疾患詳細

疾患詳細



粗な顔貌, 溝のある眉間, 幅広い低い鼻陵, 軽度の両眼隔離, 内眼角贅皮, 垂れ下がった顔の皮膚, 分厚い口唇; 分厚い頭蓋骨 (Gorlin ら 1990 より引用)

#208400
Aspartylglucosaminuria (AGU)
(Glycosylasparaginase deficiency)
(Aspartylglucosaminase deficiency)
(AGA deficiency)
(Glycoasparaginase)
(Aspartylglycosaminuria)
(Aspartylglycosaminase; AGA, included)

アスパルチルグルコサミン尿 (AGU)
(グリコシルアスパラギナーゼ欠損症)
(アスパルチルグクコサミナーゼ欠損症)
(AGA 欠損症)
(アスパルチルグリコサミン尿)
指定難病19 ライソゾーム病
小児慢性特定疾病 代83 アスパルチルグルコサミン尿症

責任遺伝子:613228 Aaspartylglucosaminidase (AGA) <4q32-q33>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Abnormality of amino acid metabolism (アミノ酸代謝異常) [HP:0004337] [2035]
 Aspartylglucosaminuria (アスパルチルグルコサミン尿) [HP:0012068] [2098]
 Delayed speech and language development (言語発達遅滞) [HP:0000750] [01201]
 Dyskinesia (ジスキネジア) [HP:0100660] [02605]
 Gingival overgrowth (歯肉過成長) [HP:0000212] [0808]
 Hypertelorism (両眼開離) [HP:0000316] [06607]
 Intellectual disability (知的障害) [HP:0001249] [0120]
 Large face (大きな顔) [HP:0100729] [0436]
 Mandibular prognathia (下顎突出) [HP:0000303] [0541]
 Microtia (小耳) [HP:0008551] [090111]
 Neurological speech impairment (神経学的発語障害) [HP:0002167] [023]
 Scoliosis (側弯) [HP:0002650] [161502]
 Short nose (短鼻) [HP:0003196] [0705]
 Thick vermilion border (分厚い口唇唇紅部) [HP:0012471] [0552]
 Umbilical hernia (臍ヘルニア) [HP:0001537] [1201]
 Wide nasal bridge (幅広い鼻梁) [HP:0000431] [0703]
 
 <30%-79%>
 Abnormal cortical bone morphology (骨皮質形態異常) [HP:0003103] [1600]
 Abnormality of the ulna (尺骨異常) [HP:0002997] [1607]
 Anterior beaking of lumbar vertebrae (前方くちばし状腰椎) [HP:0008430] [161505]
 Carious teeth (齲歯) [HP:0000670] [08314]
 Coarse facial features (粗な顔貌) [HP:0000280] [0408]
 Macroglossia (巨舌) [HP:0000158] [08109]
 Macroorchidism (巨大睾丸) [HP:0000053] [14021]
 Pectus carinatum (鳩胸) [HP:0000768] [1105]
 Thickened calvaria (頭蓋冠肥厚) [HP:0002684] [160113]
 
 <5%-29%>
 Arthritis (関節炎) [HP:0001369] [15115]
 Chronic otitis media (慢性中耳炎) [HP:0000389] [014231]
 Delayed skeletal maturation (骨成熟遅滞) [HP:0002750] [160001]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Inguinal hernia (鼠径ヘルニア) [HP:0000023] [1201]
 Joint stiffness (関節硬直) [HP:0001387] [15100]
 Malabsorption (吸収障害) [HP:0002024] [18045]
 Pes planus (扁平足) [HP:0001763] [15601]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Seizures (けいれん) [HP:0001250] [01405]
 Sleep disturbance (睡眠障害) [HP:0002360] [0152]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Vascular skin abnormality (皮膚血管異常) [HP:0011276] [-]
 
 
 Abnormality of metabolism/homeostasis (代謝-ホメオスターシス異常) [HP:0001939]
 Acne (ニキビ) [HP:0001061] [18000]
 Angiokeratoma corporis diffusum (びまん性体部被角血管腫) [HP:0001071] [2302]
 Anteverted nares (上向きの鼻孔) [HP:0000463] [0740]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Beaking of vertebral bodies (くちばし状脊椎骨) [HP:0004568] [161505]
 Brachycephaly (短頭) [HP:0000248] [03004]
 Broad face (幅広い顔) [HP:0000283] [0407]
 Cataract (白内障) [HP:0000518] [0640]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Decreased prothrombin time (プロトロンビン時間短縮) [HP:0032198] [22071]
 Depressed nasal bridge (低い鼻梁) [HP:0005280] [0722]
 Developmental regression (発達退行) [HP:0002376] [0125]
 Diarrhea (下痢) [HP:0002014] [01806]
 Dysostosis multiplex (多発性異骨症) [HP:0000943] [-]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Hernia (ヘルニア) [HP:0100790] [120]
 Hoarse voice (粗い声) [HP:0001609] [02370]
 Hypoplastic frontal sinuses (前頭洞低形成) [HP:0002738] [0525]
 Joint laxity (関節弛緩) [HP:0001388] [15102]
 Kyphosis (後弯) [HP:0002808] [161500]
 Microcephaly (小頭) [HP:0000252] [03013]
 Mitral regurgitation (僧帽弁弁逆流) [HP:0001653] [1120]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Neutropenia (好中球減少) [HP:0001875] [22102]
 Pathologic fracture (病的骨折) [HP:0002756] [160017]
 Platyspondyly (扁平脊椎) [HP:0000926] [161505]
 Short stature (低身長) [HP:0004322] [0130]
 Spasticity (痙縮) [HP:0001257] [0241]
 Spondylolisthesis (脊椎辷り症) [HP:0003302] [161507]
 Spondylolysis (脊椎分離症) [HP:0003304] [161507]
 Thick lower lip vermilion (厚い下口唇唇紅部) [HP:0000179] [05522]
 Vacuolated lymphocytes (空胞性リンパ球) [HP:0001922] [2212]
 Wide mouth (幅広い口) [HP:0000154] [0802]

(UR-DBMS)
【一般】知能悪化 (小児期)
 精神遅滞 (6-8 歳までに)
 発達遅滞, 言語遅滞
 低身長
 反復性呼吸器感染症
 腹部膨満
 肝腫, 脾腫
 ミオクローヌスけいれん (成人)
 下痢
【神経】嗄声
 不器用
 行動変化
 周期性多動
 情緒不安定
 筋緊張低下
 痙縮
【頭】短頭
 非対称性の頭蓋骨
 小頭
【顔】粗い顔貌 (学童), 幅広い顔
 分厚い口唇
 分厚い垂れ下がった頬部
 前頭洞未発達
【眼】白内障 (結晶様水晶体混濁)
 両眼開離
 斜視
 内眼角贅皮
【鼻】幅広い鼻梁
 低い鼻梁
 上向きの鼻孔
【口】幅広い口
 咽頭扁桃拡大 (小児期)
 巨舌
【頸部】短頸
【心】心筋症, MI
【体幹】臍 / 鼠径ヘルニア
【性器】巨大精巣
【四肢】関節弛緩
【X線】分厚い頭蓋骨
 J 型 トルコ鞍
 側弯
 後弯
 扁平脊椎
 軽度の多発性異骨症
 幅広い'形成不全の' (管形成不全の) 中手骨
 薄い骨端
 特異な形の手根骨
 骨成熟遅延
 椎体骨平坦化および前方くちばし
 脊椎分離症
 脊椎すべり症
 病的骨折
 大脳萎縮
【皮膚】毛細血管拡張
 びまん性躯幹被角血管腫
 面皰
【検査】*アスパルチルグルコサミン尿 (2-acetamido-1-beta-L-aspartamido-1,2-dideoxy-beta-D-glucose)
 ムコ多糖尿 / オリゴ糖尿
 リソソーム aspartylglucosaminidase (リンパ球, 血漿, 皮膚線維芽細胞, 羊水細胞, 絨毛膜繊毛)
【血液学】リンパ球空胞化 (5-10%)
 好中球減少
 プロトロンビン時間減少
【その他】フィンランド人に多い
 フィンランド人症例の98%は1つの変異による
 フィンランドでの保因者頻度は1/40
 2-6歳で発症

(要約)
●Aspartylglucosaminuria (AGU) (aspartylglycosaminuria)は, まれな常染色体劣性のリソソーム蓄積症である
 →N-aspartyl-beta-glucosaminidase (aspartylglucosaminidase) 活性欠乏が原因である
  正常ではリソソームでオリゴ糖を分解する
 欠乏では, オリゴ糖が蓄積する
 AGU は7つの糖タンパク蓄積症の1つである ((Mucolipidosis II; I-cell disease); Mucolipidosis III (pseudo-Hurler polydystrophy); Aspartylglucosaminuria; Fucosidosis; Mannosidosis; Sialidosis (mucolipidosis I); galactosialidosis)
●診断
 症状は, 精神運動発達遅滞, 粗な顔貌, 肝脾腫, 腹部ヘルニア, 骨格異常である
 フィンランド人遺伝病の1つである
 aspartylglucosamine 尿とaspartylglucosaminidase 活性低下 (血液, 皮膚) の証明
●疫学
 フィンランド:1/17,000 人
 3番目に多いMCA/MR 症候群である (1. Down 症候群, 2. 脆弱X症候群)
●寿命
 乳児期には正常発達である
 2-4歳ころ, 発達遅滞のサインを示し始めるが, 発達はまだ進行する
 初発症状は, 不器用+/-言語遅滞かもしれない
 上気道感染が増える
 発達は思春期ころまで続くが, 13-16歳の患者は5-6歳レベルの精神遅滞と運動発達遅滞を示す
 →進行性で25-28歳まで低下が続き, 急速な障害が始まり重度の精神遅滞となる
●治療
 けいれんへの対処

<小児慢性特定疾病 代83 アスパルチルグルコサミン尿症>
概要・定義
1. 概要・定義
アルパルチルグルコサミニダーゼ欠損により生じる常染色体劣性遺伝病である。この酵素は, オリゴ糖や糖蛋白質のN-アセチルグルコサミンおよびアスパラギン間の結合を切断する働きを持つ。本酵素の活性低下により, 当該領域が分解されないオリゴ糖や糖蛋白質がリソソームに蓄積することになり, 患者は, 易感染や精神発達遅延, 粗な顔貌および骨異常などの症状を示す。
症状
2―4歳頃から始まる精神運動発達遅延, てんかん発作, 呼吸器感染症等の易感染性などを呈する。顔貌異常, 頭蓋冠肥厚, 骨粗鬆症の所見などが特徴である。
診断
臨床症状から疑った場合, リンパ球の空胞形成, 尿中のアスパルチルグルコサミンの検出が重要である。確定診断は末梢血白血球, 培養皮膚線維芽細胞のアスパルチルグルコサミニダーゼの測定もしくはアスパルチルグルコサミニダーゼの遺伝子検査で可能である。
診断方法
臨床所見, 生化学分析, および遺伝子解析に基づいて行う。
1. 臨床症状;2—4歳頃から始まる精神運動発達遅延, てんかん発作, 呼吸器感染症等の易感染性などを呈する。顔貌異常, 頭蓋冠肥厚, 骨粗鬆症の所見
2. 臨床検査;リンパ球の空胞形成, 尿中のアスパルチルグルコサミンの検出
確定診断;末梢血白血球, 培養皮膚線維芽細胞のアスパルチルグルコサミニダーゼの測定, アスパルチルグルコサミニダーゼの遺伝子検査
当該事業における対象基準
全A  疾患名に該当する場合
治療
症状に対する支持療法が中心となる。造血幹細胞移植の報告が海外である。
成人期以降
支持療法が中心であり, 進行したあとは経管栄養, 気管切開, 人工呼吸器の適応について検討を要する

(オリジナル) Jenner and Pillot (1967)
(頻度) > 200 例 (特にフィンランド)
(鑑別診断) MPS, mucolipidosis
(責任遺伝子) *613228 Aaspartylglucosaminidase (AGA) <4q34.3>
.0001 Aspartylglucosaminuria, Finnish type (208400) [AGA, CYS163SER] (dbSNP:rs121964904) (ExAC:rs121964904) (RCV000000243...) (Ikonen et al. 1991; Fisher et al. 1991; Mononen et al. 1991; Fisher andAronson 1991; Isoniemi et al., 1995)
.0002 Aspartylglucosaminuria [AGA, GLY302ARG] (dbSNP:rs121964905) (RCV000000244) (Ikonen et al. 1991)
.0003 Aspartylglucosaminuria [AGA, CYS306ARG] (dbSNP:rs121964906) (RCV000000245) (Ikonen et al. 1991)
.0004 Aspartylglucosaminuria [AGA, GLY60ASP] (dbSNP:rs121964907) (RCV000000246) (Ikonen et al. 1991)
.0005 Aspartylglucosaminuria [AGA, ALA101VAL] (dbSNP:rs121964908) (RCV000000247) (Ikonen et al. 1991)
.0006 Aspartylglucosaminuria [AGA, 7-BP DEL, NT102-108DEL, FS34TER] (dbSNP:rs386833417) (RCV000000248) (Ikonen et al. 1991)
.0007 Aspartylglucosaminuria [AGA, 1-BP INS, 800T [dbSNP:rs386833436] (RCV000000250) (Ikonen et al. 1991)
.0008 Aspartylglucosaminuria [AGA, 6-BP INS, NT127 [dbSNP:rs386833418] (RCV000000250) (Ikonen et al. 1991)
.0009 Aspartylglucosaminuria [AGA, IVS8DS, G-T, +1] (RCV000000251) (Ikonen et al.1991)
.0010 Aspartylglucosaminuria [AGA, 1-BP DEL, 800T] (dbSNP:rs794728009) (RCV000000252) (Ikonen et al. 1991)
.0011 MOVED TO 613228.0009
.0012 Aspartylglucosaminuria [AGA, SER72PRO [dbSNP:rs121964909] (RCV000000253) (Peltola et al. 1996)

*AGA: aspartylglucosaminidase; (346 aa)
・asparagine 連結性糖タンパクのペプチドにオリゴ糖を参加させる GlcNAc-Asn 結合を分割する

(ノート)
A number sign (#) is used with this entry because aspartylglucosaminuria (AGU) is caused by homozygous or compound heterozygous mutation in the AGA gene (613228) on chromosome 4q34.

●アスパルチルグルコサミン尿は,中枢神経を含み,骨格異常や結合織病変を生じる重度の常染色体劣性リソソーム蓄積症である
 最も特徴的症状は,進行性精神遅滞である
 本疾患はリソソーム酵素である glycosylasparaginase 活性の欠乏が原因である
 → glycoasparagines のシリーズ (還元端での aspartylglucosamine moiety との糖抱合) の体液および組織への蓄積を生じる
 アスパルチルグルコサミン尿は,フィンランド人疾患胃酸とよばれる疾患群に属する (Mononen et al., 1993 and Arvio and Arvio, 2002)

Clinical Features
Aspartylglucosaminuria was first reported by Jenner and Pollitt (1967) and Pollitt et al. (1968), who found urinary excretion of abnormal amounts of 2-acetamido-1-(beta-L-aspartamido)-1,2-dideoxyglucose in a 32-year-old female and her 20-year-old brother with mental retardation. An enzyme responsible for hydrolyzing this compound is normally present in seminal fluid but was absent in that of the brother. A generalized lack of this enzyme was postulated. Both sibs had thick sagging skin of the cheeks, a finding not present in normal members of the family.

Palo and Mattsson (1970) reported 11 cases in Finland. The parents of 1 patient were first cousins. The Finnish cases showed, in addition to severe mental retardation, sagging cheeks, broad nose and face, short neck, cranial asymmetry, scoliosis, periodic hyperactivity, and vacuolated lymphocytes. Diarrhea and frequent infections were problems in infancy. Aspartylglucosaminuria has also been observed in Finns living in Norway (Borud and Torp, 1976).

Gehler et al. (1981) described affected brother and sister in a consanguineous Italian sibship; one of the patients showed angiokeratoma corporis diffusum. Yoshida et al. (1991) and Vargas-Diez et al. (2002) also described the occurrence of angiokeratoma corporis diffusum in 2 Japanese patients and 1 Spanish patient, respectively, with aspartylglucosaminuria.

Stevenson et al. (1982) reported this disorder in an 18-year-old American. The family name was Scottish-Irish. The mother was said to have been aged 13 years and the father was unknown--circumstances suggesting incest. Mental retardation, recurrent infections, cardiomyopathy, and emotional lability were features.

Hreidarsson et al. (1983) reported a case in an American black and an American white of uncertain parentage. Radiographic changes in the hands were noted: thin epiphyses, broad 'poorly modeled' (undertubulated) metacarpals, and peculiarly shaped carpal bones.

Isenberg and Sharp (1975) reported the case of a girl of Mexican-Italian extraction living in the U.S.

Musumeci et al. (1984) reported a child with both enzymopathic methemoglobinemia (250800) and AGU. Since the structural genes for the enzymes deficient in these 2 disorders are on separate chromosomes, a single mutation such as a small deletion is not likely to be the basis. Furthermore, a sib had only AGU. The parents were consanguineous.

Chitayat et al. (1988) described 3 Puerto Rican brothers, with first-cousin parents, who had AGU. Two of the brothers were monozygotic twins. Macroorchidism became evident in all 3 boys at the time of puberty. This feature had not previously been noted in AGU, although other endocrinologic abnormalities had been described.

Yoshida et al. (1991) described the first Japanese patients with AGU--a brother and sister, aged 45 and 41, respectively. Both sibs had mental retardation, coarse facial features, angiokeratoma, and myoclonic seizures.

Zlotogora et al. (1997) diagnosed this disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem.

Gordon et al. (1998) described a Canadian family in which 4 of 12 sibs were affected, 2 brothers and 2 sisters. Though apparently normal at birth, their developmental milestones, particularly speech, were slow, and they acquired only a simple vocabulary. There was a progressive coarsening of facial features; 3 had inguinal hernia and recurrent diarrhea; all became severely retarded and by the fourth decade showed evident deterioration of both cognitive and motor skills; and 2 exhibited cyclic behavioral changes. Three of the sibs had died, at 33, 39, and 44 years of age.

Arvio et al. (1999) studied 66 Finnish patients with AGU for changes in the oral mucosa and 44 of those for changes in facial skin. Nine patients had facial angiofibromas. Edema of the buccal mucosa and gingival overgrowths were more frequent in AGU patients than in controls (P less than 0.001). Of 16 oral mucosal lesions studied histologically, 15 represented fibroepithelial or epithelial hyperplasias. Cytoplasmic vacuolization was evident in only 4. Expression of AGA in mucosal lesions of AGU patients did not differ from that seen in corresponding lesions of normal subjects.

Diagnosis
Mononen et al. (1994) described a fluorometric glycosylasparaginase assay for neonatal screening for AGU.

Zlotogora et al. (1997) stated that the clinical diagnosis of AGU is difficult, in particular early in the course of the disease; most of the patients are diagnosed after the age of 5 years. They noted that since patients with AGU excrete large amounts of aspartylglucosamine in urine, biochemical detection is easy by urine chromatography.

Clinical Management
Arvio et al. (2001) described the state of health, intellectual skills, and dysmorphic features of 19 young patients with aspartylglucosaminuria. Of the 19, 5 had undergone a successful bone marrow transplantation between 1991 and 1997. The first 2 patients who received transplants were, after 7 and 5 years' follow-up, more severely mentally retarded than the nontransplanted patients. The general health of the latter group was quite good, whereas the 5 patients who underwent bone marrow transplantation had posttransplant complications. Arvio et al. (2001) concluded that bone marrow transplantation should not be encouraged for the treatment of patients with aspartylglucosaminuria after infancy.

Mapping
In 12 AGU families with 15 affected persons and 50 carriers (determined by reduced activity of enzyme in lymphocytes), Gron et al. (1989, 1990) studied linkage to chromosome 4 markers and concluded that the locus is distal to MNS (111300). They suggested the order cen--ADH--EGF--FG--MNS--AGU.

Population Genetics
Aspartylglucosaminuria occurs worldwide, but is enriched in the Finnish population (Arvio and Arvio, 2002).

Palo and Mattsson (1970) estimated that there are at least 130 cases in the total population of 4.5 million in Finland.

Autio (1980) estimated the frequency at 1 in 26,000 in Finland. A total of 128 cases in 97 families had been identified.

Mononen et al. (1991) found a frequency of 1 in 3,643 in a study of children in eastern Finland. This frequency is consistent with a carrier rate of 1 in 30 and indicates that this disorder, after trisomy 21 and the fragile X syndrome, is the most common genetic cause of mental retardation.

Molecular Genetics
In Finnish patients with aspartylglucosaminuria, Ikonen et al. (1991) and Fisher and Aronson (1991) independently identified homozygosity for a cys163-to-ser (C163S; 613228.0001) mutation in the AGA gene. The C163S mutation is responsible for 98% of the cases of AGU in Finland (Isoniemi et al., 1995).

Ikonen et al. (1991) described the spectrum of 10 AGU mutations found in 12 unrelated patients of non-Finnish origin. Since 11 of the 12 were homozygotes, consanguinity appears to be a common denominator in most AGU families, although consanguinity could be confirmed in only 2 of the families. Screening for the unknown gene defects was done using single-strand conformation polymorphism (SSCP) analysis. The mutations were distributed over the entire coding region of the AGU cDNA, except in the carboxyl-terminal 17-kD subunit in which they were clustered within a 46-amino acid region. Based on the character of the mutations, Ikonen et al. (1991) concluded that most of the mutations probably affected the folding and stability of the molecule and did not directly affect the active site of the enzyme. There were 3 non-Finnish patients who had the 'Finnish' cys163-to-ser mutation (613228.0001) but 2 of them were Norwegian and 1 was Swedish. These patients presumably had Finnish ancestry (Borud and Torp, 1976).

Tollersrud et al. (1994) reported on 9 patients from 7 families identified in northern Norway. All were homozygous for the Finnish C163S founder mutation. Genealogic investigation of 9 parents proved Finnish ancestry in all pedigrees. These Finnish immigrants originated in the main from the Tornio valley in northern Finland in a continuous immigration movement from 1700 to 1900.

Ikonen and Peltonen (1992) reviewed a total of 11 AGA mutations causing AGU published to that time.

Animal Model
Through targeted disruption of the mouse Aga gene in embryonic stem cells, Kaartinen et al. (1996) generated mice that completely lack Aga activity. At the age of 5 to 10 months, a massive accumulation of aspartylglucosamine was detected in Aga-null mice along with lysosomal vacuolization, axonal swelling in the gracile nucleus, and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but was most likely related to the impaired function of the nervous system. The findings were considered consistent with the pathogenesis of AGU and provided further data explaining the impaired neurologic function in AGU patients.

Gonzalez-Gomez et al. (1998) reported that after the age of 10 months the general condition of the null mutant mice created by Kaartinen et al. (1996) gradually deteriorated. They suffered from progressive motor impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. The oldest animals (20 months old) displayed neuronal loss and gliosis, particularly in the regions where the most severe neuronal vacuolation was found. The severe ataxic gait of the older mice was probably due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. The mice thus appeared to be a suitable animal model for testing therapeutic strategies in AGU.

(ノート2)
●アスパルチルグルコサミン尿は, いろんな組織や体液に糖タンパク由来のアスパルチルグルコサミンが蓄積するオリゴ糖蓄積症で, Jenner and Pollit (1967)により英国で最初に記載された
 証明された患者の大多数はフィンランド人である (Aula P et al 1986, Autio 1972, Autio S et al 1973)
 フィンランドでのアスパルチルグルコサミン尿は, 他の多くの集団でフェニールケトン尿症に相当する
 頻度はフィンランドでは 1/26, 000 と推定される (Autti T et al 1997)
 →しかし, 少なくとも 1/18, 500 と再計算された (Arvio M et al 1993)
 Mononen et al (1991) は, 東部フィンランド小児の研究で 1/3643 を発見した
● アスパルチルグルコサミン尿 は, ノルウェーに住むフィンランド人でもみられる (Tollersrud OK et al 1994)
●少数の症例が他の人種で報告されている
 →プエルトリコ (Chitayat D et al 1988), イタリア (Gehler J et al 1981), オランダ (Engelen J et al 1992), モーリタニア (Park H et al 1996), パレスチナ (Zlotogora J et al 1997), その他

●遺伝は常染色体劣性である
●基盤となる障害は, aspartylglucosaminidase (1-aspartamido-alpha-N-acetylglucosaminine amidohydrolase) 欠乏である
 ヘテロ接合体が証明されうる (Hietala M et al 1993, Mononen T et al 1991)
 出生前診断が可能である (Aula P et al 1989)
●遺伝子は 4q32-q33 (Aula P et al 1984) に局在し, 13kb にスパンする9つのエクソンからなる
 疾患アレルの高率のホモ接合性がフィンランド人で示唆される
 109家系のアスパルチルグルコサミン尿患者115例では, 常に C163S と R161Q 変異が連関するわけではないが, これらは調べたアスパルチルグルコサミン尿の98%で発見された (Thomas GH, Beaudet AL 1995)
 さらに, 2つの変異は関連のない対照120例には発見されなかった
 フィンランド以外のアスパルチルグルコサミン尿は, 多くの多様な遺伝子変異の結果のようだ (Ikonen E et al 1991)
●マウスモデルが報告されている (Jalanko A et al 1998)
●乳児期と小児期は, 通常, 反復性下痢, 臍及び鼠径ヘルニア, 頻回の呼吸器および耳感染症が特徴であるが, 全てが6歳以後は減少する (Arvio M et al 1993)
 早期発症の脾腫が腹部膨満とともに出現する
 寿命は通常45歳以下である

顔貌
●患者間には著明な類似性がある
 頭蓋は非対称性であることが多い
 顔貌は小児期の間に次第に粗となる
 →鼻梁は幅広く低い
  鼻孔は上向きで, 口唇は厚い
  軽度の両眼隔離, 内眼角贅皮および結晶様水晶体混濁が約半数でみられる
  特に眼瞼や頬部の顏の皮膚が年齢とともに垂れ下がる傾向がある
  脂漏性および紅斑性顔面皮膚が思春期で始まる (Arvio P et al 1999)
  特に顏の痤瘡が数例でみられている (Thomas GH, Beaudet AL 1995)

骨格症状
●鼠径+/-より多くは臍ヘルニアが患者の1/3以上で3か月以前にみられている
 筋緊張低下が約20%に存在する
 外反膝が少なくとも75%でみられる
 外科治療が必要な内反足が報告されている
 長管骨, 中手骨, 指骨は薄い皮質をもつ
 脊椎すべり症や脊椎分離症が記載されている (Aula P et al 1986)
 後弯または側弯および腹部突出も頻回に報告されている
 乳児期の過大な成長と早期思春期成長スパートがある (Arvio P et al 1999)
 成長遅滞は15歳以後にのみみられる
 頭蓋冠は特徴的に肥厚し短頭である
 前頭および上顎洞は欠損または発達不全である
 脊椎の軽度の多発性異骨症がよくみられる
 尺骨はいくらか短い (Schmidt H et al 1988)

神経系
●10歳代でIQ 40 未満の進行性精神遅滞が一定した特徴である
 →通常は5歳あたりまで明らかではない
 言語は重度遅滞である
 約1/3の患者で, 声は成人でかすれ声となる
 周期的多動, 易刺激性+/-攻撃的反応が約50%の患者でみられる

●軽度〜中等度難聴が成人患者の約20%でみられる
 不器用な歩行と手協調運動不全が早期にみられる
 12例でのMR検査 (Autti T et al 1997) は, アスパルチルグルコサミン尿は主に灰白質疾患で, 髄鞘形成遅延により白質も障害することを示した

皮膚
●患者の約20%が顏の角化血管腫をもつ (Schmidt H et al 1988)

その他
●巨大精巣が記載されている (Aula P et al 1986)
●女性での無月経および乏月経および疎な顎髭と恥毛が知られている (Autio S 1976)

口腔症状
●歯間隔離がみられることが多い
 歯冠サイズと歯冠形は正常であるが, 歯列不正が多い
 81例の研究では, 異常に大きい舌がほぼ全例で報告された (Arvio P et al 1997)
 →前方解放咬合を生じる
 歯肉の線維性上皮過形成と口腔粘膜白皮症が多い (Autio 1972)
 診断は歯肉生検で行われている (Bonnaure-Mallet M et al 1997)

検査所見
●末梢血リンパ球の5-20%の空胞がが患者の75%でみられる
 約半数の患者が好中球減少とプロトロンビン時間の減少を示す
 確定診断は, 薄層クロマト, ペーパークロマト, 電気泳動で大量の尿アスパルチルグルコサミン所見による (Thomas GH, Beaudet AL 1995)
 最終診断は通常白血球または線維芽細胞での aspartyl-glucosaminidase 活性測定による
 培養羊水細胞または直接絨毛生検による出生前診断が行われている (Aula P et al 1989)

(文献)
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