粗な顔, 眼球突出, 開いた幅広い口, 歯肉過形成, 多毛, 舟状頭, 凸背, 短指, わし手; 著明な歯肉肥厚 (Copyright Center for Birth Defects Information Services, Inc.; Oxford University Press)
Mucolipidosis II alpha/beta
(Mucolipidosis II; ML II)
(ML II, alpha-beta)
(I-cell disease; ICD)
ムコリピドーシス II α/β
小児慢性特定疾病 代95 ムコリピドーシスⅡ型（I-cell病）
責任遺伝子：607840 N-acetylglucosamin-2-phosphotransferase, alpha/beta subunits (GNPTA) <12q23.3>
Abnormality of nervous system morphology (神経形態異常) [HP:0012639]
Abnormality of the thorax (胸郭異常) [HP:0000765] 
Coarse facial features (粗な顔貌) [HP:0000280] 
Corneal erosion (角膜びらん) [HP:0200020] 
Failure to thrive (成長障害) [HP:0001508] 
Generalized hirsutism (全身性多毛) [HP:0002230] 
Hepatomegaly (肝腫) [HP:0002240] 
Hernia (ヘルニア) [HP:0100790] 
Mucopolysacchariduria (ムコ多糖症) [HP:0008155] 
Severe global developmental delay (重度全般的発達遅滞) [HP:0011344] 
Short long bone (短い長管骨) [HP:0003026] 
Short stature (低身長) [HP:0004322] 
Splenomegaly (脾腫) [HP:0001744] 
Anteverted nares (上向きの鼻孔) [HP:0000463] 
Depressed nasal bridge (低い鼻梁) [HP:0005280] 
Epicanthus (内眼角贅皮) [HP:0000286] 
Lack of skin elasticity (皮膚弾性喪失) [HP:0100679] 
Long philtrum (長い人中) [HP:0000343] 
Thin skin (薄い皮膚) [HP:0000963] 
Abnormal heart valve morphology (心弁形態異常) [HP:0001654] 
Broad alveolar ridges (幅広い歯槽隆起) [HP:0000187] 
Carpal bone hypoplasia (手根骨低形成) [HP:0001498] 
Carpal bone hypoplasia (手根骨低形成) [HP:0001498] 
Congestive heart failure (うっ血性心不全) [HP:0001635] 
Corneal dystrophy (角膜ジストロフィー) [HP:0001131] 
Kyphosis (後弯) [HP:0002808] 
Megalocornea (巨大角膜) [HP:0000485] 
Opacification of the corneal stroma (角膜間質混濁) [HP:0007759] 
Progressive alveolar ridge hypertropy (進行性歯槽隆起肥大) [HP:0009092] 
Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] 
Weight loss (体重喪失) [HP:0001824] 
Abnormality of the rib cage (肋骨胸郭異常) [HP:0001547] 
Aortic regurgitation (大動脈弁逆流) [HP:0001659] 
Atlantoaxial dislocation (環軸椎脱臼) [HP:0003414] 
Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
Beaking of vertebral bodies T12-L3 (くちばし状T12-L3椎体骨) [HP:0004562] 
Bullet-shaped phalanges of the hand (弾丸型指骨) [HP:0009769] 
Cardiomegaly (心拡大) [HP:0001640] 
Death in childhood (小児期死亡) [HP:0003819] 
Deficiency of N-acetylglucosamine-1-phosphotransferase (N-acetylglucosamine-1-phosphotransferase 欠乏) [HP:0003264]
Diastasis recti (腹直筋開離) [HP:0001540] 
Flared iliac wings (腸骨翼フレア) [HP:0002869] 
Flat acetabular roof (平坦な臼蓋) [HP:0003180] 
Global developmental delay (全般的発達遅滞) [HP:0001263] 
Heart murmur (心雑音) [HP:0030148]
High forehead (高い額) [HP:0000348] 
Hip dislocation (股関節脱臼) [HP:0002827] 
Hoarse voice (粗い声) [HP:0001609] 
Hypertrophic cardiomyopathy (肥大型心筋症) [HP:0001639] 
Hypoplasia of the odontoid process (歯状突起低形成) [HP:0003311] 
Hypoplastic scapulae (肩甲骨低形成) [HP:0000882] 
Increased serum beta-hexosaminidase (beta-hexosaminidase 増加) [HP:0003333]
Increased serum iduronate sulfatase activity (iduronate sulfatase 活性増加) [HP:0003538]
Inguinal hernia (鼠径ヘルニア) [HP:0000023] 
Large sella turcica (大きなトルコ鞍) [HP:0002690] 
Lower thoracic interpediculate narrowness (低位胸椎椎弓根間狭窄) [HP:0008470] 
Macroglossia (巨舌) [HP:0000158] 
Metaphyseal widening (幅広い骨幹端) [HP:0003016] 
Myelopathy (ミエロパチー) [HP:0002196] 
Narrow forehead (狭い額) [HP:0000341] 
Neonatal hypotonia (新生児筋緊張低下) [HP:0001319] 
Osteopenia (骨減少) [HP:0000938] 
Ovoid vertebral bodies (卵形椎体骨) [HP:0003300] 
Palpebral edema (眼瞼腫脹) [HP:0100540] 
Pathologic fracture (病的骨折) [HP:0002756] 
Protuberant abdomen (腹部膨満) [HP:0001538] 
Recurrent bronchitis (反復性気管支炎) [HP:0002837] 
Recurrent otitis media (反復性中耳炎) [HP:0000403] 
Recurrent pneumonia (反復性肺炎) [HP:0006532] 
Severe postnatal growth retardation (重度生後の成長遅滞) [HP:0008850] 
Sparse and thin eyebrow (疎で薄い眉毛) [HP:0000535] 
Split hand (裂手) [HP:0001171] 
Talipes equinovarus (内反尖足) [HP:0001762] 
Thickened calvaria (頭蓋冠肥厚) [HP:0002684] 
Thoracolumbar kyphoscoliosis (胸腰部後側弯) [HP:0003423]  
Umbilical hernia (臍ヘルニア) [HP:0001537] 
Varus deformity of humeral neck (上腕骨頸部の内反変形) [HP:0006362] 
Wide intermamillary distance (乳頭開離) [HP:0006610] 
反復性気管支炎, 肺炎, 中耳炎
Aortic insufficiency, 弁膜症, 心雑音
【体幹】腹直筋解離, 臍ヘルニア, 鼠径ヘルニア
【骨盤】腸骨翼フレア , 水平の寛骨臼蓋s
【皮膚】tight puffy 皮膚 (d上気道感染症ng 乳児期)
血清 beta-hexosaminidase 増加(10-20倍)
血清 iduronate sulfatase 増加 (10-20倍)
血清 arylsulfatase A 増加 (10-20倍)
封入体 (膜と結合した空胞; 線維芽細胞)
Carrier rate of 1 in 39 in the Saguenay-Lac-Saint-Jean region of Quebec
(要約) ムコリピドーシス II
(I-Cell 病, 封入細胞病, ML II, ムコリピドーシス II α/β (ML II α/β), Pacman 異形成)
●封入体細胞 (I-cell) 病 (ムコリピドーシス II, ML II) は, リソソーム蓄積症で, phosphotransferase 障害が原因である (Golgi 器の酵素)
Golgi 器は, リソソームタンパクをリソソームへ標的できない
N-acetylglucosamine-1-phosphotransferase の適切な機能がないと, 酵素がリソソーム内を移動できず, かわりに酵素は体質的に細胞外へ分泌され, 物質の蓄積が生じる
これらの物質または廃棄物は, 炭水化物, 脂質およびタンパクが含まれ, 封入体として知られる腫瘤へ蓄積される
● ムコリピドーシス II (ML II, I-cell 病) は緩徐進行性の先天代謝異常で, 出生時に発症し早期小児期に死亡することが最も多い
皮膚は分厚くなり, 顔貌は粗で, 歯肉は肥大する
出生時に存在する整形外科的異常には, 胸郭変形, 後弯, 内反足, 長管骨変形+/-股関節脱臼がある
全例が心病変をもち, 僧帽弁肥厚や不全が最も多く, 大動脈弁異常が続く
進行性粘膜肥厚は気道を狭くし, 胸郭の緩徐な拘縮が, 最も多い死因である呼吸不全に貢献する
●診断：ほぼ全てのリソソーム hydrolases 活性はｍ血漿や他の体液で正常の5〜20倍高い (ML IIでは白血球では正常である)
→リソソーム acid hydrolases のリソソームへの不適切な標的化による
・GNPTAB (UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase) →二方向シークェンシングにより95％の患者で2つの原因変異を検出する
●常染色体劣性疾患で GlcNAc phosphotransferase 欠乏が原因である
細胞内のゴルジ器でN連鎖糖タンパクの mannose 残基を mannose-6-phosphate へリン酸化する
リソソームへの標的となる mannose-6-phosphate がないと, 酵素はゴルジ器から細胞外腔へ輸送され, 大きな細胞内封入体となる
血流へ分泌された hydrolase は中性のpHでは不活化されるため問題とはならない
大きく丸い頬部, 平坦な顏, 浅い顔貌, 低い鼻梁
整形外科的所見：後弯を含む胸郭変形, 内反足, 長管骨変形, 股関節脱臼
大および小長管骨の骨幹拡大, 短縮したモデル化不全の骨幹, 骨端異形成と骨幹端下の過剰狭窄
小長管骨の短縮 (手足) および手足根骨および骨端骨化遅延
前後径が短縮した椎体骨と前上部低形成 (下部胸椎と上部腰椎), 椎体骨は前部より後部が高い (前部, 上部, 下部縁の凹）
骨盤異形成, 臼蓋傾斜, 外反股
・重症患者では, くる病や骨減少症に似た一過性サインと軟部組織の点状石灰化 (足根骨に多い)
β-D-hexosaminidase (EC 22.214.171.124), β-D-glucuronidase (EC 126.96.36.199), β-D-galactosidase (EC 188.8.131.52), α-L-fucosidase (EC 184.108.40.206)の増加
※ Pacman 異形成は ML II の出生前症状である
●頻度：ポルトガル 1:123,500 生産児
＜小児慢性特定疾病 代95 ムコリピドーシスⅡ型（I-cell病）＞
N-アセチルグルコサミン-1-リン酸基転移酵素（GNPT）活性欠損が本疾患の病因である。GNPTは, α2β2γ2の6つのサブユニットからなり, 責任遺伝子はαおよびβサブユニットをコードするGNTPAB遺伝子およびγサブユニットをコードするGNPG遺伝子の2つである。酵素欠損によって，生成されたライソゾーム酵素群はライソゾームへのターゲティングに異常をきたし，細胞外マトリックスに分泌される。ライソゾーム酵素群が機能するためにはライソゾーム内の酸性環境が必要であるため，患者では，あらゆるライソゾーム酵素が細胞内で欠損することにより多様な基質がライソゾーム内に蓄積する。
ライソゾーム酵素群は，通常，酵素蛋白の糖鎖に付くマンノース-6-リン酸残基の存在によりライソゾーム膜上のマンノース-6-リン酸受容体によって認識され, ライソゾーム内に運ばれる。N-アセチルグルコサミン-1-リン酸基転移酵素（GNPT）活性欠損により, ライソゾーム酵素群はライソゾームに入ることができず, ほぼすべてのライソゾーム酵素活性が欠損する状態になる。このため, 種々の糖脂質, 糖タンパクがライソゾーム内に蓄積する。常染色体性劣性遺伝である。
症状：ムコ多糖症によく似た身体所見を呈する。ムコリピドーシスII型では, 乳児期より症状が発現する。発達は, 歩行までは至らない。ムコリピドーシスIII型は, 2～3歳ころに骨の変形や関節拘縮に気付かれるが, 重症度の幅は広い。骨の変形が主な症状で, 肝腫大もあまり見られない。知的障害も軽度である。 臨床検査：全身骨X線で多発性の骨形態変化を認める。ムコ多糖症と異なり, 尿中ムコ多糖の異常は認めない。末梢リンパ球に空胞化がみられる。
末梢リンパ球, 培養線維芽細胞中で複数のライソゾーム酵素の活性が軽度から中等度（正常の50～80％）に低下し, 血漿中のライソゾーム酵素活性は, 正常の5～10倍に上昇することから確定診断ができる。遺伝子診断も可能である。
(頻度) 30例以上, 日本で多い
(オリジナル) Leroy and Demars (1967)
(責任遺伝子) *607840 N-acetylglucosamin-2-phosphotransferase, alpha/beta subunits (GNPTAB) <12q23.2>
(1) Mucolipidosis III alpha/beta (252600)
.0001 Mucolipidosis III alpha/beta, atypical [GNPTAB, G-A, EX7] (rs281865025) (RCV000031990...) (Steet et al. 2005)
.0002 Mucolipidosis III alpha/beta [GNPTAB, ASP407GLY] (rs137852895) (RCV000002889) (Tiede et al. 2005)
.0013 Mucolipidosis III alpha/beta [GNPTAB, IVS17DS, T-G, +6] (rs34788341) (gnomAD:rs34788341) (RCV000031982...) (Kudo et al. 2006)
.0014 Mucolipidosis III alpha/beta [GNPTAB, LYS4GLN] (rs34159654) (gnomAD:rs34159654) (RCV000031965...) (Kudo et al. 2006)
.0015 Mucolipidosis III alpha/beta (Mucolipidosis II alpha/beta, included) [GNPTAB, PHE374LEU] (rs137852900) (RCV000002904...) (Otomo et al. 2009)
(2) Mucolipidosis II alpha/beta (252500)
.0003 Mucolipidosis II alpha/beta [GNPTAB, GLN104TER] (rs137852896) (RCV000002890) (Paik et al. 2005)
.0004 Mucolipidosis II alpha/beta (Mucolipidosis III alpha/beta, included) [GNPTAB, ARG1189TER] (rs137852897) (gnomAD:rs137852897) (RCV000002892...) (Paik et al. 2005, Otomo et al. 2009)
.0005 Mucolipidosis II alpha/beta [GNPTAB, SER1058TER] (rs137852898) (gnomAD:rs137852898) (RCV000002893) (Paik et al. 2005)
.0006 Mucolipidosis II alpha/beta [GNPTAB, 2-BP DEL, 3474TA ] (rs281865038) (RCV000002894) (Paik et al. 2005)
.0007 Mucolipidosis II alpha/beta [GNPTAB, TRP894TER] (rs137852899) (RCV000002895) (Paik et al. 2005)
.0008 Mucolipidosis II alpha/beta [GNPTAB, IVS13, G-A, +1] (rs281865031) (gnomAD:rs281865031) (RCV000031976...) (Paik et al. 2005)
.0009 Mucolipidosis II alpha/beta [GNPTAB, 2-BP DEL, 2574GA] (rs281865029) (gnomAD:rs281865029) (RCV000031974...) (RCV000031974) (Paik et al. 2005)
.0010 Mucolipidosis II alpha/beta [GNPTAB, 1-BP INS, 1625C] (rs281865027) (RCV000002898) (Tiede et al. 2005)
.0011 Mucolipidosis II alpha/beta Mucolipidosis III alpha/beta, included) [GNPTAB, 2-BP DEL, 3665TC] (rs34002892) (gnomAD:rs34002892) (RCV000082192...) ( (Kudo et al. 2006; Plante et al. 2008; Encarnacao et al. 2009; Coutinho et al. 2011)
.0012 Mucolipidosis II alpha/beta [GNPTAB, IVS17DS, G-A, +1] (rs34940801) (gnomAD:rs34940801) (RCV000002901) (Kudo et al. 2006)
●(#) は, ムコリピドーシス II α/β (I-cell 病としても知られる) は, GNPTAB gene (607840) 遺伝子のホモ接合体または複合ヘテロ接合体変異が原因なため
●ムコリピドーシス III α/β (252600) または, 偽性 Hurler ポリジストロフィーも GNPTAB 遺伝子変異が原因である.
● ムコリピドーシス III γ (252605) と呼ばれるムコリピドーシスバリアントは GNPTG 遺伝子 (607838)変異が原因である
●Cathey et al. (2008) は, ムコリピドーシス II と III のアップデートされた命名分類システムを報告した
ML II は ML II α/βと改名された
IIIA は ML III α/β と改名された
ML IIIC は ML III γと改名された.
● ムコリピドーシス II α/βは常染色体劣性疾患で, 低身長, 骨格異常, 心拡大, 発達遅滞が特徴である
表現型的にアレリックな疾患であるムコリピドーシス III α/βより重症である (Paik et al., 2005)
●ムコリピドーシス II は, Hurler 様疾患で, 重度の臨床およびX線的特徴, 特異な線維芽細胞封入体があり, 過剰なムコ多糖尿はない
先天性股関節脱臼, 胸部変形, ヘルニア, 歯肉過形成が, 生後すぐ明らかである
●Leroy et al. (1969)は最初に本疾患を記載し, I-cell 病 ( 'inclusion cell disease’)と命名した
2家系で同胞が患者で, Spranger and Wiedemann (1970) の患者1例の両親はいとこであった
●Michels et al. (1982) は, ML II は子宮内骨折を生じうる疾患のリストに加えるべきだと指摘した
Beck et al. (1995) analyzed the inter- and intrafamilial variability in I-cell disease based on 9 patients. Although they all had disproportionate dwarfism, coarse facial features, and mental retardation, there was remarkable variability in age of onset, organ manifestation, and radiologic findings. Some had unusual clinical symptoms, including pericardial effusion and profound brain atrophy. Differences were seen even in 2 affected sibs: a brother survived to the age of 8 years, dying of bronchial pneumonia, whereas a sister died from cardiac failure at the age of 2 months, and another sister died at 29 days following a similar course.
Encarnacao et al. (2009) reported 9 unrelated patients with ML II alpha/beta. All had onset before 1 year of age, except 2 who had onset at 4 and 22 months, respectively. Clinical features included psychomotor retardation, coarse dysmorphic facial features, gingival hyperplasia, hip dysplasia, growth retardation, and restricted joint movement. Biochemical studies showed increased activity of several lysosomal enzymes in the serum and decreased activity of these enzymes in fibroblasts.
Leroy et al. (1972) found no accumulation of lipid in brain and viscera and no accumulation of mucopolysaccharide in these tissues or fibroblasts. For this reason they questioned the appropriation of the designation 'mucolipidosis.'
Deficiency of sialidase (neuraminidase) has been reported in cultured fibroblasts (Thomas et al., 1976) and in leukocytes (Strecker et al., 1976). Furthermore, a sialyl-hexasaccharide is excreted in the urine in considerable amounts (Strecker et al., 1976). Sialic acid levels were increased 3- to 4-fold in cultured ML II cells, but were normal in 9 other lysosomal diseases.
Vladutiu and Rattazzi (1975) found electrophoretic abnormality of lysosomal hydrolases excreted by cultured fibroblasts in I-cell disease and alteration of this mobility by treatment with neuraminidase. Presumably the higher electronegative charge of I-cell hydrolases at pH 6 resulted from sialic acid residues not present on enzyme excreted by normal cells.
Complementation studies suggested that ML II and ML III are determined by mutations at separate loci (Wright et al., 1979). However, by cell fusion studies, Honey et al. (1981) and Shows et al. (1982) demonstrated 2 ML II complementation groups and 3 ML III complementation groups. No complementation was observed between one of the ML II types and one of the ML III types.
Honey et al. (1981) found differing electrophoretic patterns of lysosomal enzymes in cases with the ML II phenotype, suggesting heterogeneity (at least 2 classes). In all cases of both ML II and ML III, deficiency has been found in only one enzyme, the GlcNAc-1-P transferase that attaches GlcNAc-1-P to mannose residues of multiple lysosomal enzymes. Defects in the diesterase that exposes the mannose-6-phosphate marker have not been identified (Sly, 1981). Different defects in the transferase have been found, e.g., an abnormality of the enzyme such that it does not recognize mannose as a substrate. The receptor for lysosomal enzyme necessary for transfer of enzymes to lysosomes is present in all tissues. No receptor-negative mutants had yet been recognized.
Thomas et al. (1982) reported studies of a patient with an atypical form of ML II and presented evidence that the patient was mosaic for 2 populations of cells, one with the I-cell mutation and one normal. They found no evidence of twin chimerism from genetic marker studies.
Okada et al. (1983) showed heterogeneity of ICD lines in the ability of sucrose loading in vitro to induce hydrolases. ML II illustrates nicely the principle that demonstration of an intermediate level of enzyme activity in heterozygotes is a valuable indicator that that enzyme is the site of the primary defect. Although the activity of lysosomal enzymes is low in cells of affected persons, normal levels are found in heterozygotes. (An exception to this statement is the report by Potier et al. (1979) who found intermediate levels of neuraminidase activity in obligatory heterozygotes.) On the other hand, the activity of GlcNAc-1-P transferase is intermediate in ML II heterozygotes (Shows, 1983).
Ben-Yoseph et al. (1987) found abnormally small N-acetylglucosamine 1-phosphotransferase enzyme in Golgi membranes from fibroblasts of patients with I-cell disease and classical pseudo-Hurler polydystrophy, which comprised 1 complementation group characterized by deficiency toward both artificial and natural acceptor substrates. The size of the enzyme varied from 151-174 kD, compared with the normal of 225-278 kD. The mutant enzyme from cell lines of patients with variant forms of pseudo-Hurler polydystrophy, which comprised another complementation group characterized by normal activity toward monosaccharide and oligosaccharide substrates, was significantly larger than the normal enzyme, ranging from 321-356 kD in 2 families and from 528-547 kD in a third family.
In a review of genetic defects of intracellular membrane transport, Olkkonen and Ikonen (2000) referred to ML II as the prototypic genetic disorder affecting the machinery of protein sorting.
Wiesmann et al. (1971) concluded that the defect leads to leakage of lysosomal enzymes from the cell. Cultured fibroblasts showed low levels of 4 lysosomal enzymes whereas the level of these enzymes in the culture medium was high.
Hickman and Neufeld (1972) presented evidence for their hypothesis that the mutation in I-cell disease is in an enzyme which modifies several lysosomal enzymes to guarantee their recognition by cells and re-entry into cells from the intercellular space into which the enzymes have been secreted by the synthesizing cells. There was precedence for the idea that carbohydrate side chains of glycoproteins control entry of the proteins into liver cells (Morell et al., 1971). This hypothesis would explain why multiple enzymes are high in the medium in which I-cells are grown and low in the cells themselves. It was an alternative to the 'leaky lysosome' hypothesis of Wiesmann et al. (1971). The evidence presented by Hickman and Neufeld (1972) was of several types. For example, they found that alpha-1-iduronidase produced by I-cells did not 'correct' Hurler cells whereas semipurified iduronidase from urine and medium in which normal cells have grown does correct the metabolic defect of Hurler cells. The Neufeld hypothesis was an alternative to the Novikoff hypothesis which suggested that the acid hydrolases are packaged in the lysosomes directly after synthesis in the Golgi apparatus. This may indeed be true for some lysosomal enzymes because acid phosphatase and beta-glucosidase have normal activities in I cells.
Sly et al. (1977) presented evidence that lysosomal enzymes that are capable of being taken up by cells through pinocytosis (high uptake form of lysosomal enzymes) are phosphoglycoproteins. This is consistent with the destruction of uptake by treatment of the enzyme with periodate or with alkaline phosphatase. More specifically a phosphomonoester of mannose appears to be the recognition marker for many lysosomal enzymes.
Varki et al. (1981) showed that the basic defect in mucolipidoses II and III is in 1 of the 2 enzymes involved in generation of the phosphomannosyl residues on acid hydrolases that serve as specific recognition markers for targeting these enzymes to lysosomes. The first of these enzymes, N-acetylglucosamine-1-phosphotransferase (GNPTA; 607840), was deficient in 5 cases of I-cell disease and 10 cases of pseudo-Hurler polydystrophy. No enzyme activity was found in the first group; residual enzyme activity in the second group provides an explanation for the milder phenotype. These may be allelic disorders. Presumably a defect in the second enzyme involved in generating the phosphomannosyl residues, acetylglucosaminyl phosphodiesterase, could also lead to mucolipidosis. In the cases studied, the second enzyme was normal or elevated.
By the study of cell lines deficient in the mannose 6-phosphate receptor, Gabel et al. (1983) demonstrated that an alternative mechanism for delivery of acid hydrolases to lysosomal organelles exists in some cells. A succinct statement of the usual mechanism was given, and the review by Sly and Fischer (1982) was referenced.
Kornfeld (1986) reviewed the 'trafficking of lysosomal enzymes in normal and disease states.' He gave a table of 6 types of lysosomal storage diseases, with examples: those in which no immunologically detectable enzyme is produced (includes conditions with grossly abnormal structural genes); those in which a catalytically inactive polypeptide is synthesized (includes mutations affecting stability or transport of the polypeptide); those in which a catalytically active enzyme is synthesized but not segregated into lysosomes; those in which a catalytically active enzyme is synthesized but is unstable in prelysosomal or lysosomal compartments; those in which an activator protein of a lipid-degrading hydrolase is missing, e.g., 249900; and those in which lysosomal enzyme deficiencies result from intoxication by an inhibitor of a lysosomal enzyme. Kornfeld (1986) provided a graphic diagram of the pathway of lysosomal enzyme targeting to lysosomes. See 154570 for a further illustration of the elucidation of lysosomal enzyme trafficking by study of another 'experiment of nature.' Herzog et al. (1987) found that thyroglobulin (188450) carries the lysosomal recognition marker mannose-6-phosphate. This finding is consistent with the fact that the ultimate destination of TG is the lysosomal compartment, where thyroid hormones are released by proteolytic degradation. However, the thyroglobulin is first exported to the thyroid follicle and then recaptured for the release of thyroid hormone.
Vidgoff et al. (1982) studied a population isolate with several couples at risk for ICD and concluded that carriers can be identified by serum levels of beta-D-hexosaminidase B (Vidgoff and Buist, 1977).
Ben-Yoseph et al. (1988) demonstrated the usefulness of specific enzyme diagnosis on the basis of chorion villus samples.
Saul et al. (2005) reported a female sib of a male fetus that had previously been diagnosed with Pacman dysplasia (167220) by Miller et al. (2003). She had a clinical course and biochemical, cytologic, and radiographic features consistent with the diagnosis of ML II. Saul et al. (2005) suggested that what is called Pacman dysplasia may represent a prenatal manifestation of ML II. Wilcox et al. (2005) argued that Pacman dysplasia is distinct from ML II, but that radiographic and morphologic criteria cannot be used to distinguish between them. In order to make a definitive diagnosis, pathologic material must be examined for lysosomal storage or enzyme assays must be performed.
Vidgoff et al. (1982) found possible linkage of ML II to MN (111300) with a lod score of 1.3. Mueller et al. (1987)determined the chromosome assignment of the structural gene altered in the common forms of ML II and ML III, designated GNPTA, by linkage analysis, somatic cell hybrids, and gene dosage. Linkage data with ML II families indicated that the ML II locus is located between GC (139200) and MNS (111300). The combined data indicated that GNPTA maps to 4q21-q23.
Canfield et al. (1998) stated that the GNPTA gene maps to chromosome 12p.
Canfield et al. (1998) found that in 4 of 4 patients with mucolipidosis II, the GNPTA transcript was absent. In 2 of 2 patients with mucolipidosis IIIA, the GNPTA transcript was present but greatly reduced. In all ML II and ML III patients examined, GNPTAG (607838) was present at normal levels.
In 3 unrelated Korean girls with type II mucolipidosis characterized by a decelerating growth pattern from infancy and cardiac abnormalities, Paik et al. (2005) identified compound heterozygosity for 5 different mutations in the GNPTAB gene (607840.0003-607840.0007).
In 6 patients with clinically and biochemically diagnosed mucolipidosis II, Tiede et al. (2005) identified homozygosity or compound heterozygosity for 7 mutations in the GNPTAB gene, all resulting in premature translational termination (e.g., 607840.0010).
Bargal et al. (2006) studied GNPTAB mutations in 24 patients. They suggested that there is a clinical continuum between ML III and ML II, and that the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.
Otomo et al. (2009) identified 18 GNPTAB mutations, including 14 novel mutations, among 25 unrelated Japanese patients with ML II and 15 Japanese patients with ML III. The most common mutations were R1189X (607840.0004), which was found in 41% of alleles, and F374L (607840.0015), which was found in 10% of alleles. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the more severe phenotype. In all, 73 GNPTAB mutations were detected in the 80 alleles. In a review of the reported clinical features, most ML II patients had impairment in standing alone, walking without support, and speaking single words compared to those with ML III. The frequencies of heart murmur, inguinal hernia, and hepatomegaly and/or splenomegaly did not differ between ML II and III patients.
Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being a 2-bp deletion (607840.0011) that was found in 45% of the mutant alleles; one patient was homozygous for a missense mutation. Three additional patients with a less severe phenotype consistent with ML III had missense mutations. Encarnacao et al. (2009) concluded that patients with ML II alpha/beta are almost all associated with the presence of nonsense or frameshift mutations in homozygosity, whereas the presence of at least 1 mild mutation in the GNPTAB gene is associated with ML III alpha/beta.
In the French-Canadian population of the Saguenay-Lac St. Jean region of Quebec province, De Braekeleer (1991)estimated the prevalence at birth of ML II to be 1/6,184, giving a carrier frequency of 1/39.
In 27 parents of 16 deceased French Canadian children with ML II, Plante et al. (2008) identified a 2-bp deletion (3503delTC; 607840.0011) in the GNPTAB gene. All parents carried the mutation in the heterozygous state, indicating that the children were likely homozygous. Genealogic data showed 6 founders (3 couples) with a high probability of having introduced the mutation in the population; all originated from France and were married in the Quebec region in the second half of the 17th century.
By haplotype analysis of 44 carriers of the 3503delTC mutation from various populations, Coutinho et al. (2011)found that 59 (97%) of 61 mutant chromosomes shared a common haplotype covering 4 of the 5 polymorphic markers analyzed, indicating a strong founder effect. The 2 remaining chromosomes, both from Italian patients, differed by alleles only at 1 marker. A common haplotype encompassing the 3503delTC mutation was shared by individuals of Italian, Arab-Muslim, Turkish, Argentinean, Brazilian, Irish Traveller, Portuguese, and Canadian origin. The mutation was estimated to have occurred about 2,063 years ago, most likely in a peri-Mediterranean region.
Bosshard et al. (1996) described spontaneous mucolipidosis in a cat, which they suggested might be useful in the study of human I-cell disease. The cat showed facial dysmorphism, large paws in relation to body size, dysostosis multiplex, and poor growth, as well as leukocytes and cultured fibroblasts which had the appearance of inclusion cells (I-cells). Activities of a set of lysosomal hydrolases were abnormally low in fibroblasts and excessive in blood plasma. Radiologic findings in the same cat by Hubler et al. (1996) revealed a severely deformed spinal column, bilateral hip luxation with hip dysplasia, an abnormally shaped skull and generalized decreased bone opacity.
Mazrier et al. (2003) described the inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II. They found that the activities of 3 lysosomal enzymes were high in serum but low in cultured fibroblasts that contained inclusion bodies (I-cells), reflecting the unique enzyme defect in ML II. Serum lysosomal enzyme activities of adult obligate carriers were intermediate between normal and affected values. Clinical features in affected kittens were observed from birth and included failure to thrive, behavioral dullness, facial dysmorphia, and ataxia. Radiologic lesions included metaphyseal flaring, radial bowing, joint laxity, and vertebral fusion. In contrast to human ML II, diffuse retinal degeneration leading to blindness by 4 months of age was seen in affected kittens. All clinical signs were progressive and euthanasia or death invariably occurred within the first few days to 7 months of life, often due to upper respiratory disease or cardiac failure.
I-cell disease, formerly known as mucolipidosis II, was originally described in 1967 by Leroy and DeMars (Lemaitre L et al 1978, Leroy JG, DeMars RI, Leroy JG, Spranger JW 1970, Leroy JG et al 1972). It is characterized by severe psychomotor retardation, marked shortness of stature, facial features reminiscent of MPS I-H, impressive gingival enlargement, a rapid deteriorating course, and death from heart failure (hypertrophic cardiomyopathy), bronchopneumonia, or pulmonary atelectasis, usually by the age of 5 years (Beck M et al 1995, Komfeld S, Sly WS 1995). However, survival of patients with I-cell disease into their teens has been described (Okada S et al 1985). In a French-Canadian population, a prevalence at birth of 1/6184, has been found for mucolipidosis II, giving a carrier frequency of 1/39 (De Braekeleer 1991). This disorder, like Hurler polydystrophy, is the result of a deficiency in recognition marker phosphotransferase. Inheritance is autosomal recessive, and consanguinity is high (Okada S et al 1985). The disease may be somewhat more frequent in Japan and there is probably genetic heterogeneity (Okada S et al 1983, Shows TB et al 1982). The gene locus has been identified at 4q21-q23 (Mueller OT et al 1996). Important negative signs and symptoms are absent splenomegaly, equivocal or absent corneal cloudiness, and normal urinary excretion of MPS (Gilbert EF et al 1973, Spranger JW, Wiedemann H-R 1970).
This disorder received the name of I-cell disease because of the numerous granular inclusions in the cytoplasm of cultured fibroblasts and amniotic fluid cells observed under phase-contrast microscopy (DeMars RI, Leroy JG 1967, Leroy JG, DeMars RI 1967). The inclusions are large lysosomes containing heterogeneous undegraded material (Gilbert EF et al 1973).
At birth, the infants are small (< 10th centile) and have coarse facies, muscular hypotonia, and dislocated hips. Inguinal hernias occur in males, and both genders may have tight and thickened skin that becomes more pliable with age (Beck M et al 1995, Cippoloni C et al 1980, Pazzaglia UE et al 1992). Hirsutism has been noted in about 60% of cases. During the first year, infants have a history of recurrent upper respiratory tract infections (rhinitis, otitis media), failure to thrive, and marked lack of psychomotor development. The full clinical picture is reached by I year of age (Beck M et al 1995). There is severe shortness of stature, with most never reaching the average height of a l-year-old child and growth ceasing by the third year. This phenomenon differs markedly from MPS I-H, where excessive growth from 6 to 18 months of age has been frequently documented.
Motor retardation is more severe than mental retardation. Many patients do not accomplish unaided ambulation, but several older patients can walk without support. Most patients over 4 years of age can speak two-word sentences and are toilet trained.
Some patients have exhibited premature lightening of hair color. Head circumference remains normal with respect to stature. The facies is reminiscent of that in MPS I-H patients, with small orbits, flat supraorbital ridges, puffy eyelids, a slight degree of exophthalmos, and a pattern of tortuous veins around the orbits and temporal areas (Beck M et al 1995). The cheeks are full and pink, partly because of multiple fine telangiectasias. The gingiva shows marked enlargement. Intermittent copious nasal discharge has been noted, but to a lesser degree than in MPS I-H patients. Hearing impairment has been reported (Ichiyama T et al 1991)
Mild corneal clouding has been documented as a late sign in about 40% of cases, but vision is not impaired. However, on slit lamp examination, all patients have some degree of corneal opacification. Glaucoma and megalocornea have been occasionally noted (Libert J et al 1977).
Shortness of the neck and a deformed thoracic cage are common. Umbilical and/or inguinal hernias are found in up to 75% of cases. Despite hypotonia, there is considerable restriction of joint mobility, particularly in the shoulders and wrists. The hands and fingers are stubby and the wrists broadened. Restriction of motion is less impaired in the lower limbs, which appear hypotrophic. Thoracolumbar kyphosis with gibbus formation may be present, but is not observed in any patient who can stand upright. The costochondral junctions are knob-like. Pes valgus has been noted in 25% of neonates.
Radiographically, generalized demineralization, a coarse trabecular pattern, and extensive periosteal cloaking of all long bones are seen in early infancy (Pazzaglia UE et al 1989). This phenomenon is also observed in newborns with GM1 gangliosidosis type I and the disorders cannot be differentiated radiographically at this stage. Congenital fractures have been reported (Michels VV et al 1982). Periosteal new bone formation can be observed until 4-6 months of age. Subsequently, this overgrowth becomes confluent with the underlying cortex and disappears entirely at between 8 and 12 months of age. From that point on, dysostosis multiplex is observed as in MPS I-H, the bony abnormalities being more severe in I-cell disease patients than in MPS-I-H patients at comparable ages. Other differences are minor involvement of the calvaria and minor to moderate diaphyseal widening in long bones, particularly of the lower limbs in I-cell disease (Cippoloni C et al 1980, Whelan DT et al 1983). Stippled epiphyses, particularly of the calcaneus and knees, and pathologic fractures have been documented (Kozlowski K et al 1991, Lemaitre L et al 1978), as have dysharmonic epiphyseal ossification and butterfly vertebral bodies (Herman TE, McAlister WH 1996). Premature synostosis of skull sutures has also been reported (Yamada H et al 1987). No lamina dura is found around the teeth. The metacarpals are proximally pointed, with the distal phalanges being poorly modeled (Kozlowski K et al 1991).
Minimal to moderate hepatomegaly, evident at birth, occurs in 40% of cases.
Enlargement of the gingiva and anterior alveolar process is present as early as 4 months of age and is slowly progressive. In some patients, it reaches grotesque proportions (Leroy JG, Spranger JW 1970) and together with a thick tongue prevents proper closure of the mouth. Usually the teeth are deeply buried in the hypertrophic tissue or do not erupt at all. Radiographic examination of the teeth reveals that the enamel is quite hypocalcified and that there is accumulation of storage material about the crowns of unerupted first molar teeth.
Peripheral lymphocytes contain large lysosomal cytoplasmic inclusions. The urinary excretion of GAGs is normal. All cultured fibroblasts contain an abundance of coarse cytoplasmic inclusions (hence I-cell disease), with a characteristic inclusion-free perinuclear zone (Leroy JG, DeMars RI 1967).
Most lysosomal acid hydrolase activities, such as hexosaminidase, iduronate sulfatase, and arylsulfatase A, are considerably increased (up to 10- to 20-fold) in the serum but are decreased(10% to 20% of normal) in cultured fibroblasts. The ratio of extracellular to intracellular enzyme activities can also be used (Leroy JG et al 1972).
The enzymatic defect is UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-l-phosphotransferase (Komfeld S, Sly WS 1995). This enzyme is defective in both mucolipidosis II and III. The enzyme catalyzes the first step in the synthesis of the recognition marker, necessary for targeting the lysosomal enzymes to lysosomes (Komfeld S, Sly WS 1995). Heterozygotes have intermediate levels of phosphotransferase activity in cultured fibroblasts and isolated white blood cells (Komfeld S, Sly WS 1995). Measuring the activity of acid hydrolases in amniotic fluid and cultured amniotic cells is reliable for prenatal diagnosis (Besley GTN et al 1990, Poenaru L et al 1990). This has also been accomplished by assay of N-acetylglucosamine-l-phosphotransferase assay of chorionic villi (Ben-Yoseph Y et al 1988).
(1) Demars, R. I., Leroy, J. G. The remarkable cells cultured from a human with Hurler's syndrome. An approach to visual selection for in vitro genetic studies. In Vitro 2: 107, 1967
(2) Leroy JG, Demars RI: Mutant enzymatic and cytological phenotypes in cultured human fibroblasts. Science 157: 804-806, 1967
(3) Leroy JG et al. I-cell disease. BDOAS V(4): 174-185, 1969
(4) Leroy JG, Spranger JW: I-cell disease continued. N Engl J Med 283:598-599, 1970
(5) Maroteaux P et al.Presse Med 78: 179, 1970
(6) Spranger JW, Wiedemann HR: The genetic mucolipidoses: diagnosis and differential diagnosis. Humangenetik 9: 113-139, 1970
(7) Hanai, J., Leroy, J., O'Brien, J. S. Ultrastructure of cultured fibroblasts in I-cell disease. Am. J. Dis. Child. 122: 34-38, 1971
(8) Leroy JG et al. J Pediatr 79: 360-365, 1971
(9) Morell, A. G., Gregoriadis, G., Scheinberg, I. H., Hickman, J., Ashwell, G. The role of sialic acid in determining the survival of glycoproteins in the circulation. J. Biol. Chem. 246: 1461-1467, 1971
(10) Wiesmann, U. N., Rossi, E. E., Herschkowitz, N. N. Treatment of metachromatic leukodystrophy in fibroblasts by enzyme replacement. New Eng. J. Med. 284: 672-673, 1971
(11) Hickman S, Neufeld EF: A hypothesis for I-cell disease: defective hydrolases that do not enter lysosomes. Biochem Biophys Res Commun 49: 992-999, 1972
(12) Leroy, J. G., Demars, R. I., Opitz, J. M. I-cell disease. Birth Defects Orig. Art. Ser. V(4): 174-185, 1969. 26. Leroy, J. G., Ho, M. W., MacBrinn, M. C., Zielke, K., Jacob, J., O'Brien, J. S. I-cell disease: biochemical studies. Pediat. Res. 6: 752-757, 1972
(13) Capotorti L et al. Minerva Pediatr 27: 483, 1973
(14) Gilbert, E. F., Dawson, G., ZuRhein, G. M., Opitz, J. M., Spranger, J. W. I-cell disease, mucolipidosis II. Pathological, histochemical, ultrastructural and biochemical observations in four cases. Z. Kinderheilk. 114: 259-292, 1973
(15) Blank E et al.: Pediatrics 54: 797, 1974
(16) Jonnard A et al.: Pediatrie 29: 825, 1974
(17) Bianchi E et al.: Minerva Pediatr 27: 1694, 1975
(18) Leroy JG et al.: BDOAS 11(6): 283-294, 1975
(19) Martin JJ et al.: Acta Neuropathol 33: 285, 1975
(20) Taber P et al. Roentgenographic manifestations of Leroy's I-cell disease. Am J Roentgen 118: 213, 1973
(21) Terashima Y: Am J Dis Child 129: 1083-1090, 1975
(22) Vladutiu, G. D., Rattazzi, M. C. Abnormal lysosomal hydrolase excreted by cultured fibroblasts in I-cell disease (mucolipidosis II). Biochem. Biophys. Res. Commun. 67: 956-964, 1975
(23) Strecker, G., Hondi-Assah, T., Fournet, B., Spik, G., Montreuil, J., Maroteaux, P., Durand, P., Farriaux, J.-P. Structure of the three major sialyl-oligosaccharides excreted in the urine of five patients with three distinct inborn diseases: 'I-cell disease' and two new types of mucolipidosis. Biochim. Biophys. Acta 444: 349-358, 1976
(24) Strecker, G., Michalski, J. C., Montreuil, J., Farriaux, J.-P. Defect in neuraminidase associated with mucolipidosis II (I-cell disease). Biomedicine 25: 238-240, 1976
(25) Thomas, G. H., Tiller, G. E., Jr., Reynolds, L. W., Miller, C. S., Bace, J. W. Increased levels of sialic acid associated with a sialidase deficiency in I-cell disease (mucolipidosis II) fibroblasts. Biochem. Biophys. Res. Commun. 71: 188-195, 1976
(26) Champion, M. J., Shows, T. B. Correction of human mucolipidosis II: enzyme abnormalities in somatic cell hybrids. Nature 270: 64-66, 1977
(27) Champion, M. J., Shows, T. B. Electrophoretic abnormalities of lysosomal enzymes in mucolipidosis fibroblast lines. Am. J. Hum. Genet. 29: 149-163, 1977
(28) Jonnard A et al.: Pediatrie 29: 825, 19al case. Acta Path Jpn 27: 251-264, 1977
(29) Libert J et al: Ocular findings in I-cell disease (mucolipidosis type II). Am J Ophthalmol 83:617 628, 1977
(30) Nagashima, K., Sakakibara, K., Endo, H., Konishi, Y., Nakamura, N., Suzuki, Y., Abe, T. I-cell disease (mucolipidosis II): pathological and biochemical studies of an autosomal case. Acta Path. Jpn. 27: 251-264, 1977
(31) Partriquin HB et al.: Neonatal mucolipidosis II (I-cell disease): clinical and radiologic features in three cases. Am J Roenten 129: 37, 1977
(32) Sly, W. S., Achord, D. T., Kaplan, A. Correction of enzyme deficient fibroblasts: evidence for a new type of pinocytosis receptor which mediates uptake of lysosomal enzymes. Clin. Res. 25: 471A, 1977
(33) Strecker, G., Peers, M.-C., Michalski, J.-C., Hondi-Assah, T., Fournet, B., Spik, G., Montreuil, J., Farriaux, J.-P., Maroteaux, P., Durand, P. Structure of nine sialyl-oligosaccharides accumulated in urine of eleven patients with three different types of sialidosis (mucolipidosis II and two new types of mucolipidosis). Europ. J. Biochem. 75: 391-403, 1977
(34) Vidgoff, J., Buist, N. R. Serum hexosaminidase activity in I-cell disease carriers. Hum. Genet. 36: 307-316, 1977
(35) Baggio P: Minerva Pediatr 30: 865, 1978
(36) Lemaitre L et al: Radiological signs of mucolipidosis II or I-cell disease. PediatrRadiol 7:97-105, 1978
(37) Okada, S., Kato, T., Miura, S., Yabuuchi, H., Nishigaki, M., Kabata, A., Chiyo, H., Furuyama, J.-I. Hypersialyloligosacchariduria in mucolipidoses: a method for diagnosis. Clin. Chim. Acta 86: 159-167, 1978
(38) Spritz RA et al.: J Pediatr 93: 854, 1978
(39) Potier, M., Melancon, S. B., Dallaire, L., Chicoine, R., Mameli, L., Belisle, M. Neuraminidase in cultured fibroblasts and leucocytes of homozygotes and heterozygotes for the mucolipidosis II gene (I-cell disease). Am. J. Med. Genet. 4: 191-200, 1979
(40) Wright, C. E., Miller, A. L., Shows, T. B. Complementation analysis of the mucolipidoses demonstrates genetic heterogeneity. Am. J. Hum. Genet. 31: 66A, 1979
(41) Cippoloni C et al: Neonatal mucolipidosis II (I-cell disease) clinical, radiological and biochemical studies in a case. Helv Paediatr Acta 35:85-95, 1980
(42) d'Azzo, A., Konings, A., Verkerk, A., Jongkind, J. F., Galjaard, H. Fusion with enucleated fibroblasts corrects 'I-cell' defect. Exp. Cell Res. 127: 484-488, 1980
(43) d'Azzo, A., Halley, D. J. J., Hoogeveen, A., Galjaard, H. Correction of I-cell defect by hybridization with lysosomal enzyme deficient human fibroblasts. Am. J. Hum. Genet. 32: 519-528, 1980
(44) Honey, N. K., Mueller, O. T., Miller, A. L., Shows, T. B. Genetic heterogeneity within pseudo-Hurler polydystrophy. Am. J. Hum. Genet. 33: 146A, 1981
(45) Honey, N. K., Miller, A. L., Shows, T. B. The mucolipidoses: identification by abnormal electrophoretic patterns of lysosomal hydrolases. Am. J. Med. Genet. 9: 239-253, 1981
(46) Varki, A., Reitman, M. L., Kornfeld, S. The enzymatic defect in I-cell disease (ML II) and pseudo-Hurler polydystrophy (ML III). Clin. Res. 29: 514A, 1981
(47) Michels, V. V., Dutton, R. V., Caskey, C. T. Mucolipidosis II: unusual presentation with a congenital angulated fracture. Clin. Genet. 21: 225-227, 1982
(48) Shows, T. B. Personal Communication. 1983. Buffalo, N. Y. 44. Shows, T. B., Mueller, O. T., Honey, N. K., Wright, C. E., Miller, A. L. Genetic heterogeneity of I-cell disease is demonstrated by complementation of lysosomal enzyme processing mutants. Am. J. Med. Genet. 12: 343-353, 1982
(49) Sly WS, Fischer HD: The phosphomannosyl recognition systems for intracellular and intercellular transport of lysosomal enzymes. J Cell. Biochem 18: 67-85, 1982
(50) Thomas, G. H., Miller, C. S., Toomey, K. E., Reynolds, L. W., Reitman, M. L., Varki, A., Vannier, A., Rosenbaum, K. N., Bias, W. B., Schofield, B. H. Two clonal cell populations (mosaicism) in a 46,XY male with mucolipidosis II (I-cell disease)--an autosomal recessive disorder. Am. J. Hum. Genet. 34: 611-622, 1982
(51) Varki, A., Reitman, M. L., Vannier, A., Kornfeld, S., Grubb, J. H., Sly, W. S. Demonstration of the heterozygous state for I-cell disease and pseudo-Hurler polydystrophy by assay of N-acetylglucosaminylphosphotransferase in white blood cells and fibroblasts. Am. J. Hum. Genet. 34: 717-729, 1982
(52) Vidgoff J et al. Localization of the gene for I-cell disease (mucolipidosis II). Am J Hum Genet 34: 64A, 1982
(53) Gabel, C. A., Goldberg, D. E., Kornfeld, S. Identification and characterization of cells deficient in the mannose 6-phosphate receptor: evidence for an alternate pathway for lysosomal enzyme targeting. Proc. Nat. Acad. Sci. 80: 775-779, 1983
(54) Mueller, O. T., Honey, N. K., Little, L. E., Miller, A. L., Shows, T. B. Mucolipidosis II and III: the genetic relationships between two disorders of lysosomal enzyme biosynthesis. J. Clin. Invest. 72: 1016-1023, 1983
(55) Okada, S., Kato, T., Oshima, T., Yutaka, T., Yabuuchi, H. Heterogeneity in mucolipidosis II (I-cell disease). Clin. Genet. 23: 155-159, 1983
(56) Whelan, D. T., Chang, P. L., Cockshott, P. W. Mucolipidosis II: the clinical, radiological and biochemical features in three cases. Clin. Genet. 24: 90-96, 1983
(57) Carta F et al.: Metab Ped Syst Ophthal 8: 21-25, 1984
(58) Okada, S., Owada, M., Sakiyama, T., Yutaka, T., Ogawa, M. I-cell disease: clinical studies of 21 Japanese cases. Clin. Genet. 28: 207-215, 1985
(59) Bavkock DS et al.: Fetal mucolipidosis II (I-cell disease): radiologic and pathologic correlation. Pediatr Radiol 16: 32-39, 1986
(60) Carrol JE et al.: Pediatr Neurol 2: 67-71, 1986
(61) Kornfeld S: Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest 77: 1-6, 1986
(62) Mogle P et al.: Eur J Pediatr 145: 226-227, 1986
(63) Ben-Yoseph, Y., Potier, M., Mitchell, D. A., Pack, B. A., Melancon, S. B., Nadler, H. L. Altered molecular size of N-acetylglucosamine 1-phosphotransferase in I-cell disease and pseudo-Hurler polydystrophy. Biochem. J. 248: 697-701, 1987
(64) Herzog, V., Neumuller, W., Holzmann, B. Thyroglobulin, the major and obligatory exportable protein of thyroid follicle cells, carries the lysosomal recognition marker mannose-6-phosphate. EMBO J. 6: 555-560, 1987
(65) Mueller, O. T., Wasmuth, J. J., Murray, J. C., Lozzio, C. B., Lovrien, E. W., Shows, T. B. Chromosomal assignment of N-acetylglucosaminylphosphotransferase, the lysosomal hydrolase targeting enzyme deficient in mucolipidosis II and III. Cytogenet. Cell Genet. 46: 664, 1987
(66) Yamada H et al: Craniosynostosis and hydrocephalus in I-cell disease (mucolipidosis II). Childs Nerv Syst 3:55-57, 1987
(67) Ben-Yoseph, Y., Mitchell, D. A., Nadler, H. L. First trimester prenatal evaluation for I-cell disease by N-acetyl-glucosamine 1-phosphotransferase assay. Clin. Genet. 33: 38-43, 1988
(68) Poenaru L et al.: Eur J Pediatr 147: 321-327, 1988
(69) Sakaguchi T et al.: Acta Paediatr Scand 77: 608-609, 1988
(70) Goodman ML et al.: Pediatr Neurosci 14: 315-318, 1989
(71) Pazzaglia UE et al.: Eur J Pediatr 148: 553-557, 1989
(72) Pazzaglia UE et al.: Mucolipidosis II: correlation between radiological features and histopathology of the bones. Pediatr Radiol 19: 406-413, 1989
(73) Pazzaglia UE et al: Neonatal mucolipidosis 2. The spontaneous evolution of early bone lesions and the effect of vitamin D treatment. Report of two cases. Pediatr Radiol 20:80-84, 1989
(74) Besley GTN et al: Prenatal diagnosis of mucolipidosis II by early amniocentesis. Lancet 1:1164-1165, 1990
(75) Poenaru L et al: Prenatal diagnosis of mucolipidosis II on first-trimester amniotic fluid. Prenat Diagn 10:231-235, 1990
(76) De Braekeleer, M. Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). Hum. Hered. 41: 141-146, 1991
(77) Ichiyama T et al: Hearing impairment in two boys with I-cell disease. Brain Dev 13:363-365, 1991
(78) Kozlowski K et al: Mild I-cell disease, or severe pseudo-Hurler polydystrophy in three siblings: Further evidence for intermediate forms of mucolipidosis II and III. Radiological features. Radiol Med (Torino) 82:847-851, 1991
(79) Pazzaglia UE et al: Bone changes of mucolipidosis II at different ages: Postmortem study of three cases. Clin Orthop 276:283-290, 1992
(80) Beck, M., Barone, R., Hoffmann, R., Kratzer, W., Rakowsky, T., Nigro, F., Fiumara, A. Inter- and intrafamilial variability in mucolipidosis II (I-cell disease). Clin. Genet. 47: 191-199, 1995
(81) Komfeld S, Sly WS: I-Cell disease and pseudo-Hurler polydystrophy: Disorders of Iysosomal enzyme phosphorylation and localization. In: The Metabolic Basis of Inherited Disease, 7th ed, Scriver CR et al (eds), McGraw-Hill, New York, pp 2495-2508, 1995
(82) Bosshard, N. U., Hubler, M., Arnold, S., Briner, J., Spycher, M. A., Sommerlade, H.-J., von Figura, K., Gitzelmann, R. Spontaneous mucolipidosis in a cat: an animal model of human I-cell disease. Vet. Path. 33: 1-13, 1996
(83) Herman TE, McAlister WH: Neonatal mucolipidosis (I-cell disease) with dysharmonic epiphyseal ossification and butterfly vertebral body. J Perinatol 16:400-402, 1996
(84) Hubler, M., Haskins, M. E., Arnold, S., Kaser-Hotz, B., Bosshard, N. U., Briner, J., Spycher, M. A., Gitzelmann, R., Sommerlade, H. -J., von Figura, K. Mucolipidosis type II in a domestic shorthair cat. J. Small Anim. Pract. 37: 435-441, 1
(85) Mueller OT et al: Chromosomal assignment of N-acetylglucosaminyl phosphotransferase, the Iysosomal hydrolase targeting enzyme deficient in mucolipidosis II and III. Cytogenet Cell Genet 46:664, 1996
(86) Canfield, W. M., Bao, M., Pan, J., Brewer, A. D. K., Pan, H., Roe, B., Raas-Rothschild, A. Mucolipidosis II and mucolipidosis IIIA are caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene on chromosome 12p. Am. J. Hum. Genet. 63: A15-only, 1998
(87) Wilcox, W. R., Lucas, B. C., Loebel, B., Bachman, R. P., Lachman, R. S., Rimoin, D. L. Pacman dysplasia: report of two affected sibs. Am. J. Med. Genet. 77: 272-276, 1998
(88) Olkkonen VM, Ikonen E: Genetic defects of intracellular-membrane transport. New Eng. J. Med. 343: 1095-1104, 2000
(89) Mazrier, H.; Van Hoeven, M.; Wang, P.; Knox, V. W.; Aguirre, G. D.; Holt, E.; Wiemelt, S. P.; Sleeper, M. M.; Hubler, M.; Haskins, M. E.; Giger, U. : Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease. J. Hered. 94: 363-373, 2003
(90) Miller, S. F., Proud, V. K., Werner, A. L., Field, F. M., Wilcox, W. F., Lachman, R. S., Rimoin, D. L. Pacman dysplasia: a lethal skeletal dysplasia with variable radiographic features. Pediat. Radiol. 33: 256-260, 2003
(91) Paik, K. H.; Song, S. M.; Ki, C. S.; Yu, H.-W.; Kim, J. S.; Min, K. H.; Chang, S. H.; Yoo, E. J.; Lee, I. J.; Kwan, E. K.; Han, S. J.; Jin, D.-K. : Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II or type IIIA. Hum. Mutat. 26: 308-314, 2005
(92) Saul, R. A.; Proud, V.; Taylor, H. A.; Leroy, J. G.; Spranger, J. : Prenatal mucolipidosis type II (I-cell disease) can present as Pacman dysplasia. Am J Med Genet 135A: 328-332, 2005
(93) Tiede, S.; Storch, S.; Lubke, T.; Henrissat, B.; Bargal, R.; Raas-Rothschild, A.; Braulke, T. : Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nature Med. 11: 1109-1112, 2005
(94) Wilcox, W. R.; Lachman, R. S.; Rimoin, D. L.; Wenger, D. A. : Distinguishing Pacman dysplasia from mucolipidosis II: comment on Saul et al. . Am J Med Genet 135A: 333 only, 2005
(95) Bargal, R.; Zeigler, M.; Abu-Libdeh, B.; Zuri, V.; Mandel, H.; Neriah, Z. B.; Stewart, F.; Elcioglu, N.; Hindi, T.; Le Merrer, M.; Bach, G.; Raas-Rothschild, A. : When mucolipidosis III meets mucolipidosis II: GNPTA gene mutations in 24 patients. Molec. Genet. Metab. 88: 359-363, 2006
(96) Cathey, S. S.; Kudo, M.; Tiede, S.; Raas-Rothschild, A.; Braulke, T.; Beck, M.; Taylor, H. A.; Canfield, W. M.; Leroy, J. G.; Neufeld, E. F.; McKusick, V. A. : Molecular order of mucolipidosis II and III nomenclature. (Letter) Am. J. Med. Genet. 146A: 512-513, 2008
(97) Plante, M.; Claveau, S.; Lepage, P.; Lavoie, E.-M.; Brunet, S.; Roquis, D.; Morin, C.; Vezina, H.; Laprise, C. : Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population. Clin. Genet. 73: 236-244, 2008
(98) Encarnacao, M., Lacerda, L., Costa, R., Prata, M. J., Coutinho, M. F., Ribeiro, H., Lopes, L., Pineda, M., Ignatius, J., Galvez, H., Mustonen, A., Vieira, P., Lima, M. R., Alves, S. Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations. Clin. Genet. 76: 76-84, 2009
(99) Otomo, T., Muramatsu, T., Yorifuji, T., Okuyama, T., Nakabayashi, H., Fukao, T., Ohura, T., Yoshino, M., Tanaka, A., Okamoto, N., Inui, K., Ozono, K., Sakai, N. Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation. J. Hum. Genet. 54: 145-151, 2009
(100) Coutinho, M. F., Encarnacao, M., Gomes, R., da Silva Santos, L., Martins, S., Sirois-Gagnon, D., Bargal, R., Filocamo, M., Raas-Rothschild, A., Tappino, B., Laprise, C., Cury, G. K., Schwartz, I. V., Artigalas, O., Prata, M. J., Alves, S. Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity. Clin. Genet. 80: 273-280, 2011