疾患詳細

疾患詳細



十字サイン (T2)

#146500
Multiple system atrophy 1, susceptibility to (MSA1)
(MSA1, susceptibility to)
(Autonomic failure, pure, included)
(Hypotension, orthostatic, included)

多系統萎縮症1, への感受性
(自律神経機能不全, 純粋)
(低血圧, 起立性 )
(低血圧, 起立性 )
指定難病17 多系統萎縮症

責任遺伝子:609825 Coenzyme Q2 lyprenyltransferase (COQ2) <4q21.23>
遺伝形式:常染色体優性

(症状)
(GARD)
 <30%-79%>
 Abnormal brain FDG positron emission tomography (脳 FDG positron emission tomography 異常) [HP;0012658]
 Abnormal pyramidal sign (錐体路サイン異常) [HP:0007256] [02140][01405][0213][0241][0242][02613][0274]
 Abnormal rapid eye movement sleep (REM 睡眠異常) [HP:0002494]
 Autonomic bladder dysfunction (膀胱自律神経機能不全) [HP:0005341]
 Autonomic erectile dysfunction (勃起自律神経機能不全) [HP:0008652]
 Axial dystonia (体軸ジストニア) [HP:0002530] [0240]
 Bradykinesia (寡動) [HP:0002067] [02608]
 Camptocormia (腰曲がり, 前屈症) [HP:0100595]
 Central sleep apnea (中枢性睡眠時無呼吸) [HP:0010536 ] [01600]
 Constipation (便秘) [HP:0002019] [01803]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Female anorgasmia (女性無オルガスム症) [HP:0030015]
 Frequent falls (頻回の転倒) [HP:0002359]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Gaze-evoked nystagmus (注視誘発性眼振) [HP:0000640] [06609]
 Orofacial dyskinesia (口腔顔面ジスキネジア) [HP:0002310] [02605]
 Orthostatic hypotension due to autonomic dysfunction (自律神経機能障害による起立性低血圧) [HP:0004926] [01416]
 Orthostatic syncope (起立性失神) [HP:0012670] [0151]
 Parkinsonism (パーキンソニズム) [HP:0001300] [028]
 Postural instability (姿勢不安定) [HP:0002172] [028]
 Postural tremor (姿勢振戦) [HP:0002174] [02604]
 Progressive cerebellar ataxia (進行性小脳失調) [HP:0002073] [028]
 Raynaud phenomenon (レーノー現象) [HP:0030880] [2203]
 Resting tremor (安静時振戦) [HP:0002322] [02604]
 Rigidity (固縮) [HP:0002063] [0240]
 Stridor (喘鳴) [HP:0010307] [01602]
 
 <5%-29%>
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 
 
 Adult onset (成人発症) [HP:0003581]
 Anhidrosis (無汗) [HP:0000970] [18013]
 Ataxia (運動失調) [HP:0001251] [028]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Hypohidrosis (低汗) [HP:0000966] [18013]
 Impotence (インポテンツ) [HP:0000802] [1408]
 Iris atrophy (虹彩萎縮) [HP:0001089] [06110]
 Neurodegeneration (神経変性) [HP:0002180] [0201]
 Olivopontocerebellar atrophy (オリーブ核橋小脳萎縮) [HP:0002542] [16013] [160133] [160134]
 Orthostatic hypotension (起立性低血圧) [HP:0001278] [01416]
 Progressive (進行性) [HP:0003676]
 Ptosis (眼瞼下垂) [HP:0000508] [06807]
 Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] [0270]
 Sporadic (散発性) [HP:0003745]
 Tremor (振戦) [HP:0001337] [02604]
 Urinary incontinence (遺尿) [HP:0000020] [0192]
 Urinary urgency (尿意逼迫) [HP:0000012] [0195]

(UR-DBMS)
【一般】起立性低血圧
 遺尿
 不完全な膀胱排泄
 尿意逼迫
【神経】パーキンソン症候群
 動作緩慢
 強直
 振戦
 姿勢不安定
 小脳性失調
 構音障害
 開扇反射
 反射亢進
 自律神経障害
 軽度の認知障害 (数例で)
 グリア細胞でα-synuclein を含む細胞内封入体
 小脳の神経変性
 基底核の神経変性
 黒質の神経変性
 黒質線条体変性
 オリーブ核橋小脳変性
【眼】注視誘発性眼振
 外眼球運動傷害
【性器】勃起障害
【皮膚】発汗減少
【その他】中年発症
 進行性疾患
 多様な表現型
 L-dopa に反応が悪い
 COQ2 のヘテロ接合, ホモ接合および複合ヘテロ接合変異が証明されている

【一般】知能正常
【神経】振戦
 筋萎縮
【眼】虹彩萎縮
 眼瞼下垂

<指定難病17 多系統萎縮症>
概要
 多系統萎縮症 (multiple system atrophy: MSA) は, 成年期 (30 歳以降, 多くは 40 歳以降)に発症し, 組織学的には神経細胞とオリゴデンドログリアに不溶化したαシヌクレインが蓄積し, 進行性の細胞変性脱落をきたす疾患である。
 初発から病初期の症候が
 ●小脳性運動失調であるものはオリーブ橋小脳萎縮症 (olivopontocerebellar atrophy: OPCA),
 OPCA1/ OPCA4 Spinocerebellar ataxia 1 (SCA1)  Ataxin 1 (ATXN1) <6p22.3>
 OPCA2 Spinocerebellar ataxia 2 (SCA2) Ataxin-2 (ATXN2) <12q24.12>
 OPCA3  Spinocerebellar ataxia 7 (SCA7)  Spinocerebellar ataxia 7 (SCA7)
 OPCA5 ?
 OPCA, X-linked  Spinocerebellar ataxia, X-linked 1 (SCAX1)  ATPase, Ca(2+)-transporting, plasma membrane, 3 (ATP2B3)
 ●パーキンソニズムであるものは線条体黒質変性症,  (Nucleoporin, 62-kD (NUP62))
 ●そして特に起立性低血圧など自律神経障害の顕著であるものは各々の原著に従いシャイ・ドレーカー症候群 (現在は破棄) と称されてきた。
 いずれも進行するとこれら三大症候は重複してくること, 画像診断でも脳幹と小脳の萎縮や線条体の異 常等の所見が認められ, かつ組織病理も共通していることから多系統萎縮症と総称されるようになった。

※α-シヌクレイン はSNCA (Synuclein, alpha) 遺伝子によってエンコードされるアミノ酸140残基からなるタンパク質.
このタンパクの断片が, アルツハイマー病に蓄積するアミロイド中の (主な構成成分であるアミロイドベータとは別の) 成分として発見され, もとのタンパク質がNACP (Non-Abeta component precursor 非アミロイド成分の前駆体) と命名された。後にこれがシビレエイ属のシヌクレインタンパクと相同であることがわかり, ヒトα-シヌクレインと呼ばれるようになった。
α-シヌクレインの蓄積は, パーキンソン病をはじめとする神経変性疾患 (いわゆるシヌクレイノパチー) の原因とされている

原因
 MSA は小脳皮質, 橋核, オリーブ核, 線条体, 黒質, 脳幹や脊髄の自律神経核に加えて大脳皮質運動野などの神経細胞の変性, オリゴデンドログリア細胞質内の不溶化したαシヌクレインからなる封入体 (グリア 細胞質内封入体: GCI)を特徴とするが, 神経細胞質内やグリア・神経細胞核内にも封入体が見られる。殆どは孤発例であるが, ごく希に家族内発症がみられ, その一部では遺伝子変異が同定されている。現在, 発症機序について封入体や遺伝要因を手がかりに研究が進められているが, まだ十分には解明されていない。

症状
 わが国で最も頻度の高い病型は OPCA である。OPCA は中年以降に起立歩行時のふらつきなどの小脳性運動失調で初発し主要症候となる。初期には皮質性小脳萎縮症との区別が付きにくく二次性小脳失調症との鑑別が重要である。
 線条体黒質変性症は,筋固縮, 無動, 姿勢反射障害などの症候が初発時よりみられるのでパーキンソン病との鑑別を要する。パーキンソン病と比べて, 安静時振戦が少なく, 進行は早く, 抗パーキンソン病薬の反応に乏しい。
 起立性低血圧や排尿障害など自律神経症候で初発するものは, シャイ・ドレーガー (Shy-Drager)症候群とよばれる。その他, 頻度の高い自律神経症候としては, 勃起障害(男性), 呼吸障害, 発汗障害などがある。注意すべきは睡眠時の喘鳴や無呼吸などの呼吸障害であり, 早期から単独で 認められることがある。呼吸障害の原因として声帯外転障害が知られているが, 呼吸中枢の障害によるも のもあるので気管切開しても突然死があり得ることに注意して説明が必要である。
 何れの病型においても, 経過と共に小脳症候, パーキンソニズム, 自律神経障害は重複し, さらに錐体路徴候を伴うことが多い。自律神経障害で発症して数年を経過しても, 小脳症候やパーキンソニズムなど他の系統障害の症候を欠く場合は, 他の疾患との鑑別を要する。
 多系統萎縮症は頭部の X 線 CT や MRI で, 小脳, 橋(特に底部)の萎縮を比較的早期から認める。この変化をとらえるには T1 強調画像矢状断が有用である。また, T2 強調画像水平断にて,比較的早期から橋中部に十字状の高信号(十字サイン), 中小脳脚の高信号化が認められる。これらの所見は診断的価値が高い。
 被殻の萎縮や鉄沈着による被殻外側部の直線状の T2 高信号, 被殻後部の低信号化などもよく認められる。

治療法
 パーキンソン症候があった場合は, 抗パーキンソン病薬は, 初期にはある程度は有効であるので治療を 試みる価値はある。また, 自律神経症状や小脳失調症が加わってきたときには, それぞれの対症療法を行 う。呼吸障害には非侵襲性陽圧換気法などの補助が有用で, 気管切開を必要とする場合が在る。嚥下障害が高度なときは胃瘻が必要となることも多い。リハビリテーションは残っている運動機能の活用, 維持に有効であり積極的に勧め, 日常生活も工夫して寝たきりになることを少しでも遅らせることが大切である。

予後
 多系統萎縮症では線条体が変性するので, パーキンソン病に比べて抗パーキンソン病薬は効きが悪い。 また, 小脳症状や自律神経障害も加わってくるため全体として進行性に増悪することが多い。我が国での 230 人の患者を対象とした研究結果では, それぞれ中央値として発症後平均約 5 年で車椅子使用, 約 8 年 で臥床状態となり, 罹病期間は 9 年程度と報告されている。

<指定難病診断基準>
Probable MSA, Definite MSA を対象とする。

1.共通事項
 成年期 (>30 歳)以降)に発症する。主要症候は小脳性運動失調, パーキンソニズム, 自律神経障害である。発病初期から前半期にはいずれかの主要症候が中心となるが, 進行期には重複してくる。殆どは孤発性 であるが, ごく希に家族発症がみられることがある。

2.主要症候
 ①小脳症候:歩行失調(歩行障害)と声帯麻痺, 構音障害, 四肢の運動失調又は小脳性眼球運動障害
 ②パーキンソニズム:筋強剛を伴う動作緩慢, 姿勢反射障害(姿勢保持障害)が主で(安静時)振戦などの不随意運動はまれである。特に, パーキンソニズムは本態性パーキンソン病と比較してレボドパへの反応に乏しく, 進行が早いのが特徴である。例えば, パーキンソニズムで発病して3年以内に姿勢保持障害, 5年以内に嚥下障害をきたす場合はMSAの可能性が高い。
 ③自律神経障害:排尿障害, 頻尿, 尿失禁, 頑固な便秘, 勃起障害(男性の場合), 起立性低血圧, 発汗低下, 睡眠時障害(睡眠時喘鳴, 睡眠時無呼吸, REM睡眠行動異常(RBD))など。
 ④錐体路徴候:腱反射亢進とバビンスキー徴候・チャドック反射陽性, 他人の手徴候/把握反射/反射性ミオクローヌス
 ⑤認知機能・ 精神症状:幻覚(非薬剤性), 失語, 失認, 失行(肢節運動失行以外), 認知症・認知機能低下

3.画像検査所見
 ①MRI/CT:小脳・脳幹・橋の萎縮を認め※, 橋に十字状のT2高信号, 中小脳脚のT2高信号化を認める。被殻の萎縮と外縁の直線状のT2高信号, 鉄沈着による後部の低信号化を認めることがある。(※X線CTで認める小脳と脳幹萎縮も, 同等の診断的意義があるが, 信号変化を見られるMRIが望ましい。)
 ②脳PET/SPECT:小脳・脳幹・基底核の脳血流・糖代謝低下を認める。黒質線条体系シナプス前ドパミン障害の所見を認めることがある。

4.病型分類
 初発症状による分類(MSA の疾患概念が確立する以前の分類)
 オリーブ橋小脳萎縮症: 小脳性運動失調で初発し, 主要症候であるもの→孤発性OPCAはMSA, 遺伝性OPCAはSCAに分類されることが多い
 線条体黒質変性症:パーキンソニズムで初発し, 主要症候であるもの。
 シャイ・ドレーガー症候群:自律神経障害で初発し, 主要症候であるもの。

 国際的 Consensus criteria による分類
 MSA-C: 診察時に小脳性運動失調が主体であるもの
 MSA-P:診察時にパーキンソニズムが主体であるもの

5.診断のカテゴリー
 ①Possible MSA:パーキンソニズム(筋強剛を伴う運動緩慢, 振戦若しくは姿勢反射障害)又は小脳症候(歩行失調, 小脳性構音障害, 小脳性眼球運動障害, 四肢運動失調)に自律神経症候(②の基準に満たない程度の起立性低血圧や排尿障害, 睡眠時喘鳴, 睡眠時無呼吸若しくは勃起不全)を伴い, かつ錐体路徴候が陽性であるか, 若しくは画像検査所見(MRI若しくはPET・SPECT)で異常を認めるもの。
 ②Probable MSA:レボドパに反応性の乏しいパーキンソニズムもしくは小脳症候のいずれかに明瞭な自律神経障害を呈するもの(抑制困難な尿失禁, 残尿などの排尿力低下, 勃起障害, 起立後3分以内において収縮期血圧が30mmHgもしくは拡張期血圧が15mmHg以上の下降, のうちの1つを認める。)。
 ③Definite MSA:病理学的に確定診断されたもの。

6.鑑別診断
 皮質性小脳萎縮症, 遺伝性脊髄小脳変性症, 二次性小脳失調症, パーキンソン病, 皮質基底核変性症, 進行性核上性麻痺, レビー小体型認知症, 2 次性パーキンソニズム, 純粋自律神経不全症, 自律神経ニュー ロパチーなど。

(Responsible gene) *609825 Coenzyme Q2 lyprenyltransferase (COQ2) <4q21.23>
(1) Coenzyme Q10 deficiency, primary, 1 (607426)
.0001 Coenzyme Q10 deficiency, primary, 1 [COQ2, TYR297CYS] (rs121918230) (gnomAD:rs121918230) (RCV000001501...) (Quinzii et al. 2006; Lopez-Martin et al. 2007; Quinzii et al. 2010)
.0002 Coenzyme Q10 deficiency, primary, 1 [COQ2, 1-BP DEL, 1198T] (rs750710187) (gnomAD:rs750710187) (RCV000001502...) (Mollet et al. 2007)
.0003 Coenzyme Q10 deficiency, primary, 1 [COQ2, ARG197HIS] (rs121918231) (gnomAD:rs121918231) (RCV000001503...) (Diomedi-Camassei et al. 2007; Quinzii et al. 2010)
.0004 Coenzyme Q10 deficiency, primary, 1 [COQ2, ASN228SER] (rs121918232) (gnomAD:rs121918232) (RCV000416407...) (Diomedi-Camassei et al. 2007)
.0005 Coenzyme Q10 deficiency, primary, 1 [COQ2, SER146ASN] (rs121918233) (gnomAD:rs121918233) (RCV000416406...) (Diomedi-Camassei et al. 2007)
(2) Multiple system atrophy 1, susceptibility to (146500)
.0006 Multiple system atrophy 1, susceptibility to [COQ2, MET128VAL] (rs778094136) (gnomAD:rs778094136) (RCV000054428...) (Jeon et al. 2014; The Multiple-System Atrophy Research Collaboration 2013)
.0007 Multiple system atrophy 1, susceptibility to [COQ2, VAL393ALA] (rs397514727) (RCV000054429) (Jeon et al. 2014; The Multiple-System Atrophy Research Collaboration 2013; Sharma et al. 2014; Schottlaender and Houlden 2014)
.0008 Multiple system atrophy 1, susceptibility to [COQ2, ARG387TER] (rs751185256) (gnomAD:rs751185256) (RCV000416412...) (The Multiple-System Atrophy Research Collaboration 2013)
.0009 Multiple system atrophy 1, susceptibility to [COQ2, ARG387GLN] (rs763562410) (gnomAD:rs763562410) (RCV000054431) (The Multiple-System Atrophy Research Collaboration 2013)

(ノート)
A number sign (#) is used with this entry because of evidence that susceptibility to multiple system atrophy-1 (MSA1) can be conferred by heterozygous, homozygous, or compound heterozygous mutation in the COQ2 gene (609825) on chromosome 4q21.

●多系統萎縮症 (MSA) は得々の臨床病理学的疾患で, 進行性成人発症神経変性疾患である
 →パーキンソン症候群, 小脳, 自律神経, 尿および錐体路機能障害の多様な組合せをもつ
 病理学的には, 変性変化とグリア細胞質封入体が特徴である
 →異常にリン酸化された alpha-synuclein (SNCA; 163890) または tau (MAPT; 157140) からなる (Gilman et al., 1998; Scholz et al., 2009)
'Subtype C' of MSA has been reported to be more prevalent than 'subtype P' in the Japanese population (65-67% vs 33-35%), whereas 'subtype P' has been reported to be more prevalent than 'subtype C' in Europe (63% vs 34%) and North America (60% vs 13%, with 27% of cases unclassified) (summary by the The Multiple-System Atrophy Research Collaboration, 2013).

●MSA は, パーキンソン病や Lewy 小体認知症と臨床的および病理学的に類似していた
● SNCA 遺伝子変異が原因の PARK1 (168601)を参照

●純粋自律神経不全は, 起立性低血圧と神経病変のない他の自律神経異常としてみられる
 ある程度の表現型オーバーラップがあるが, 純粋自律神経不全と MSA との関係は不明である (Vanderhaeghen et al., 1970; Schatz, 1996)

Clinical Features
MSA typically shows onset in middle age. Parkinsonian features include bradykinesia, rigidity, postural instability, hypokinetic speech, and tremor; response to L-dopa is poor. Cerebellar dysfunction includes gait ataxia, dysarthria, and disorders of extraocular movement. Autonomic insufficiency results in orthostatic hypotension, erectile dysfunction, constipation, and decreased sweating. Urinary symptoms include urgency, frequency, incomplete bladder emptying, nocturia, and incontinence. Less commonly, corticospinal dysfunction may manifest as hyperreflexia (Gilman et al., 1998).

Shy and Drager (1960) described a syndrome of adult-onset orthostatic hypotension, bladder and bowel incontinence, anhidrosis, iris atrophy, amyotrophy, ataxia, rigidity and tremor; intellect was unaffected.

Vanderhaeghen et al. (1970) reported a 71-year-old woman with severe orthostatic hypotension and urinary incontinence. A year later, she developed parkinsonism, amyotrophy of the small hand muscles, and hyperreflexia. She died following cardiopulmonary complications. Neuropathologic examination showed pallor of the substantia nigra, neuronal rarefaction, and cytoplasmic hyaline inclusions. An unrelated male patient, with a history of radiotherapy to the neck, presented at age 73 with orthostatic hypotension. He had absence of ankle reflexes, but no ataxia or extrapyramidal signs. After death, postmortem exam showed increased microglia and concentric hyaline bodies within some neurons. Vanderhaeghen et al. (1970) concluded that there are 2 forms of orthostatic hypotension: one accompanied by neurologic features consistent with MSA, and another devoid of additional neurologic signs.

Wullner et al. (2004) reported a German mother and daughter with probable MSA. The mother presented at age 68 with akinetic parkinsonism that responded to L-dopa treatment for 7 years. She later developed urinary incontinence and orthostatic hypotension, as well as gait ataxia. At age 77, she had severe ataxia, dysarthria, smooth expressionless face, brisk tendon reflexes, and cogwheel rigidity. The daughter presented at age 46 with gait ataxia. Within 2 years, she developed urge incontinence, orthostatic dysfunction, and mild unilateral parkinsonism. Other features included limb ataxia, dysarthria, and mild cogwheel rigidity. Neither patient had cognitive impairment. Brain MRI of both patients showed brainstem and cerebellar atrophy. Single photon emission CT (SPECT) of both patients showed asymmetric massive reduction of presynaptic dopamine transporter and a moderate loss of dopamine D2 receptors (DRD2; 126450). Wullner et al. (2004) noted that whereas MSA is usually considered to be a sporadic disorder, their family suggested a rare instance of autosomal dominant inheritance. Wullner et al. (2009) reported postmortem examination of the German mother with MSA described by Wullner et al. (2004). The brain showed severe atrophy of the putamen, depigmentation of the substantia nigra, and pontine and cerebellar atrophy. Microscopic analysis showed profound neuronal loss and gliosis in the striatum, globus pallidus, substantia nigra, pontine nuclei, and inferior olivary nuclei, as well as marked loss of Purkinje cells and demyelination of cerebellar white matter. There were widespread SNCA-positive cytoplasmic inclusions. The neuropathologic findings confirmed the diagnosis of MSA.

Hara et al. (2007) reported 4 unrelated Japanese families in each of which 2 sibs had findings consistent with MSA. One of the families was consanguineous, suggesting autosomal recessive inheritance. Among the 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The mean age at onset was 65.9 years. The most frequent clinical feature was parkinsonism, observed in 5 patients. All had a poor response to L-dopa treatment. Six patients showed pontine atrophy with 'cross sign' or 'slitlike' signal changes at the posterolateral pontine margin on brain MRI. The patterns were consistent with autosomal recessive inheritance. No mutations were found in several genes for hereditary ataxia or in the SNCA gene.

Diagnosis
Gilman et al. (1998) reported the conclusions of a consensus report for the diagnosis of MSA. Clinical criteria for inclusion centered on 4 domains: autonomic failure/urinary dysfunction, parkinsonism, cerebellar ataxia, and corticospinal dysfunction. Definitive diagnosis requires pathologic confirmation, with the findings of glial cytoplasmic inclusions and degenerative changes in various brain regions.

Gilman et al. (2008) reported the conclusions of a second consensus report for the diagnosis of MSA, which falls into 3 groups. Definite MSA requires neuropathologic demonstration of SNCA-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Autonomic failure can manifest as genitourinary dysfunction or orthostatic hypotension. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least 1 feature suggesting autonomic dysfunction plus 1 other feature that may be a clinical or a neuroimaging abnormality.

Shahnawaz et al. (2020) showed that the alpha-synuclein (163890)-protein misfolding cyclic amplification (PMCA) assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson disease (168600) and samples from patients with MSA, with an overall sensitivity of 95.4%. Shahnawaz et al. (2020) used a combination of biochemical, biophysical, and biologic methods to analyze the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson disease and MSA. They also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggested that alpha-synuclein aggregates that are associated with Parkinson disease and MSA corresponded to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA, and may enable the development of a biochemical assay to discriminate between Parkinson disease and MSA.

Inheritance
Although multiple system atrophy is generally considered to be a sporadic disorder, genetic factors may influence the pathogenesis and development of the disease (Scholz et al., 2009).

Lewis (1964) described a family in which 6 persons in 3 generations had orthostatic hypotension, with 2 instances of possible male-to-male transmission. Two affected family members had ataxia and parkinsonism. Walton (1969) also observed male-to-male transmission.

Nee et al. (1991) found higher frequencies of neurologic diseases and autonomic symptoms among 148 first-degree relatives of 33 MSA patients compared to control subjects. However, no secondary cases of MSA were identified. Of note, patients with MSA had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population, suggesting that environmental factors may also play a role.

Wenning et al. (1993) reported a higher frequency of parkinsonism among first-degree or second-degree relatives of 38 patients with autopsy-proven MSA. However, there were no familial cases of MSA, and the authors believed that the parkinsonism could be a chance occurrence. Wenning et al. (1993) concluded that MSA is most likely a sporadic disease.

Pathogenesis
Bannister et al. (1983) noted that the pathologic feature of MSA is a unique degeneration of both pigmented catecholamine-containing cells in the brainstem and cholinergic cells in the intermediolateral columns, with distal ganglionic and postganglionic degeneration. A subgroup, the parkinsonian variety, shows hyaline eosinophilic cytoplasmic neuronal inclusions (Lewy bodies) in the brainstem. Degeneration of melanin-containing and catecholamine-containing cells in the brainstem suggests a genetic metabolic defect.

Chalmers and Swash (1987) described electrophysiologic studies in patients with MSA that revealed selective damage to the somatic efferent innervation of the external urinary sphincter musculature. The findings implied selective vulnerability of the motor neurons of Onuf's nucleus in the sacral cord. This nucleus is known to innervate the striated components of the anal and urinary sphincter muscles.

Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress is implicated in the pathogenesis of some of these disorders. Giasson et al. (2000) used antibodies to specific nitrated tyrosine residues in alpha-synuclein to demonstrate extensive and widespread accumulation of nitrated alpha-synuclein in the signature inclusions of Parkinson disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer disease (127750), and multiple system atrophy brains. The authors also showed that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selected and specific nitration of alpha-synuclein in these disorders provides evidence to link oxidative and nitrative damage directly to the onset and progression of neurodegenerative synucleinopathies.

Using detailed biochemical studies, Anderson et al. (2006) found that the predominant form of alpha-synuclein within Lewy bodies isolated from brains of patients with Lewy body dementia, multiple system atrophy, and PARK1 was phosphorylated at ser129. A much smaller amount of ser129-phosphorylated alpha-synuclein was found in the soluble fraction of both control and diseased brains, suggesting that ser129-phosphorylated alpha-synuclein shifts from the cytosol to be deposited in Lewy bodies, and that phosphorylation enhances inclusion formation. Other unusual biochemical characteristics of alpha-synuclein in Lewy bodies included ubiquitination and the presence of several C-terminally truncated alpha-synuclein species.

In Lewy body diseases, including Parkinson disease with or without dementia, dementia with Lewy bodies, and Alzheimer disease with Lewy body copathology, alpha-synuclein aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy, alpha-synuclein accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs). Peng et al. (2018) reported that pathologic alpha-synuclein in GCIs and Lewy bodies is conformationally and biologically distinct. GCI-alpha-synuclein forms structures that are more compact and is about 1,000-fold more potent than Lewy body alpha-synuclein in seeding alpha-synuclein aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-synuclein and Lewy body alpha-synuclein show no cell-type preference in seeding alpha-synuclein pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. Peng et al. (2018) found that oligodendrocytes, but not neurons, transform misfolded alpha-synuclein into a GCI-like strain, highlighting the fact that distinct alpha-synuclein strains are generated by different intracellular milieus. Moreover, GCI-alpha-synuclein maintains its high seeding activity when propagated in neurons. Thus, alpha-synuclein strains are determined by both misfolded seeds and intracellular environments.

Mapping
In a genomewide association study of 413 patients with MSA and 3,974 controls, followed by replication in 108 MSA patients and 537 controls, Scholz et al. (2009) found the most significant associations between MSA and rs3857059 in intron 4 of the SNCA gene on chromosome 4q22.1 (combined p value = 2.1 x 10(-10); OR, 5.9) and rs11931074 located downstream of the SNCA locus (combined p value = 5.5 x 10(-12); OR, 6.2). The findings were significant because the genetic factors overlap those found in Parkinson disease, which shows similar pathologic and clinical features.

Among 100 Korean patients with MSA and 100 Korean controls, Yun et al. (2010) did not find a significant association between MSA and rs11931074. The frequency of the T risk allele was 58% in both patient and control groups, which was significantly higher than that reported by Scholz et al. (2009) in Caucasian patients (10%) and controls (8%). The findings indicated that population-specific variation in the frequency needs to be considered when assessing the genetic risk for MSA.

Cytogenetics
Using whole-genome copy number variation (CNV) microarray analysis of a pair of monozygotic twins discordant for MSA,Sasaki et al. (2011) found that the affected twin had a 350-kb heterozygous deletion of the subtelomere of chromosome 19p13.3, whereas this change was not seen in the unaffected twin. Whole-genome CNV analysis found heterozygous loss of this region in 10 (30%) of 31 unrelated patients with MSA, although the breakpoints differed in each patient. CNV of this region was not seen in 2 control cohorts totaling 125 individuals, yielding an odds ratio (OR) of 8.98 (p = 1.04 x 10(-8)). The region identified in the twins encompasses 4 genes, including SHC2 (605217); SHC2 was deleted in the affected twin and in the MSA patients with 19p deletions, suggesting that it may be a candidate gene for predisposition to the disorder.

Molecular Genetics
The association between variation in the COQ2 gene and susceptibility to multiple system atrophy is controversial.

In affected members of 2 unrelated Japanese families with multiple system atrophy, one of which was reported by Hara et al. (2007), The Multiple-System Atrophy Research Collaboration (2013) identified homozygous or compound heterozygous mutations in the COQ2 gene (609825.0006-609825.0008). The mutations were found in the first family by linkage analysis combined with whole-genome sequencing. Subsequent sequencing of the COQ2 gene in 363 Japanese patients with sporadic MSA and 2 sets of controls (520 individuals and 2,383 individuals) identified putative heterozygous or biallelic pathogenic variants in 33 patients (see, e.g., 609825.0009). The most common variant was V393A (609825.0007), which was also found in heterozygous state in 17 controls. Rare pathogenic variants were also found in 4 of 223 European patients with sporadic disease and in 1 of 172 North American patients with sporadic disease. In vitro functional expression assays in yeast Coq2-null strains showed that the mutations caused variable growth defects and variably low COQ2 activities in patient cell lines. The findings suggested that mutations in the COQ2 gene may cause susceptibility to the disorder. Patients with COQ2 mutations had increased frequency of the cerebellar variant compared to the parkinsonism variant. Four additional families with MSA, including the German family reported by Wullner et al. (2009), did not have COQ2 mutations, indicating genetic heterogeneity.

Quinzii et al. (2014) commented that 2 Japanese sibs with COQ2 mutations reported by The Multiple-System Atrophy Research Collaboration (2013) had retinitis pigmentosa and low levels of COQ10 in the cerebellum, similar to that observed in patients with primary COQ10 deficiency (607426).

Jeon et al. (2014) did not find an association between the V393A variant in the COQ2 gene (609825.0007) and multiple system atrophy among 299 Korean patients with the disorder and 365 controls (minor allele frequency 2.7% of cases versus 2.6% of controls). Sharma et al. (2014) did not find the V393A variant in a large cohort of 788 European patients with MSA or 600 European controls. Schottlaender and Houlden (2014) did not find the V393A variant in more than 300 European patients with MSA or 262 European controls. These authors suggested that variation in the COQ2 gene may not represent a risk factor for the development of multiple system atrophy.

Exclusion Studies

Among 47 patients with MSA, Morris et al. (2000) excluded pathogenic mutations and association with variation in the SNCA (163890), MAPT (157140), synphilin (SNCAIP; 603779), and APOE (107741) genes.

Heterogeneity
The Multiple System Atrophy Research Collaboration (2013) excluded COQ2 mutations in 3 of the Japanese families reported byHara et al. (2007) and in the German family reported by Wullner et al. (2004, 2009), indicating genetic heterogeneity.

Population Genetics
In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000; of these, 7% were thought to have the Shy-Drager syndrome.

Nomenclature
Schatz (1996) pointed out that a consensus statement generated by the American Autonomic Society and the American Academy of Neurology, defining the various neurogenic causes of autonomic dysfunction, suggested abandonment of the term 'Shy-Drager' syndrome. The consensus statement suggested that the nosology for autonomic disorders include: (1) primary pure autonomic failure (previously called idiopathic orthostatic hypotension or the Bradbury-Eggleston syndrome) in which no neurologic defects other than autonomic dysfunction are present; and (2) multiple system atrophy, a sporadic, progressive, adult-onset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. Secondary autonomic failure can occur in diabetes mellitus, amyloidosis, dopamine beta-hydroxylase deficiency (223360), and drug toxicity.

Another report from a consensus conference on MSA (Gilman et al., 1998) also concluded that the term 'Shy-Drager' syndrome had been misused and should no longer be used. They recommended the term 'multiple system atrophy,' which could also be subgrouped into MSA-P, if parkinsonian features predominate, or MSA-C, if cerebellar symptoms predominate. MSA-P and MSA-C replace the previous terms 'striatonigral degeneration' and 'olivopontocerebellar atrophy,' respectively. Another confusing term, 'multisystem degeneration,' was deemed inappropriate and its use discouraged.

History
The possibility of an infectious or immunologic basis led Bannister et al. (1983) to look for an HLA association. In 16 patients, 12 of whom had multiple system atrophy in addition to pure autonomic failure, they found that HLA-Aw32 was 13 times more common than in healthy controls, giving a relative risk of pure autonomic failure with this HLA type of 28.7.

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