(GM2-gangliosidosis, type II)
(Hexosaminidase A and B deficiency)
(Sandhoff disease, adult type, included)
(Sandhoff disease, juvenile type, included)
(Sandhoff disease, infantile type, included)
(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)
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>
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] 
Ataxia (運動失調) [HP:0001251] 
Blindness (盲) [HP:0000618] 
Cherry red spot of the macula (チェリーレッド斑) [HP:0010729] 
Failure to thrive (成長障害) [HP:0001508] 
Hearing impairment (難聴) [HP:0000365] 
Kyphosis (Hunched back) (後弯) [HP:0002808] 
Macrocephaly (大頭) [HP:0000256] 
Motor deterioration (運動悪化) [HP:0002333] 
Progressive psychomotor deterioration (進行性精神運動発達悪化) [HP:0007272] 
Seizures (けいれん) [HP:0001250] 
Full cheeks (大きな頬部) [HP:0000293] 
Hepatomegaly (肝腫) [HP:0002240] 
Muscle weakness (筋力低下) [HP:0001324] 
Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] 
Splenomegaly (脾腫) [HP:0001744] 
Congestive heart failure (うっ血性心不全) [HP:0001635] 
Skeletal dysplasia (骨格異形成) [HP:0002652] 
Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
Cardiomegaly (心拡大) [HP:0001640] 
Chronic diarrhea (慢性下痢) [HP:0002028] 
Coarse facial features (粗な顔貌) [HP:0000280] 
Dysarthria (構音障害) [HP:0001260] 
Episodic abdominal pain (エピソード性腹痛) [HP:0002574] 
Fasciculations (攣縮) [HP:0002380] 
Hepatosplenomegaly (肝脾腫) [HP:0001433]  
Hyperhidrosis (多汗) [HP:0000975] 
Hyperreflexia (反射亢進) [HP:0001347] 
Hypohidrosis (低汗) [HP:0000966] 
Impaired thermal sensitivity (温覚障害) [HP:0006901] 
Impotence (インポテンツ) [HP:0000802] 
Macroglossia (巨舌) [HP:0000158] 
Orthostatic hypotension (起立性低血圧) [HP:0001278] 
Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] 
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] 
けいれん (12-15 か月までに)
【検査】Hexosaminidase B beta chain 欠損 (血清, 組織)
●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
臨床的に Sandhoff 病は Tay-Sachs 病 (beta-hexosaminidase A 異常)と区別できない
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
古典的乳児型は, Sandhoff 病は臨床的に Tay-Sachs 病と区別できない
→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
●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
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＞
(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)
.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)
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).
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.
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.
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.
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.
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.
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.
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.
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).
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.
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