疾患詳細

疾患詳細



(A, C) T1-weighted image showed cerebral atrophy predominantly in parieto-occipital region. (B) T2-weighted image showed high-intensity areas in posterior periventricular white matter and some high-intensity spots in the centrum semiovale. (Umehara F et al. Neurologic manifestations of Kanzaki disease. Neurology 62: 1604-1606, 2004)

#609242
Kanzaki disease
(Alpha-N-acetylgalactosaminidase deficiency, type II)
(Alpha-N-acetylgalactosaminidase deficiency, adult-onset)
(NAGA deficiency, type II)
(Schindler disease, type II)

神崎病
(Alpha-N-acetylgalactosaminidase 欠損症 II 型)
(Alpha-N-acetylgalactosaminidase 欠損症, 成人発症)
(NAGA 欠損症 II 型)
(Schindler 病 II 型)
指定難病19 ライソゾーム病

遺伝形式:常染色体劣性
責任遺伝子:104170 N- acetyl- alpha- D- galactosaminidase (NAGA) <22q11>

(症状)
(GARD)
 <80%-99%>
 Angiokeratoma corporis diffusum (びまん性体部被角血管腫) [HP:0001071] [2302]
 Hyperkeratosis (過角化症) [HP:0000962] [18019]
 Intellectual disability, mild (軽度知的障害) [HP:0001256] [0120]
 Lip telangiectasia (口唇毛細血管拡張) [HP:0000214] [18036]
 Papule (丘疹) [HP:0200034] [18007]
 Subcutaneous nodule (皮下結節] [HP:0001482] [18027]
 Telangiectasia of the oral mucosa (口腔粘膜毛細血管拡張) [HP:0007428] [18036]
 Telangiectasia of the skin (皮膚の毛細血管拡張] [HP:0100585] [18036]
 Vertigo (眩暈] [HP:0002321] [01427]
 
 <30%-79%>
 Cardiomegaly (心拡大) [HP:0001640] [1121]
 Coarse facial features (粗な顔貌) [HP:0000280] [0408]
 Depressed nasal bridge (低い鼻梁) [HP:0005280] [0722]
 Hearing impairment (難聴) [HP:0000365] [091]
 Lymphedema (リンパ浮腫) [HP:0001004] [18024]
 Opacification of the corneal stroma (角膜間質混濁) [HP:0007759] [0620]
 Peripheral neuropathy (末梢ニューロパチー) [HP:0009830] [0204]
 Thick vermilion border (分厚い口唇唇紅部) [HP:0012471] [0552]
 Tinnitus (耳鳴) [HP:0000360] [01424]
 
 
 Abnormality of the eye (眼異常) [HP:0000478] [06]
 Adult onset (成人発症) [HP:0003581]
 Aminoaciduria (アミノ酸尿) [HP:0003355] [20351]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Axonal degeneration (軸索変性) [HP:0040078] [0201]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Distal muscle weakness (遠位筋力低下) [HP:0002460] [0270]
 Distal sensory impairment (遠位感覚障害) [HP:0002936] [025]
 Distal sensory impairment of all modalities (全遠位感覚障害) [HP:0003409] [025]
 Dry skin (乾いた皮膚) [HP:0000958] [18039]
 Increased urinary O-linked sialopeptides (尿中O連結sialopeptides増加) [HP:0003461] [2058]
 Peripheral axonal neuropathy (末梢性軸索ニューロパチー) [HP:0003477] [0204]
 Sensorineural hearing impairment (感音難聴) [HP:0000407] [0910]
 Thick lower lip vermilion (厚い下口唇唇紅部) [HP:0000179] [05522]
 White mater abnormalities in the posterior periventricular region (後部脳室周囲白質異常) [HP:0006812] [160127]

(UR-DBMS)
【一般】軽度の知能障害
 眩暈
【神経】末梢軸索ニューロパチー
 遠位四肢筋力低下
 遠位感覚障害 (全感覚)
 有髄線維濃度の減少と軸索変性 (腓腹神経生検)
【顔】粗な顔貌
 分厚い口唇
【眼】結膜は拡張した血管を示す
 眼底はコルク栓抜き様蛇行を伴う血管拡張を示す
【鼻】鼻尖拡大
 鼻梁平低
【耳】感音難聴
 Meniere 症候群
【皮膚】びまん性躯幹被角血管腫 (発症は10-20歳代; Kanzaki 病) (Fabry 病に類似する)
 角化症
 乾燥皮膚
 びまん性斑状丘疹
 口唇と口腔粘膜の毛細血管拡張
 リンパ浮腫
【X線】大脳萎縮 (MRI) (一部の患者で)
 後部脳室周囲領域の白質異常
【検査】alpha-N-acetylgalactosaminidase 蛋白の減少または欠損
 alpha-N-acetylgalactosaminidase 活性の減少または欠損
 いろんな組織細胞型 (血管内皮細胞, 脂肪細胞, Schwann 細胞, 白血球) が, 膜で境界された細胞質小水疱と無形体の線維性物質をもつ
 グリコアミノ酸尿
 尿中O-連鎖シアロペプチドの増加
【その他】成人発症
 Schindler 病 (609241) とアレリック

【一般】成長正常
 軽度の低身長
 神経学的症状なし
【心】 狭心症
【消化器】胃粘膜毛細血管拡張
【皮膚】毛細血管拡張

(要約)
●Schindler 病 (神崎病, Alpha-N-acetylgalactosaminidase 欠乏症) は, まれな先天代謝異常症である
 リソソーム蓄積病で, alpha-NAGA (alpha-N-acetylgalactosaminidase) 欠損が原因である
 →22q11 の NAGA 遺伝子変異による
 全身でのスフィンゴ糖脂質 (glycosphingolipids) 蓄積を生じる
●常染色体劣性である
●3つの主要なタイプがある
1) I 型乳児型
 約1歳までは正常に発達する
 身体協調運動および知能的行動を含む以前に獲得した技術の喪失が始まる
 他に, 筋緊張減弱, 虚弱, 不随意性急速眼球運動, 視力喪失, けいれんが生じうる
 経過とともに症状は悪化し, 筋強直により特定の筋を動かせなくなる
 外的刺激への反応も減少する
 その他, 出生時からの神経軸索ジストロフィー, 皮膚色素異常, 毛細血管拡張または血管拡張がみられる
2) II 型成人型
 より軽症で, 30歳まで症状がみられないかもしれない
 角化血管腫, 顔貌の粗野化, 軽度の知能障害がみられる
3) III 型中間型
 症状は多様で, けいれんと精神遅滞を伴うより重症型から, 言語遅滞, 軽度の自閉症様症状+/-行動異常を伴うより軽症がたまである
● Schindler 病の乳児は, 生後4歳以内に死亡する傾向があるので治療は姑息的となる
 II 型 Schindler 病は, 遅発性で神経変性は特徴ではない
●診断
 出生前:羊水穿刺または胎盤絨毛
 生後:尿検査, 血液検査, 皮膚生検, 遺伝子検査

(責任遺伝子) *104170 N- acetyl- alpha- D- galactosaminidase (NAGA) <22q11>
(1) Schindler disease, type I, Schindler disease, type III (609241 AR)
.0001 Schindler disease, type I [NAGA, GLU325LYS] (dbSNP:rs121434529) (Wang et al. 1990; Bakker et al. 2001)
.0004 Schindler disease, type III [NAGA, SER160CYS] (dbSNP:rs121434532) (Keulemans et al. 1996)
(2) Kanzaki disease (609242 AR)
.0002 Kanzaki disease [NAGA ARG329TRP] (dbSNP:rs121434530) (Wang et al. 1994)
.0003 Kanzaki disease [NAGA, GLU193TER ] ((dbSNP:rs121434531) Keulemans et al. 1996)
.0005 Kanzaki disease [NAGA, ARG329GLN] (dbSNP:rs121434533) (Kodama et al. 2001)

(Note)
A number sign (#) is used with this entry because of evidence that Kanzaki disease is caused by homozygous mutation in the gene encoding alpha-N-galactosaminidase (NAGA; 104170) on chromosome 22q13.

See also the more severe infantile and childhood forms of the disorder (609241), which are also caused by mutation in the NAGA gene.

Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder with atypical features. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy (609241); type II, also known as Kanzaki disease, is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder (see 609241) with mild to moderate neurologic manifestations (Desnick and Schindler, 2001).

Clinical Features
Kanzaki et al. (1989) described a 46-year-old Japanese woman with disseminated angiokeratoma, and demonstrated numerous cytoplasmic vacuoles in cells of the kidney and skin. Enzyme activities against synthetic and natural substrates were normal in leukocytes and fibroblasts. Her urine contained a large amount of sialylglycoaminoacids, with predominant excretion of an O-glycoside-linked glycoaminoacid. No information was provided on the patient's family. The enzyme studies excluded Fabry disease (301500), fucosidosis (230000), galactosialidosis (256540), and the various mucolipidoses and mucopolysaccharidoses. Kanzaki et al. (1991) determined that the enzymatic defect in this patient was a deficiency of alpha-N-acetylgalactosaminidase. The findings confirmed that there are 2 forms of alpha-N-acetylgalactosaminidase deficiency with sialopeptiduria: a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions (609241), and an adult-onset form with angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides, and the absence of detectable neurologic involvement.

Kanzaki et al. (1993) gave an extensive description of the patient originally described in 1989 (Kanzaki et al., 1989). The angiokeratomas first appeared on her lower torso when she was 28 years old and later became diffusely distributed. Her 2 unaffected children had half-normal enzyme levels, consistent with autosomal recessive inheritance. The woman had mild intellectual impairment and peripheral neuroaxonal degeneration. She was the product of a first-cousin marriage and worked in a hospital as a nurse's aide. Endoscopic examination demonstrated telangiectasia on the gastric mucosa. Dilated blood vessels were present on the ocular conjunctiva and dilated vessels with corkscrew-like tortuosity were observed in the fundi.

Umehara et al. (2004) presented neurologic findings in the patient reported by Kanzaki et al. (1989). The 59-year-old woman reported progressive distal muscle weakness and numbness beginning at age 40 years. She also developed recurrent vertigo attacks and bilateral sensorineural hearing loss. Physical examination showed impairment of all sensory modalities in the distal upper and lower extremities. Sural nerve biopsy showed decreased density of myelinated fibers and axonal degeneration. Brain MRI showed cerebral atrophy and posterior periventricular white matter abnormalities. Umehara et al. (2004) concluded that Kanzaki disease involves both the central and peripheral nervous systems.

Chabas et al. (1994) reported 2 adult Spanish sibs with angiokeratoma, lymphedema, and vacuolization in dermal cells, but no neurologic signs. Fibroblast activity of alpha-NAGA was decreased to 0.6 to 2% of normal controls. Urinary analysis showed abnormal excretion of sialyloligosaccharides. The patients were clinically similar to the patient described by Kanzaki et al. (1989).

Kodama et al. (2001) reported a 47-year-old Japanese woman, born of consanguineous parents, with Kanzaki disease confirmed by genetic analysis (104170.0005). She developed angiokeratoma corporis diffusum on her lower trunk at age 28 years, which spread to her entire body and oral mucosa. Her conjunctiva and fundi showed mildly dilated blood vessels. After experiencing bilateral tinnitus, hearing difficulty, and vertigo for many years, she was diagnosed with Meniere syndrome (see 156000) and wore a hearing aid. Neurologic examination showed normal IQ with no mental deficits, and some peripheral sensory loss. Echocardiogram revealed partial hypertrophy of the interventricular septum with normal cardiac function. Biochemical studies showed decreased alpha-NAGA activity at 0.77% of control values, and she had urinary excretion of O-linked glycoaminoacid. Kodama et al. (2001) suggested that Meniere syndrome may be another manifestation of Kanzaki disease.

Molecular Genetics
In the Japanese woman with disseminated angiokeratoma reported by Kanzaki et al. (1989), Wang et al. (1990, 1994) identified a homozygous mutation in the NAGA gene (104170.0002).

Keulemans et al. (1996) showed by PCR and sequence analysis that the Spanish brother and sister with Kanzaki disease described by Chabas et al. (1994) were homozygous for a mutation in the NAGA gene (104170.0003).

(文献)
(1) Kanzaki T et al. Clinical and ultrastructural studies of novel angiokeratoma corporis diffusum. Clin Res 36: 377A, 1988
(2) Kanzaki T et al. Novel lysosomal glycoaminoacid storage disease with angiokeratoma corporis diffusum. Lancet I: 875-876, 1989
(3) Wang AM et al. Alpha-N-acetylgalactosaminidase gene: homology with human alpha-galactosidase A, and identification and confirmation of the mutations causing type I and II Schindler disease. Am J Hum Genet 47 (suppl.): A169, 1990
(4) Kanzaki T et al. Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria. J Clin Invest 88: 707-711, 1991
(5) Kanzaki T et al. Angiokeratoma corporis diffusum with glycopeptiduria due to deficient lysosomal alpha-N-acetylgalactosaminidase activity: clinical, morphologic, and biochemical studies. Arch Derm 129: 460-465, 1993
(6) Chabas A et al. Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. J Inherit Metab Dis 17: 724-731, 1994
(7) Wang AM et al. The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria. J Clin Invest 94: 839-845, 1994
(8) Keulemans JLM et al. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. J Med Genet 33: 458-464, 1996
(9) Desnick, R. J.; Schindler, D. : Alpha-N-acetylgalactosaminidase deficiency: Schindler disease.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. III. New York: McGraw-Hill (8th ed.) Pp. 3483-3505, 2001
(10) Kodama, K.; Kobayashi, H.; Abe, R.; Ohkawara, A.; Yoshii, N.; Yotsumoto, S.; Fukushige, T.; Nagatsuka, Y.; Hirabayashi, Y.; Kanzaki, T. : A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Meniere's syndrome and without mental retardation. Brit. J. Derm. 144: 363-368, 2001
(11) Umehara, F.; Matsumuro, K.; Kurono, Y.; Arimura, K.; Osame, M.; Kanzaki, T. : Neurologic manifestations of Kanzaki disease. Neurology 62: 1604-1606, 2004

2009/06/08
2015/10/13 SNP ノート改訂
2016/12/23 症状改訂