2 protein. Cytoplasmic vacuoles could be seen in about 10% of skeletal muscle fibres in the proband and in approximately 1% of fibers in 1 cousin. No vacuoles were observed in the skeletal muscle of the other cousin. There was immunoreactivity to complement components C5b-9 of the membrane attack complex in some of the vacuoles, but not on the fiber surface.

Balmer et al. (2005) reported a mother and son with Danon disease confirmed by genetic analysis. The boy presented at age 2.5 years with mild left ventricular hypertrophy and mild myopathy. His heart disease progressed, resulting in death at age 16 years shortly before planned heart transplantation. His affected mother developed severe dilated cardiomyopathy and died at age 46 years. Postmortem analysis showed fibrosis and necrosis of the myocardium. Balmer et al. (2005) emphasized that cardiac transplantation is the only effective therapeutic option in Danon disease.

Prall et al. (2006) reported the ophthalmic manifestations of genetically proven Danon disease in 4 females and 2 males. The females demonstrated a peripheral pigmentary retinopathy, lens changes, myopia, abnormal electroretinogram, and abnormal visual fields. The males demonstrated a nearly complete loss of pigment in the retinal pigment epithelium. Prall et al. (2006) suggested that retinopathy could potentially be used to identify asymptomatic carriers.

Schorderet et al. (2007) identified diffuse retinal dysfunction, affecting the cones more than the rods, in 2 brothers and their maternal aunt with Danon disease caused by a mutation in LAMP2. Expression of the disease was milder in the aunt, who was an obligate carrier, than in the hemizygous boys, possibly due to lyonization.

Taylor et al. (2007) identified genetically confirmed Danon disease (309060.0012) in and reported long-term follow-up on the family that presented with dilated cardiomyopathy and was linked to the DMD gene (300337) by Towbin et al. (1993). The original female proband and her 3 sons had dilated cardiomyopathy; subsequently, 3 other male relatives developed severe concentric cardiac hypertrophy associated with Wolff-Parkinson-White syndrome. Other features in this family included skeletal myopathy with high serum creatine kinase, mild cognitive impairment in males, and a pigmentary retinopathy in females. Cardiac biopsy specimens showed extensive vacuolar changes in an affected adult male, but the skeletal muscle biopsy in a 13-month-old mutation-carrying male showed no vacuolization by standard histology. Taylor et al. (2007) concluded that X-linked dilated cardiomyopathy may be the presenting sign of Danon syndrome and that the absence of vacuolar myopathy in biopsies from young patients may not exclude Danon disease.

Maron et al. (2009) reported the clinical course and outcome of 7 young patients (6 boys and 1 girl) in whom LAMP2 mutations were previously identified by Arad et al. (2005). Over a mean follow-up period of 8.6 years and by ages 14 to 24 years, the patients developed left ventricular systolic dysfunction and cavity enlargement, with adverse clinical consequences including death from progressive refractory heart failure in 4 patients, sudden death in 1, aborted cardiac arrest in 1, and cardiac transplantation in 1. Left ventricular hypertrophy was particularly marked, with massive ventricular septal thickness in 2 patients of 60 mm and 65 mm at age 23 and 14 years, respectively. In 6 patients, a ventricular preexcitation pattern at study entry was associated with markedly increased R-wave or S-wave voltages and deeply inverted T-waves. Autopsy findings included a combination of histopathologic features that were consistent with lysosomal storage disease, such as clusters of vacuolated myocytes, but also typical of CMH due to sarcomere protein mutations (see, e.g., 192600), such as myocyte disarray, small vessel disease, and myocardial scarring. Maron et al. (2009) noted that 7 female LAMP2 obligate carriers in 2 of the families, aged 19 to 51 years, had remained asymptomatic, underscoring the striking differences in clinical phenotypes and outcomes between female carriers and affected male patients.

Boucek et al. (2011) presented data on 82 patients with Danon disease from 36 families. Men were severely affected with cognitive disabilities (100%), hypertrophic cardiomyopathy (88%), and muscle weakness (80%). Men had a high morbidity and were unlikely to reach the age of 25 years without a cardiac transplantation. Women were less severely affected but reported higher than expected levels of cognitive (47%) and skeletal muscle complaints (50%) and manifesting an equal prevalence of dilated cardiomyopathy and hypertrophic cardiomyopathy. Combining their data with that of 63 other Danon disease case reports in the literature, Boucek et al. (2011) determined that the average ages of first symptom, cardiac transplantation, and death were 12.1, 17.9, and 19.0 years in men and 27.9, 33.7, and 34.6 years in women, respectively. Boucek et al. (2011) concluded that women with Danon disease present with clinical symptoms and events approximately 15 years after men and report a higher proportion of cognitive and skeletal muscle problems than had been recognized.

Inheritance
Byrne et al. (1986) described a family in which 7 members of 3 generations had cardioskeletal myopathy with accumulation of glycogen in lysosomes but normal acid maltase levels. Cardiomyopathy dominated the clinical picture with death between ages 18 and 40 years. There was no male-to-male transmission, but 3 affected females were as severely affected as the 4 males.

Dworzak et al. (1994) found reports of 12 young boys with mild myopathy, varying degrees of mental retardation, and severe cardiomyopathy, whose skeletal muscle examination showed lysosomal glycogen storage not due to acid maltase deficiency. Only 2 cases were sporadic. All of the 10 other cases had a brother or male relative in the maternal line who was either equally affected or had died from heart disease in the second decade. In most cases females were also affected, but cardiomyopathy was the only reported phenotypic expression. The females generally died in the fourth decade. The pattern suggested X-linked dominant inheritance.

Molecular Genetics
In 10 unrelated patients with Danon disease, Nishino et al. (2000) identified 10 different mutations in the LAMP2 gene (see, e.g.,309060.0001-309060.0006). All of the mutations resulted in premature truncation of the LAMP2 protein. Several patients had previously been reported by Danon et al. (1981), Dworzak et al. (1994), Riggs et al. (1983), and Byrne et al. (1986). Western blot analysis of skeletal muscle biopsies from the patients showed marked deficiency or complete absence of the LAMP2 protein. From these results, and the finding that Lamp2-deficient mice manifest a singular vacuolar cardioskeletal myopathy, Nishino et al. (2000) concluded that primary LAMP2 deficiency is the cause of Danon disease. The authors stated that this was the first example of human cardiomyopathy caused by mutations in a lysosomal structural protein rather than an enzymatic protein.

Charron et al. (2004) analyzed the LAMP2 gene in 50 patients with hypertrophic cardiomyopathy (CMH; see 192600) who were negative for mutations in 9 sarcomeric genes and did not have autosomal dominant inheritance. The authors identified 2 different mutations in the LAMP2 gene (309060.0008 and 309060.0009) in 2 patients, both with skeletal muscle weakness on examination and PAS-positive sarcoplasmic vacuoles on skeletal muscle biopsy by light microscopy, who died at ages 22 and 25 years, respectively. The prevalence of Danon disease was therefore 1% of patients with CMH (2 of 197 patients initially screened with CMH in this study) or 4% of enrolled index cases (2 of 50 index patients who were screened for LAMP2 mutations). Danon disease was responsible for 50% of the cases of CMH with clinical skeletal myopathy (2 of 4 patients); none of the 41 patients with isolated CMH had Danon disease.

In genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiogram suggesting ventricular preexcitation, Arad et al. (2005) found 4 LAMP2 mutations (see, e.g., 309060.0010). Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of 2 serum proteins. Mutations in heterozygous state appeared to be responsible for unusual heart disease in some females.

In the family ('XLCM-2') that presented with dilated cardiomyopathy and was linked to the DMD gene by Towbin et al. (1993),Taylor et al. (2007) identified a 1-bp deletion in the LAMP2 gene (309060.0012).

Genotype/Phenotype Correlations
In a male patient with hypertrophic cardiomyopathy, exercise intolerance, and hyperCKemia consistent with a mild form of Danon disease, Musumeci et al. (2005) identified a missense mutation in the LAMP2 gene (309060.0011). The patient did not have muscle weakness or mental retardation. Musumeci et al. (2005) noted that all previous mutations in the LAMP2 gene causing Danon disease resulted in premature truncation of the protein, and stated that this was the first missense mutation reported in the LAMP2 gene.

Nomenclature
Although this disorder was originally described as a type of glycogen storage disease, Danon et al. (1981) recognized that acid alpha-glucosidase and other enzymes of glycogen metabolism were normal in affected patients. The subsequent identification of the structural lysosome-associated membrane protein-2 gene as responsible for the disorder enabled the proper identification of Danon disease as resulting from a defect of the lysosomal membrane (Nishino et al., 2000). Former designations for this disorder are retained here for historical purposes.

(文献)
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