临床特征.

共济失调伴维生素E缺乏症，通常发生在在5-15岁之间的童年晚期或青少年早期。首发症状包括渐进性共济失调、双手笨拙、本体感受丧失和反射消失。其他经常观察到的体征是: 轮替运动障碍、构音障碍、隆伯格（Romberg）征（+）、头部震颤、视力下降，及巴宾斯基征（+）。在不同的家庭中有不同的致病性变异，表型和疾病严重程度相差很大；在一个特定的家庭中，发病年龄和病程更为一致，但是症状和疾病的严重程度在同胞间却可能不一样。

Summary

Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens between ages five and 15 years. The first symptoms include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The 表型 and disease severity vary widely among families with different pathogenic variants; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.

以下为英文英文：
Summary

Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens between ages five and 15 years. The first symptoms include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The 表型 and disease severity vary widely among families with different pathogenic variants; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.

Suggestive Findings

Ataxia with vitamin E deficiency (AVED) should be suspected in individuals who typically present at the beginning of puberty with the following:

Clinical features

• Progressive ataxia
• Clumsiness of the hands
• Loss of proprioception (especially distal joint position and vibration sense)
• Areflexia
• Dysdiadochokinesia
• Positive Romberg sign
• Head titubation
• Decreased visual acuity
• Positive Babinski sign
• Macular atrophy, retinitis pigmentosa

Laboratory findings

• Normal lipid and lipoprotein profile
• Very low plasma vitamin E (α-tocopherol) concentration
  Note: (1) There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories. In Finckh et al [1995], the normal range lies between 9.0 and 29.8 µmol/L (mean ± 2 SD). In El Euch-Fayache et al [2014] the normal range is given as 16.3-34.9 µmol/L, while individuals with AVED had vitamin E levels between 0.00 and 3.76 µmol/L (mean 0.95 µmol/L, SD 1.79 µmol/L; n=132). In individuals with AVED, the plasma vitamin E concentration is generally lower than 4.0 µmol/L (<1.7 mg/L) [Cavalier et al 1998, Mariotti et al 2004]. (2) Because oxidation of α-tocopherol by air may invalidate test results, the following precautions should be taken:
  • Centrifugation of the EDTA blood soon after venipuncture
  • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen
  • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen)
  • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube
  • Shipment of the sample to the test laboratory in dry ice

Electrophysiologic findings

• In a large study of 132 individuals with AVED from North Africa, 45 individuals were investigated neurophysiologically (e.g., median and peroneal nerve motor conduction velocity, compound muscle action potential, median and saphenous nerve sensory action potential, and sensory action potential) [El Euch-Fayache et al 2014].
  • 9% had normal findings.
  • 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]).
  • 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN).
  • 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response).
  • Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%).
• Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20), increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [Schuelke et al 1999].

Note: No electrophysiologic findings are specific to or diagnostic of AVED; even a severe neuropathy does not exclude AVED.

Neuroimaging

• Cerebellar atrophy [Mariotti et al 2004]; present in approximately half of reported individuals
• Small T2 high-intensity spots in the periventricular region and the deep white matter [Usuki & Maruyama 2000]; inconsistent finding in some individuals

Note: No radiologic findings are specific to or diagnostic of AVED.

Histopathology findings [Larnaout et al 1997, Yokota et al 2000, El Euch-Fayache et al 2014, Ulatowski et al 2014]

• Spinal sensory demyelination with neuronal atrophy and axonal spheroids
• Dying back-type degeneration of the posterior columns
• Neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, spinal horns, and posterior root ganglia
• Fiber type grouping of the peroneus brevis muscle
• Mild loss of Purkinje cells

Establishing the Diagnosis

Presently no consensus diagnostic criteria for ataxia with vitamin E deficiency (AVED) exist.

The diagnosis of AVED is established in a 先证者 with all of the following:

• Friedreich ataxia-like neurologic 表型
• Markedly reduced plasma vitamin E (α-tocopherol) concentration
• Normal lipoprotein profile
• Exclusion of diseases that cause fat malabsorption

Identification of 双等位基因的TTPA pathogenic variants on 分子遗传学检测 (see Table 1) establishes the diagnosis if clinical and laboratory features are inconclusive and confirms the diagnosis in individuals with the above features.

Molecular testing approaches can include single-基因 testing, use of a 表型靶向检测, and more comprehensive 基因组的 testing:

• Single-基因 testing. Sequence analysis of TTPA is performed first and followed by gene-targeted deletion/duplication analysis if only one or no 致病性变异 is found. Targeted analysis for TTPA pathogenic variant c.744delA can be performed first in individuals of Mediterranean or North African ancestry.
• A 表型靶向检测 that includes TTPA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and 敏感性 of multi-gene panels vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include 序列分析, deletion/duplication analysis, and/or other non-sequencing based tests.
  For more information on multi-基因 panels click here.
• More comprehensive 基因组的 testing (when available) including 外显子组测序 and 基因组测序 may be considered if serial single-基因 testing (and/or use of a 表型靶向检测) fails to confirm a diagnosis in an individual with features of AVED. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For more information on comprehensive 基因组的 testing click here.
   

  Table 1.

  Molecular Genetic Testing Used in Ataxia with Vitamin E Deficiency

  View in own window

  Gene 1	Test Method	Proportion of Probands with Pathogenic Variants 2 Detectable by This Method
  TTPA	Sequence analysis 3	>90% 4, 5
  	Gene-targeted deletion/duplication analysis 6	Unknown 7

  
  1.

  See Table A. Genes and Databases for 染色体位点 and protein.

  
  2.

  See Molecular Genetics for information on allelic variants detected in this 基因.

  
  3.

  Sequence analysis detects variants that are benign, likely benign, of 意义不确定, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and 错义, nonsense, and 剪接位点 variants; typically, 外显子 or whole-基因 deletions/duplications are not detected. For issues to consider in interpretation of 序列分析 results, click here.

  
  4.

  Ouahchi et al [1995], Hentati et al [1996], Cavalier et al [1998], Schuelke [personal observation]. Sequence analysis identified at least one abnormal 等位基因 in 46 of 51 individuals with the AVED 表型, who had clearly reduced plasma vitamin E concentration [Schuelke, personal observation]. In 132 Tunisian individuals with AVED, 91.7% were 纯合性 for the c.744delA致病性变异; 8.3% of individuals were homozygous for other pathogenic variants (c.205-1G>T, c.400C>T, c.552+2T>A) [El Euch-Fayache et al 2014]. Sequence analysis of cDNA was used to confirm a synonymous pathogenic variant resulting in loss of 剪接位点 [Schuelke et al 1999] (see Molecular Genetics).

  
  5.

  Most individuals are 纯合性 or 复合杂合 for one of the known pathogenic variants.

  
  6.

  Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a 基因-targeted microarray designed to detect single-外显子 deletions or duplications.

  
  7.

  No data on detection rate of 基因-targeted deletion/duplication analysis are available. A single whole-gene deletion has been reported [Kara et al 2008].

临床表现Clinical Description

疾病表型和疾病的严重程度在共济失调伴维生素E缺乏症(AVED)相差很大。虽然在给定的家庭中发病年龄和病程往往比较一致，但同胞之间[Shorer et al 1996]的症状和疾病严重程度会有所不同。然而，AVED通常表现为晚期儿童或早期青少年在5岁至15岁之间的儿童中，但该范围可能从2岁到37岁不等，这是由来自132名北非人的研究(El euch - fayache et al 2014)所报道的。首发症状为进行性共济失调，手笨拙，本体感觉丧失，尤其是振动和关节位置感，书写恶化，极少数人，学校的表现会因为智力的丧失而下降，下肢肌腱反射常常不存在，足底反射强度增加。受累的个体在黑暗中行走困难，而且经常有罗姆伯格征（+）。很大一部分受累的个体(例如,在一个系列11个体占8个)有视力减退[Benomar et al 2002]。在许多个体中，小脑征如轮替运动障碍，构音障碍，伴有扫描的语音模式。三分之一的人有特征性的头部震颤。在一些人，精神病发作，智力衰退，和肌张力异常发作。很少表现为手臂或颈部肌张力障碍[Becker et al 2016]。大多数未经治疗的人由于共济失调和/或腿部虚弱在11到50岁之间不得不坐轮椅。[Harding等人1985年，Ouahchi et al 1995,Hentati et al 1996,Cavalier et al 1998,Gabsi et al 2001,Benomar et al 2002,Mariotti et al 2004]。根据一项对来自北非132人的大型研究[El euch - fayache et al 2014]，这些体征和症状包括(按发生频率的递减排序)：

The 表型 and disease severity of ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, symptoms and disease severity can vary among sibs [Shorer et al 1996].

AVED generally manifests in late childhood or early teens between ages five and 15 years, however, the range may be from age two to 37 years as reported in a series of 132 North African individuals [El Euch-Fayache et al 2014]. The first symptoms include progressive ataxia, clumsiness of the hands, and loss of proprioception, especially of vibration and joint position sense. Handwriting deteriorates. In rare individuals, school performance declines secondary to loss of intellectual capacities. Tendon reflexes of the lower extremities are generally absent and the plantar reflexes increase in intensity. Affected individuals have difficulty walking in the dark and often have a positive Romberg sign. A high percentage of 受累的 individuals (e.g., 8/11 individuals in one series) experience decreased visual acuity [Benomar et al 2002].

In many individuals, cerebellar signs such as dysdiadochokinesia and dysarthria with a scanning speech pattern are present. One third of individuals have a characteristic head tremor (head titubation). In some persons, psychotic episodes, intellectual decline, and dystonic episodes have been described. Rarely, AVED may manifest as arm or cervical dystonia [Becker et al 2016].

Most untreated individuals become wheelchair dependent as a result of ataxia and/or leg weakness between ages 11 and 50 years [Harding et al 1985, Ouahchi et al 1995, Hentati et al 1996, Cavalier et al 1998, Gabsi et al 2001, Benomar et al 2002, Mariotti et al 2004].

According to a large study on 132 individuals from North Africa [El Euch-Fayache et al 2014], the signs and symptoms include (in decreasing order of frequency):

• 反射消失Areflexia (94.7%)
• 步态障碍Gait impairment (93.4%)
• Babinski征（+）Positive Babinski sign (85.5%)
• 深感觉障碍Deep sensory disturbances (67.1%)
• 构音障碍Dysarthria (61.8%)
• 头震颤Head tremor (40.8%)
• 尿急Urinary urgency (22.4%)
• 眼球震颤Nystagmus (5.3%)
• 尿失禁Urinary incontinence (4.0%)
• 色素性视网膜炎Retinitis pigmentosa (2.3%)
• 心肌肥大Cardiomyopathy (1.5%)

基因型和表型的相关性Genotype-Phenotype Correlations

到目前为止，只有两种致病变异已明确显示 基因型-表型相关性：To date, only two pathogenic variants have shown clear-cut 基因型-表型 correlations:

• p.His101Gln 与疾病的迟发性(年龄>30岁)有关，是一种轻度的病程，色素视网膜病变发生的风险增加。这种变异主要见于日本人的后裔。is associated with late-onset disease (age >30 years), a mild course, and increased risk for pigmentary retinopathy. This variant is primarily reported in individuals of Japanese descent.
• c.744delA 与早期发病、严重的病程和心肌病的风险轻微增加有关。这种变异主要见于地中海或北非的个体。然而，疾病的严重程度可能会有很大的差异，即使是同一家族的人，其症状的发作在3到12岁之间可能不同。is associated with early onset, a severe course, and slightly increased risk for cardiomyopathy. This variant is mainly observed in individuals of Mediterranean or North African descent. However, disease severity may vary considerably, and even in persons from the same family the onset of symptoms may vary between ages three and 12 years [Cavalier et al 1998, Marzouki et al 2005].

下列致病性变异如果以纯合子形式出现，基因型-表型相关性尚不清晰，疾病表现为：A less clear 基因型-表型相关性 can be seen for the following pathogenic variants if they occur in 纯合性 form. Manifestation of disease:

• 10岁之前 Before age ten years. p.Arg59Trp, p.Arg134Ter, p.Glu141Lys, c.486delT, c.513_514insTT, c.530-531AG>GTAAGT (see Table 3)
• 10岁以后 After age ten years. p.Arg221Trp, p.Ala120Thr (see Table 3) [Cavalier et al 1998]

外显率Penetrance

AVED患者：对TTPA致病性变异的纯合子或者复合杂合显示AVED接近完全外显率。AVED shows nearly complete 外显率 in individuals who are 纯合性 or 复合杂合 for a TTPA致病性变异.

命名法Nomenclature

AVED首先被称为 Friedreich共济失调伴选择性维生素E缺乏症。AVED was first called “Friedreich ataxia 表型 with selective vitamin E deficiency” [Ben Hamida et al 1993].

患病率Prevalence

有几个有限群体的研究。Gotoda et al(1995)发现了一个TTPA致病性变异(p.His101Gln)。在801个随机选择的日本岛居民中有21个，其中一个先前被诊断出患有AVED。这相当于计算患病率，每1500名居民有一个纯合子个体。来自东京的150名不相关的个体中没有发现这种致病性变异。在摩洛哥的一项研究中,有Friedreich ataxia-like表型的患者有20%被诊断为AVED(Benomar、个人通信)。在挪威东南部的一项群体研究中，有171个体有遗传性共济失调中有一人是AVED，这表明其患病率为0.6:100万(Elkamil et al,2015)。Anheim等[2010]评估102位疑似常染色体隐性遗传小脑性共济失调患者;在57个个体中(56%)可以建立分子诊断。这些其中36位有 Friedreich共济失调(FRDA),七个有共济失调伴动眼神经的失用症2型(AOA2), 4人共济失调伴毛细血管扩张ataxia-telangiectasia(AT),3人有Marinesco-Sjogren综合症(MSS),3人有共济失调伴动眼神经的失用症1型(AOA1),两人有常隐Charlevoix-Saguenay痉挛性共济失调(ARSACS),1个常隐小脑性共济失调(ARCA2),和1人有共济失调伴维生素E缺乏症(AVED)。根据他们的研究结果，作者推断出法国阿尔萨斯地区AVED大约1:18万的发病率。Zortea等[2004]对意大利帕多瓦省的遗传性共济失调进行了一项流行病学研究，发现有3.5:1，000， 000的患病率。TTPA基因敲除小鼠对脑性疟疾具有抵抗性，并且可以通过补充维生素E(Herbas et al 2010a,Herbas et al 2010b)来消除这种抵抗性。TTPA的致病性变异体加到几个保护免受疟疾的变异中，从而使保护免受疟疾[Lopez et al . 2010]，并可以解释在地中海周围，有这种致病变异有相对高发病率。Several restricted population-based studies have been performed.

Gotoda et al [1995] found one TTPA致病性变异 (p.His101Gln) in 21 of 801 randomly selected inhabitants of a Japanese island on which one individual had previously been diagnosed with AVED. This would amount to a calculated prevalence of one 纯合性 individual per 1500 inhabitants. This pathogenic variant was not detected in 150 unrelated individuals from Tokyo.

In a Moroccan study, AVED was diagnosed in 20% of individuals with a Friedreich ataxia-like 表型 [Benomar, personal communication].

In a population study in southeast Norway, 1 in 171 individuals with hereditary ataxia was found to have AVED, suggesting a prevalence of 0.6:1,000,000 [Elkamil et al 2015].

Anheim et al [2010] evaluated102 individuals with suspected 常染色体隐性遗传 cerebellar ataxia; in 57 individuals (56%) a molecular diagnosis could be established. Of these, 36 had Friedreich ataxia (FRDA), seven had ataxia with oculomotor apraxia type 2 (AOA2), four had ataxia-telangiectasia (AT), three had Marinesco-Sjögren syndrome (MSS), three had ataxia with oculomotor apraxia type 1 (AOA1), two had AR spastic ataxia of Charlevoix-Saguenay (ARSACS), one had AR cerebellar ataxia (ARCA2), and one had ataxia with vitamin E deficiency (AVED). From their findings, the authors infer a prevalence for AVED in the Alsace region of France of approximately 1:1,800,000.

Zortea et al [2004] performed an epidemiologic study of inherited ataxias in the Italian province of Padua and found a prevalence of 3.5:1,000,000 for AVED.

It also appears to be of interest that TTPA knockout mice are resistant to cerebral malaria and that this resistance can be abrogated by supplementation with vitamin E [Herbas et al 2010a, Herbas et al 2010b]. This may add TTPA pathogenic variants to several inherited alterations that confer protection against malaria [López et al 2010] and could explain the comparatively high prevalence of such pathogenic variants around the Mediterranean Sea.

Clinical Description

The 表型 and disease severity of ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, symptoms and disease severity can vary among sibs [Shorer et al 1996].

AVED generally manifests in late childhood or early teens between ages five and 15 years, however, the range may be from age two to 37 years as reported in a series of 132 North African individuals [El Euch-Fayache et al 2014]. The first symptoms include progressive ataxia, clumsiness of the hands, and loss of proprioception, especially of vibration and joint position sense. Handwriting deteriorates. In rare individuals, school performance declines secondary to loss of intellectual capacities. Tendon reflexes of the lower extremities are generally absent and the plantar reflexes increase in intensity. Affected individuals have difficulty walking in the dark and often have a positive Romberg sign. A high percentage of 受累的 individuals (e.g., 8/11 individuals in one series) experience decreased visual acuity [Benomar et al 2002].

In many individuals, cerebellar signs such as dysdiadochokinesia and dysarthria with a scanning speech pattern are present. One third of individuals have a characteristic head tremor (head titubation). In some persons, psychotic episodes, intellectual decline, and dystonic episodes have been described. Rarely, AVED may manifest as arm or cervical dystonia [Becker et al 2016].

Most untreated individuals become wheelchair dependent as a result of ataxia and/or leg weakness between ages 11 and 50 years [Harding et al 1985, Ouahchi et al 1995, Hentati et al 1996, Cavalier et al 1998, Gabsi et al 2001, Benomar et al 2002, Mariotti et al 2004].

According to a large study on 132 individuals from North Africa [El Euch-Fayache et al 2014], the signs and symptoms include (in decreasing order of frequency):

• Areflexia (94.7%)
• Gait impairment (93.4%)
• Positive Babinski sign (85.5%)
• Deep sensory disturbances (67.1%)
• Dysarthria (61.8%)
• Head tremor (40.8%)
• Urinary urgency (22.4%)
• Nystagmus (5.3%)
• Urinary incontinence (4.0%)
• Retinitis pigmentosa (2.3%)
• Cardiomyopathy (1.5%)

Genotype-Phenotype Correlations

To date, only two pathogenic variants have shown clear-cut 基因型-表型 correlations:

• p.His101Gln is associated with late-onset disease (age >30 years), a mild course, and increased risk for pigmentary retinopathy. This variant is primarily reported in individuals of Japanese descent.
• c.744delA is associated with early onset, a severe course, and slightly increased risk for cardiomyopathy. This variant is mainly observed in individuals of Mediterranean or North African descent. However, disease severity may vary considerably, and even in persons from the same family the onset of symptoms may vary between ages three and 12 years [Cavalier et al 1998, Marzouki et al 2005].

A less clear 基因型-表型相关性 can be seen for the following pathogenic variants if they occur in 纯合性 form. Manifestation of disease:

• Before age ten years. p.Arg59Trp, p.Arg134Ter, p.Glu141Lys, c.486delT, c.513_514insTT, c.530-531AG>GTAAGT (see Table 3)
• After age ten years. p.Arg221Trp, p.Ala120Thr (see Table 3) [Cavalier et al 1998]

Penetrance

AVED shows nearly complete 外显率 in individuals who are 纯合性 or 复合杂合 for a TTPA致病性变异.

Nomenclature

AVED was first called “Friedreich ataxia 表型 with selective vitamin E deficiency” [Ben Hamida et al 1993].

Prevalence

Several restricted population-based studies have been performed.

Gotoda et al [1995] found one TTPA致病性变异 (p.His101Gln) in 21 of 801 randomly selected inhabitants of a Japanese island on which one individual had previously been diagnosed with AVED. This would amount to a calculated prevalence of one 纯合性 individual per 1500 inhabitants. This pathogenic variant was not detected in 150 unrelated individuals from Tokyo.

In a Moroccan study, AVED was diagnosed in 20% of individuals with a Friedreich ataxia-like 表型 [Benomar, personal communication].

In a population study in southeast Norway, 1 in 171 individuals with hereditary ataxia was found to have AVED, suggesting a prevalence of 0.6:1,000,000 [Elkamil et al 2015].

Anheim et al [2010] evaluated102 individuals with suspected 常染色体隐性遗传 cerebellar ataxia; in 57 individuals (56%) a molecular diagnosis could be established. Of these, 36 had Friedreich ataxia (FRDA), seven had ataxia with oculomotor apraxia type 2 (AOA2), four had ataxia-telangiectasia (AT), three had Marinesco-Sjögren syndrome (MSS), three had ataxia with oculomotor apraxia type 1 (AOA1), two had AR spastic ataxia of Charlevoix-Saguenay (ARSACS), one had AR cerebellar ataxia (ARCA2), and one had ataxia with vitamin E deficiency (AVED). From their findings, the authors infer a prevalence for AVED in the Alsace region of France of approximately 1:1,800,000.

Zortea et al [2004] performed an epidemiologic study of inherited ataxias in the Italian province of Padua and found a prevalence of 3.5:1,000,000 for AVED.

It also appears to be of interest that TTPA knockout mice are resistant to cerebral malaria and that this resistance can be abrogated by supplementation with vitamin E [Herbas et al 2010a, Herbas et al 2010b]. This may add TTPA pathogenic variants to several inherited alterations that confer protection against malaria [López et al 2010] and could explain the comparatively high prevalence of such pathogenic variants around the Mediterranean Sea.

初步诊断后评估Evaluations Following Initial Diagnosis
 

为了确定共济失调伴维生素E缺乏症患者的疾病程度，建议进行以下评估：

To establish the extent of disease and needs in an individual diagnosed with ataxia with vitamin E deficiency (AVED), the following evaluations are recommended:

• 临床神经学检查，特别是反射状态、振动和位置感觉、步态、巴宾斯基症、震颤、构音障碍。Clinical neurologic examination – particularly reflex status, vibratory and position sense, gait, Babinski sign, tremor, dysarthria
• 眼科检查：视网膜黄斑变性或色素性视网膜炎及视力减退，视网膜电流图 (ERG）Ophthalmologic examination for evidence of macular degeneration or retinitis pigmentosa and decreased visual acuity; electroretinogram (ERG)
• 心脏检查;超声心动图和心电图评估心肌病Cardiac examination; echocardiography and ECG to assess for cardiomyopathy
• 神经生理学检查;神经传导速度(NCV)和体感电位(特别是中枢传导时间[Schuelke et al 1999])，这是补充维生素E后神经系统改善的客观指标Neurophysiologic examination; nerve conduction velocity (NCV) and somatosensory potentials (especially the central conduction time [Schuelke et al 1999]), which are good objective measures of neurologic improvement after vitamin E supplementation
• 由临床遗传学家和/或遗传顾问咨询。Consultation with a clinical geneticist and/or genetic counselor

治疗症状Treatment of Manifestations

AVED治疗，选择的方法是终生服用高剂量口服维生素E。一些症状(如共济失调和智力衰退)如果在疾病早期开始治疗(Schuelke et al 1999)，则可以逆转。在老年个体中，疾病的进展可以被阻止，但本体感觉的缺陷和步态的不稳定通常仍然存在[Gabsi et al 2001, Mariotti et al 2004, El Euch-Fayache et al 2014]。治疗后，血浆中的维生素E浓度会变得正常。在有前驱症状的个体中，如果维生素E的补充是在早期(El Euch-Fayache et al 2014)开始的，就可以预防AVED症状的出现。进行大规模的治疗研究没有确定最佳的维生素E剂量和评估结果。已报道维生素E剂量范围从800毫克到1500毫克(或40毫克/公斤体重对儿童)[Burck et al 1981, Harding et al 1985, Amiel et al 1995, Cavalier et al 1998, Schuelke et al 1999, Schuelke et al 2000b, Gabsi et al 2001, Mariotti et al 2004]。下列其中一种维生素E准备使用。The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. Some symptoms (e.g., ataxia and intellectual deterioration) can be reversed if treatment is initiated early in the disease process [Schuelke et al 1999]. In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [Gabsi et al 2001, Mariotti et al 2004, El Euch-Fayache et al 2014]. With treatment, plasma vitamin E concentrations can become normal.

In presymptomatic individuals, the manifestations of AVED can be prevented if vitamin E supplementation is initiated early [El Euch-Fayache et al 2014].

No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes.

The reported vitamin E dose ranges from 800 mg to 1500 mg (or 40 mg/kg body weight in children) [Burck et al 1981, Harding et al 1985, Amiel et al 1995, Cavalier et al 1998, Schuelke et al 1999, Schuelke et al 2000b, Gabsi et al 2001, Mariotti et al 2004].

One of the following vitamin E preparations is used:

• 化学制成的消旋体,all-rac-α-生育酚醋酸The chemically manufactured racemic form, all-rac-α-tocopherol acetate
• 天然形成的形式,RRR-α-生育酚。The naturally occurring form, RRR-α-tocopherol
  目前未知是否受累的人应该接受all-rac-α-维生素E醋酸或RRR-α-生育酚。众所周知,alpha-TTP(αTPP)立体选择性结合和传输2 r-α-生育酚[1996年Weiser et al,Hosomi等1997年,伦纳德等人2002)。一些TTPA的致病性变异,这个立体选择结合能力丢失，受累个体不能区分RRR-和SRR-α-生育酚[Traber et al 1993、骑士等1998)。在这种情况下,如果受累个体补充all-rac-α-生育酚，他们也可以吸收non-2R-α-生育酚立体异构体到他们的身体。由于合成立体异构体的潜在副作用没有详细研究,似乎用RRR-α-生育酚治疗是适当的,尽管成本较高。

It is currently unknown whether 受累的 individuals should be treated with all-rac-α-tocopherol acetate or with RRR-α-tocopherol. It is known that alpha-TTP (αTPP) stereoselectively binds and transports 2R-α-tocopherols [Weiser et al 1996, Hosomi et al 1997, Leonard et al 2002]. For some TTPA pathogenic variants, this stereoselective binding capacity is lost and affected individuals cannot discriminate between RRR- and SRR-α-tocopherol [Traber et al 1993, Cavalier et al 1998]. In this instance, affected individuals would also be able to incorporate non-2R-α-tocopherol stereoisomers into their bodies if they were supplemented with all-rac-α-tocopherol. Since potential adverse effects of the synthetic stereoisomers have not been studied in detail, it seems appropriate to treat with RRR-α-tocopherol, despite the higher cost.

预防的主要表现Prevention of Primary Manifestations

If vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), the symptoms of AVED do not develop [Amiel et al 1995, El Euch-Fayache et al 2014].

监督Surveillance

在维生素E治疗期间，血浆中的维生素E浓度应定期检测(如每6个月)，特别是儿童。理想情况下，血浆维生素E浓度应保持在正常值高限范围内。一些说明书要求测量血浆(TRAP)的捕获自由基的总抗氧化剂参数。尽管α-生育酚只有TRAP的5% - -10%, 这个参数似乎是最好作为临床改善的替代标记[Schuelke et al 1999]。中断补充维生素E，即使是暂时性的，也会导致血浆中的维生素E浓度在2 - 3天内下降，即使再重新补充维生素E(Kohlschutter et al 1997, Schuelke et al 2000b)之后，也会导致TRAP的持续下降。
During vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high normal range.

Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [Schuelke et al 1999]. Discontinuation of vitamin E supplementation, even temporarily, leads to a drop in plasma vitamin E concentration within two to three days and to a prolonged drop in TRAP, even after reinitiating vitamin E supplementation [Kohlschütter et al 1997, Schuelke et al 2000b].

避免的代理/环境
Agents/Circumstances to Avoid

有AVED的个体应该避免：Individuals with AVED should avoid:

• 吸烟，因为它大大降低了TRAP，降低了血浆中维生素E的浓度。Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [Sharpe et al 1996];
• 需要快速反应或保持良好平衡的职业Occupations requiring quick responses or good balance.

评估亲属的风险Evaluation of Relatives at Risk

预防性检测应该对先证者的所有兄弟姐妹,及时治疗,补充维生素E可以完全避免疾病的临床表现Predictive testing should be offered to all sibs of a 先证者, as timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

• 所有亲戚都存在风险,尤其是先证者的弟弟妹妹,应评估维生素E缺乏症。All relatives at risk, especially younger sibs of a 先证者, should be evaluated for vitamin E deficiency.
• 如果血浆维生素E浓度很低,发现先证者有TTPA致病性变异,这样患者有双等位基因的致病性变异应及时治疗给予维生素E补充剂。If plasma vitamin E concentration is low, the person should be tested for presence of the TTPA pathogenic variants found in the 先证者 so that individuals with 双等位基因的 pathogenic variants can be treated promptly with vitamin E supplementation.

请参阅遗传咨询相关的有关检测亲属风险的问题。See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 purposes.

孕期管理Pregnancy Management

维生素E水平减少与老鼠的低生育和胚胎吸收有关[Traber &Mentor2012],α-维生素E转运蛋白高表达在人类胎盘(2004年Muller-Schmehl等);因此，建议在怀孕期间保持正常范围内高限的维生素E水平。Reduced vitamin E levels are associated with low fertility and embryo resorption in mice [Traber & Manor 2012] and α-tocopherol transfer protein is highly expressed in the human placenta [Müller-Schmehl et al 2004]; therefore, it is advisable to keep vitamin E levels in the high normal range during pregnancy.

Therapies Under Investigation

查阅临床研究的临床资料，以获得疾病的宽范围和（发生）条件。注意:这种疾病可能没有临床试验
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

由于异常的四肢位置觉，有AVED的人体骑自行车或开车都有困难。试图开车之前,受累的个人需要通过医生来测试确定是否能安全驾驶。
Because of abnormal position sense in the extremities, individuals with AVED may have difficulty riding a bicycle or driving a car. Before attempting to drive a car, 受累的 individuals need to be tested by a physician to determine whether they can drive safely.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ataxia with vitamin E deficiency (AVED), the following evaluations are recommended:

• Clinical neurologic examination – particularly reflex status, vibratory and position sense, gait, Babinski sign, tremor, dysarthria
• Ophthalmologic examination for evidence of macular degeneration or retinitis pigmentosa and decreased visual acuity; electroretinogram (ERG)
• Cardiac examination; echocardiography and ECG to assess for cardiomyopathy
• Neurophysiologic examination; nerve conduction velocity (NCV) and somatosensory potentials (especially the central conduction time [Schuelke et al 1999]), which are good objective measures of neurologic improvement after vitamin E supplementation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. Some symptoms (e.g., ataxia and intellectual deterioration) can be reversed if treatment is initiated early in the disease process [Schuelke et al 1999]. In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [Gabsi et al 2001, Mariotti et al 2004, El Euch-Fayache et al 2014]. With treatment, plasma vitamin E concentrations can become normal.

In presymptomatic individuals, the manifestations of AVED can be prevented if vitamin E supplementation is initiated early [El Euch-Fayache et al 2014].

No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes.

The reported vitamin E dose ranges from 800 mg to 1500 mg (or 40 mg/kg body weight in children) [Burck et al 1981, Harding et al 1985, Amiel et al 1995, Cavalier et al 1998, Schuelke et al 1999, Schuelke et al 2000b, Gabsi et al 2001, Mariotti et al 2004].

One of the following vitamin E preparations is used:

• The chemically manufactured racemic form, all-rac-α-tocopherol acetate
• The naturally occurring form, RRR-α-tocopherol

It is currently unknown whether 受累的 individuals should be treated with all-rac-α-tocopherol acetate or with RRR-α-tocopherol. It is known that alpha-TTP (αTPP) stereoselectively binds and transports 2R-α-tocopherols [Weiser et al 1996, Hosomi et al 1997, Leonard et al 2002]. For some TTPA pathogenic variants, this stereoselective binding capacity is lost and affected individuals cannot discriminate between RRR- and SRR-α-tocopherol [Traber et al 1993, Cavalier et al 1998]. In this instance, affected individuals would also be able to incorporate non-2R-α-tocopherol stereoisomers into their bodies if they were supplemented with all-rac-α-tocopherol. Since potential adverse effects of the synthetic stereoisomers have not been studied in detail, it seems appropriate to treat with RRR-α-tocopherol, despite the higher cost.

Prevention of Primary Manifestations

If vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), the symptoms of AVED do not develop [Amiel et al 1995, El Euch-Fayache et al 2014].

Surveillance

During vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high normal range.

Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [Schuelke et al 1999]. Discontinuation of vitamin E supplementation, even temporarily, leads to a drop in plasma vitamin E concentration within two to three days and to a prolonged drop in TRAP, even after reinitiating vitamin E supplementation [Kohlschütter et al 1997, Schuelke et al 2000b].

Agents/Circumstances to Avoid

Individuals with AVED should avoid:

• Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [Sharpe et al 1996];
• Occupations requiring quick responses or good balance.

Evaluation of Relatives at Risk

Predictive testing should be offered to all sibs of a 先证者, as timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

• All relatives at risk, especially younger sibs of a 先证者, should be evaluated for vitamin E deficiency.
• If plasma vitamin E concentration is low, the person should be tested for presence of the TTPA pathogenic variants found in the 先证者 so that individuals with 双等位基因的 pathogenic variants can be treated promptly with vitamin E supplementation.

See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 purposes.

Pregnancy Management

Reduced vitamin E levels are associated with low fertility and embryo resorption in mice [Traber & Manor 2012] and α-tocopherol transfer protein is highly expressed in the human placenta [Müller-Schmehl et al 2004]; therefore, it is advisable to keep vitamin E levels in the high normal range during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Because of abnormal position sense in the extremities, individuals with AVED may have difficulty riding a bicycle or driving a car. Before attempting to drive a car, 受累的 individuals need to be tested by a physician to determine whether they can drive safely.

Mode of Inheritance

共济失调伴维生素E缺乏症的的遗传方式是常染色体隐性遗传 。Ataxia with vitamin E deficiency (AVED) is inherited in an 常染色体隐性遗传 manner.

家族成员的风险Risk to Family Members

先证者的父母 Parents of a 先证者

• 受累孩子的父母是专性的杂合子（例如，TTPA致病性变异的携带者）。The parents of an 受累的 child are obligate heterozygotes (i.e., carriers of one TTPA致病性变异).
• 杂合子(携带者)是无症状的，不存在发展疾病的风险。Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

先证者的同胞  Sibs of a 先证者

• 理论上讲,受累个体的每个同胞有25%的几率受累,50%的几率成为一个无症状携带者,和25%的几率而不受累也不会成为携带者。At conception, each sib of an 受累的 individual has a 25% chance of being affected, a 50% chance of being an asymptomatic 携带者, and a 25% chance of being unaffected and not a carrier.
• 杂合子(携带者)是无症状的，不存在发展疾病的风险。Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

先证者的子代of a 先证者. 有AVED个体的子代是TTPA致病变异的专性杂合子。The offspring of an individual with AVED are obligate heterozygotes (carriers) for a 致病性变异 in TTPA.先证者的其他家族成员，先证者的父母的每一个同胞都有50%的机会成为TTPA致病变异的携带者。

Other family members of a 先证者. Each sib of the proband's parents is at a 50% risk of being a 携带者 of a 致病性变异 in TTPA.

携带者（杂合子）检测 Carrier (Heterozygote) Detection

对高危亲属的携带者检测要求在家族中事先鉴定TTPA致病变异。在杂合子个体，血浆维生素E浓度中度降低，敏感程度不够以区分杂合的携带者和非携带者。Carrier testing for at-risk relatives requires prior identification of the TTPA pathogenic variants in the family.

The moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between 杂合的 carriers and non-carriers.

遗传咨询的相关问题Related Genetic Counseling Issues

对高危家庭成员的预测检测。因为维生素E治疗用于前症状个体可以防止有AVED的症状发生(Amiel et al 1995),所以对高危家庭成员的预测检测(尤其是先证者弟弟妹妹)是适当的。见管理、评估亲属的风险信息，为早期诊断和治疗的目的评估高危亲属。计划生育：Predictive testing of at-risk family members. Because vitamin E treatment initiated in presymptomatic individuals can prevent the findings of AVED [Amiel et al 1995], predictive testing of at-risk family members (particularly younger sibs of the 先证者) is appropriate. See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• 在怀孕之前，确定遗传风险的最佳时间,区分携带者地位,和讨论产前检测可行性的。The optimal time for determination of genetic risk, clarification of 携带者 status, and discussion of the availability of prenatal testing is before pregnancy.
• 对年轻人受累者,携带者,或者成为携带者的风险提供遗传咨询(包括讨论后代的潜在风险和生殖选项)是适当的。It is appropriate to offer 遗传咨询 (including discussion of potential risks to offspring and reproductive options) to young adults who are 受累的, are carriers, or at risk of being carriers.

DNA储存库是储存DNA(通常是从白血球中提取)以备将来使用。因为检测方法学及我们对基因，等位变异, 和疾病的理解将会得到改进, 应该考虑建立受累的人体DNA库。DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of 受累的 individuals.

产前检查和胚胎植入前遗传学诊断。Prenatal Testing and Preimplantation Genetic Diagnosis

一个受累的家庭成员一旦TTPA致病性变异确定, 对孕妇患病AVED的风险增加，进行产前诊断和植入前遗传诊断是可能的。医学专业人员和家庭内部对于产前检查的使用可能存在不同的观点，尤其当如果考虑到妊娠终止的目的而不是早期诊断的检测。尽管大多数中心会考虑产前检查的决定是家长的选择，但讨论这些问题是适当的。Once the TTPA pathogenic variants have been identified in an 受累的 family member, prenatal testing for a pregnancy at increased risk and 植入前遗传诊断 for AVED are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Mode of Inheritance

Ataxia with vitamin E deficiency (AVED) is inherited in an 常染色体隐性遗传 manner.

Risk to Family Members

Parents of a 先证者

• The parents of an 受累的 child are obligate heterozygotes (i.e., carriers of one TTPA致病性变异).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a 先证者

• At conception, each sib of an 受累的 individual has a 25% chance of being affected, a 50% chance of being an asymptomatic 携带者, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a 先证者. The offspring of an individual with AVED are obligate heterozygotes (carriers) for a 致病性变异 in TTPA.

Other family members of a 先证者. Each sib of the proband's parents is at a 50% risk of being a 携带者 of a 致病性变异 in TTPA.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the TTPA pathogenic variants in the family.

The moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between 杂合的 carriers and non-carriers.

Related Genetic Counseling Issues

Predictive testing of at-risk family members. Because vitamin E treatment initiated in presymptomatic individuals can prevent the findings of AVED [Amiel et al 1995], predictive testing of at-risk family members (particularly younger sibs of the 先证者) is appropriate. See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of 携带者 status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer 遗传咨询 (including discussion of potential risks to offspring and reproductive options) to young adults who are 受累的, are carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of 受累的 individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TTPA pathogenic variants have been identified in an 受累的 family member, prenatal testing for a pregnancy at increased risk and 植入前遗传诊断 for AVED are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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Suggested Reading

• Christopher Min K. Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED. Vitam Horm. 2007;76:23鈥�43. [PubMed: 17628170]
• Koenig M. Friedreich ataxia and AVED. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 232. Available online.
• Manor D, Morley S. The alpha-tocopherol transfer protein. Vitam Horm. 2007;76:45鈥�65. [PubMed: 17628171]

Revision History

• 13 October 2016 (sw) Comprehensive update posted live
• 2 November 2010 (me) Comprehensive update posted live
• 4 September 2007 (me) Comprehensive update posted to live Web site
• 20 May 2005 (me) Review posted to live Web site
• 4 October 2004 (ms) Original submission