疾患詳細

疾患詳細





#253550
Spinal muscular atrophy, type II (SMA2)
(SMA II)
(Muscular atrophy, spinal, intermediate type)
(Muscular atrophy, spinal, infantile chronic form)

脊髄性筋萎縮 II
(筋萎縮, 脊髄性, 中間型)
(筋萎縮, 脊髄性, 乳児慢性型)
小児慢性特定疾病 神30 脊髄性筋萎縮症

責任遺伝子:600354 Survival of motor neuron 1, telomeric (SMN1) <5q13.2>
遺伝形式:常染色体劣性

(症状)
(GARD)
 
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Degeneration of anterior horn cells (前角細胞変性) [HP:0002398]
 EMG abnormality (筋電図異常) [HP:0003457]
 Hand tremor (手振戦) [HP:0002378] [02604]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Spinal muscular atrophy (脊髄性筋萎縮) [HP:0007269] [0270]
 Tongue fasciculations (舌線維束性攣縮) [HP:0001308] [02604]

(UR-DBMS)
【一般】呼吸器感染症
 *虚弱
 不整脈
 遺尿
 呼吸不全
【神経】*筋緊張低下
 *深部腱反射低下
 筋萎縮 (3-15 か月で発症)
 筋力低下, 対称性, 近位 (上肢より下肢が重い), 運動ニューロン症による
 EMG は神経原性異常を示す
 感覚喪失なし
 筋線維束攣縮
 舌筋線維束攣縮/筋線維性攣縮
 前角細胞変性
 手 振戦
【心】心筋症
【四肢】関節拘縮
【X線】骨粗鬆症
 側弯
【その他】6-18か月で受診
 2歳〜若年成人で死亡
 呼吸器感染症または不全により死亡
 小児は支持なしで座れることが多いが歩行できない
 NAIP 遺伝子 (600355) 欠失が SMA2 患者の18%でみられる

<小児慢性特定疾病 神30 脊髄性筋萎縮症>
診断方法
Ⅰ.主要臨床症状
1. 運動発達遅滞 (I型,II型)
2. 筋緊張低下
3. 筋力低下(必須)進行性
4. 手指や舌の線維束性収縮 (fasciculation)
5. 深部腱反射が減弱から消失
Ⅱ.本症では認めない臨床症状
1. 痙縮
2. 深部腱反射亢進
3. 病的反射陽性
Ⅲ.重要な検査所見
1. 筋電図にて高振幅電位や多相性電位など神経原性所見を認める。
2. survival motor neuron (SMN)遺伝子に変異を認める。(レポート添付)(必須)
Ⅳ. その他の参考所見
1. 関節拘縮・側弯
2. 摂食・嚥下障害
3. 呼吸障害

IV. 診断基準
必須項目Ⅱを認めず,Ⅰ,Ⅲ-2を満たす場合本症と診断する。

当該事業における対象基準
神経B
運動障害が続く場合又は治療として強心薬, 利尿薬, 抗不整脈薬, 末梢血管拡張薬, β遮断薬, 肺血管拡張薬, 呼吸管理(人工呼吸器, 気管切開術後, 経鼻エアウェイ等の処置を必要とするものをいう。), 酸素療法, 中心静脈栄養若しくは経管栄養のうち一つ以上を継続的に行っている場合

概念・定義
 脊髄性筋萎縮症(spinal muscular arophy; SMA)は, 脊髄の前角細胞の変性による筋萎縮と進行性筋力低下を特徴とする下位運動ニューロン病である。上位運動ニューロン徴候は伴わない。体幹, 四肢の近位部優位の筋力低下, 筋萎縮を示す。発症年齢, 臨床経過に基づき, I型(OMIM#253300), II型(OMIM#253550), III型(OMIM#253400), IV型(OMIM#27115)に分類される。I, II型の95%にSMN遺伝子欠失が認められ, III型の約半数, IV型の1-2割においてSMN(survival motor neuron)遺伝子変異を認める。
疫学
 諸外国の調査では, 発症は出生10,000につき1人, 保因者頻度は50~90人に1人とされている。我が国では, 乳児期~小児期に発症するSMAは10万人あたり1~2人と考えられ, 推定患者数は約1,000人前後との結果が得られている

病因
 原因遺伝子は, 1995年, 第5染色体長腕5q13.2に存在するSMN(survival motor neuron)遺伝子として同定された。I, II型のSMAにおいては, SMN遺伝子の欠失の割合は9割を超えることが明らかになっており, 遺伝子診断も可能である。また,SMN遺伝子の近傍には, NAIP(neuronal apoptosis inhibitory protein)遺伝子, SERF1(small EDRK-rich factor 1)遺伝子などが存在し, それらはSMAの臨床症状を修飾するといわれている。III, IV型においては, SMN遺伝子変異が同定されない例も多く, 他の原因も考えられている

症状
I型:重症型, 急性乳児型, ウェルドニッヒ・ホフマン(Werdnig-Hoffmann)病 
発症は出生直後から生後6ヶ月まで。フロッピーインファントの状態を呈する。肋間筋に対して横隔膜の筋力が維持されているため吸気時に腹部が膨らみ胸部が陥凹する奇異呼吸を示す。定頸の獲得がなく, 支えなしに座ることができず, 哺乳困難, 嚥下困難, 誤嚥, 呼吸不全を伴う。舌の線維束性収縮がみられる。深部腱反射は消失, 上肢の末梢神経の障害によって, 手の尺側偏位と手首が柔らかく屈曲する形のwrist dropが認められる。人工呼吸管理を行わない場合, 死亡年齢は平均6~9カ月である。

II型:中間型, 慢性乳児型, デュボビッツ(Dubowitz)病 
発症は1歳6ヶ月まで。支えなしの起立, 歩行ができず, 座位保持が可能である。舌の線維束性収縮, 手指の振戦がみられる。腱反射の減弱または消失。次第に側彎が著明になる。II型のうち, より重症な症例は呼吸器感染に伴って, 呼吸不全を示すことがある。

III型:軽症型, 慢性型, クーゲルベルグ.ウェランダー(Kugelberg-Welander)病 
発症は1歳6ヶ月以降。自立歩行を獲得するが, 次第に転びやすい, 歩けない, 立てないという症状がでてくる。後に, 上肢の挙上も困難になる。

Ⅳ型:成人期以降の発症のSMAをIV型とする。小児期発症のI, II, III型と同様のSMN遺伝子変異によるSMAもある。一方, 孤発性で成人から老年にかけて発症し, 緩徐進行性で, 上肢遠位に始まる筋萎縮, 筋力低下, 筋線維束性収縮, 腱反射低下を示す場合もある。これらの症状は徐々に全身に拡がり, 運動機能が低下する。また, 四肢の近位筋, 特に肩甲帯の筋萎縮で初発する場合もある。
SMAにおいては, それぞれの型の中でも臨床的重症度は多様である
治療
根本治療はいまだ確立していない。I型, II型では, 授乳や嚥下が困難なため経管栄養が必要な場合がある。また, 呼吸器感染, 無気肺を繰り返す場合は, これが予後を大きく左右する。I型のほぼ全例で, 救命のためには気管内挿管, 後に気管切開と人工呼吸管理が必要となる。II型においては非侵襲的陽圧換気療法(=鼻マスク陽圧換気療法:NIPPV)は有効と考えられるが, 小児への使用には多くの困難を伴う。また, 全ての型において, 筋力にあわせた運動訓練, 理学療法を行う。III型, Ⅳ型では歩行可能な状態の長期の維持や関節拘縮の予防のために, 理学療法や装具の使用などの検討が必要である。小児においても上肢の筋力が弱いため, 手動より電動車椅子の使用によって活動の幅が広くなる。I型やII型では胃食道逆流の治療が必要な場合もある。II型の脊柱変形に対しては脊柱固定術が行われる

予後
I型は1歳までに呼吸筋の筋力低下による呼吸不全の症状をきたす。人工呼吸器の管理を行わない状態では, ほとんどの場合2歳までに死亡する。II型は呼吸器感染, 無気肺を繰り返す例もあり, その際の呼吸不全が予後を左右する。III型, Ⅳ型は生命的な予後は良好である

成人期以降の注意点
 呼吸障害,嚥下障害の進行が予後を左右する.側弯の合併も高頻度であり,重度な例では手術を考慮する.心筋症の合併はない.近年,在宅人工呼吸療法,胃瘻などの適切な介入により,生命予後が改善している.

(要約) 脊髄性筋萎縮症→253300
(Responsible gene) *600354 Survival of motor neuron 1, telomeric (SMN1) <5q13.2>
(1) Spinal muscular atrophy, type I (253300)
.0001 Spinal muscular atrophy, type I [SMN1, 11-BP DUP, 801-811] (RCV000009733) (Parsons et al. 1996)
.0004 Spinal muscular atrophy, type I [SMN1, TYR272CYS [dbSNP:rs104893922] (RCV000009737) (Lefebvre et al. 1995)
.0005 Spinal muscular atrophy, type I [SMN1, GLY279VAL] (dbSNP:rs76163360) (RCV000009738) (Talbot et al. 1997)
.0009 Spinal muscular atrophy, type I [SMN1, 5-BP DEL, NT425] (RCV000009744) (Sossi et al. 2001)
.0011 Spinal muscular atrophy, type I (Spinal muscular atrophy, type II, included) (Spinal muscular atrophy, type III, included) (271150 Spinal muscular atrophy, type IV, included) [SMN1, 4-BP DEL, 133AGAG] (RCV000009750...) (Cusco et al. 2003)
.0015 Spinal muscular atrophy, type I (Spinal muscular atrophy, type II, included) [SMN1, ALA111GLY [dbSNP:rs104893935] (RCV000009754...) (Sun et al. 2005)
.0017 Spinal muscular atrophy, type I [SMN1, ILE116PHE [dbSNP:rs104893933] (RCV000009757) (Cusco et al. 2004; Sanchez et al. 2013)
.0018 Spinal muscular atrophy, type I [SMN1, GLN136GLU [dbSNP:rs104893934] (RCV000009758) (Cusco et al. 2004)
(2) Spinal muscular atrophy, type II (253550)
.0002 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, THR274ILE] (dbSNP:rs76871093) (RCV000009734...) (Hahnen et al. 1997)
.0006 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, ALA2GLY] (dbSNP:rs75030631) (RCV000009740...) (Parsons et al. 1998)
.0007 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, EX8DEL] (RCV000009742...) (Gambardella et al. 1998)
.0010 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, TRP102TER] (dbSNP:rs77804083) (RCV000009747...) (Sossi et al. 2001)
.0012 Spinal muscular atrophy, type II [SMN1, ASP30ASN [dbSNP:rs104893930] (RCV000009752) (Sun et al. 2005)
(3) Spinal muscular atrophy, type III (253400)
.0003 Spinal muscular atrophy, type III [SMN1, SER262ILE] (dbSNP:rs75660264) (RCV000009736) (Hahnen et al. 1997)
.0008 Spinal muscular atrophy, type III [SMN1, IVS7DS, T-G, +6] (RCV000009743) (Lorson et al. 1999)
.0013 Spinal muscular atrophy, type III [SMN1, ASP44VAL [dbSNP:rs104893931] (RCV000009745) (Sun et al. 2005)
.0014 Spinal muscular atrophy, type III [SMN1, GLY95ARG [dbSNP:rs104893927] (RCV000009753) (Sun et al. 2005)
.0016 Spinal muscular atrophy, type III [SMN1, SER262GLY [dbSNP:rs104893932] (RCV000009756) (Sun et al. 2005)
.0019 Spinal muscular atrophy, type III [SMN1, TYR130CYS [dbSNP:rs397514517] (RCV000032708) (Fraidakis et al. 2012)
.0020 Spinal muscular atrophy, type III [SMN1, TYR130HIS [dbSNP:rs397514518] (RCV000032709) (Fraidakis et al. 2012)
.0021 Spinal muscular atrophy, type III [SMN1, DEL] (RCV000032710) (Fraidakis et al. 2012)

(Note)
A number sign (#) is used with this entry because spinal muscular atrophy type II (SMA2) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13.

This gene is also involved in the more severe SMA type I (253300) and the less severe SMA type III (253400) and SMA type IV (271150).

Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetric muscle weakness and atrophy. SMA is the second most common lethal, autosomal recessive disease in Caucasians after cystic fibrosis (CF; 219700) (Wirth, 2000).

Clinical Features
Fried and Emery (1971) suggested the existence of a distinct form of spinal muscular atrophy intermediate in severity between the infantile form SMA type I and juvenile form SMA III. The intermediate form, which they designated SMA II, is characterized by onset usually between 3 and 15 months and survival beyond 4 years and usually until adolescence or later. Proximal muscle weakness is the cardinal feature as in other forms of spinal muscular atrophy. They presented 14 cases, of whom 2 were sibs. The parents were all unaffected and nonconsanguineous.

Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II.

Pearn et al. (1973) used a method of sib-sib correlation introduced by Haldane (1941) to support the existence of separate 'acute' and 'chronic' forms of spinal muscular atrophy.

Hanson and Bundey (1974) described 2 brothers in a sibship of 4. They suggested that SMA I and SMA III may be due to homozygosity of allelic genes, and SMA II could represent the genetic compound.

Hausmanowa-Petrusewicz et al. (1985) referred to this as the infantile chronic form of SMA.

Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II.

Mapping
On the basis of 13 clinically heterogeneous SMA families, Brzustowicz et al. (1990) concluded that 'chronic' childhood-onset SMA (including intermediate SMA, or SMA type II, and Kugelberg-Welander syndrome, or SMA type III) is genetically homogeneous, mapping to chromosomal region 5q11.2-q13.3. Their data indicated that the acute childhood SMA (type I or Werdnig-Hoffmann disease) maps to the same or a closely linked locus on 5q. The findings suggested that all 3 forms of SMA, types I, II, and III, are allelic.

In 24 multiplex families of distinct ethnic origin with chronic forms of proximal SMA, i.e., types II and III, Melki et al. (1990) demonstrated linkage to the DNA marker D5S39, thus mapping the locus to 5q12-q14. No evidence for genetic heterogeneity for types II and III was found.

To confirm the localization of the chronic forms of SMA, types II and III, to 5q12-q14 and to test for genetic homogeneity in the French-Canadian population, Simard et al. (1992) studied 8 families. They showed tight linkage to marker locus D5S39 and loose linkage to D5S6. They also presented a family that appeared to be discordant for the localization on chromosome 5; however, the family contained an apparently asymptomatic individual who was shown to be homozygous for the mutant SMA alleles.

Genetic Heterogeneity

In a linkage study of 161 families in which individuals suffered from the intermediate or mild form of SMA, Merette et al. (1994) found support for the hypothesis of linkage heterogeneity, with 5% of the families unlinked to the region 5q11.2-q13.3.

Nevo et al. (1998) presented evidence that there may be a form of type II SMA (intermediate SMA with onset between 3 and 18 months) that is unrelated to the SMN1 region on 5q13.

Molecular Genetics
Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 12 patients (7 Belgian and 5 Turkish) with SMA II. This assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 11 of the 12 patients, homozygous deletion of exon 7 of the SMN gene was detected. Of these 11, the deletion was associated with homozygous deletion of exon 8 in 10 and with heterozygous deletion of exon 8 in 1. Deletion of the SMN gene was not found in 1 Turkish patient with atypical manifestations of SMA II.

Samilchuk et al. (1996) carried out deletion analysis of the SMN gene and the neighboring NAIP (600355) gene in 11 cases of type I SMA and in 4 type II SMA cases. The patients were of Kuwaiti origin. They also analyzed samples from 41 healthy relatives of these patients and 44 control individuals of Arabic origin. Samilchuk et al. (1996) found homozygous deletions of exons 7 and 8 of the SMN gene in all SMA patients studied. Exon 5 of the NAIP gene was homozygously absent in all type I SMA patients but was retained in the type II patients. They noted that there findings were consistent with the previously reported observations that the incidence of NAIP deletion is much higher in the clinically more severe cases (type I SMA) than in the milder forms, and all of the type II SMA patients in their study had at least one copy of the intact NAIP gene.

Modifying Factors

Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of the biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene (601627). In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification.

Stratigopoulos et al. (2010) evaluated blood levels of PLS3 (300131) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. Stratigopoulos et al. (2010) concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.

Biochemical Features
In fibroblast cultures from patients with SMA1, SMA2, or SMA3, Andreassi et al. (2004) found a significant increase in SMN2 gene (601627) expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA.

Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription.

In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability.

History
Brzustowicz et al. (1990) noted that HEXB (606873) maps to the same region and that deficiency of the product of this gene (as well as of the product of the HEXA gene) has been found in association with chronic cases of SMA.

(文献)
(1) Haldane JBS: The relative importance of principal and modifying genes in determining some human diseases. J Genet 41: 149-157, 1941
(2) Fried K, Emery AEH: Spinal muscular atrophy type II. A separate genetic and clinical entity from type I (Werdnig-Hoffmann disease) and type III (Kugelberg-Welander disease). Clin Genet 2: 203-209, 1971
(3) Pearn JH et al. The genetic identity of acute infantile spinal muscular atrophy. Brain 96: 463-470, 1973
(4) Hanson JE, Bundey SE: Spinal muscular atrophy: an unusual variant with infantile onset and prolonged survival. BDOAS X(4): 339-340, 1974
(5) Hausmanowa-Petrrusewics I et al. Chronic proximal spinal muscular atrophy of childhood and adolescence: problems of classification and genetic counselling. J Med Genet 22: 350-353, 1985
(6) Bruzustowicz LM et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 344: 540-541, 1990
(7) Melki J et a. Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature 344: 767-768, 1990
(8) Simard LR et al. Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): confirmation of close linkage to D5S39 in French Canadian families. Genomics 14: 188-190, 1992
(9) Merette C et al. An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy. Genomics 21: 27-33, 1994
(10) Imai T et al. Preservation of central motor conduction in patients with spinal muscular atrophy type II. Brain Dev 17: 432-435, 1995
(11) Matthijs G et al. Unusual molecular findings in autosomal recessive spinal muscular atrophy. J Med Genet 33: 409-474, 1996
(12) Samilchuk E et al. Deletion analysis of the SMN and NAIP genes in Kuwaiti patients with spinal muscular atrophy. Hum. Genet. 98: 524-527, 1996
(13) Nevo Y et al. SMA type 2 unrelated to chromosome 5q13. Am J Med Genet 75: 193-195, 1998
(14) Andreassi, C.; Angelozzi, C.; Tiziano, F. D.; Vitali, T.; De Vincenzi, E.; Boninsegna, A.; Villanova, M.; Bertini, E.; Pini, A.; Neri, G.; Brahe, C. : Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Europ. J. Hum. Genet. 12: 59-65, 2004
(15) Grzeschik, S. M.; Ganta, M.; Prior, T. W.; Heavlin, W. D.; Wang, C. H. : Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann. Neurol. 58: 194-202, 2005
(16) Brichta, L.; Holker, I.; Haug, K.; Klockgether, T.; Wirth, B. : In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann. Neurol. 59: 970-975, 2006
(17) Jedrzejowska, M.; Borkowska, J.; Zimowski, J.; Kostera-Pruszczyk, A.; Milewski, M.; Jurek, M.; Sielska, D.; Kostyk, E.; Nyka, W.; Zaremba, J.; Hausmanowa-Petrusewicz, I. : Unaffected patients with a homozygous absence of the SMN1 gene. Europ. J. Hum. Genet. 16: 930-934, 2008
(18) Stratigopoulos, G., Lanzano, P., Deng, L., Guo, J., Kaufmann, P., Darras, B., Finkel, R., Tawil, R., McDermott, M. P., Martens, W., Devivo, D. C., Chung, W. K. Association of plastin 3 expression with disease severity in spinal muscular atrophy only in postpubertal females. Arch. Neurol. 67: 1252-1256, 2010

2010/07/24
2011/07/28
2012/01/11
2012/11/10
2016/07/08 SNP
2017/05/02 ノート改訂
2017/06/24 RCV