疾患詳細

疾患詳細





#272750
GM2-gangliosidosis, AB variant
(Hexosaminidase activator deficiency)
(GM2-gangliosidosis, type AB)
(AB variant GM2-gangliosidosis)
(Tay-Sachs disease, AB vriant)

Tay-Sachs 病, AB バリアント
(ヘキソサミニダーゼ活性化因子欠損)
(GM2-ガングリオシドーシス, AB 型)
(GM2-ガングリオシドーシス, AB バリアント)
(GM2 活性化因子; GM2A)
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:613109 GM2 activator (GM2A) <5q33.1>
遺伝形式:常染色体劣性

(症状)
【一般】精神運動発達遅滞
 けいれん
 認知症
 誤嚥 (肺炎)
 早期死亡
【神経】驚愕反応増加
 体軸筋緊張低下
 筋緊張低下
 反射亢進
 頸定不全
 無感動
 麻痺
 筋萎縮
 痙性四肢不全麻痺
 視覚不注意
 神経変性
 獲得能力喪失
 認知低下
 発語喪失
 錐体路サイン
 ジストニア
 舞踏病
 原始反射
 大脳萎縮
 脳生検は膜性ニューロン細胞質封入体を示す
 星状細胞性封入体
【頭】大頭
【眼】チェリー・レッド斑 (大多数の患者で)
 さまよう眼球運動
 網膜中心窩周囲の灰白色領域
 盲
【耳】聴覚過敏
【検査】組織でのGm2-ganglioside 蓄積
【その他】乳児期または小児期発症
 多様な重症度

(要約)
 6〜12か月令での進行性筋力低下と運動機能喪失と, 驚愕反射の増加, チェリーレッド斑, 正常サイズの肝脾は, 特に Ashkenazi ユダヤ人では急性乳児性hexosaminidase A 欠乏症 (Tay-Sachs 病)の診断を強く示唆する
 activator 欠乏性Tay-Sachs 病はもう一つの非常にまれな乳児性GM2 ganglioside蓄積症である
 → HEX A と HEX B の酵素活性は正常であるが, GM2 ganglioside の分解に必要なリソソーム内糖タンパク"GM2 activator"の欠乏によりGM2 ganglioside蓄積が生じる
 表現型は, 古典的Tay-Sachs 病と同じである

<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

(責任遺伝子) *613109 GM2 activator (GM2A) <5q33.1>
.0001 GM2-gangliosidosis, AB variant (272750) [GM2A, CYS138ARG [dbSNP:rs137852797] (RCV000000421) (Schroder et al. 1991)
.0002 GM2-gangliosidosis, AB variant [GM2A, ARG169PRO] (dbSNP:rs104893892) (RCV000000422) (Schroder et al. 1993)
.0003 GM2-gangliosidosis, AB variant [GM2A, 3-BP DEL, LYS88DEL] (RCV000000423) (Schepers et al. 1996)
.0004 GM2-gangliosidosis, AB variant [GM2A, 1-BP DEL, FS170TER] (RCV000000424) (Schepers et al. 1996)
.0005 GM2-gangliosidosis, AB variant [GM2A, GLU54TER] (dbSNP:rs104893897) (RCV000000425) (Chen et al. 1999)
.0006 GM2-gangliosidosis, AB variant [GM2A, PRO55LEU [dbSNP:rs730882196] (ExAC:rs730882196) (RCV000162097...) (Salih et al. 2015)

(Note)
A number sign (#) is used with this entry because GM2-gangliosidosis AB variant is caused by homozygous mutation in the GM2A gene (613109) on chromosome 5q33.

The GM2-gangliosidoses are a group of disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes, mainly of neuronal cells. GM2-gangliosidosis AB variant is characterized by normal hexosaminidase A (HEXA; 606869) and hexosaminidase B (HEXB; 606873) but the inability to form a functional GM2 activator complex. The clinical and biochemical phenotype of the AB variant is very similar to that of classic Tay-Sachs disease (see 272800) (Gravel et al., 2001).

Clinical Features
●Sandhoff et al. (1971) は, Sandhoff 病 (268800) をバリアントOと呼び (hexosaminidase A と B の両方が欠損しているから), 古典的 Tay-Sachs 病をバリアントBと呼んだ (hexosaminidase A は欠損しているが, hexosaminidase B は増加して存在するから)
 彼らは, 彼らがバリアント AB と呼んだ3番目の型をもつ1例を調べた
   Hex-A と Hex-B の両方の量が増加しているから
 Sandhoff の ABバリアントの患者は, 臨床的に Boston にいた Hugo Moser により調べられた
 男女同胞2例が患者であった
 ABバリアントでは, Gm2-ganglioside が, Hex-A と Hex-B の両方が存在するにもかかわらず, 他の2つの型でのように蓄積していた
 患者はフランス系カナダ人であった (Phillips, 1983)

De Baecque et al. (1975) reported a black female infant with the AB variant of GM2-gangliosidosis. She had normal early development, but showed loss of developmental skills beginning around 9 months of age. At age 12 months, she presented with a prolonged generalized seizure, and was found to have increased startle to sound, hypotonia, and cherry-red macular spots. By age 14 months, she could no longer sit or roll over. Brain biopsy showed neurons and astrocytes with cytoplasmic membranous inclusions of storage material, and HEXA and HEXB were normal.

Chen et al. (1999) reported a new patient with deficiency of the GM2 activator protein. No consanguinity was identified in the family, but the patient was derived from a geographically isolated, small Laotian hill tribe. The child was thought to be normal until the age of approximately 5 months when he was noted to have delayed motor milestones and increasing weakness. At age 9 months, magnetic resonance imaging showed increased signal density in the periventricular white matter and altered signal density in the basal ganglia. Ophthalmologic evaluation showed bilateral macular cherry red spots. At age 2.5 years, he was evaluated for his neurodegenerative course. The patient was experiencing approximately 3 major motor seizures and hundreds of myoclonic jerks per day. Hyperacusis was extreme, with an exaggerated startle response. Physical examination showed a nondysmorphic, profoundly hypotonic child, who was unresponsive to his environment. Despite normal Hex-A levels in lymphocytes, the clinical diagnosis strongly suggested Tay-Sachs disease.

Sakuraba et al. (1999) described complete absence of the GM2 activator protein by Western blot analysis and metabolic studies in a Japanese patient with a progressive neurologic disorder that began with muscular weakness and hypotonia at 1 month of age. The patient later developed a startle reaction, severe psychomotor retardation, and myoclonic seizures. Northern blot analysis demonstrated normal levels of mRNA of the appropriate size, and no mutations were detected in the protein coding region of the GM2 activator gene. The authors speculated that there may be other factors affecting the activity or stability of the GM2 activator.

Clinical Variability

Salih et al. (2015) reported 3 patients from a highly consanguineous Saudi family with childhood onset of a neurodegenerative disorder. The patients developed normally until 7 or 8 years of age, at which time they showed some abnormal behavior, including increased anxiety and phobias. Thereafter, all showed loss of developmental skills, including speech, cognition, and motor function. They developed spastic quadriparesis, limb dystonia, pyramidal signs, and generalized chorea. The hyperkinetic disorder gradually gave way to a rigid akinetic state, and all patients lost independent ambulation in the teenage years. Brain imaging showed cortical atrophy; biopsies were not reported. None of the patients had hyperacusis or cherry-red macular spots. Exome sequencing identified a homozygous mutation in the GM2A gene (P55L; 613109.0006). Functional studies of the variant and studies of patient cells were not performed. Salih et al. (2015) noted that the phenotype in this family was milder than that usually observed in patients with this disorder, thus expanding the phenotypic spectrum associated with GM2A mutations.

Inheritance
The transmission pattern of the AB variant of GM2-gangliosidosis in the family reported by Salih et al. (2015) was consistent with autosomal recessive inheritance.

Pathogenesis
Conzelmann and Sandhoff (1978) showed that an activating factor necessary for the degradation of GM2-ganglioside by HEXA is defective in the AB variant. This activating factor is necessary for the interaction of lipid substrates and the water-soluble hydrolase. The factor is normal in Tay-Sachs and Sandhoff diseases.

Molecular Genetics
In cultured fibroblasts derived from a black female infant, born of unrelated parents, with immunologically proven GM2 activator protein deficiency, Schroder et al. (1991) and Xie et al. (1992) identified a homozygous missense mutation in the GM2A gene (C138R; 613109.0001). The patient was originally reported by de Baecque et al. (1975).

By RT-PCR of the GM2A gene in a patient with deficiency of GM2-activator protein, Chen et al. (1999) detected some normal-sized cDNA and a smaller cDNA species, which was not seen in the RT-PCR products from normal controls. Sequencing revealed that although the patient's normal-sized cDNA contained a single nonsense mutation in exon 2, his smaller cDNA was the result of an in-frame deletion of exon 2. Long PCR was used to amplify introns 1 and 2 from the patient and normal genomic DNA, and no differences in size, in 5-prime and 3-prime end sequences, or in restriction-mapping patterns were observed. From these data, Chen et al. (1999) developed a set of 4 PCR primers that could be used to identify GM2A mutations. With this procedure, they demonstrated that the patient was probably homozygous for a nonsense mutation, glu54 to ter (613109.0005). Chen et al. (1999) pointed to the work of Dietz et al. (1993) and of others, indicating that shortened reading frames (i.e., early stop codons) can lead not only to mRNA instability, but also to the in-frame skipping of the constitutive exon in which the mutation is found. They also noted that Valentine and Heflich (1997), from a study of the association of nonsense mutations with exon skipping in hprt mRNA of Chinese hamster ovary cells, concluded that the association was the result of an RT-PCR artifact. Chen et al. (1999) interpreted their results as supporting the conclusion of Valentine and Heflich (1997).

Animal Model
Liu et al. (1997) generated mice with a disrupted Gm2a gene as a model; knockout mouse models for Tay-Sachs and Sandhoff disease had previously been studied. Mice with disruption of the Hexa gene (the Tay-Sachs disease model) were asymptomatic, whereas those with absence of Hexb (the Sandhoff disease model) were severely affected. The mice with disruption of Gm2a demonstrated neuronal storage, but only in restricted regions of the brain, reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in these mice consisted of GM2 with a low amount of GA2. Their results demonstrated that the activator protein is required for GM2 degradation and also may indicate a role for GM2 activator in GA2 degradation.

History
O'Neill et al. (1978) described a 22-year-old non-Jewish female who, although slow in school, had no recognized neurologic abnormality until age 18 when seizures began. They considered this an adult-onset form of the AB variant of GM2-gangliosidosis. However, Gravel et al. (2001) concluded that this was most likely not a case of the AB variant because the brain gangliosides showed only minor relative increases of monosialogangliosides, a highly nonspecific finding seen in many neurodegenerative disorders, and because no evidence of impaired GM2 ganglioside degradation was provided.

(文献)
(1) Sandhoff K et al. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem 18: 2409-2489, 1971
(2) Conzelmann E, Sandhoff K: AB variant of infantile Gm2-gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside Gm2 and glycolipid Ga2. Proc Nat Acad Sci 75: 3979-3983, 1978
(3) O'Neill B et al. Adult-onset Gm2-gangliosidosis: seizures, dementia, and normal pressure hydrocephalus associated with glycolipid storage in the brain and arachnoid granulation. Neurology 28: 1117-1123, 1978
(4) Li SC et al. A new variant of type-AB GM2-gangliosidosis. Biochem Biophys Res Commun 101: 479-485, 1981
(5) Hechtman P et al. Deficiency of the hexosaminidase A activator protein in a case of GM2 gangliosidosis, variant AB. Pediat Res 16: 217-222, 1982
(6) Inui K et al. Immunological evidence for deficiency in an activator protein for sulfatide sulfatase in a variant form of metachromatic leukodystrophy. Proc Nat Acad Sci 80: 3074-3077, 1983
(7) Li Y-T et al. Differentiation of two variants of type-AB Gm-2-gangliosidosis using chromogenic substrates. Am J Hum Genet 35: 520-522, 1983
(8) Li Y-T et al. Presence of activator proteins for the enzymic hydrolysis of GM1 and GM2 gangliosides in normal human urine. Am J Hum Genet 35: 629-634, 1983
(9) Burg J et al. Mapping of the gene coding for the human GM2 activator protein to chromosome 5. Ann Hum Genet 49: 41-45, 1985
(10) Kleyn PW et al. Spinal muscular atrophy is not the result of mutations at the beta-hexosaminidase or GM(2) -activator locus. Neurology 41: 1418-1422, 1991
(11) Schroder M et al. A mutation in the gene of a glycolipid-binding protein (GM2 activator) that causes GM2-gangliosidosis variant AB. FEBS Lett 290: 1-3, 1991
(12) Xie B et al. Identification of a processed pseudogene related to the functional gene encoding the G-M2 activator protein: localization of the pseudogene to human chromosome 3 and the functional gene to human chromosome 5. Genomics 14: 796-798, 1992
(13) Xie B et al. A cys138-to-arg substitution in the G-M2 activator protein is associated with the AB variant form of G-M2 gangliosidosis. Am J Hum Genet 50: 1046-1052, 1992
(14) Heng HHQ et al. Refined mapping of the GM2 activator protein (GM2A) locus to 5q31.3-q33.1, distal to the spinal muscular atrophy locus. Genomics 18: 429-431, 1993
(15) Schroder M et al. Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells. Hum Genet 92: 437-440, 1993
(16) Swallow DM et al. Regional localization of the gene coding for the GM2 activator protein (GM2A) to chromosome 5q32-33 and confirmation of the assignment of GM2AP to chromosome 3. Ann Hum Genet 57: 187-193, 1993
(17) Yamanaka S et al. The mouse gene encoding the G(M2) activator protein (Gm2a): cDNA sequence, expression, and chromosome mapping. Genomics 24: 601-604, 1994
(18) Schepers U et al. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am. J. Hum. Genet. 59: 1048-1056, 1996
(19) Liu Y et al. Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment. Proc. Nat. Acad. Sci. 94: 8138-8143, 1997
(20) Chen B ET AL. Structure of the GM2A gene: identification of an exon 2 nonsense mutation and a naturally occurring transcript with an in-frame deletion of exon 2. Am. J. Hum. Genet. 65: 77-87, 1999
(21) Sakuraba H et al. GM2 gangliosidosis AB variant: clinical and biochemical studies of a Japanese patient. Neurology 52: 372-377, 1999
(22) Gravel, R. A.; Kaback, M. M.; Proia, R. L.; Sandhoff, K.; Suzuki, K.; Suzuki, K. : The GM2 gangliosidoses.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. III (8th ed.) New York: McGraw-Hill 2001
(23) Salih, M. A., Seidahmed, M. Z., El Khashab, H. Y., Hamad, M. H. A., Bosley, T. M., Burn, S., Myers, A., Landsverk, M. L., Crotwell, P. L., Bilguvar, K., Mane, S., Kruer, M. C. Mutation in GM2A leads to a progressive chorea-dementia syndrome. Tremor Other Hyperkinet. Mov. 5: 306, 2015

2009/11/06
2010/12/16
2016/07/19 ノート/文献追加
2016/07/19 SNP 変異追加
2016/07/22 ノート改訂
2016/10/22 SNP
2019/06/05 RCV