临床特点.

Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F)是一种进行性的、涉及到外周运动神经和外周感觉神经的神经病，它有着多变的临床表现和电生理表现。Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is characterized by a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. 发病年龄从10岁到50岁均有发现；在一些病例中，该病能在婴儿时期发作。Disease onset ranges from the first to the fifth decade of life; in some cases disease onset can be in infancy. 因为进行性的远端肌无力和下肢肌肉萎缩，受累个体无法正常行走、跑动。Affected individuals have difficulty walking and running because of progressive distal weakness and wasting of the muscles of the lower limbs. 不同个体的下肢远端部分的麻痹症状也有不同，从轻微的无力到远端肌肉群的完全瘫痪均有出现。Paresis in the distal part of the lower limbs varies from mild weakness to a complete paralysis of the distal muscle groups. 肌腱反射减弱或消失。Tendon reflexes are diminished or absent. Sensory signs虽不起主要作用，却存在于所有受累个体体内。Sensory signs are not prominent but are present in all 受累的 individuals. 弓形足，槌状趾，以及爪形手经常出现在受累个体上。Pes cavus, hammer toes, and claw hands are frequently observed. 受累个体通常能够保留步行能力。Ambulation is generally preserved.

诊断/检测.

在大多数受累个体中，神经传导速率（NCVs）严重或一定程度地降低至CMT1型的NCVs指标范围 (比如正中运动神经传导速率<38 m/sec)，尽管也有受累个体拥有接近正常的NCVs。In most individuals, nerve conduction velocities (NCVs) are severely to moderately reduced and fall within the CMT1 range (i.e., <38 m/sec for the motor median nerve), although near-normal NCVs have been described. NEFL是编码神经微丝轻链蛋白的基因，也是已知的唯一与CMT2E/1F相关的基因。NEFL, encoding the protein neurofilament light chain, is the only 基因 known to be associated with CMT2E/1F.

管理.

对症状的治疗：受累个体一般通过多学科综合治疗小组来对病症进行评估与管理，这些小组包括神经病学医师，物理治疗医师，骨科医师，物理治疗师以及职业治疗师。Treatment of manifestations: Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. 治疗手段可能包括：能够有效保护踝关节的特质鞋子，每日的跟腱拉伸练习，踝足矫正器，针对高弓内翻足的整形外科手术，用于提高稳定性的拐杖或手杖。Treatment may include: special shoes with good ankle support, daily heel cord stretching exercises, ankle/foot orthoses, orthopedic surgery for severe pes cavus deformity, and crutches or canes for stability. 要鼓励锻炼。Exercise is encouraged. 疼痛现象要对症治疗。Pain is treated symptomatically.对次要并发症的预防：每日的跟腱拉伸练习以防止跟腱缩短。

Prevention of secondary complications: Daily heel cord stretching exercises to prevent Achilles' tendon shortening.监测：监控步态和足部状况来决定是否需要支持杆，特质鞋子，手术。 

Surveillance: Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.要避免的状况：肥胖，因为肥胖会增加步行的难度；会造成神经损伤的药物以及治疗（比如：长春新碱，异烟肼，紫杉酚，顺铂，呋喃妥因）

Agents/circumstances to avoid: Obesity because it makes walking more difficult; drugs and medications (e.g., vincristine, isoniazid, taxol, cisplatin, nitrofurantoin) that are known to cause nerve damage.

基因咨询.

CMT2E/1F一般通过常染色体显性遗传的方式传递；偶尔通过常染色体隐性遗传。CMT2E/1F is usually inherited in an 常染色体显性遗传 manner; on rare occasion it can be inherited in an 常染色体隐性遗传 manner.常染色体显性遗传的CMT2E/1F：大多数受累个体都有一对受累的父母。

Autosomal dominant CMT2E/1F: Most individuals with 常染色体显性遗传 CMT2E/1F have an 受累的 parent. 新生致病变异在有严重表型的个体上更典型。De novo pathogenic variants are more typical for individuals with a severe 表型. 兄弟姐妹的患病风险取决与先证者父母的遗传状态The risk to sibs depends on the genetic status of the 先证者's parents. 受累个体的每一个小孩都有50%的概率继承这个致病性变异。Each child of an individual with autosomal dominant CMT2E/1F has a 50% chance of inheriting the 致病性变异.常染色体隐性遗传的CMT2E/1F：理论上，受累个体的兄弟姐妹有25%的概率患病，50%的概率成为一个无症状携带者，25%的概率既无症状也非携带者。

Autosomal recessive CMT2E/1F: The risk to each sib of an 受累的 individual at conception is 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.如果致病性变异在家族中已有出现，需要对常染色体显性遗传和常染色体隐性遗传的CMT2E/1F两种情况均进行产前检查。

Prenatal testing for pregnancies at increased risk for both 常染色体显性遗传 and 常染色体隐性遗传 CMT2E/1F is possible if the 致病性变异(s) in the family are known.

临床诊断

Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F)在患有外周运动神经病或外周感觉神经病的个体中值得被怀疑。Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F) is suspected in individuals with a progressive peripheral motor and sensory neuropathy.神经传导速度（NCVs）分布范围很广。在大多数受累个体中，NCVs严重或一定程度地降低至CMT1型的NCVs指标范围 ，比如正中运动神经传导速率低于38 m/sec，尽管也有部分受累个体的NCVs接近正常。

Nerve conduction velocities (NCVs) vary widely. In most individuals, NCVs are severely to moderately reduced and fall within the CMT1 range, i.e., less than 38 m/sec for the motor median nerve, although near-normal NCVs have also been described. 受累个体中有报导地，最低的NCV为12 m/sec。The lowest reported NCV in an individual with CMT2E/1F is 12 m/sec. 复合动作电位的振幅通常会严重降低。The amplitudes of the compound action potentials are usually severely reduced. 感觉神经的动作电位通常不可记录。Sensory nerve action potentials are often unrecordable.肌电图 (EMG) 

Electromyogram (EMG). 同心针肌电图表现出慢性神经源性变化。Concentric needle EMG shows chronic neurogenic alterations.外周神经活检不是诊断的必须流程。

Peripheral nerve biopsy is not obligatory for diagnosis. 针对腓肠神经的组织病理学研究发现了一种脱髓鞘和轴突的混合异常病理学状态，特征是粗神经纤维、薄髓鞘有髓轴突、轴突再生簇、洋葱鳞茎生成减少 [Jordanova et al 2003, Züchner et al 2004]。Histopathologic studies of sural nerve biopsies showed a mixed (demyelinating and axonal) pathology, characterized by reduction mainly of large nerve fibers, thinly myelinated axons, axonal regeneration clusters, and onion bulb formation [Jordanova et al 2003, Züchner et al 2004]. 无序神经纤维细丝聚集在巨轴突病灶处的现象也有发现 [Fabrizi et al 2004, Fabrizi et al 2007]。Giant axons with focal accumulation of disorganized neurofilaments are also described [Fabrizi et al 2004, Fabrizi et al 2007]. 在常染色体隐性遗传的CMT2E/1F患病个体中，有观察到有髓鞘轴突大量减少，只有小直径有髓鞘轴突缺乏中间纤维 [Yum et al 2009]。In an individual with 常染色体隐性遗传 CMT2E/1F, a markedly reduced number of myelinated axons and only small diameter myelinated axons lacking intermediate filaments are observed [Yum et al 2009].

分子遗传学检测

基因. NEFL，编码神经丝轻链蛋白，是已知的、唯一病变后能导致CMT2E/1F的基因。NEFL, encoding the protein neurofilament light chain, is the only 基因 in which pathogenic variants are known to cause CMT2E/1F.测序分析.

Sequence analysis. 目前已知的致病变异包括单核苷酸突变，小片段缺失，插入，NEFL基因内的碱基插入或缺失，均可通过序列分析确定。Pathogenic variants identified to date are single-nucleotide variants, small deletions, insertions, or in/dels in NEFL, all of which are identifiable by 序列分析.目前，外显子或整个基因的缺失或重复现象还没有发现。

To date, 缺失 or 重复 of exons or of the entire 基因 has not been reported.

检测结果的解释.Interpretation of test results. 因为隐性致病变异以及编码区正常变异（以Table 2为例）均有存在，变异的分离应该在家族中追溯（如果可能的话），正常对照组也应被检测。Because of the presence of recessive pathogenic variants, as well as normal variants in the 编码区 (see Table 2 for examples), 分离 of the variants should be traced in the family (when possible) and normal controls should be tested. 例如，Jordanova et al [2003]报导了一个拥有p.Pro8Arg，p.Glu7Lys两个NEFL变异的个体。For example, Jordanova et al [2003] reported an individual with two NEFL variants p.Pro8Arg and p.Glu7Lys. 后续的研究证明这些变异均为反式结构，而且p.Glu7Lys是正常变异，p.Pro8Arg是致病变异 [Pérez-Ollé et al 2004, Yamamoto et al 2004]。Further studies demonstrated that these variants were in trans configuration and p.Pro8Arg was transmitted to the 受累的 children while p.Glu7Lys was a 正常变异 [Pérez-Ollé et al 2004, Yamamoto et al 2004].

检测策略

在先证者 (拥有进行性外周运动和感觉神经疾病)中确诊/建立诊断需要完整的NEFL编码序列的序列分析。To confirm/establish the diagnosis in a 先证者 with a progressive peripheral motor and sensory neuropathy requires 序列分析 of the complete NEFL coding sequence.对有风险、无症状的家族成年人进行预测性检测需要预先在家族中确定致病性变异。

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the 致病性变异(s) in the family.对有风险怀孕的产前诊断与植入前诊断需要预先在家族中确定致病性变异。

Prenatal diagnosis and 植入前遗传诊断 (PGD) for at-risk pregnancies require prior identification of the 致病性变异(s) in the family.

临床描述

CMT2E/1F是一种进行性的、涉及到外周运动神经和外周感觉神经的神经病，它有着多变的临床表现和电生理表现。CMT2E/1F is a progressive peripheral motor and sensory neuropathy with variable clinical and electrophysiologic expression. 发病年龄从10岁到50岁均有发现，并表现出广泛的临床表型，从早发型严重表型到更轻微的表型。The disease onset is within the first five decades of life and presents with a broad clinical 表型 – from an early-onset severe phenotype to milder forms.一些受累个体发病于婴儿时期或儿童早期，并表现出肌张力减退，以及动作发展延迟。

Some 受累的 individuals have onset in infancy or early childhood and may display hypotonia and mildly delayed motor milestones. 在大多数受累个体中，现有的症状是因为因为进行性的远端肌无力和下肢肌肉萎缩导致的无法行走、跑步。The presenting symptoms in most individuals are difficulties in walking and running as a result of progressive distal weakness and wasting of the lower limbs. 不同个体的下肢远端部分的麻痹症状也有不同，从轻微的无力到远端肌肉群的完全瘫痪均有出现。Paresis in the distal part of the lower limbs varies from mild weakness to a complete paralysis of the distal muscle groups. 在大多数严重受影响的人群中，能发现轻度至中度的近臂虚弱和肩胛带虚弱。In the most severely affected people, mild-to-moderate proximal arm and shoulder girdle weakness can be observed.肌腱反射减弱或消失。

Tendon reflexes are diminished or absent. Sensory signs虽不起主要作用，却存在于所有受累个体体内。

Sensory signs are not prominent but are present in all 受累的 individuals. 弓形足，槌状趾，以及爪形手经常出现在受累个体上。

Pes cavus is the most frequently observed limb deformity, together with hammer toes and claw hands. 偶尔可以见到小脑功能失调，震颤，听力丧失。

Cerebellar dysfunction, tremor, and hearing loss are occasionally observed. 受累个体通常能够保留步行能力。

Ambulation is generally preserved during life. 只有一个患者被报导需要终身坐在轮椅上。Only one individual is reported to be wheelchair bound. 受累个体没有明显放大的神经，足部溃烂，声带或膈部麻痹。

Affected individuals do not have palpably enlarged nerves, ulcerated feet, or paralysis of the vocal cords and/or diaphragm.

基因型-表型相关性

由于很少有报导的NEFL致病变异个体，目前没有明显的基因型/表型相关性。There are no obvious 基因型/表型 correlations, mainly because of the small number of reported individuals with NEFL pathogenic variants. 然而，Miltenberger-Miltenyi et al [2007]提出，位于NEFL头部结构域的致病性变异可以得到比在2B螺旋结构域的致病性变异更严重的神经传导速度减慢。However, Miltenberger-Miltenyi et al [2007] noted that pathogenic variants in the head 结构域 of NEFL may cause more severe slowing of nerve conduction velocity than pathogenic variants in the coil 2B domain.拥有常染色体隐性遗传的CMT2E/1F患者通常有更严重的表型，诊断为CMT1F。

Individuals with 常染色体隐性遗传 CMT2E/1F usually have more a severe 表型, diagnosed as CMT1F.

外显率

Penetrance is most likely to be complete.
外显率几乎为100%。

遗传早现

No clear evidence of 遗传早现 is available in the literature.
目前文献中没有遗传早现的证据报导。

系统命名过程

在第一个报导的家族中，NCVs位于CMT2型的范围内；因此这个CMT变异体最开始被命名为CMT2E [Mersiyanova et al 2000]。In the first reported family, NCVs were within the CMT2 range; thus this CMT variant was initially described as CMT2E [Mersiyanova et al 2000]. 后来在来自相似家族和单发案例（比如没有家族病史的人）的个体中观察到的缓慢NCVs现象给疾病分类产生了难题：OMIM把有CMT2型电生理表型的个体分类为CMT2E [Mersiyanova et al 2000]，同时把有CMT1型电生理表型的个体分类为CMT1F。The subsequent observation of slow NCVs in individuals belonging to similar families and in 单发的 cases (i.e., those with no family history of the disorder) created a nosologic problem: OMIM classifies individuals with a CMT2 electrophysiologic 表型 as having CMT2E [Mersiyanova et al 2000], while those with a CMT1 electrophysiologic phenotype are classified as having CMT1F. CMT1F的特征是缓慢地进行性的远端肌萎缩与肌无力，肌腱反射消失，高弓足，NCV减慢 (<38 m/sec)。

CMT1F is characterized by slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, hollow feet, and reduced nerve conduction velocities (<38 m per sec). 发病年龄在婴儿早期或者儿童时期，症状通常更严重。Onset is in early infancy or childhood and the course is usually more severe. 这些个体通常被诊断为代-索二氏综合征 (Dejerine-Sottas syndrome, DSS)，DSS的表型与此类似，并且受累个体在很多基因均有致病变异；因此当考虑CMT的疾病分类时，DSS加剧了分类的难度。These individuals are often diagnosed as having Dejerine-Sottas syndrome (DSS), a term that refers to this 表型 and can be observed in individuals with pathogenic variants in a number of genes; thus, the term DSS has become more confusing than helpful when considering the nosology of CMT. 目前报导的该病的显性与隐性两种遗传模式进一步增加了疾病分类的难度。

The reported 常染色体显性遗传 as well as 常染色体隐性遗传遗传模式 of the disease further complicates the nosologic classification.

患病率

CMT2E/1F真实的患病率目前未知。The true prevalence of CMT2E/1F is not known. 初步的数据表明NEFL致病变异占到有CMT表型个体的2% - 5%，在有神经病的一岁个体中占到大约1% [Baets et al 2011]。Preliminary data indicate that NEFL pathogenic variants account for 2%-5% of individuals presenting with a CMT 表型 and for about 1% of the individuals with neuropathy onset within the first year of life [Baets et al 2011].

初步诊断后评估

为了确定CMT2E/1F患者的病变程度，建议采用以下评估手段：To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 2E/1F (CMT2E/1F), the following evaluations are recommended:

• 体格检查以确定虚弱和萎缩，弓形足，步态稳定，感觉障碍的程度Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• 检测神经传导速率以帮助区分脱髓鞘神经病，轴突神经病，以及混合型神经病NCV to help distinguish demyelinating, axonal, and mixed neuropathies
• 完成家族史调查Complete family history
• 咨询临床遗传学家和/或遗传咨询师Consultation with a cinical geneticist and/or genetic counselor

对症治疗

受累个体一般通过多学科综合治疗小组来对病症进行系统地评估与管理，这些小组包括神经病学医师，物理治疗医师，骨科医师，物理治疗师以及职业治疗师 [Grandis & Shy 2005]。Treatment is symptomatic and 受累的 individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Grandis & Shy 2005].

• 特质鞋子，能够有效保护踝关节。Special shoes, including those with good ankle support, may be needed.
• 每日的跟腱拉伸练习，防止跟腱缩短。Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
• 踝足矫正器，纠正足下垂并辅助步行。Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking.
• 整形外科手术，修正严重的高弓足畸形 [Holmes & Hansen 1993, Guyton & Mann 2000]。Orthopedic surgery may be required to correct severe pes cavus deformity [Holmes & Hansen 1993, Guyton & Mann 2000].
• 前臂拐杖或手杖，提升步态稳定性；不到5%的患者需要轮椅。Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
• 在能力允许的条件下，鼓励患者锻炼，很多患者仍保持身体锻炼。Exercise is encouraged within the individual's capability and many individuals remain physically active.
• 职业选择要考虑到手或脚的持续性虚弱。Career and employment choices may be influenced by persistent weakness of hands and/or feet.
• 疼痛现象要对症治疗 [Gemignani et al 2004]。Pain should be treated symptomatically [Gemignani et al 2004].

对次要并发症的预防

每日的跟腱拉伸练习以防止跟腱缩短。Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.

监测

监控步态和足部状况来决定是否需要支持杆，特质鞋子，手术。Monitoring of gait and condition of feet to determine need for bracing, special shoes, surgery is appropriate.

要避免的状况

肥胖，因为肥胖会增加步行的难度Obesity is to be avoided because it makes walking more difficult. 对CMT患者有毒或可能有毒的治疗，包括一系列风险，从极端高风险到微不足道的风险。点击here (pdf)可获得最新列表。

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

亲缘风险评估

见遗传咨询 关于高危亲属遗传咨询为目的的相关测试。See Genetic Counseling for issues related to evaluation of at-risk relatives for 遗传咨询 purposes.

研究中的治疗手段

ClinicalTrials.gov 搜索获取更大范围的临床研究信息。Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. 注意：网站中可能不包含此病。Note: There may not be clinical trials for this disorder.

遗传方式

CMT2E/1F是一种典型的常染色体显性遗传病。is typically inherited in an 常染色体显性遗传 manner. 目前有两个家庭被报导为常染色体隐性遗传的CMT2E/1F (由纯合的无义突变造成) [Abe et al 2009, Yum et al 2009]。

To date, two families with 常染色体隐性遗传 CMT2E/1F (caused by 纯合性nonsense variants) have been reported [Abe et al 2009, Yum et al 2009].

家系成员的发病风险 − 常染色体显性遗传

• 大多数患有常染色体显性遗传的CMT2E/1F个体都有一位受累的父亲或母亲。Most individuals with 常染色体显性遗传 CMT2E/1F have an 受累的 parent.
• 偶尔，家族史没有其他患病个体，因为先证者是新生致病性变异或是常染色体隐性遗传。Occasionally, family history may be negative because the 先证者 has a de novo致病性变异 or inheritance is autosomal recessive.
• 对带有一个新生突变的先证者父母（比如先证者家族里无相关病史）的评估推荐使用神经病学检查和电生理检查，如果已确定先证者体内的致病性变异，推荐分子遗传学检测。Recommendations for the evaluation of parents of a 单发的 case (i.e., an individual with no family history of the disorder) include neurologic and electrophysiologic examination and, if the 致病性变异 in the 先证者 has been identified, 分子遗传学检测.

注意：尽管大多数患有常染色体显性遗传的CMT2E/1F个体都有一位受累的父亲或母亲，但是家族史仍有可能找不到相关疾病，因为没能在家族成员中识别出病症，或者父（母）亲在发病前意外死亡，或者受累父（母）亲延迟发病。Note: Although most individuals diagnosed with 常染色体显性遗传 CMT2E/1F have an 受累的 parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
 

先证者的兄弟姐妹.

• 先证者兄弟姐妹的发病风险取决于先证者父母的遗传状态。The risk to sibs depends on the genetic status of the 先证者's parents.
• 如果先证者父母有常染色体显性遗传的致病性变异，兄弟姐妹的患病风险为50%。If a parent has a 常染色体显性遗传致病性变异, the risk to the sibs of inheriting the variant is 50%.
• 兄弟姐妹中有NEFL致病性变异不能预测症状的严重程度，发病年龄，或疾病的进程。The presence of a NEFL致病性变异 in a sib does not predict the severity of symptoms, the age of onset, or the progression of the disorder.
• 如果先证者中确定的致病性变异不能在父母的白血球DNA中检测到，那么先证者很有可能是新生致病性变异。If the 致病性变异 identified in the 先证者 cannot be detected in the leukocyte DNA of either parent, it is most likely caused by a de novo pathogenic variant in the proband. 另一种微弱的可能性是胚系嵌合，但是目前还没有报导。Another remote possibility is 胚系嵌合, which has not been reported to date.

• CMT2E/1F的每一个后代都有50%的概率继承遗传性变异。Each child of an individual with CMT2E/1F has a 50% chance of inheriting the 致病性变异.
• 后代中有NEFL致病性变异不能预测症状的严重程度，发病年龄，或疾病的进程。The presence of a NEFL致病性变异 in the offspring does not predict the severity of symptoms, the age of onset, or the progression of the disorder.
• 严重受累的个体可能不能生育。Individuals who are severely 受累的 may not reproduce.

先证者家系中的其他成员. 其他家庭成员的患病风险取决于先证者父母的遗传状态。如果父母之一是患者，他或她的家庭成员有患病风险。The risk to other family members depends on the status of the proband's parents. If a parent is 受累的 or known to have a 致病性变异, his or her family members are at risk.

家系成员的发病风险 − 常染色体隐性遗传

先证者的父母.

• 父母一定是杂合子，因此携带有一个突变的等位基因。Parents of a 先证者 with CMT2E/1F inherited in an 常染色体隐性遗传 manner are obligate heterozygotes and therefore carry one mutated 等位基因.
• 杂合子（携带者）是没有症状的。Heterozygotes (carriers) are asymptomatic.

先证者的兄弟姐妹.

• 理论上，受累个体的兄弟姐妹有25%的概率患病，50%的概率成为一个无症状携带者，25%的概率既无症状也非携带者。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.
• 一旦一个有风险的兄弟姐妹确定未受累，则他/她为携带者的概率上升到2/3。Once an at-risk sib is known to be unaffected, the chance of his/her being a 携带者 is 2/3.
• 杂合子（携带者）是没有症状的。Heterozygotes (carriers) are asymptomatic.

• 先证者的后代一定是杂合子（携带者）。The offspring of a 先证者 with 常染色体隐性遗传 CMT2E/1F are obligate heterozygotes (carriers).
• 在罕见的情况下，父母的另一方是一个携带者，则后代有50%的概率受累，50%的概率成为携带者。In the rare instance that an unrelated reproductive partner is a 携带者, the offspring are at a 50% risk of being 受累的 and a 50% risk of being carriers.

先证者家系中的其他成员. 先证者父母的每一个兄弟姐妹都有50%的概率是携带者。Each sib of a proband's parents is at a 50% risk of being a 携带者.

携带者（杂合子）检测

Carrier testing for 常染色体隐性遗传 CMT2E/1F is possible once the NEFL pathogenic variants have been identified in the family.
只要家族中的NEFL致病性变异得到确认，即可检测是否为携带者。

遗传咨询相关问题

有明显新生突变的家系的可能性. Considerations in families with an apparent de novo致病性变异. 当常染色体显性疾病的先证者父母没有致病突变和/或疾病的临床证据时，有可能是先证者有一个新生突变。When neither parent of a 先证者 with an 常染色体显性遗传 condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. 然而，也存在可能的非医学解释，例如非生物学父亲或母亲（如采用了辅助生殖技术），或者保密收养。However, possible non-medical explanations including 非生物学父亲 or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.
 

生育计划Family planning

• 遗传风险确定和产前检测可行性讨论的最佳时间实在怀孕之前。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.
• 向患病的或存在遗传风险的年轻人提供遗传咨询（包括后代潜在遗传风险的讨论和辅助生殖的选择）是合适的。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 are at risk.

产前检查与植入前遗传诊断

一旦致病性变异从家系中被成功确定，就有能力进行产前检擦与植入前遗传诊断。Once the 致病性变异(s) 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 are possible.

分子遗传发病机制

神经细胞的细胞骨架主要由三种细丝组成：细胞微管，神经纤维细丝，

The cytoskeleton of neuronal cells is mainly composed of three kinds of filaments: microtubules, neurofilaments, and actin filaments [Tokutake 1990]. 神经纤维细丝 (NFs)属于中间纤维 (IF)家族，还是有髓轴突中最主要的成分 [Friede & Samorajski 1970]。Neurofilaments (NFs) belong to the family of intermediate filaments (IF) and are the most abundant component of the mature myelinated axon [Friede & Samorajski 1970]. 他们有一个中心结构域（310氨基酸组成，杆状区），形状类似一个大的α卷曲螺旋，侧面是两个非螺旋片段：N末端头部，C末端尾部。They have a central 310-amino acid 结构域 (rod-domain) shaped as a large coiled-coil α-helix flanked by two non-helical segments: the N-terminal head and the C-terminal tail. 神经纤维细丝自组装成共聚物；这个组装由每个亚基的杆状区之间的相互作用介导，然而相互作用的特异性由末端区域决定[Carpenter & Ip 1996]。Neurofilaments self-assemble into heteropolymers; this assembly is mediated by interactions among the rod domains of each subunit, whereas the specificity of the interactions is determined by the end domains [Carpenter & Ip 1996]. 脊椎动物中的神经纤维细丝由三个不同的蛋白亚基组成，又被叫做神经丝轻链 (NEFL, 68 kd)，神经丝中链 (NEFM, 160kd)，神经丝重链 (NEFH, 210kd)，三个亚基均由不同的基因编码 [Julien 1999]。

Neurofilaments in vertebrates are composed of three different protein subunits, referred to as neurofilament light chain (NEFL, 68 kd), neurofilament medium chain (NEFM, 160 kd), and neurofilament heavy chain (NEFH, 210 kd), each of these encoded by different genes [Julien 1999]. NEFL是神经纤维细丝中含量最大的亚基，并在组装过程中起到关键的作用。NEFL is the most abundant unit of neurofilaments and plays a central role in their assembly. 它是唯一一个能够在体外自组装成细丝的NF亚基 [Carpenter & Ip 1996]，并能够调节其他NF亚基的组装。It is the only NF subunit capable of self-assembling into filaments in vitro [Carpenter & Ip 1996] and also able to regulate the assembly of the other NF subunits. 通过与磷脂酰肌醇磷酸基团结合，NEFL自组装能大大加快 [Kim et al 2011]。NEFL self-assembly is accelerated by binding to phosphatidylinositol phosphates [Kim et al 2011]. 通过破坏轴突运输NF造成的神经纤维细丝聚集是许多人类运动神经疾病早期阶段的一个主要的病理特征，包括巨轴突神经元病 [Flanigan et al 1998]，

。D

isruption of axonal transport of NFs resulting in neurofilament accumulations is a major pathologic hallmark during the early stages of many human motor neuron diseases, including giant axonal neuronopathy [Flanigan et al 1998], amyotrophic lateral sclerosis [Julien 1995], Parkinson disease [Goldman et al 1983], Lewy-body-type dementia [Shepherd et al 2002], Alzheimer disease [Figlewicz et al 1994, Tomkins et al 1998, Al-Chalabi et al 1999], and spinal muscular atrophy [Cifuentes-Diaz et al 2002]. 基因结构.

Gene structure. NEFL由四个编码外显子组成。NEFL is organized in four coding exons. 更详细的基因组成与蛋白质组成信息，请看Table A。For a detailed summary of 基因 and protein information, see Table A, 基因.等位基因变异体.Gene.

Allelic variants. 目前，多种温和的和致病的序列变异已经得到报导，详见Table 2。To date, multiple benign and pathogenic sequence variants are reported. See Table 2.

正常基因产物.Normal 基因产物. NEFL编码一个由头部区，杆状区，尾部区组成的543个氨基酸大小的结构蛋白。NEFL codes for a structural protein of 543 amino acids that has head, rod, and tail domains. NEFL是一个结构蛋白，大量且仅仅表达在神经元中，主要分布在轴突中，在大有髓轴突中更多。NEFL is a structural protein, exclusively and abundantly expressed in neurons and localized principally in axons, with higher levels in large myelinated axons. 它和更大蛋白量的神经纤维细丝 (NEFM, NEFH)共同组装成4型中间纤维，从而组成神经元细胞的细胞骨架。It assembles with neurofilaments of higher molecular mass, medium (NEFM) and heavy (NEFH), into intermediate filaments type IV, and forms the cytoskeleton of the neuronal cell. NEFL在外周神经中与MTMR2蛋白（另一个CMT相关的蛋白质，在CMT4B1中突变）相互作用 [Previtali et al 2003]。NEFL interacts in peripheral nerve with myotubularin-related 2 protein phosphatase (MTMR2), another CMT-associated protein mutated in CMT4B1 [Previtali et al 2003]. 神经纤维细丝涉及到径向生长和维持大的有髓轴突的直径，因此对它们的传导速率起到关键的作用。Neurofilaments are involved in radial growth and caliber maintenance of large myelinated axons and thereby play a role in their conduction velocity.
 

异常基因产物.Abnormal 基因产物.  缺乏NEFL，NEFM和NEFH亚基无法组装成10 nm的纤维细丝。In the absence of NEFL, NEFM and NEFH subunits are unable to assemble into 10-nm filaments. 因此，缺乏NEFL的小鼠发育正常，但是轴突直径减小，损伤后再生的有髓轴突成熟延迟。As a result, mice lacking NEFL protein have normal development but reduced axonal caliber and delayed maturation of regenerating myelinated axons after nerve injury. 他们造成了轻微的感觉运动障碍，空间记忆障碍，却没有明显的瘫痪的迹象 [Dubois et al 2005]。They develop mild sensorimotor dysfunction and spatial deficit without overt signs of paresis [Dubois et al 2005]. 在日本鹌鹑的，自然产生的缺乏NEFL突变体中，有髓轴突的正常径向生长严重衰减。In Japanese quail natural mutants lacking NEFL, the normal radial growth of myelinated axons is severely attenuated. NEFL最主要的致病性变异在CMT患者中的影响，已通过转基因哺乳动物细胞和神经元来研究 [Brownlees et al 2002, Pérez-Ollé et al 2002, Pérez-Ollé et al 2004, Pérez-Ollé et al 2005, Sasaki et al 2006, Zhai et al 2007]。

The effect of dominant NEFL pathogenic variants described in individuals with CMT has been investigated in transgenic mammalian cells and neurons [Brownlees et al 2002, Pérez-Ollé et al 2002, Pérez-Ollé et al 2004, Pérez-Ollé et al 2005, Sasaki et al 2006, Zhai et al 2007]. 在转基因细胞中，最主要的NEFL突变会破坏神经纤维细丝的自组装和共组装。在转基因神经元中，至少部分突变造成轴突中神经纤维细丝的异常运输，影响其他细胞组分顺向与逆向的运输，并扰乱线粒体的定位。In transfected cells, dominant NEFL mutants disrupt both neurofilament self-assembly and co-assembly. In transfected neurons, at least some of them cause aberrant axonal transport of neurofilaments, affect the anterograde and retrograde transport of other cell components, and perturb the localization of mitochondria. 这导致进行性的神经元存活率的下降与损失。This leads to progressive degeneration and loss of neuronal viability. 相反地，隐性的 p.Glu210Ter变异体导致NEFL的损失。In contrast, the recessive p.Glu210Ter variant causes loss of NEFL protein. 在受累个体（含有纯合致病性变异）中，这会导致神经纤维细丝的缺失，以及进行性轴突的损失 [Yum et al 2009]。In 受累的 persons 纯合性 for this 致病性变异, this leads to lack of neurofilaments and progressive axonal loss [Yum et al 2009]. 两种转基因小鼠CMT2E目前已经成功生成，分别表达p.Pro22Ser和p.Glu396Lys两种致病性变异 [Dequen et al 2010, Shen et al 2011]。

Two transgenic mouse CMT2E models have been generated to date, expressing p.Pro22Ser and p.Glu396Lys pathogenic variants respectively [Dequen et al 2010, Shen et al 2011]. 转基因小鼠表现出了人类病理的特征，包括异常的后肢姿态，运动表达障碍，肌肉神经控制障碍。Transgenic mice recapitulate the hallmark features of human pathology, including abnormal hindlimb posture, motor performance deficit, and loss of muscle innervation. 重要地是，疾病发生后，抑制突变的Pro22Ser NEFL产物能够逆转小鼠中的神经病学表型。Importantly, suppression of the mutated NEFL Pro22Ser product after disease onset reverses the neurologic 表型 in mice. 这些实验说明通过废除或者中和突变NEFL等位基因有可能可以组织疾病进程甚至逆转相关的病症 [Dequen et al 2010]。These experiments indicate that therapeutic approaches aimed at abolishing or neutralizing the mutated NEFL等位基因 could potentially halt disease progression and reverse the associated disabilities [Dequen et al 2010].

引用文献

• Abe A, Numakura C, Saito K, Koide H, Oka N, Honma A, Kishikawa Y, Hayasaka K. Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype. J Hum Genet. 2009;54:94-7. [PubMed: 19158810]
• Al-Chalabi A, Andersen PM, Nilsson P, Chioza B, Andersson JL, Russ C, Shaw CE, Powell JF, Leigh PN. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet. 1999;8:157-64. [PubMed: 9931323]
• Andrigo C, Boito C, Prandini P, Mostacciuolo ML, Siciliano G, Angelini C, Pegoraro E. A novel out-of-frame mutation in the neurofilament light chain gene (NEFL) does not result in Charcot-Marie-Tooth disease type 2E. Neurogenetics. 2005;6:49-50. [PubMed: 15654615]
• Baets J, Deconinck T, De Vriendt E, Zimoń M, Yperzeele L, Van Hoorenbeeck K, Peeters K, Spiegel R, Parman Y, Ceulemans B, Van Bogaert P, Pou-Serradell A, Bernert G, Dinopoulos A, Auer-Grumbach M, Sallinen SL, Fabrizi GM, Pauly F, Van den Bergh P, Bilir B, Battaloglu E, Madrid RE, Kabzińska D, Kochanski A, Topaloglu H, Miller G, Jordanova A, Timmerman V, De Jonghe P. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011;134:2664-76. [PMC free article: PMC3170533] [PubMed: 21840889]
• Brownlees J, Ackerley S, Grierson AJ, Jacobsen NJ, Shea K, Anderton BH, Leigh PN, Shaw CE, Miller CC. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum Mol Genet. 2002;11:2837-44. [PubMed: 12393795]
• Carpenter DA, Ip W. Neurofilament triplet protein interactions: evidence for the preferred formation of NF-L-containing dimers and a putative function for the end domains. J Cell Sci. 1996;109:2493-8. [PubMed: 8923210]
• Choi BO, Lee MS, Shin SH, Hwang JH, Choi KG, Kim WK, Sunwoo IN, Kim NK, Chung KW. Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Hum Mutat. 2004;24:185-6. [PubMed: 15241803]
• Cifuentes-Diaz C, Nicole S, Velasco ME, Borra-Cebrian C, Panozzo C, Frugier T, Millet G, Roblot N, Joshi V, Melki J. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. Hum Mol Genet. 2002;11:1439-47. [PubMed: 12023986]
• De Jonghe P, Mersivanova I, Nelis E, Del Favero J, Martin JJ, Van Broeckhoven C, Evgrafov O, Timmerman V. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol. 2001;49:245-9. [PubMed: 11220745]
• Dequen F, Filali M, Larivière RC, Perrot R, Hisanaga S, Julien JP. Reversal of neuropathy phenotypes in conditional mouse model of Charcot-Marie-Tooth disease type 2E. Hum Mol Genet. 2010;19:2616-29. [PubMed: 20421365]
• Dubois M, Strazielle C, Julien JP, Lalonde R. Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation. J Neurosci Res. 2005;80:751-8. [PubMed: 15884021]
• Fabrizi GM, Cavallaro T, Angiari C, Bertolasi L, Cabrini I, Ferrarini M, Rizzuto N. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology. 2004;62:1429-31. [PubMed: 15111691]
• Fabrizi GM, Cavallaro T, Angiari C, Cabrini I, Taioli F, Malerba G, Bertolasi L, Rizzuto N. Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain. 2007;130:394-403. [PubMed: 17052987]
• Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet. 1994;3:1757-61. [PubMed: 7849698]
• Flanigan KM, Crawford TO, Griffin JW, Goebel HH, Kohlschutter A, Ranells J, Camfield PR, Ptacek LJ. Localization of the giant axonal neuropathy gene to chromosome 16q24. Ann Neurol. 1998;43:143-8. [PubMed: 9450783]
• Friede RL, Samorajski T. Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat Rec. 1970;167:379-87. [PubMed: 5454590]
• Gemignani F, Melli G, Alfieri S, Inglese C, Marbini A. Sensory manifestations in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2004;9:7-14. [PubMed: 14871449]
• Georgiou DM, Zidar J, Korosec M, Middleton LT, Kyriakides T, Christodoulou K. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family. Neurogenetics. 2002;4:93-6. [PubMed: 12481988]
• Goldman JE, Yen SH, Chiu FC, Peress NS. Lewy bodies of Parkinson's disease contain neurofilament antigens. Science. 1983;221:1082-4. [PubMed: 6308771]
• Grandis M, Shy ME. Current therapy for Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2005;7:23-31. [PubMed: 15610704]
• Guyton GP, Mann RA. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin. 2000;5:317-26. [PubMed: 11232233]
• Holmes JR, Hansen ST Jr. Foot and ankle manifestations of Charcot-Marie-Tooth disease. Foot Ankle. 1993;14:476-86. [PubMed: 8253442]
• Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler IJ, Mancias P, Papasozomenos SCh, Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain. 2003;126:590-7. [PubMed: 12566280]
• Julien JP. A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis. Biochem Cell Biol. 1995;73:593-7. [PubMed: 8714677]
• Julien JP. Neurofilament functions in health and disease. Curr Opin Neurobiol. 1999;9:554-60. [PubMed: 10508735]
• Kim SK, Kim H, Yang YR, Suh PG, Chang JS. Phosphatidylinositol phosphates directly bind to neurofilament light chain (NF-L) for the regulation of NF-L self assembly. Exp Mol Med. 2011;43:153-60. [PMC free article: PMC3068298] [PubMed: 21339697]
• Luo W, Tang B, Zhao G, Li Q, Xiao J, Yang Q, Xia J. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2003;20:169-70. [Mutation analysis of neurofilament-light gene in Chinese Charcot-Marie-Tooth disease] [PubMed: 12673592]
• Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, Petrin AN, Evgrafov OV. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet. 2000;67:37-46. [PMC free article: PMC1287099] [PubMed: 10841809]
• Miltenberger-Miltenyi G, Janecke AR, Wanschitz JV, Timmerman V, Windpassinger C, Auer-Grumbach M, Löscher WN. Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene. Arch Neurol. 2007;64:966-70. [PubMed: 17620486]
• Pérez-Ollé R, Jones ST, Liem RK. Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. Hum Mol Genet. 2004;13:2207-20. [PubMed: 15282209]
• Pérez-Ollé R, Leung CL, Liem RK. Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation. J Cell Sci. 2002;115:4937-46. [PubMed: 12432080]
• Pérez-Ollé R, Lopez-Toledano MA, Goryunov D, Cabrera-Poch N, Stefanis L, Brown K, Liem RK. Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. J Neurochem. 2005;93:861-74. [PubMed: 15857389]
• Previtali SC, Zerega B, Sherman DL, Brophy PJ, Dina G, King RH, Salih MM, Feltri L, Quattrini A, Ravazzolo R, Wrabetz L, Monaco AP, Bolino A. Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve. Hum Mol Genet. 2003;12:1713-23. [PubMed: 12837694]
• Sasaki T, Gotow T, Shiozaki M, Sakaue F, Saito T, Julien JP, Uchiyama Y, Hisanaga S. Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants. Hum Mol Genet. 2006;15:943-52. [PubMed: 16452125]
• Shen H, Barry DM, Dale JM, Garcia VB, Calcutt NA, Garcia ML. Muscle pathology without severe nerve pathology in a new mouse model of Charcot-Marie-Tooth disease type 2E. Hum Mol Genet. 2011;20:2535-48. [PMC free article: PMC3109999] [PubMed: 21493625]
• Shepherd CE, McCann H, Thiel E, Halliday GM. Neurofilament-immunoreactive neurons in Alzheimer's disease and dementia with Lewy bodies. Neurobiol Dis. 2002;9:249-57. [PubMed: 11895376]
• Tokutake S. On the assembly mechanism of neurofilaments. Int J Biochem. 1990;22:1-6. [PubMed: 2184054]
• Tomkins J, Usher P, Slade JY, Ince PG, Curtis A, Bushby K, Shaw PJ. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport. 1998;9:3967-70. [PubMed: 9875737]
• Vechio JD, Bruijn LI, Xu Z, Brown RH Jr, Cleveland DW. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Ann Neurol. 1996;40:603-10. [PubMed: 8871580]
• Yamamoto M, Yoshihara T, Hattori N, Sobue G. Glu528del in NEFL is a polymorphic variant rather than a disease-causing mutation for Charcot-Marie-Tooth disease in Japan. Neurogenetics. 2004;5:75-7. [PubMed: 14586770]
• Yoshihara T, Yamamoto M, Hattori N, Misu K, Mori K, Koike H, Sobue G. Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals. J Peripher Nerv Syst. 2002;7:221-4. [PubMed: 12477167]
• Yum SW, Zhang J, Mo K, Li J, Scherer SS. A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy. Ann Neurol. 2009;66:759-70. [PMC free article: PMC4439312] [PubMed: 20039262]
• Zhai J, Lin H, Julien JP, Schlaepfer WW. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. Hum Mol Genet. 2007;16:3103-16. [PubMed: 17881652]
• Züchner S, Vorgerd M, Sindern E, Schroder JM. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord. 2004;14:147-57. [PubMed: 14733962]

推荐阅读

• Carter GT. Rehabilitation management in neuromuscular disease. J Neurol Rehab. 1997;11:69-80.
• Chaudhry V, Chaudhry M, Crawford TO, Simmons-O'Brien E, Griffin JW. Toxic neuropathy in patients with pre-existing neuropathy. Neurology. 2003;60:337-40. [PubMed: 12552058]
• Lee MK, Marszalek JR, Cleveland DW. A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron. 1994;13:975-88. [PubMed: 7946341]
• Nelis E, Haites N, Van Broeckhoven C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat. 1999;13:11-28. [PubMed: 9888385]
• Ohara O, Gahara Y, Miyake T, Teraoka H, Kitamura T. Neurofilament deficiency in quail caused by nonsense mutation in neurofilament-L gene. J Cell Biol. 1993;121:387-95. [PMC free article: PMC2200107] [PubMed: 8468353]
• Xu Z, Cork LC, Griffin JW, Cleveland DW. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell. 1993;73:23-33. [PubMed: 8462100]
• Yamasaki H, Bennett GS, Itakura C, Mizutani M. Defective expression of neurofilament protein subunits in hereditary hypotrophic axonopathy of quail. Lab Invest. 1992;66:734-43. [PubMed: 1602743]
• Zhu Q, Couillard-Despres S, Julien JP. Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol. 1997;148:299-316. [PubMed: 9398473]

修订历史

• 27 October 2011 (me) Comprehensive update posted live
• 15 June 2006 (ca) Comprehensive update posted to live Web site
• 1 April 2004 (me) Review posted to live Web site
• 6 October 2003 (pdj) Original submission