疾患詳細

疾患詳細





#253400
Spinal muscular atrophy, type III (SMA3)
(SMA III)
(Muscular atrophy, juvenile)
(Kugelberg-Welander syndrome; KWS)
(Spinal muscular atrophy, mild childhood and adolescent form)

脊髄性筋萎縮 III
(筋萎縮, 若年性)
(Kugelberg- Welander 症候群; KWS)
(脊髄性筋萎縮,軽症乳児および思春期型)
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+性の影響

(症状)
(GARD)
 
 Areflexia of lower limbs (下肢無反射) [HP:0002522] [0242]
 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]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Limb fasciculations (四肢攣縮) [HP:0007289] [02604]
 Muscle spasm (筋スパスム) [HP:0003394] [01405]
 Progressive (進行性) [HP:0003676]
 Proximal muscle weakness (近位筋筋力低下) [HP:0003701] [0270]
 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)
【神経】対称性近位筋力低下 (近位が遠位より重度, 下肢が上肢より重度)
 近位筋萎縮 →遠位へ (2-17歳発症, 緩徐進行性または安定)
 筋けいれん
 慢性脱髄 (筋電図)
 四肢 筋線維束攣縮
 前角細胞変性
 *繊細な振戦 /
 手振戦
 低反射
 下肢無反射
【口】舌筋線維束攣縮/筋線維性攣縮
【その他】18か月以後症状あり
 患者は起立と歩行能力は生じる
 進行性疾患
 患者は起立および歩行能を発達する
 成人で死亡
 NAIP 遺伝子 (600355) 欠失が SMA2 患者の18%でみられる

【一般】呼吸器感染症
 虚弱
 遺尿
 知能正常
 不整脈
【神経】筋緊張低下
 感覚喪失なし
【心】心筋症
【四肢】関節拘縮
 四肢筋線維束攣縮
【X線】骨粗鬆症
 側弯
【検査】筋酵素正常または軽度上昇
 下位運動ニューロン疾患 (筋生検, 筋電図で)

<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
(Comment) allelic to type I, III
(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)

(Responsible gene) *601627 Survival of motor neuron 2 (SMN2) <5q13.2>
.0001 Spinal muscular atrophy, modifier of (253400) [SMN2, GLY287ARG [dbSNP:rs121909192] (ExAC:rs121909192) (RCV000008426...) (Prior et al. 2009)

(Note)
A number sign (#) is used with this entry because spinal muscular atrophy type III (SMA3) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13.

SMA is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; 253300), II (SMA2; 253550), III (SMA3), and IV (271150), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by Fraidakis et al., 2012).

Clinical Features
Kugelberg and Welander (1956) reported 5 children, among the 12 offspring of normal parents, with a juvenile form of spinal muscular atrophy; 2 of the 5 were monozygotic twins.

Levy and Wittig (1962) described proximal muscular atrophy in 2 half brothers, with onset at 13 and 16 years. Onset of the juvenile form is usually between 2 and 17 years of age. Atrophy and weakness of proximal limb muscles, primarily in the legs, is followed by distal involvement. Usually the cases are diagnosed as limb-girdle muscular dystrophy until they are studied fully. Twitchings (fasciculations) are an important differentiating sign. Muscular biopsy and electromyography show the true nature of the process as a lower motor neuron disease. Pulmonary dysfunction is often a cause of morbidity in these patients.

Samaha et al. (1994) studied forced vital capacity longitudinally in 40 SMA patients ranging in age from 5 to 18 years. Although the majority of the patients grew in height, only 35% showed an increase in height-adjusted forced vital capacity. In the most seriously affected patients, all lost height-adjusted forced vital capacity over time. Furukawa et al. (1968) reported 2 families, each with affected brother and sister. The parents in one family were first cousins. The authors pointed out that in their cases, as well as in those in the literature, the symptoms of female patients were mild and the clinical course slow whereas male sibs were severely affected. They interpreted this as sex-influence.

Bundey and Filomeno (1974) described a black sibship in which 5 sibs out of 10 had this disorder.

Pearn et al. (1978) reported a spinal muscular atrophy syndrome characterized by adolescent onset, gross hypertrophy of the calves, and a slowly progressive clinical course. One of their families with 2 affected brothers and 2 affected maternal uncles probably had Kennedy disease (313200), an X-linked form of SMA with which calf hypertrophy has been observed.

Fraidakis et al. (2012) reported 2 unrelated French men, aged 44 and 50 years, with SMA type III. Both had onset of slowly progressive proximal lower limb weakness beginning in adolescence, followed by proximal upper limb weakness. At age 44, the first patient patient had proximal lower limb amyotrophy, proximal upper and lower limb weakness, and absence of lower limb reflexes; he used a cane to walk. Muscle biopsy and EMG showed a chronic neuropathic process. The second patient developed muscle cramps and was wheelchair-bound at age 48. Physical examination showed severe motor deficit and amyotrophy in the pelvic and shoulder girdles, as well as severe motor deficit and amyotrophy in the distal limb muscles. EMG was consistent with severe chronic denervation at all extremities. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes.

Inheritance
Spira (1963) described 7 affected members in 2 sibships of a family with proximal spinal muscular atrophy. In each case the affected persons were offspring of a first-cousin marriage, consistent with autosomal recessive inheritance.

Pearn et al. (1978) reviewed 141 cases of SMA with onset before age 14 years (excluding SMA type I, or Werdnig-Hoffmann disease). Autosomal recessive inheritance could account for over 90% of cases. In these, onset was before age 5 and usually before age 2 years. The disorder was compatible with life into the third decade. A small group of cases appeared to be either new dominant mutations or phenocopies. Hausmanowa-Petrusewicz et al. (1985) called this the mild childhood and adolescent type of spinal muscular atrophy and emphasized the significance of sex influence (Hausmanowa-Petrusewicz et al., 1984). Zerres et al. (1987) advanced Becker's allelic model as a possible explanation for unusual pedigrees with spinal muscular atrophy. Because of the finding of linkage of SMA I, II (SMA2; 253550), and III to the same region, 5q11.2-q13.3 (Brzustowicz et al., 1990), it is likely that these are allelic disorders.

Clinical Management
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.

Weihl et al. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 gene transcription and result in increased production of full-length SMN protein.

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.

Cytogenetics
Brzustowicz et al. (1994) detected paternal isodisomy for chromosome 5 in a 2-year-old boy with type III SMA. Examination of 17 short-sequence repeat polymorphisms spanning a large part of the chromosome produced no evidence of maternally inherited alleles. Cytogenetic analysis showed a normal male karyotype, and fluorescence in situ hybridization with probes closely flanking the SMA locus confirmed the presence of 2 copies of chromosome 5. No developmental abnormalities other than those attributable to classic childhood-onset SMA were present.

In an analysis of uniparental disomy cases, Kotzot (1999) found only one example of uniparental disomy involving chromosome 5, that of Brzustowicz et al. (1994). No reports were found of uniparental disomy of chromosomes 12, 17, 18, and 19. On the other hand, 33 examples of chromosome 16 UPD were found, all of them maternal except 1. The bases of UPD are always 2 events: 2 meiotic; 1 meiotic and 1 mitotic; or 2 mitotic. Abnormal phenotypes result from an aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal mutations in females, and father-to-son transmission of X-linked traits. The most frequent mechanism of UPD appears to be fertilization of a disomic gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue). This mechanism might result in mosaicism in the placenta or even in a subset of fetal tissues. This low level mosaicism can remain undetected and renders the delineation of a phenotype difficult. In general, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, nonmendelian inheritance of monogenic disorders, or a combination of these factors.Kotzot (1999) reviewed the entire bibliography of UPD other than that involving chromosome 15 and found a predominance of maternal versus paternal UPD (approximately 3 in 1) and a nonuniform chromosomal distribution.

Molecular Genetics
Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 8 patients (6 Belgian and 2 Turkish) with SMA III. The SSCP assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 7 of the 8 SMA III patients, homozygous deletion of exon 7 of the SMN gene was detected. In 6 of the 7, the deletion was associated with homozygous deletion of exon 8, and in 1 it was associated with heterozygous deletion of exon 8. Deletion of the SMN gene was not found in 1 Belgian patient with typical manifestations of SMA III.

In families with proximal spinal muscular atrophy affecting individuals in 2 generations, Rudnik-Schoneborn et al. (1996) examined whether there was pseudodominant inheritance of the regular autosomal recessive form or a dominant form of SMA which is not linked to 5q (see 158590). Four families had affected members in 2 generations who showed SMN gene deletions. The range of variability in severity was striking. In family 4, the father had onset at age 16, whereas the son had onset in the first year; both had deletion of exons 7 and 8 of the SMN gene. Even more striking was family 3, in which the father had onset 'in youth' and the first son was asymptomatic thus far, whereas the second son had onset at 6 months of age (SMA I); all 3 had deletion of exons 7 and 8 of the SMN gene. Two sons had inherited different haplotypes from their affected father and shared identical maternal haplotypes. Rudnik-Schoneborn et al. (1996) noted that, although homozygous deletions in the telomeric copy of the SMN gene can be detected in 95% to 98% of patients with early-onset SMA types I and II (Hahnen et al., 1995), as many as 10% to 20% of patients with type III SMA do not show deletions. Since no molecular genetic test was available to support a locus other than that on 5q, the question of heterogeneity remained an important issue in proximal SMA. Given an incidence of more than 1/10,000 for autosomal recessive SMA (what Rudnik-Schoneborn et al. (1996) referred to as 'SMA 5q'), patients with autosomal recessive SMA have a recurrence risk of approximately 1% to their offspring.

In 2 unrelated French men with onset of SMA type III in adolescence, Fraidakis et al. (2012) identified compound heterozygosity for a deletion of the SMN1 gene (600354.0021) and a missense mutation affecting the same codon in exon 3 (Y130C, 600354.0019 and Y130H, 600354.0020, respectively). Both missense mutations affected highly conserved residues in the Tudor domain, but the patients had a relatively mild form of the disorder. One patient had 1 copy of SMN2 and the other had 2 copies of SMN2. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes.

Modifying Factors

Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.

Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 (271150) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis.

Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of a 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. 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.

In a 42-year-old woman with a mild form of SMA type III, despite a homozygous absence of SMN1 exon 7, Prior et al. (2009) identified a homozygous variant (G287R; 601627.0001) in the SMN2 gene. In vitro functional expression studies showed that the variant resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SNM2) predicted a more severe disorder (SMA1; 253300), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same G287R variant was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2).

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.

Riessland et al. (2017) identified NCALD (606722), a negative regulator of endocytosis, as a modifying factor in SMA. They identified 5 asymptomatic members of a 4-generation Mormon family from Utah who were homozygous for SMN1 deletions and had 4 SMN2 copies, resembling a genotype associated with type 3 SMA. Linkage analysis combined with transcriptome-wide expression analysis identified significant downregulation of NCALD in these individuals compared to controls. The decreased expression of NCALD was associated with 2 polymorphisms on chromosome 8q: a 2-bp insertion (rs147264092) in intron 1 of the NCALD gene and a 17-bp deletion (rs150254064) located 600-kb upstream of NCALD. These 2 variants were also found in an unrelated patient with a homozygous SMN1 deletion and only 1 copy of SMN2: this genotype would have been predicted to result in perinatal lethality, but the patient survived for 9 months. Cellular studies in SMN-deficient cells showed that knockdown of Ncald triggered motor neuron differentiation and restored neurite and axonal growth. Knockdown of Ncald in several SMA animal models ameliorated SMA-associated pathologic defects and improved endocytosis and synaptic function. The findings suggested that decreased levels of NCALD may act as a protective modifier in SMA, and that perturbed synaptic vesicle endocytosis plays a role in the pathogenesis of the disease.

Population Genetics
In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified deletion of SMN1 exon 7 in heterozygous state in 179 individuals among 1,415 screened and in homozygous state in 2, giving a carrier frequency of 0.127 (1 in 8). The carrier frequency in other populations is 1 in 35 (Hendrickson et al., 2009). One adult was homozygous for the SMA-causing deletion. She was previously reported by Chong et al. (2011). At the time of the initial evaluation she was 41 years old and asymptomatic. She subsequently died of cancer at the age of 50 without any symptoms related to SMA, according to her close relatives.

History
A dominant form represented by the mother and 2 children described by Ford (1961) may also exist and this may be the same as what has been termed scapuloperoneal amyotrophy (181400).

Animal Model
Simon et al. (2010) analyzed Smn +/- mice, a model of type III/IV SMA, electrophysiologically and histologically to characterize single motor units. Smn +/- mice exhibit progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Confocal analysis revealed pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF; 118945) is highly expressed in Schwann cells, Simon et al. (2010) investigated its role in a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF resulted in reduced sprouting and decline of muscle strength in Smn +/- mice. The authors concluded that CNTF is necessary for a sprouting response and thus may enhance the size of motor units in skeletal muscles of Smn +/- mice.

Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease.

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