疾患詳細

疾患詳細





#268800
Sandhoff disease
(GM2-gangliosidosis, type II)
(Hexosaminidase A and B deficiency)
(Sandhoff disease, adult type, included)
(Sandhoff disease, juvenile type, included)
(Sandhoff disease, infantile type, included)

Sandhoff 病
(GM2-ガングリオシドーシス II 型)
(ヘキソサミニダーゼ A および B 欠損)
(ヘキソサミニダーゼ B; HEXB)
(Sandhoff 病, 成人型)
(Sandhoff 病, 若年型)
(Sandhoff 病, 乳児型)
指定難病19 ライソゾーム病
小児慢性特定疾病 代86 GM2-ガングリオシドーシス

責任遺伝子:606873 Hexosaminidase B (HEXB) <5q13.3>
遺伝形式:常染色体劣性

(症状)
(GARD)
<80%-99%>
 Abnormality of glycosphingolipid metabolism (スフィンゴ糖脂質代謝異常) [HP:0004343]
 Abnormality of movement (運動異常) [HP:0100022] [026]
 Ataxia (運動失調) [HP:0001251] [028]
 Blindness (盲) [HP:0000618] [06011]
 Cherry red spot of the macula (チェリーレッド斑) [HP:0010729] [0650]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Hearing impairment (難聴) [HP:0000365] [091]
 Kyphosis (Hunched back) (後弯) [HP:0002808] [161500]
 Macrocephaly (大頭) [HP:0000256] [03012]
 Motor deterioration (運動悪化) [HP:0002333] [0125]
 Progressive psychomotor deterioration (進行性精神運動発達悪化) [HP:0007272] [0125]
 Seizures (けいれん) [HP:0001250] [01405]
<30%-79%>
 Full cheeks (大きな頬部) [HP:0000293] [0528]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Splenomegaly (脾腫) [HP:0001744] [01817]
<5%-29%>
 Congestive heart failure (うっ血性心不全) [HP:0001635] [0171]
 Skeletal dysplasia (骨格異形成) [HP:0002652] [16]

 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Cardiomegaly (心拡大) [HP:0001640] [1121]
 Chronic diarrhea (慢性下痢) [HP:0002028] [01806]
 Coarse facial features (粗な顔貌) [HP:0000280] [0408]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Episodic abdominal pain (エピソード性腹痛) [HP:0002574] [01420]
 Fasciculations (攣縮) [HP:0002380] [02604]
 Hepatosplenomegaly (肝脾腫) [HP:0001433] [01813] [01817]
 Hyperhidrosis (多汗) [HP:0000975] [18016]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Hypohidrosis (低汗) [HP:0000966] [18013]
 Impaired thermal sensitivity (温覚障害) [HP:0006901] [01413]
 Impotence (インポテンツ) [HP:0000802] [1408]
 Macroglossia (巨舌) [HP:0000158] [08109]
 Orthostatic hypotension (起立性低血圧) [HP:0001278] [01416]
 Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] [0270]
 Upper motor neuron dysfunction (上位運動ニューロン機能障害) [HP:0002493]
 Urinary incontinence (遺尿) [HP:0000020] [0192]

(UR-DBMS)
【一般】*進行性精神悪化および運動発達悪化 (6か月までに)
 けいれん (12-15 か月までに)
 肺臓炎
 肝脾腫
 敗血症
 起立性低血圧
 姿勢性眩暈
 慢性下痢
 エピソード性 腹痛
 軽度の遺尿
 熱不耐症
【神経】*驚愕反射
 *筋緊張低下
 痙性四肢不全麻痺 (最終的に)
 乳児筋力低下
 筋力低下
 小脳性運動失調
 構音障害
 筋線維束攣縮
 錐体路機能障害
 反射亢進
 温覚障害
【頭】大頭
【顔】人形様顔
 粗い顔貌
【眼】早期盲
 *チェリー・レッド斑
【口】巨舌
【心】心拡大
【性器】インポテンツ
【X線】高位腰部突背
【皮膚】発汗障害
【血液】*骨髄泡沫細胞
【検査】Hexosaminidase B beta chain 欠損 (血清, 組織)
【その他】通常は3歳までに致死

(要約)
●Sandhoff 病 (Jatzkewitz-Pilz 症候群; Hexosaminidase A および B 欠乏症) はまれな常染色体劣性の遺伝性脂質蓄積症である
 beta-hexosaminidase A and beta-hexosaminidase B の欠損があり組織へ GM2 gangliosides が蓄積する (リソソーム蓄積症)
 →毒性があり, 中枢神経の進行性破壊があり組織を障害し, 最終的には死亡する
●古典的乳児型, 若年型, 成人遅発型がある
 重症度と発症年齢による
 臨床的に Sandhoff 病は Tay-Sachs 病 (beta-hexosaminidase A 異常)と区別できない
1)古典的乳児型
 2か月〜9か月令で症状発症
 重症で3歳までに死亡する
 最も多く最も重症型である
 3〜6か月までは正常にみえる
 発達が遅れ, 筋緊張低下がみられる
 進行するにつれ, けいれん, 視覚および聴覚喪失, 精神遅滞, 麻痺が出現する
 チェリーレッド斑が特徴である
 一部の患者は臓器肥大や骨異常をもつ
2)若年型
 3~10歳で発症し, 15歳までに死亡する
3)成人発症型
 運動機能障害
 2)と3)は非常に少ない
●症状
 古典的乳児型は, Sandhoff 病は臨床的に Tay-Sachs 病と区別できない
 最初のサインは6か月令以前に始まり, 発達の遅れに気付く
 →座やハイハイ能力の喪失 (GM2 gangliosides の筋への蓄積による緩徐な悪化)
 筋/運動衰弱, 大きな音への鋭敏な反応, 盲, 聾, 刺激への反応なし, 呼吸障害, 感染, 精神遅滞, けいれん, チェリーレッド斑, 肝脾腫, 肺炎, 気管支肺炎がみられる
 他の2つの型は類似症状をもつが軽度である
●HEXB 遺伝子変異が原因である (特にエクソン14)
 酵素 beta-hexosaminidase A および beta-hexosaminidase B をコードする
 →神経細胞で脂質, 複合糖, 糖と連鎖する分子を分解する
 特に beta-hexosaminidase Aは GM2 ganglioside と分解する
 HEXB 遺伝子変異はこれらの酵素活性を障害し, GM2 ganglioside や他の分子を分解しにくくし, 蓄積が神経細胞を障害する
● Ashkenazi ユダヤ人に多いが, ユダヤ人以外でもみられる
 北部アルゼンチンの Creole 集団, カナダのサスカチュワンの Metlis, キプロスのマロン教会集団で多い
●診断
 肝生検, 遺伝子検査, 分子解析, 酵素アッセー

<小児慢性特定疾病 代86 GM2-ガングリオシドーシス>
概要・定義
GM2-ガングリオシドーシスは、β-ヘキソサミニダーゼAの欠損により発症するテイ・サックス病、β-ヘキソサミニダーゼAとB 両方の欠損により発症するサンドホフ病、GM2活性化蛋白の欠損により発症するGM2ガングリオシド活性化蛋白質欠損症があり、常染色体劣性遺伝形式を示す遺伝病である。脳を中心にGM2ガングリオシドなどの糖脂質が蓄積する。発症頻度はテイ・サックス病、サンドホフ病が1/30万人とされ、GM2ガングリオシド活性化蛋白質欠損症はきわめてまれである。発症時期と臨床経過により、乳児型、若年型、成人型に分類される。乳児型は生後6~7ヶ月までに発達の遅れが見られ、筋緊張低下、音に対する過敏症、眼底のチェリーレッドスポットを認める。肝脾腫、骨異常はほとんどない。若年型は2~10歳頃に発症し、臨床症状は乳児型に類似するが、やや軽度である。成人型は、発達は正常で20~30歳で発症する。歩行障害、構音障害が初期症状として多く、ジストニアなどの錐体外路症状を呈する。
疫学
日本でのテイ・サックス病の罹患率は8万~10万人に1人と考えられている。サンドホフ病は約30万人に1人とされ、GM2ガングリオシド活性化蛋白質欠損症はきわめてまれである。
病因
中枢神経に多いGM2ガングリオシドなどを分解するβ-ヘキソサミニダーゼA、BまたはGM2ガングリオシド活性化蛋白質欠損により発症する。これらに関係する遺伝子はHEXA、HEXB、GM2Aの3種類があり、HEXAの変異によりテイ・サックス病、HEXBの変異によりサンドホフ病、GM2Aの変異によりGM2ガングリオシド活性化蛋白質欠損症が発症する。
症状
テイ・サックス病、サンドホフ病、GM2ガングリオシド活性化蛋白質欠損症を臨床症状で区別するのは困難である。発症年齢により乳児型、若年型、成人遅発型に分類できる。
乳児型は3ヶ月ころまでの発達は正常な場合が多いが、その後精神運動発達遅滞や退行が見られる。眼底のチェリー・レッドスポットは特徴的である。けいれん、視覚や聴覚の障害、嚥下困難などが出現する。
若年型は比較的稀である。2歳~10歳で発症する。進行性の運動失調と協調運動障害の症状が発症し、けいれんも伴い退行が見られる。
成人遅発型は稀で、症状や経過は様々である。チェリー・レッドスポットは認めないことも多い。構音障害、ジストニア、運動失調、アテトーゼなどの錐体外路症状、精神障害など様々な症状を呈する。知的障害は軽度である。
診断
末梢リンパ球、皮膚線維芽細胞のヘキソサミニダーゼAおよびBの活性測定が有用。テイ・サックス病ではヘキソサミニダーゼAのみが、サンドホッフ病ではヘキソサミニダーゼAおよびBが欠損している。症状などから本症が疑われヘキソサミニダーゼAおよびBの活性測定が正常範囲の場合にGM2ガングリオシド活性化蛋白質欠損症を疑い、皮膚線維芽細胞を用いた特殊検査が必要となる。また、遺伝子診断としてはHEXA、HEXB、GM2Aなどの遺伝子変異を検出する。日本人テイ・サックス病では、IVS5,-1G>Tのスプライス異常が多い。
診断方法
1. 乳児型では、音に対する過敏性や眼底のチェリーレッドスポットなどが特徴的な徴候である。成人型はジストニアなどの進行性の錐体外路症状と脊椎変形が主な症状となる。
2. 酵素活性測定と遺伝子診断を行って診断を確定する。
3. 酵素活性測定では、末梢血リンパ球または培養皮膚線維芽細胞を用いてβ-ヘキソサミニダーゼA、Bの活性を測定する。
4. 遺伝カウンセリングなどの情報として、遺伝子診断は有用である。しかし、酵素活性から診断が確実となった患者でも、遺伝子診断では変異が見つからない場合がある。
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
現段階では対症療法に限られる。マラリア治療薬であるピリメサミンがシャペロンとして有効との報告があるが、臨床応用はなされていない。
予後
乳児型の患者さんは、3歳までに亡くなることが多い。若年型は、10~15歳くらいで植物状態になり亡くなることが多い。
成人型は錐体外路症状、精神障害などで生活が困難となる。
成人期以降
成人型は臨床症状や経過が様々であり、脊髓小脳変性症などとの鑑別に注意する

(Comment) HEXB causes Sandhoff disease, infantile form: Sandhoff disease, juvenile type: Spinal muscular atrophy, juvenile type
(Responsible gene) *606873 Hexosaminidase B (HEXB) <5q13.3>
(1) Sandhoff disease (268800); Sandhoff disease, juvenile type; Sandhoff disease, adult type
.0001 Sandhoff disease [HEXB, 50KB DEL] (RCV000004077) (Bikker et al.1989; Bikker et al. 1990; Mahuran 1994)
.0002 Sandhoff disease, juvenile type [HEXB, 24BP INS] (RCV000004079) (Nakano and Suzuki 1989; Dlott et al. 1990)
.0006 Sandhoff disease, juvenile type [HEXB, TYR456SER] (rs121907982) (gnomAD:rs121907982) (RCV000004081...) (Banerjee et al. 1991)
.0007 Sandhoff disease, juvenile type [HEXB, PRO417LEU] (rs28942073) (gnomAD:rs28942073) (RCV000174009...) (Wakamatsu et al. 1992; McInnes et al. 1992)
.0009 Sandhoff disease, adult type [HEXB, ARG505GLN] (rs121907983) (gnomAD:rs121907983) (RCV000004083...) (Bolhuis et al. 1993)
.0010 Sandhoff disease, adult type [HEXB, PRO405LEU] (rs28942073) (gnomAD:rs28942073) (RCV000174009...) (Gomez-Lira et al. 1995)
.0012 Sandhoff disease, infantile type [HEXB, SER62LEU] (rs820878) (gnomAD:rs820878) (RCV000869482...) (Zhang et al. 1995)
.0013 Sandhoff disease, infantile type [HEXB, PARTIAL DEL] (RCV000004087) (Zhang et al. 1995)
.0014 Sandhoff disease, chronic [HEXB, PRO504SER] (rs121907985) (gnomAD:rs121907985) (RCV000004088) (Rubin et al. 1988)
.0015 Sandhoff disease, infantile [HEXB, IVS8, G-C, +5] (RCV000004089) (Furihata et al. 1999)
.0016 Sandhoff disease, infantile [HEXB, 1-BP DEL, 76A] (RCV000004090) (Drousiotou et al. 2000)
.0017 Sandhoff disease, infantile [HEXB, ARG284TER] (rs121907986) (gnomAD:rs121907986) (RCV000004091...) (Zampieri et al. 2009)
.0018 Sandhoff disease, infantile [HEXB, 1-BP DEL, 965T] (RCV000004092) (Zampieri et al. 2009)
.0019 Sandhoff disease, adult [HEXB, ASP494GLY] (Santoro et al. 2007)
(2) Variants
.0003 Hexosaminidase B (Paris) [HEXB, 18BP INS] (RCV000004080) (Dlott et al. 1990)
.0004 MOVED TO 606873.0001
.0005 HEXB POLYMORPHISM [HEXB, ILE207VAL] (rs10805890) (gnomAD:rs10805890) (RCV000403428...) (Zhang et al. 1995; Redonnet-Vernhet et al. 1996)
.0008 HEXB polymorphsim [HEXB, LYS121ARG] (rs11556045) (gnomAD:rs11556045) (RCV000004078...) (Wakamatsu et al. 1992)
.0011 Hexosaminidase B, heat-labile polymorphism [HEXB, ALA543THR ] (rs121907984) (gnomAD:rs121907984) (RCV000079061...) (Narkis et al. 1997)

(Note)
A number sign (#) is used with this entry because Sandhoff disease is caused by mutation in the beta subunit of hexosaminidase (HEXB; 606873) on chromosome 5q13.

Sandhoff disease is a progressive neurodegenerative disorder characterized by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease (272800).

Clinical Features
Sandhoff et al. (1968) gave the initial description of the disorder that bears his name. O'Brien (1971) studied 2 Mexican-American sisters and a boy of Anglo-Saxon extraction. Most patients have been non-Jewish; however, the clinical and pathologic picture is very similar to Tay-Sachs disease (272800). Weakness begins in the first 6 months of life. Startle reaction, early blindness, progressive mental and motor deterioration, doll-like face, cherry red spots, and macrocephaly are all present as in Tay-Sachs disease. Death usually occurs by age 3 years.

In the case reported by Krivit et al. (1972), signs of heart involvement preceded those of nervous system change. A pansystolic murmur and cardiomegaly were discovered at 3 months. Neurologic deterioration was first noted at 8 months. Coarse facies, macroglossia, megaloencephaly, minimal hepatosplenomegaly and high lumbar gibbus suggested Hurler syndrome.

Der Kaloustian et al. (1981) described 7 cases in Lebanon. The largest collection of cases is represented by the 36 patients in 15 families described in a Creole population of Argentina (Dodelson de Kremer et al., 1985).

Frey et al. (2005) reported 3 adult patients, including 2 sisters, with late-onset GM2-gangliosidosis diagnosed in childhood. All had learning difficulties in school, and all had been hospitalized for either emotional lability, intermittent psychosis, or confusional state. As adults, neurologic evaluations showed variable features of muscle weakness, muscle atrophy, fasciculations, supranuclear gaze palsy, muscular atrophy, hyperreflexia, and extensor plantar responses. Serial neuropsychologic examination in 1 of the 2 sisters showed significant declines in cognitive and executive function over 10 years. In a literature review of 62 patients, Frey et al. (2005) found that 44% had some degree of cognitive dysfunction, 62% of whom showed progressive dementia. Cerebellar and cortical atrophy were common. Frey et al. (2005) concluded that patients with late-onset GM2 gangliosidosis have a high risk of dementia, and that patients with dementia often have other neurologic manifestations.

Heterogeneity
Clinical Heterogeneity

Spence et al. (1974) described a case of clinically, histologically, and chemically typical Sandhoff disease in a black male. Total hexosaminidase activity in the blood was 20 to 24% of normal (compared with the usual value of less than 5%), whereas in the liver the level was less than 2% of normal. This may be an allelic variant of Sandhoff disease.

In a 10-year-old male with progressive cerebellar ataxia and psychomotor retardation, Wood and MacDougall (1976) found almost complete absence of total hexosaminidase activity in serum, leukocytes, and cultured skin fibroblasts. In spite of disparate clinical findings, this disorder may be allelic to the classic infantile form of Sandhoff disease in view of the similarity of the enzyme deficiency. Studies of residual hexosaminidase isozymes in the juvenile and infantile forms suggested that the defects may be different allelic modifications of the beta subunit common to Hex-A and Hex-B (Wood and MacDougall, 1976). Wood (1978) found no complementation of Sandhoff and juvenile Sandhoff cells, suggesting allelism.

Johnson and Chutorian (1978) found a new form of hexosaminidase deficiency characterized clinically by mild, juvenile-onset, slowly progressive cerebellar ataxia, and macular cherry red spots. Hexosaminidase B appeared to be absent, resulting in a relative increase in Hex-A in screening tests. They suggested that this condition may be due to a mutation allelic to that for Sandhoff disease.

In one of its mutant forms, Hex-A deficiency can lead to late-onset, progressive motor neuron disease. Cashman et al. (1986) presented a case demonstrating that the same is true for Hex-B deficiency. Their female patient had a progressive motor neuron syndrome that began at age 7 years and was characterized by dysarthria, muscle wasting, fasciculations, and pyramidal tract dysfunction. Rectal biopsy at age 24 showed membranous cytoplasmic bodies in submucosal ganglion cells.

Diagnosis
Lowden et al. (1978) described Sandhoff disease in a Metis kindred of northern Saskatchewan and discussed carrier detection. Chamoles et al. (2002) described methods for enzymatic detection of Tay-Sachs and Sandhoff disease in newborns using dried blood spots on filter paper.

Differential Diagnosis

Kaback (1985) knew of no case of Sandhoff disease in a Jewish child. It may be that the rare cases are confused with Tay-Sachs disease; however, the hepatosplenomegaly should distinguish them as it did in Sandhoff's original case.

Pathogenesis
Tay-Sachs disease (272800) results from a mutation in the alpha subunit (HEXA; 606869) of the hexosaminidase A enzyme, and Sandhoff disease results from mutation in the beta subunit (HEXB; 606873) of the hexosaminidase A and B enzymes. Thus, hexosaminidases A and B are both deficient in Sandhoff disease.Srivastava and Beutler (1973) maintained that hexosaminidases A and B share a common subunit that is lacking in Sandhoff disease, whereas a subunit unique to hexosaminidase A is deficient in Tay-Sachs disease. Galjaard et al. (1974), Thomas et al. (1974), and Rattazzi et al. (1975) showed that Hex-A activity appears after fusion of Tay-Sachs and Sandhoff cells, suggesting genetic complementation. Abnormal radioactive-sulfate kinetics and mucopolysacchariduria are observed in Sandhoff disease but not in Tay-Sachs disease.

Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

Mapping
The HEXB locus (606873) has been assigned to chromosome 5 (Gilbert et al., 1975). In a child with a de novo balanced translocation t(5;13)(q11;p11), Mattei et al. (1984) found decreased levels of Hex-B, suggesting to these workers that the HEXB gene assignment can be narrowed to 5q11.

Chern et al. (1976) studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X;15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively.

Molecular Genetics
O'Dowd et al. (1986) concluded that the primary gene defect in the majority of Sandhoff cases is in the HEXB gene itself. They studied 5 juvenile cell lines, all of which were found to have normal or reduced levels of pre-beta-chain mRNA and no gross abnormalities in the HEXB gene. Of the 11 infantile type cell lines examined, 4 were found to contain no detectable pre-beta-chain mRNA. Two of the 4 contained partial gene deletions located to the 5-prime end of the HEXB genes. One of these cell lines had previously been assigned to the single complementation group in Sandhoff disease. Thus, the clinical heterogeneity in Sandhoff disease appears to be related to different allelic HEXB mutations.

Oonk et al. (1979) reported the cases of 2 adult sisters with spinocerebellar degeneration and very low activities of both Hex-A and Hex-B. Bolhuis et al. (1987)reported the autopsy findings of one of the sisters. She had suffered from progressive disabling spinocerebellar disease with motor neuron involvement, but had no dementia, seizures, or ophthalmologic abnormalities. She died of severe urosepsis at age 39. GM2-ganglioside storage was most pronounced in the cerebellum. Only very small amounts of mature beta chain were synthesized. Bolhuis et al. (1987) concluded that the disorder was the result of a 'destabilizing mutation' in the HEXB locus. Bolhuis et al. (1993) demonstrated that these 2 sisters were compound heterozygotes for an mRNA-negative allele on 1 chromosome 5 and an R505Q mutation (606873.0009) on the homologous chromosome. Transfection of COS cells with a cDNA construct containing the R505Q mutation resulted in the expression of a labile form of beta-hexosaminidase, thus confirming their earlier conclusion.

Brown et al. (1992) and Kleiman et al. (1994) gave updates on the HEXB mutations in the Argentinian deme described by Dodelson de Kremer et al. (1985).

Neufeld (1989) provided a review of the disorders related to mutations in the HEXA and HEXB genes. Mahuran (1998) stated that he maintains a database of published hexosaminidase and GM2A (613109) mutations and that the database contains 23 HEXB mutations, 86 HEXA (606869) mutations, and 4 GM2A mutations.

Among 12 unrelated Italian patients with Sandhoff disease, 11 of whom had the infantile type, Zampieri et al. (2009) identified 11 different mutations in the HEXB gene, including 6 novel mutations (see, e.g., 606873.0017 and 606873.0018). The common 16-kb deletion (606873.0001) was not identified in this patient cohort.

Population Genetics
Cantor and Kaback (1985) stated that the gene frequency for Sandhoff disease was about 1/1000 in Jews and 1/600 in non-Jews.

Drousiotou et al. (2000) noted that in the previous 15 years, 4 patients with the infantile form of Sandhoff disease had been identified in 4 different families in Cyprus (population, 703,000; birth rate, 1.7%). Three of these cases came from the Christian Maronite community (less than 1% of the population) and 1 from the Greek community (84% of the population). This relatively large number of patients prompted Drousiotou et al. (2000) to initiate an epidemiologic study to establish the frequency of the mutant gene in Cyprus. Measuring beta-hexosaminidases A and B in both leukocytes and serum, they identified 35 carriers among 244 random Maronite samples and 15 among 28 Maronites with a family history of Sandhoff disease, but only 1 carrier out of 115 random samples from the Greek community. Of 50 Maronite carriers examined, 42 were found to have deletion of adenine at nucleotide 76 (606873.0016).

Animal Model
Sango et al. (1995) found that mice generated through disruption of the HEXB gene have severe neurologic involvement, representing a satisfactory model of Sandhoff disease. In contrast, disruption of the HEXA gene with the intent of producing a model of Tay-Sachs disease resulted in no neurologic abnormality, although the mice exhibited biochemical and pathologic features of the disease. Differences in the ganglioside degradative pathway between mice and humans were revealed by the studies. Phaneuf et al. (1996) likewise found that mice with disruption of the Hexa gene suffered no obvious behavioral or neurologic deficit while those homozygous for a disruption of the Hexb gene developed a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor, and ataxia. They proposed that homozygous Hexa deficient mice escaped disease through particle catabolism of accumulated GM2 via GA2 through the combined action of sialidase and beta-hexosaminidase B.

Huang et al. (1997) found that neuron death in HEXB-/- mice is associated with apoptosis occurring throughout the central nervous system, while HEXA-/- mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. Huang et al. (1997) suggested that neuron death is caused by unscheduled apoptosis, implicating accumulated GM2 ganglioside or a derivative in triggering of the apoptotic cascade.

The mucopolysaccharidosis phenotype is not seen in patients with either Tay-Sachs disease or Sandhoff disease and is also not seen in the knockout mice that have been created as a model of these 2 disorders by homozygosity for a defect in either HEXA or HEXB. However, double knockout mice lacking both subunits of lysosomal beta-hexosaminidase were found by Sango et al. (1996) to display both gangliosidosis and mucopolysaccharidosis. Lack of mucopolysaccharide storage in Tay-Sachs and Sandhoff diseases is presumably due to functional redundancy in the beta-hexosaminidase enzyme system.

Liu et al. (1999) explored a new treatment paradigm for glycosphingolipid storage disorders, namely substrate depletion therapy, by constructing a genetic model in mice. Sandhoff disease mice, which abnormally accumulate glycosphingolipids, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span; however, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results supported the validity of substrate deprivation therapy, but also highlighted limitations.

A possible therapeutic strategy for treating Sandhoff disease and related disorders is substrate deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which had been in clinical trials for the potential treatment of type I Gaucher disease (230800), a related disorder that involves glycosphingolipid storage in peripheral tissues but not in the central nervous system. It had also been used in the treatment of Tay-Sachs disease in mice (Platt et al., 1997). Jeyakumar et al. (1999) evaluated whether this drug could also be applied to the treatment of diseases for central nervous system storage and pathology. They found that in the mouse model of Sandhoff disease there was delay of symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offered a potentially general therapy for this family of lysosomal storage diseases, including those with central nervous system disease.

Yamaguchi et al. (2004) found that the progressive neurologic disease induced in Hexb -/- mice, the animal model for Sandhoff disease, was associated with the appearance of antiganglioside autoantibodies. Both elevation of serum antiganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the disease in Hexb -/- mice; serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor gamma gene (FCER1G; 147139) was additionally disrupted in Hexb -/- mice, as it plays a key role in immune complex-mediated autoimmune diseases. Clinical symptoms were improved and life spans were extended in the double-null mice; the number of apoptotic cells was also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied Sandhoff disease patient. Taken together, these findings suggested that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in Sandhoff disease and therefore provides a target for therapy.

(文献)
(1) Sandhoff K et al. Deficient hexosaminidase activity in an exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral organs. Life Sci 7: 283-288, 1968
(2) O'Brien JS: Ganglioside storage diseases. In Harris H, Hirschhorn K (eds.): Advances in Human Genetics. New York: Plenum Press, Pp. 39-98, 1971
(3) Sandhoff K et al. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem 18: 2469-2489, 1971
(4) Krivit W etal. Generalized accumulation of neutral glycosphingolipids with G(m2) ganglioside accumulation in the brain. Sandhoff's disease (variant of Tay-Sachs disease). Am J Med 52: 763-770, 1972
(5) Okada S et al. Sandhoff's disease (Gm2 gangliosidosis type 2): clinical, chemical, and enzyme studies in five patients. Pediat Res 6: 606-615, 1972
(6) Srivastava SK, Beutler E. Hexosaminidase-A and hexosaminidase-B: studies in Tay-Sachs' and Sandhoff's disease. Nature 241: 463, 1973
(7) Suzuki Y et al. Sandhoff disease: diagnosis of heterozygous carriers. Clin Chim Acta 48: 153-158, 1973
(8) Galjaard H et al. Tay-Sachs and Sandhoff's disease: intergenic complementation after somatic cell hybridization. Exp Cell Res 87: 444-448, 1974
(9) Lalley PA et al. Human beta-D-N-acetylhexosaminidase A and B: expression and linkage relationships in somatic hybrids. Proc Nat Acad Sci 71: 1569-1573, 1974
(10) Spence MW et al. A new variant of Sandhoff's disease. Pediat Res 8: 628-637, 1974
(11) Swallow DM et al. Differences between the N-acetyl hexosaminidase isozymes in serum and tissues. Ann Hum Genet 37: 287-302, 1974
(12) Thomas GH et al. Genetic complementation after fusion of Tay-Sachs and Sandhoff cells. Nature 250: 580-582, 1974
(13) Gilbert F et al. Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes. Proc Nat Acad Sci 72: 263-267, 1975
(14) Rattazzi MC et al. Tay-Sachs and Sandhoff-Jatzkewitz diseases: complementation of hexosaminidase A deficiency by somatic cell hybridization. BDOAS XI(3): 232-235, 1975
(15) Chern CJ et al. Characterization of heteropolymeric hexosaminidase A in human X mouse hybrid cells. Proc Nat Acad Sci 73: 3637-3640, 1976
(16) Wood S, MacDougall BG: Juvenile Sandhoff disease: some properties of the residual hexosaminidase in cultured fibroblasts. Am J Hum Genet 28: 489-495, 1976
(17) Dreyfus JC et al. Characterization of a variant of beta-hexosaminidase: 'hexosaminidase Paris.'. Am J Hum Genet 29: 287-293, 1977
(18) George DL, Francke U. Regional mapping of human genes for hexosaminidase B and diphtheria toxin sensitivity on chromosome 5 using mouse X human hybrid cells. Somat. Cell Genet 3: 629-638, 1977
(19) MacLeod PM et al. Progressive cerebellar ataxia, spasticity, psychomotor retardation, and hexosaminidase deficiency in a 10-year-old child: juvenile Sandhoff disease. Neurology 27: 571-573, 1977
(20) George DL, Francke U. Evidence for localization of the gene for hexosaminidase B to the cen-q13 region of human chromosome 5 using mouse-human hybrid cells. Cytogenet Cell Genet 22: 408-411, 1978
(21) Johnson WG, Chutorian AM: Inheritance of the enzyme defect in a new hexosaminidase deficiency disease. Ann Neurol 4: 399-403, 1978
(22) Lowden JA et al. Carrier detection in Sandhoff disease. Am J Hum Genet 30: 38-45, 1978
(23) O'Brien JS: Suggestions for a nomenclature for the GM2 gangliosidoses making certain (possibly unwarranted) assumptions. (Comments). Am J Hum Genet 30: 672-675, 1978
(24) Wood S Juvenile Sandhoff disease: complementation tests with Sandhoff and Tay-Sachs disease using polyethylene glycol-induced cell fusion. Hum Genet 41: 325-329, 1978
(25) Hechtman P, Rowlands A. Apparent hexosaminidase B deficiency in two healthy members of a pedigree. Am J Hum Genet 31: 428-438, 1979
(26) Oonk JGW et al. Spinocerebellar degeneration: hexosaminidase A and B deficiency in two adult sisters. Neurology 29: 380-384, 1979
(27) Messer G et al. Ultrastructure of the conjunctiva, skin, and gingiva: a case of Sandhoff's disease in a Jewish patient. Arch Path Lab Med 104: 123-129, 1980
(28) Der Kaloustian VM et al. Sandhoff disease: a prevalent form of infantile Gm2 gangliosidosis in Lebanon. Am J Hum Genet 33: 85-89, 1981
(29) Navon R et al. Hereditary heat-labile hexosaminidase B: its implication for recognizing Tay-Sachs genotypes. Am J Hum Genet 33: 907-915, 1981
(30) Dana S, Wasmuth JJ: Selective linkage disruption in human-Chinese hamster cell hybrids: deletion mapping of the leuS, hexB, emtB, and chr genes on human chromosome 5. Molec Cell. Biol 2: 1220-1228, 1982
(31) Mahuran DJ et al. Evidence for two dissimilar polypeptide chains in the beta(2) subunit of hexosaminidase. Proc Nat Acad Sci 79: 1602-1605, 1982
(32) Gautron S et al. Evidence for the presence of beta-subunit of hexosaminidase in a case of Sandhoff disease using a blotting technique. Hum Genet 63: 258-261, 1983
(33) Fox MF et al. Regional localization of alpha-galactosidase (GLA) to Xpter-q22, hexosaminidase B (HEXB) to 5q13-qter, and arylsulfatase B (ARSB) to 5pter-q13. Cytogenet Cell Genet 38: 45-49, 1984
(34) Mattei JF et al. De novo balanced translocation (5; 13)(q11; p11) in a child with Franceschetti syndrome and significant decrease of hexosaminidase B. Cytogenet Cell Genet 37: 532, 1984
(35) Cantor RM, Kaback MM: Sandhoff disease (SHD) heterozygote frequencies (HF) in North American (NA) Jewish (J) and non-Jewish (NJ): opulations: implications for carrier (C) screening. Am J Hum Genet 37: A48, 1985
(36) Dodelson de Kremer R et al. Sandhoff disease: 36 cases from Cordoba, Argentina. J Inherit Metab Dis 8: 46, 1985
(37) Navon R et al. Hereditary heat-labile hexosaminidase B: a variant whose homozygotes synthesize a functional HEX A. Am J Hum Genet 37: 138-146, 1985
(38) Neuwelt EA et al. Characterization of a new model of G(M2)-gangliosidosis (Sandhoff's disease) in Korat cats. J Clin Invest 76: 482-490, 1985
(39) O'Dowd BF et al. Isolation of cDNA clones coding for the beta subunit of human beta-hexosaminidase. Proc Nat Acad Sci 82: 1184-1188, 1985
(40) Cashman NR et al. N-acetyl-beta-hexosaminidase beta locus defect and juvenile motor neuron disease: a case study. Ann Neurol 19: 568-572, 1986
(41) Killary AM et al. Assignment of the genes encoding dihydrofolate reductase and hexosaminidase B to mouse chromosome 13. Am J Hum Genet 39: A159, 1986
(42) O'Dowd BF et al. Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (0-variant G(M2) gangliosidosis). J Biol Chem 261: 12680-12685, 1986
(43) Bolhuis PA et al. Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff's disease. Neurology 37: 75-81, 1987
(44) Proia RL: Gene encoding the human beta-hexosaminidase beta chain: extensive homology of intron placement in the alpha- and beta-chain genes. Proc Nat Acad Sci 85: 1883-1887, 1988
(45) Rubin M et al. Adult onset motor neuropathy in the juvenile type of hexosaminidase A and B deficiency. J. Neurol. Sci. 87: 103-119, 1988
(46) Bikker H et al. Demonstration of a Sandhoff disease-associated autosomal 50-kb deletion by field inversion gel electrophoresis. Hum Genet 81: 287-288, 1989
(47) Nakano T, Suzuki K. Genetic cause of a juvenile form of Sandhoff disease: abnormal splicing of beta-hexosaminidase beta chain gene transcript due to a point mutation within intron 12. J Biol Chem 264: 5155-5158, 1989
(48) Neufeld EF: Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase. J Biol Chem 264: 10927-10930, 1989
(49) Bikker H et al. Distribution and characterization of a Sandhoff disease-associated 50-kb deletion in the gene encoding the human beta-hexosaminidase beta-chain. Hum Genet 85: 327-329, 1990
(50) Dlott B et al. Two mutations produce intron insertion in mRNA and elongated beta-subunit of human beta-hexosaminidase. J Biol Chem 265: 17921-17927, 1990
(51) Mitsuo K et al. Juvenile Sandhoff disease: a Japanese patient carrying a mutation identical to that found earlier in a Canadian patient. J Neurol Sci 98: 277-286, 1990
(52) Navon R, Adam A: Thermolabile hexosaminidase (Hex) B: diverse frequencies among Jewish communities and implication for screening of sera for Hex A deficiencies. Hum. Hered. 40: 99-104, 1990
(53) Neote K et al. Structure and distribution of an Alu-type deletion mutation in Sandhoff disease. J Clin Invest 86: 1524-1531, 1990
(54) Banerjee P et al. Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease. Biochem Biophys Res Commun 181: 108-115, 1991
(55) Bolhuis PA, Bikker H: Deletion of the 5-prime-region in one or two alleles of HEXB in 15 out of 30 patients with Sandhoff disease (Letter) Hum. Genet. 90: 328-329, 1992
(56) Brown CA et al. Characterization of two HEXB gene mutations in Argentinian patients with Sandhoff disease. Biochim. Biophys. Acta 1180: 91-98, 1992
(57) McInnes B et al. An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds. J Clin Invest 90: 306-314, 1992
(58) Wakamatsu N et al. A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3-prime splice site selection. J Biol Chem 267: 2406-2413, 1992
(59) Bolhuis PA et al. Molecular basis of an adult form of Sandhoff disease: substitution of glutamine for arginine at position 505 of the beta-chain of beta-hexosaminidase results in a labile enzyme. Biochim Biophys Acta 1182: 142-146, 1993
(60) Banerjee P et al. Preferential beta-hexosaminidase (Hex) A (alpha-beta) formation in the absence of beta-Hex B (beta-beta) due to heterozygous point mutations present in beta-Hex beta-chain alleles of a motor neuron disease patient. J. Biol. Chem. 269: 4819-4826, 1994
(61) Hara Y et al. Mutation analysis of a Sandhoff disease patient in the Maronite community in Cyprus. Hum Genet 94 (2): 136-40, 1994
(62) Kleiman FE et al. Sandhoff disease in Argentina: high frequency of a splice site mutation in the HEXB gene and correlation between enzyme and DNA-based tests for heterozygote detection. Hum Genet 94 (3): 279-82, 1994
(63) Zhang ZX et al. Impact of premature stop codons on mRNA levels in infantile Sandhoff disease. Hum Mol Genet Jan 1994 3 (1): 139-45, 1994
(64) Gomez-Lira M et al. A common beta hexosaminidase gene mutation in adult Sandhoff disease patients. Hum Genet 96 (4): 417-22, 1995
(65) Sango K et al. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nature Genet 11: 170-176, 1995
(66) Zhang ZX et al. A second, large deletion in the HEXB gene in a patient with infantile Sandhoff disease. Hum Mol Genet 4 (4): 777-80, 1995
(67) Pennybacker M et al. Identification of domains in human beta-hexosaminidase that determine substrate specificity. J. Biol. Chem. 271: 17377-17382, 1996
(68) Phaneuf D et al. Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff disease. Hum Molec Genet 5: 1-14, 1996
(69) Redonnet-Vernhet I et al. Significance of two point mutations present in each HEXB allele of patients with adult G-M2 gangliosidosis (Sandhoff disease): homozygosity for the ile207-to-val substitution is not associated with a clinical or biochemical phenotype. Biochim. Biophys. Acta 1317: 127-133, 1996
(70) Sango K et al. Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nature Genet. 14: 348-352, 1996
(71) Narkis F et al. Molecular basis of heat labile hexosaminidase B among Jews and Arabs. Hum. Mutat. 10: 424-429, 1997
(72) Hou Y et al. A pro504-ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of G(M2) ganglioside, resulting in chronic Sandhoff disease. J. Biol. Chem. 273: 21386-21392, 1998
(73) Furihata K et al. Novel splice site mutation at IVS8 nt 5 of HEXB responsible for a Greek-Cypriot case of Sandhoff disease. Hum. Mutat. 13: 38-43, 1999
(74) Jeyakumar M et al. Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc. Nat. Acad. Sci. 96: 6388-6393, 1999
(75) Liu Y et al. A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder. J. Clin. Invest. 103: 497-505, 1999
(76) Drousiotou A et al. Sandhoff disease in Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community. Hum. Genet. 107: 12-17, 2000
(77) Chamoles NA et al. Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. Clin. Chim. Acta 318: 133-137, 2002
(78) Myerowitz, R.; Lawson, D.; Mizukami, H.; Mi, Y.; Tifft, C. J.; Proia, R. L. : Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum. Molec. Genet. 11: 1343-1350, 2002
(79) Yamaguchi, A.; Katsuyama, K.; Nagahama, K.; Takai, T.; Aoki, I.; Yamanaka, S. : Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses. J. Clin. Invest. 113: 200-208, 2004
(80) Frey, L. C.; Ringel, S. P.; Filley, C. M. : The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis. Arch. Neurol. 62: 989-994, 2005
(81) Zampieri, S.; Filocamo, M.; Buratti, E.; Stroppiano, M.; Vlahovicek, K.; Rosso, N.; Bignulin, E.; Regis, S.; Carnevale, F.; Bembi, B.; Dardis, A. : Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles. Neurogenetics 10: 49-58, 2009

2009/04/11
2016/07/15 変異改訂
2020/04/21 SNP改訂 変異追加