疾患詳細

疾患詳細





#277460
Ataxia with vitamin E deficiency (AVED)
(Ataxia, Friedreich-like, with selective vitamin E deficiency)
(Vitamin E deficiency, familial isolated; VDED)
(Friedreich-like ataxia)

運動失調-ビタミンE欠乏症
(運動失調, Friedreich-様-選択的ビタミン E 欠損症)
(ビタミン E 欠損症, 家族性単独)

責任遺伝子:600415 Tochopherol (alpha) transfer protein (TTPA) <8q12.3>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Abnormal pyramidal sign (錐体路サイン異常) [HP:0007256] [02140][01405]
 Areflexia (無反射) [HP:0001284] [0242]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 
 <30%-79%>
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysdiadochokinesis (ジスジアドコキネーゼ) [HP:0002075] [02605]
 Dysmetria (ジスメトリア) [HP:0001310] [02605]
 Gait disturbance (歩行障害) [HP:0001288] [028]
 Nyctalopia (夜盲) [HP:0000662] [06007]
 Nystagmus (眼振) [HP:0000639] [06609]
 Pes cavus (凹足) [HP:0001761] [15602]
 Scoliosis (側弯) [HP:0002650] [161502]
 Sensory neuropathy (感覚ニューロパチー) [HP:0000763] [025]
 
 <5%-29%>
 Abnormality of retinal pigmentation (網膜色素異常) [HP:0007703] [06524]
 Abnormality of visual evoked potentials (視覚誘発電位異常) [HP:0000649] [0690]
 Arrhythmia (不整脈) [HP:0011675] [01700]
 Developmental regression (発達退行) [HP:0002376] [0125]
 Diabetes mellitus (糖尿病) [HP:0000819] [2013]
 Dystonia (ジストニア) [HP:0001332] [0240]
 Hemiplegia/hemiparesis (片麻痺/片不全麻痺) [HP:0004374] [026131]
 Hypertonia (筋緊張亢進) [HP:0001276] [0241]
 Hypertrophic cardiomyopathy (肥大型心筋症) [HP:0001639] [0273]
 Mental deterioration (知的悪化) [HP:0001268] [0125]
 Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] [0270]
 Tremor (振戦) [HP:0001337] [02604]
 Visual impairment (視力障害) [HP:0000505] [06011]
 
 
 Ataxia (運動失調) [HP:0001251] [028]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Hypercholesterolemia (高コレステロール血症) [HP:0003124] [20172]
 Hypertriglyceridemia (高トリグリセリド血症) [HP:0002155] [20174]
 Increased LDL cholesterol concentration (LDL コレステロール増加) {HP:0003141] [20176]
 Tendon xanthomatosis (腱黄色腫) [HP:0010874] [2330]
 Vitamin E deficiency (ビタミンE欠乏症) [HP:0100513] [2099]
 Xanthelasma (眼瞼黄色腫) [HP:0001114 ] [2330]

(UR-DBMS)
【一般】慢性脂肪便
【神経】脊髄小脳性変性
 失調歩行, 無反射
 著明な固有覚喪失
【検査】コレステロール/中性脂肪/ベータリポ蛋白高値
 血清 ビタミン E 検出不能; 肝 'トコフェロール結合蛋白'異常
【腫瘍】黄色板 (xanthelasmata)
 アキレス腱黄色腫

(要約) 運動失調, ビタミンE欠乏症を伴う
(AVED; 運動失調, 単独ビタミンE欠乏症を伴う; 家族性単独ビタミンD欠乏症; Friedreich-様運動失調)
● ビタミンE欠乏症を伴う運動失調 (AVED) は一般的に5〜15歳の小児期後半または早期10代にみられる
 初発症状は, 進行性運動失調, 手の不器用さ, 固有覚の喪失 (特に振動と関節位置覚) および無反射がある
 その他よくみられる特徴には, 拮抗運動反復不全, 構音障害, 進行性Romberg サイン陽性, 頭部揺動, 視力低下および Babinskiサイン陽性, 黄斑萎縮, 色素性網膜炎がある
 表現型と重症度は異なる変異をもつ家系間で大きな変化をもつ
 発症年齢と経過は同一家系でより一定しているが, 症状と重症度は同胞間でさえ変化がある
●診断:主要な基準は, Friedreich様神経学的表現型と吸収不全の原因のない著明な血漿ビタミンE (α-tocopherol) 濃度の減少と正常なリポ蛋白プロフィールである
 → TTPA (α-tocopherol 輸送タンパクの遺伝子) の変異で確認
 2アレル性 TTPA 病的バリアントの証明 (>90%で)→診断確定
●治療:大量のビタミンE補給で正常高値にビタミンEを保つ (生涯)→6か月に1回モニターする
 早期治療で運動失調と知的悪化をある程度改善できるかも
●遺伝:常染色体劣性
●検査:ビタミンE 4.0 µmol/L (<1.7 mg/L) 未満 (正常値 9.0 〜 29.8) [EDTA 容器を使用]
●電気生理学: 正中および腓骨運動神経伝達速度, 複合筋活動電位, 正中および伏在神経感覚活動電位など
 9% は正常
 47% は軽度ニューロパチー (少なくとも1つの検査で正常下限の70~100%)
 27% は中等度ニューロパチー (少なくとも1つの検査で正常下限の30%-70%)
 17% は重度ニューロパチー (少なくとも1つの検査で正常下限の <30%)
 ニューロパチーは純粋感覚性 (34%), 純粋運動性r (24%), または混合性 (42%).
●画像
 小脳萎縮:およそ50%で
 脳室周囲と深部白質の小さなT2強調斑点:一部の患者で
●病理組織学
 脊髄感覚性脱髄とニューロン萎縮および軸索スフェロイド
 後脚の dying back 型変性
 大脳皮質第3層, 視床, 外側膝状体, 脊椎角, 後根神経節でのニューロンのlipofuscin沈着
 短腓骨筋の線維型グループ化
 Purkinje 細胞の軽度の喪失
●症状頻度
 無反射 (94.7%)
 歩行障害 (93.4%)
 陽性 Babinski サイン (85.5%)
 深部感覚障害 (67.1%)
 構音障害 (61.8%)
 頭部揺動 (40.8%)
 尿意逼迫 (22.4%)
 眼振 (5.3%)
 遺尿 (4.0%)
 色素性網膜炎 (2.3%)
 心筋症 (1.5%)
●遺伝子型-表現型相関
 p.His101Gln →遅発 (30歳以後), 軽症経過, 色素性網膜炎と連関 (主に日本人で)
 c.744delA →早期発症, 重症経過, 心筋症と連関 (家系内多様性あり) (地中海または北アフリカで)
(はっきりしない相関, 以下がホモ接合)
 早期発症→p.Arg59Trp, p.Arg134Ter, p.Glu141Lys, c.486delT, c.513_514insTT, c.530-531AG>GTAAGT
 10歳以後発症→. p.Arg221Trp, p.Ala120Thr
●浸透度;ホモ接合または複合ヘテロ接合でほぼ100%
●頻度:日本, モロッコ, ノルウェー, イタリア
●鑑別診断
1) Friedreich 運動失調 (FRDA)
症状の違い
      FRDA  AVED
凹足     +  まれ
末梢神経症  +  軽度
I 型糖尿病   +  (+)
頭部揺動   まれ  +
筋萎縮    +  –
Babinski   +  (+)
ジストニア  –  +
色素性網膜炎 –  (+)
視力低下   まれ  +
心伝導障害  +  まれ
心筋症    +  (+)
筋力低下   +  –
糖尿病    +  –
2) 無βリポ蛋白血症 (Bassen-Kornzweig) および低βリポ蛋白血症
3)栄養障害/ビタミンE摂取減少
4) Refsum 病
5) Charcot-Marie-Tooth ニューロパチー 1A型 (CMT1A)
6)運動失調と眼球運動失行1および2型 (AOA1, AIA2)
7) その他の運動失調症

(Commnet) abetalipoproteinemia (200100) = most severe state of vitamin E deficiency
(Responsible gene) *600415 Tochopherol (alpha) transfer protein (TTPA) <8q12.3>
.0001 Ataxia, Friedreich-like, with isolated vitamin E deficiency (277460) [TTPA, 1BP DEL] (dbSNP:rs397515377) (RCV000009707...) (Ouahchi et al. 1995)
.0002 Ataxia and retinitis pigmentosa with isolated vitamin E deficiency [TTPA, HIS101GLN] (dbSNP:rs121917849) (RCV000009708...) (Gotoda et al. 1995; Yokota et al. 1996)
.0003 Ataxia, Friedreich-like, with isolated vitamin E deficiency [TTPA, 1-BP DEL, 485T DEL, FS176TER] (dbSNP:rs397515378) (RCV000009709...) (Hentati et al. 1996)
.0004 Ataxia, Friedreich-like, with isolated vitamin E deficiency [TTPA, 2-BP INS, FS176TER] (dbSNP:rs397515379) (ExAC:rs397515379) (RCV000009710...) (Hentati et al. 1996)
.0005 Ataxia, Friedreich-like, with isolated vitamin E deficiency [TTPA, ARG192HIS] (dbSNP:rs121917850) (ExAC:rs121917850) (RCV000009711...) (Hentati et al. 1996)
.0006 Ataxia, Friedreich-like, with isolated vitamin E deficiency [TTPA, ARG134TER] (dbSNP:rs121917851) (ExAC:rs121917851) (RCV000009712...) (Cavalier et al. 1998)
.0007 Ataxia, Friedreich-like, with isolated vitamin E deficiency [TTPA, 552G-A] (RCV000009713) (Schuelke et al. 1999)

*TTPA: Tochopherol (alpha) transfer protein (278 amino acids)
・alpha-trocopherol と結合する可溶性タンパクをコードする
・膜小胞間のビタミンE輸送によるビタミンEレベルの調節し, 肝細胞から循環リポ蛋白へのビタミンE分泌促進で重要な役割をもつ

(Note)
A number sign (#) is used with this entry because of evidence that ataxia with vitamin E deficiency (AVED) is caused by homozygous or compound heterozygous mutation in the TTPA gene (600415) on chromosome 8q12.

▼ Clinical Features
Harding et al. (1985) described a young woman with spinocerebellar degeneration thought to be due to a selective defect in vitamin E absorption. There was no evidence of fat malabsorption. Binder et al. (1967) suggested a relationship between neurologic dysfunction and vitamin E deficiency in patients with chronic steatorrhea. This was subsequently confirmed in patients with abetalipoproteinemia (200100), the most severe state of vitamin E deficiency known. When studied at age 23, the proband had no vitamin E in the serum. A progressive neurologic disorder comprising ataxia, areflexia and marked loss of proprioception developed at age 13. She also had increased serum concentrations of cholesterol, triglyceride and beta-lipoprotein and showed xanthelasmata and xanthomas of the Achilles tendon. Improvement in the neurologic disease accompanied administration of vitamin E. The proband's mother had tendinous xanthomas and elevated serum cholesterol. Both parents and 4 brothers had low or low-normal serum vitamin E levels consistent with the heterozygous state of a disorder for which the proband was homozygous. The lipid disturbance in the proband and her mother was thought to be familial hypercholesterolemia. Evidence was cited that the mechanism of absorption of vitamin E may be different from that for the other fat-soluble vitamins. A progressive development of ataxia and areflexia with a 'dying back' of the peripheral nerves, along with spinocerebellar degeneration, are characteristic of vitamin E deficiency. Several patients have been described who, like the patient of Harding et al. (1985), had neurologic abnormalities similar to those of vitamin E deficiency but had no evidence of fat malabsorption (Burck et al., 1981; Kohlschutter et al., 1988; Laplante et al., 1984; Krendel et al., 1987; Yokota et al., 1987; Sokol et al., 1988). Sokol et al. (1988) studied 2 affected sisters, a brother, and an isolated case in another family. No consanguinity was observed, but no other affected persons were demonstrated by studies in these families. These patients all had normal lipid absorption, gastrointestinal, pancreatic, and intestinal function, and lipoproteins, but when consuming a normal diet, they had exquisitely low plasma vitamin E levels and developed neurologic abnormalities characteristic of vitamin E deficiency. With the addition of daily vitamin E supplements (400-1,200 IU) to the diet, normal plasma vitamin E levels could be maintained and in several patients improvement in neurologic function was reported. When vitamin E supplementation was interrupted, plasma tocopherol fell sharply to suboptimal levels.

Selective vitamin E deficiency shows clinical features very similar, and in some cases identical, to those of Friedreich ataxia (FRDA; 229300). Ben Hamida et al. (1993) pointed out that cardiomyopathy like that in Friedreich ataxia had not been reported in patients with isolated vitamin E deficiency.

▼ Mapping
During a search for recombinants between the 9q13-q21 markers and the disease locus in FRDA families, Ben Hamida et al. (1993, 1993) found 5 with apparent recombinations that turned out, in fact, to be segregating a Friedreich-like disease associated with selective vitamin E deficiency. Since 3 such families of Tunisian origin were large and highly inbred, they were used to search for the defective locus by a combination of homozygosity mapping and sib comparisons. Linkage was found to 2 microsatellite markers located about 400 kb apart on proximal 8q. The other 2 families, one Tunisian and one Italian, also showed homozygosity and linkage with these markers, as did a sixth family of Albanese origin for which serum vitamin E levels could not be obtained. By combining all 6 families and by computing the consanguinity loops, a maximum lod score of 17.9 was obtained at theta = 0.0 for a haplotype combining the 2 microsatellite marker loci. The lod-1 confidence interval was 2.4 cM on either side of these markers. Doerflinger et al. (1995) performed linkage studies in 6 new and 2 previously described families and demonstrated genetic homogeneity despite significant clinical variability. They refined the AVED position to a 1-cM interval on 8q. Haplotype analysis using tightly linked microsatellite markers demonstrated a predominant, although not unique, mutation as responsible for the disorder in North African populations, where this condition is unusually frequent. Doerflinger et al. (1995) also constructed a YAC contig over this interval to facilitate the search for the AVED gene.

▼ Molecular Genetics
The tocopherol-binding protein is also known as alpha-tocopherol transfer protein and TTP1. In patients with familial isolated vitamin E deficiency, Traber et al. (1990) demonstrated a defect in the incorporation of alpha-tocopherol into lipoproteins secreted by the liver. They suggested that these patients are lacking or have a defective liver tocopherol-binding protein that incorporates alpha-tocopherol into nascent very-low-density lipoprotein.

The implication of TTP1 in ataxia with isolated vitamin E deficiency was established by the identification of frameshift mutations in the TTPA gene. A 744delA mutation (600415.0001) accounted for 68% of the mutant alleles in 17 families analyzed by Ouahchi et al. (1995) and appeared to have spread in North Africa and Italy. Although only the C-terminal tenth of the protein was altered, this mutation correlated with a severe phenotype. Two other mutations were found in single families. Hentati et al. (1996) described the structure of the TTPA gene and identified several TTPA mutations that were associated with familial vitamin E deficiency.

Schuelke et al. (1999) described a 14-year-old male with ataxia and mental symptoms who was found to be homozygous for a 552G-A mutation in the TTPA gene (600415.0007). After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete.

Aoki et al. (1990) reported 2 sibs who had an atypical spinocerebellar syndrome with isolated vitamin E deficiency. On restudy of one of these patients, mutation in the TTPA gene was excluded, suggesting the existence of another gene for familial isolated vitamin E deficiency (Shiojiri et al., 1999).

Cellini et al. (2002) reported a patient with progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, as well as cerebellar atrophy and vitamin E deficiency. She had expanded CTA/CAG repeats suggestive of SCA8 (608768) and also had compound heterozygosity for mutations in the TTPA gene (600415.0004 and 600415.0006), yielding a nonfunctional protein. Supplementation with vitamin E did not improve symptoms. Cellini et al. (2002) suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit.

▼ Heterogeneity
Bouhlal et al. (2008) reported an unusual, highly consanguineous Tunisian family in which 11 individuals had autosomal recessive ataxia caused by 3 distinct gene defects. Seven patients who also had low vitamin E levels were all homozygous for the common 744delA mutation in the TTPA gene (600415.0001), consistent with a diagnosis of AVED. Two patients with normal vitamin E levels were homozygous for a mutation in the FXN gene (606829.0001), consistent with a diagnosis of FRDA (229300). The final 2 patients with normal vitamin E levels carried a mutation in the SACS gene (604490), consistent with a diagnosis of ARSACS (270550). The clinical phenotype was relatively homogeneous, although the 2 patients with SACS mutations had hyperreflexia of the knee. One asymptomatic family member was compound heterozygous for the TTPA and FXN mutations. Bouhlal et al. (2008) emphasized the difficulty of genetic counseling in deeply consanguineous families.

(文献)
(1) Binder HJ et al. Neuromuscular disease in patients with steatorrhoea. Gut 8: 605-611, 1967
(2) Burck U et al. Neuromyopathy and vitamin E deficiency in man. Neuropediatrics 12: 267-278, 1981
(3) Laplante P et al. A progressive neurological syndrome associated with an isolated vitamin E deficiency. Canad J Neurol Sci 11: 561-564, 1984
(4) Harding AE et al. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. New Eng J Med 313: 32-35, 1985
(5) Krendel DA et al. Isolated deficiency of vitamin E with progressive neurologic deterioration. Neurology 37: 538-540, 1987
(6) Yokota T et al. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 22: 84-87, 1987
(7) Kohlschutter A et al. A treatable familial neuromyopathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E. J Inherit Metab Dis 11: 149-152, 1988
(8) Sokol RJ et al. Isolated vitamin E deficiency in the absence of fat malabsorption--familial and sporadic cases: characterization and investigation of causes. J Lab Clin Med 111: 548-559, 1988
(9) Traber MG et al. Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver. J Clin Invest 85: 397-407, 1990
(10) Ben Hamida C et al. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nature Genet 5: 195-200, 1993
(11) Ben Hamida C et al. Localization of Friedreich ataxia phenotype associated with selective vitamin E deficiency to proximal 8q by homozygosity mapping. Human Genome Mapping Workshop 93 0: 15, 1993
(12) Ben Hamida M et al. Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology 43: 2179-2183, 1993
(13) Doerflinger N et al. Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families. Am J Hum Genet 56 (5): 1116-24, 1995
(14) Ouahchi K et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9 (2): 141-5, 1995
(15) DiDonato S: Can we avoid AVED? [news] Nat Genet 9 (2): 106-7, 1995
(16) Hentati A et al. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol 39: 295-300, 1996
(17) Schuelke M et al. Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency. J. Pediat. 134: 240-244, 1999
(18) Shiojiri T et al. Familial ataxia with isolated vitamin E deficiency not due to mutation of alpha-TTP. (Letter) J. Neurol. 246: 982 only, 1999
(19) Cellini, E.; Piacentini, S.; Nacmias, B.; Forleo, P.; Tedde, A.; Bagnoli, S.; Ciantelli, M.; Sorbi, S. : A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia. Arch. Neurol. 59: 1952-1953, 2002

2004/07/03
2013/11/28
2017/03/26 RCV
2017/03/27 要約改訂
2021/03/19 症状改訂