概述
临床表现.
4H型神经病变型腓骨肌萎缩（Charcot-Marie-Tooth neuropathy type 4H，CMT4H）是CMT的一种脱髓鞘型，它以早发性（通常在3岁之前发病；范围：从出生到10岁）和发病迟缓为特征。在受累的个体之间，远端肌肉无力和肌萎缩变化的程度与足畸形，脊柱侧凸和感官的参与的出现或缺失及它们的严重程度有关。神经病理性疼痛还未被报道。到目前为止，来自13个家庭的被分子证实的CMT4H的18个个体的调查结果已经被报道。Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is a demyelinating form of CMT that is characterized by early onset (usually before age 3 years; range: birth to age 10 years) and slow progression. The degree of distal muscle weakness and amyotrophy varies between 受累的 individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement. Neuropathic pain has not been reported. To date, findings in18 individuals with molecularly confirmed CMT4H from 13 families have been reported.
诊断/测试。Diagnosis/testing.
CMT4H在有CMT典型表现（远端肌萎缩，足畸形，早发性和发病迟缓）的个体中被怀疑。运动神经传导速度（Motor nerve conduction velocities，MNCVs）和感觉神经传导速度（sensory nerve conduction velocities，SNCVs）异常。诊断是建立在FGD4双等位基因的致病性变异的出现上的。CMT4H is suspected in individuals with typical findings of CMT (distal amyotrophy, foot deformities), early onset, and slow progression. Motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs) are abnormal. The diagnosis is established by the presence of 双等位基因的FGD4 pathogenic variants.
治疗。Management.
治疗的表现：Treatment of manifestations: 通常是被多学科（康复）综合小组所治疗，包括神经学家，理疗医师，整形外科医生及物理治疗师和职业治疗师。治疗是根据症状的并且可能包括：踝/足矫形器（ankle/foot orthoses，AFOs）；物理疗法（每日足跟部伸展运动和体育活动去防止挛缩，有助于保持灵活性）；手术矫正严重的弓形足畸形和/或脊柱畸形；前臂拐杖，手杖和/或轮椅来提高移动性。肌肉骨骼疼痛可能会使用对乙酰氨基酚和非甾体类抗炎药（nonsteroidal anti-inflammatory drugs，NSAIDs）来治疗。Often management is by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment is symptomatic and may include: ankle/foot orthoses (AFOs); physiotherapy (daily heel cord stretching exercises and physical activity to prevent contractures and help preserve flexibility); surgery to correct severe pes cavus deformity and/or spine deformities; and forearm crutches, canes, and/or wheelchairs for mobility. Musculoskeletal pain may be treated with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs).监测：
Surveillance: 定期（年度）评估确定神经系统状况和功能残疾。Regular (annual) evaluation to determine neurologic status and functional disability.避免的因子/情况：
Agents/circumstances to avoid: 肥胖，因为它会使行走变得困难；给CMT患者服用有毒或潜在有毒的药物。Obesity because it makes walking more difficult; medications that are toxic or potentially toxic to persons with CMT.
遗传咨询。Genetic counseling.
CMT4H是以常染色体隐性遗传方式所遗传。根据这个概念，每个受累的个体的同胞有25%的概率患病，50%的概率是没有症状的携带者，25%的概率不患病且不是一个携带者。如果家系的致病突变已经被确定，那么对有风险的家庭成员做携带者检测和有增加风险的怀孕进行产前诊断是可能的。CMT4H is inherited in an 常染色体隐性遗传 manner. 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. Carrier testing for at-risk family members and 产前诊断 for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
诊断Diagnosis
临床诊断Clinical Diagnosis
CMT4H正式的诊断指南还没有。注意：即使CMT神经病变评分（CMT Neuropathy Score，CMTNS）和CMTNS版本2（CMTNS version 2，CMTNS2）被广泛地应用在CMT的诊断中[Shy et al 2005, Murphy et al 2011]，它们对于测试十岁以下的儿童的疾病的残疾和严重程度能力有限[Haberlová & Seeman 2010, Pagliano et al 2011]，使得它们应用在早期儿童发病的疾病（像CMT4H）中的诊断是有问题的。Formal diagnostic guidelines for Charcot-Marie-Tooth type 4H (CMT4H) do not exist.
Note: Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [Shy et al 2005, Murphy et al 2011], their limited ability to measure disability and severity of the disease in children under age ten years [Haberlová & Seeman 2010, Pagliano et al 2011] makes their use in the diagnosis of early childhood-onset disease like CMT4H problematic.对CMT4H的诊断在以下个体中被怀疑，
The diagnosis of Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is suspected在CMT患者中被明显观察到的特征（远端肌萎缩，足畸形）和以下症状（见表1）：in individuals with findings typically observed in CMT (distal amyotrophy, foot deformities) and the following (see also Table 1):
- 早发性。可获得的不精确的回顾性数据表明在三岁之前会出现明显的症状，推定的范围为从出生到十岁。Early onset. The imprecise retrospective data available indicate that symptoms typically appear before age three years, with a range presumed to be birth to ten years.
- 发病迟缓。虽然是早发性的，但这个疾病病情稳定，进展缓慢。Slow progression. Despite early onset, the disease is stable with only very slow progression.
- 脊柱侧凸；在十岁之前发病（在一些患者中观察到，但不是全部）Scoliosis; onset before age ten years (observed in some, but not all, 受累的 individuals)
- 异常的运动神经传导速度（motor nerve conduction velocities，MNCVs）和感觉神经传导速度（sensory nerve conduction velocities，SNCVs）。在下肢中，MNCVs在8/9的被测个体中是不值得记录的，在1/9的个体中是严重降低的；SNCVs在全部的被测个体中是不值得记录的。在上肢中，MNCVs在3/16的个体中是不值得记录的，在13/16的个体中是严重下降的；SNCVs在8/9的个体中是不值得记录的，在1/9的个体中是下降的（详情见表2[pdf]）。Abnormal motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs). In the lower limbs, MNCVs were non-recordable in 8/9 individuals tested and severely reduced in one; SNCVs were non-recordable in 8/8 individuals tested. In the upper limbs, MNCVs were non-recordable in 3/16 and severely reduced in 13/16; SNCVs were non-recordable in 8/9 and reduced in one (for details see Table 2 [pdf]).
- 家族史符合常染色体隐性遗传模式。父母近亲婚配是很常见的；父母是不受累的除非有几代血缘关系存在。注意：疾病的严重程度和残疾程度甚至在相同的家庭中也会不一样（即，在有相同致病突变的个体中）。Family history consistent with 常染色体隐性遗传 inheritance. Parental 近亲婚配 is common; parents are not 受累的 unless multigenerational consanguinity exists. Note: Disease severity and disability vary even within the same family (i.e., among individuals with the same pathogenic variants).
CMT4H的诊断建立在The diagnosis of CMT4H is established 有FGD4双等位基因的致病突变的个体上[De Sandre-Giovannoli et al 2005, Delague et al 2007, Reddy et al 2008]（表1）。in individuals with 双等位基因的FGD4 pathogenic variants [De Sandre-Giovannoli et al 2005, Delague et al 2007, Reddy et al 2008] (Table 1).
表1.Table 1.
应用在CMT4H中的分子遗传学检测概述Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4H
| 基因 1 Gene 1 | 检测方法Test Method | 致病突变检测 2 Pathogenic Variants Detected 2 | 通过检测方法对序列进行突变检测 3 Variant Detection Frequency by Test Method 3 |
|---|---|---|---|
| FGD4 | 序列分析 4 Sequence analysis 4 | 序列变异 5 Sequence variants 5 | 13/13 6 |
2.
见分子遗传学获取等位基因突变的信息。See Molecular Genetics for information on allelic variants.
3.
应用在检测出现在指示基因中的突变的检测方法的能力。The ability of the test method used to detect a variant that is present in the indicated 基因
4.
序列分析检测良性的，可能良性的，意义不确定的，可能致病的或者致病的突变。致病突变可能包括基因内小片段的缺失/插入和错义，无义，和剪接位点变异；通常，外显子或全基因缺失/重复是未检测出的。对序列分析结果解释考虑的问题，点击这里。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.
5.
测试方法检测不到FGD4中的大基因组的重排。然而，除了在CMT1A中的缺失/重复，大的基因组重排不是CMT疾病中常见的分子缺陷。The test method does not allow detection or large 基因组的 rearrangements within FGD4. However, except for deletions/duplications in CMT1A, large genomic rearrangements are not known as frequent molecular defects in CMT disease.
6.
患有CMT4H的个体或者具有符合CMT4H临床症状的常染色体隐性遗传脱髓鞘CMT的个体[Delague et al 2007, Stendel et al 2007, Fabrizi et al 2009, Houlden et al 2009, Hayashi et al 2013]。几乎所有的被描述的致病突变都是纯合性的，并且这些个体是由近亲婚配的父母所生。Individuals with CMT4H or 常染色体隐性遗传 demyelinating CMT with clinical signs consistent with CMT4H [Delague et al 2007, Stendel et al 2007, Fabrizi et al 2009, Houlden et al 2009, Hayashi et al 2013]. Almost all pathogenic variants described to date were 纯合性 and in individuals born to 近亲婚配的 parents.
注意：当不能获得分子遗传学检测时，可以考虑腓肠神经活检；然而，组织学的研究结果是不特定的CMT4H，因此是不确定的。Note: When 分子遗传学检测 is not available, sural nerve biopsy can be considered; however, histologic findings are not specific to CMT4H, and thus not confirmatory.组织学的研究结果与CMT4H的诊断是一致的。
Histologic findings consistent with the diagnosis of CMT4H. 中度至重度有髓纤维丢失，主要影响大口径纤维，至今报道的在所有接受神经活检患CMT4H的个体中观察到可能会有继发性脱髓鞘的髓鞘再生过程（见表2[pdf]）。剩下的纤维通常有先天的低髓鞘化的特征（例如，髓鞘增厚）和改变髓鞘形成的其他症状（例如，洋葱鳞茎和髓磷脂外折术）。即使髓磷脂外折术不特定存在于CMT4H中，它们仅在一些CMT的亚型中被观察到（CMT4B1, CMTB2, and CMT4F），因此能够支持FGD4的分子遗传学检测。Moderate to severe loss of myelinated fibers, mainly affecting large caliber fibers, probably secondary to a demyelination-remyelination process is observed in all individuals with CMT4H undergoing nerve biopsy reported to date (see Table 2 [pdf]). The remaining fibers usually have features of 先天的 hypomyelination (e.g., myelin thickening) and other signs of altered myelination (e.g., onion bulbs and myelin outfoldings). Although myelin outfoldings are not specific to CMT4H, they are observed in only a few CMT subtypes (CMT4B1, CMTB2, and CMT4F), and thus could support 分子遗传学检测 of FGD4.
临床特征Clinical Characteristics
临床描述Clinical Description
CMT4H，CMT的一种常染色体隐性遗传的脱髓鞘形式，以早发性和发病迟缓为特征。在发表的报告中来自13个家庭的18个受累的个体，已被分子证实患有CMT4H，在他们中观察到的最常见的结果被总结在表3中（见表2[pdf]，获得一个全面的总结）。在受累的个体之间，远端肌肉无力和肌萎缩变化的程度与足畸形，脊柱侧凸和感官的参与的出现或缺失及它们的严重程度有关。即使患有CMT的个体经历了通常是轻度的神经病理性疼痛，这些疼痛优先出现在四肢，并且在CMT4H患者中相称的[Ribiere et al 2012]，神经病理性疼痛还没有被记录。Charcot-Marie-Tooth neuropathy type 4H (CMT4H), an 常染色体隐性遗传 demyelinating form of CMT, is characterized by early onset and slow progression. The most common findings observed in published reports of 18 受累的 individuals from 13 families with molecularly confirmed CMT4H are summarized in Table 3 (see Table 2 [pdf] for a comprehensive summary).
The degree of distal muscle weakness and amyotrophy varies between 受累的 individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement.
Although individuals with CMT do experience neuropathic pain that is usually moderate, preferentially located in the extremities, and symmetric [Ribiere et al 2012], neuropathic pain has not been documented in CMT4H.
表3.Table 3.
来自13个家庭的18个CMT4H患者的临床表现Clinical Characteristics of CMT4H in 18 Individuals from 13 Families
| 病人 1 Patient 1 | 国家Origin | 出现首发症状的年龄/最后一次检测Age in Yrs at First Symptoms / Last Exam | 可以行走的月龄Age in Mos at Walking | 远端肌肉Distal Muscles | 足畸形 4 Foot Deformity 4 | 脊柱侧凸 5 Scoliosis 5 | 远端感觉缺失 6 Distal Sensory Loss 6 | 功能性障碍Functional Impairment | 参考Reference | |
|---|---|---|---|---|---|---|---|---|---|---|
| 虚弱 2 Weakness 2 | 肌肉萎缩 3 Muscle Atrophy 3 | |||||||||
| Ia 7 | 黎巴嫩Lebanon | 1-2 / 15 | 延迟的Delayed, 15-36 | +++ | ++ | ++ | +++ | ++ | 中度至重度：不稳定步态，使用步行助行器Moderate to severe: unsteady gait, walking w/out aid | Delague et al [2007] |
| Ib 7 | 黎巴嫩Lebanon | 1-2 / 18 | 延迟的Delayed, 15-36 | +++ | ++ | ++ | - | ++ | 轻度：不稳定步态，使用步行助行器Mild: unsteady gait, walking w/out aid | |
| Ic 7 | 黎巴嫩Lebanon | 4 / 13 | 12 | +++ | ++ | + | ++ | ++ | 未知Unknown | Stendel et al [2007] |
| II | 阿尔及利亚Algeria | 2 / 未知unknown | 未知Unknown | ++ | ++ | + | + | 未知Unknown | 中度：使用步行助行器，鸭步Moderate: walking w/out aid, waddling gait | Delague et al [2007] |
| III | 土耳其Turkey | <1 / 30 | 延迟的Delayed | +++ | ++ | + | - | + | 未知Unknown | Stendel et al [2007] |
| IV | 土耳其Turkey | 2 / 未知unknown | 延迟的Delayed, 26 | ++ | + | - | - | - | 未知Unknown | |
| V | 泰米尔Tamil | 9 / 未知unknown | 16 | + | + | - | - | - | 未知Unknown | |
| VIa | 北爱尔兰Northern Ireland | 童年Childhood 8 / 58 | 未知Unknown | + | + | + | - | ++ | 中度：在58岁时使用步行助行器Moderate: walking w/out aid at 58 yrs | Houlden et al [2009] |
| VIb | 北爱尔兰Northern Ireland | 童年Childhood 9 / 50 | 未知Unknown | ++ | 未知Unknown | + | - | ++ | 中度：在50岁使用拐杖或轮椅Severe: at 50, walking w/2 crutches or wheelchair | |
| VII | 意大利Italy | <1 / 20 | 17 | + | + | + | + | + | 中度：不稳定步态，跨阈步态Moderate: unsteady gait w/steppage | Fabrizi et al [2009] |
| VIII | 黎巴嫩Lebanon | 5 / 21 | 14 | + | + | + | - | 中度：使用步行助行器Moderate: walking w/out aid | Baudot et al [2012] | |
| IX | 阿尔及利亚Algeria | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | |
| Xa | 突尼斯Tunisia | 3 / 6 | 16 | +++ | ++ | + | + | - | 用脚尖走路Walking on tiptoes | Boubaker et al [2013] |
| Xb | 突尼斯Tunisia | 3 / 18 | 正常Normal | +++ | ++ | + | ++ | + | ||
| Xc | 突尼斯Tunisia | 3 / 22 | 正常Normal | +++ | ++ | + | +++ | + | 在16岁做了脊柱外科手术Spine surgery at age 16 | |
| XI | 日本Japan | 童年Childhood / 未知unknown | 未知Unknown | 未知Unknown | 未知Unknown | + | 未知Unknown | 未知Unknown | 使用步行辅助设备直到65岁；从68岁开始有严重的步态障碍Walked w/out assistance until 65 years; severe gait disturbance from 68 yrs | Hayashi et al [2013] |
| XII | 日本Japan | 出生Birth / 未知unknown | 11 | 未知Unknown | 未知Unknown | + | 未知Unknown | 未知Unknown | 3岁开始有异常的步态Abnormal gait from 3 yrs | |
| XIII | 日本Japan | 4 / 未知unknown | 14 | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | 未知Unknown | 4岁开始频繁摔倒；6岁开始跛行Frequent falls from age 4 years; walked w/limp from 6 yrs | |
1.
罗马数字=家庭；字母=同胞Roman numerals = family; letters = sibs
2.
- =未患病；+ =下肢轻度；++ =下肢显著；+++ =也影响了手和前臂- = not affected; + = mild in the lower extremities; ++ = marked in the lower extremities; +++ = also affected the hands and forearms
3.
- =患病；+ =轻度；++ =重度- = affected; + = mild; ++ = severe
4.
- =无畸形；+ =高足弓和锤状趾；++ =马蹄足和脚趾缩- = no deformities; + = pes cavus and hammer toes; ++ = pes equinus and toes retraction
5.
- =没有；+ =轻度；++ =重度；+++ =需要做手术- = none; + = mild; ++ = severe; +++ = surgery required
6.
- =没有亏损；+ =降低的敏感性；+++ =没有感觉- = no deficit; + = decreased sensibility; +++ = no sensibility
7.
病人Ia,Ib,和Ic来自相同的黎巴嫩家庭的不同分支。同样见表5。Patients Ia, Ib, and Ic are from three different branches of the same Lebanese family. See also Table 5.
8.
跑步障碍和平衡性差Difficulty running and poor balance
9.
笨拙Clumsiness
基因型-表型的相关性Genotype-Phenotype Correlations
在来自13个家庭已经被分子证实的18位CMT4H患者中，没有基因型-表型相关性可以建立；明显地，无义突变或移码变异的纯合性个体比起错义突变的患者没有更严重的表现（详情总结在表2[pdf]）。No 基因型-表型 correlations can be established in the 18 受累的 individuals from 13 families with molecularly confirmed CMT4H; remarkably, individuals 纯合性 for nonsense or frameshift variants do not have more severe manifestations than individuals with 错义 variants (summarized in detail in Table 2 [pdf]).
患病率Prevalence
CMT4H是很罕见的并且很难估计它的发病率。至今只有被分子证实患有CMT4H的13个家庭被报道。表4总结了在已发表的CMT4的研究中，CMT4H个体所占的比例。这些研究已经表明在近亲婚配的家庭中已被确定FGD4致病性变异是最常见的纯合性变种。CMT4H is rare and it is difficult to estimate its prevalence. Only 13 families with molecularly confirmed CMT4H have been published to date.
Table 4 summarizes the proportion of individuals with CMT4H in published studies of CMT4. These studies have shown that FGD4 pathogenic variants are most commonly 纯合性 variants identified in 近亲婚配的 families.
表4.Table 4.
在已发表的研究中患CMT4H个体的比例Proportion of Individuals with CMT4H in Published Studies
| # 患CMT4H的个体/全部 of Individuals with CMT4H / Total # 患CMT4的个体of Individuals with CMT4 | # 患CMT4H的个体/of Individuals with CMT4H / # 在研究中被确定的有致病变异的个体of Individuals in the Study w/an Identified Pathogenic Variant | 参考References |
|---|---|---|
| 3/103 (~3%) | 3/7 (43%) | Hayashi et al [2013] |
| 2/45 (~4.5%) 1 | 2/28 (7%) | Baets et al [2011] |
| 4/63 (~6.3%)2 | 未知Unknown | Stendel et al [2007] |
| 1/12 (~8.3%) | 未知Unknown | Houlden et al [2009] |
| 5/108 (~4.6%) | 未知Unknown | Delague et al [2007]; Delague, personal communication |
CMT4H的比例可能比显示的要高，在这一系列的个体中有一些成员是常染色体显性遗传。The proportion of CMT4H is probably higher than indicated, as a number of individuals in this series have 常染色体显性遗传 inheritance.
2.
所有受累的个体存在下列情况（1）在发病的第一个十年内有脱髓鞘型的感觉运动性神经病（2）至少有以下一种情况：（a）父母近亲婚配或至少有一个其他的患病同胞；（b）严重放缓的NCVs（电机正中神经的速度为<15 m/s）；（c）突出的脊柱侧凸;(d)髓磷脂外折术神经活检。没有受累个体的父母有CMT的临床或者神经电生理分析。All 受累的 individuals had (1) demyelinating sensorimotor neuropathy with onset in the first decade and (2) at least one of the following: (a) parental 近亲婚配 or at least one other affected sib; (b) severely slowed NCVs (<15 m/s for the motor median nerve); (c) prominent scoliosis; and (d) myelin outfoldings on nerve biopsy. No parents of affected individuals had clinical or neurophysiologic findings of CMT.
遗传相关（等位基因）紊乱Genetically Related (Allelic) Disorders
除了在这个GeneReview上被讨论的，没有其他症状与FGD4的致病变异有关。No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in FGD4.
不同的诊断Differential Diagnosis
见See 神经病变型腓骨肌萎缩 Charcot-Marie-Tooth Neuropathy.
治疗Management
初步诊断后的评价Evaluations Following Initial Diagnosis
为了确定疾病的范围和诊断为CMT4H的个体的需要，下列评估是被推荐的：To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4H (CMT4H), the following evaluations are recommended:
- 通过身体检查确定无力和萎缩的程度，高弓足，步态稳定性，感觉缺失，和骨骼畸形。在患CMT的儿童中，应当使用被Burns et al [2012]确定的CMTPedS评分，一个可靠的，耐受良好的，有效的及敏感的全球通用方法，这个方法可以检测从3岁开始患CMT的儿童的残疾[Burns et al 2012]。Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, sensory loss, and skeletal deformities. In children with CMT, one should use the CMTPedS score defined by Burns et al [2012], a reliable, well-tolerated, valid, and sensitive global measure of disability for children with CMT from the age of 3 years [Burns et al 2012].即使CMT神经病变评分（CMTNS）和CMTNS2被广泛应用于CMT的诊断中[Shy et al 2005, Murphy et al 2011]，在检测10岁以下儿童的残疾以及疾病的严重程度中，这些方法表现出了有限的潜力[Haberlová & Seeman 2010, Pagliano et al 2011]。Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [Shy et al 2005, Murphy et al 2011], they have shown limited potential in measuring disability and disease severity in children younger than age ten years [Haberlová & Seeman 2010, Pagliano et al 2011].从应用在儿童上的CMTPedS到应用在成人上的CMTNS2的转变已经被评估[Burns et al 2013]；同时，这两种方法为患有CMT的病人提供了一种终身检测连续体。The transition from the CMTPedS in childhood to the CMTNS2 in adulthood has been evaluated [Burns et al 2013]; together, the two measures provide a continuum for lifelong measurement of disability in patients with CMT.
- 整形咨询评估诸如足畸形（高弓足）和脊柱侧凸的骨骼畸形，并且确定外科手术和/或踝/足矫形器的需要。Orthopedic consultation to evaluate skeletal deformities such as foot deformities (pes cavus) and scoliosis and to determine the need for a surgery and/or ankle/foot orthoses
- 临床遗传学咨询和/或小儿神经科会诊Clinical genetics consultation and/or pediatric neurology consultation
治疗的表现Treatment of Manifestations
患有CMT4H的个体经常被一个多学科团队评估和治疗，包括神经学家，理疗医师，整形外科医生，及物理治疗师和职业治疗师[Carter et al 1995, Grandis & Shy 2005]。治疗是根据症状的并且可能包括以下方法：Individuals with CMT4H are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 1995, Grandis & Shy 2005].
Treatment is symptomatic and may include the following:
- 踝/足矫形器（Ankle/foot orthoses，AFOs）矫正足下垂和辅助行走[Carter et al 1995]Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [Carter et al 1995]
- 每日足跟部伸展运动理疗帮助防止Achilles的肌腱缩短和适合每个个体能力的体力活动去防止挛缩和有助于保持灵活性Physiotherapy with daily heel cord stretching exercises to help prevent Achilles' tendon shortening and physical activity adapted to the abilities of each individual to prevent contractures and help preserve flexibility
- 整形手术矫正重度弓形足畸形[Guyton & Mann 2000, Ward et al 2008]Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000, Ward et al 2008]
- 矫正脊柱畸形的手术Surgery to correct spine deformities
- 前臂拐杖或手杖提高步态稳定性Forearm crutches or canes for gait stability
- 由于步态不稳，需要轮椅Wheelchairs as needed because of gait instability
- 对乙酰氨基酚或非甾体类抗炎药（nonsteroidal anti-inflammatory drugs，NSAIDs）治疗肌肉骨骼疼痛[Carter et al 1998]Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) [Carter et al 1998]
监测Surveillance
合适的监测包括一个团队每年的评估，这个团队包括理疗医师，神经学家以及物理治疗师和职业治疗师，去检测神经功能状态及功能障碍。Appropriate surveillance includes annual evaluation by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.
避免的因子/情况Agents/Circumstances to Avoid
肥胖需要避免，因为它会使行走变得困难。避免对患CMT的病人使用有毒的或潜在有毒的药物，风险范围包括确定的高风险到可以忽略的风险。点击这里(pdf)获取最新信息。Obesity is to be avoided because it makes walking more difficult.
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.
亲属风险评估Evaluation of Relatives at Risk
见遗传咨询，以获得关于有风险的亲属的检测问题，以达到遗传咨询的目的。See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 purposes.
在调查中的治疗方法Therapies Under Investigation
搜索ClinicalTrials.gov以得到大范围关于疾病和条件的临床研究信息。注意：这个网站上可能没有这个疾病的临床试验。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.
遗传咨询Genetic Counseling
遗传咨询是给病人及其家属提供关于遗传病的本质，遗传和含义信息的过程，帮助他们得到医疗告知以及做出个人决定。以下部分涉及遗传风险评估，使用家族史和遗传检测对家庭成员的遗传状况进行说明。这个部分不是用来解决所有个人的，文化的以及个人可能或面临的伦理问题，或者去替代专业的遗传咨询。--ED。Genetic counseling is the process ofproviding individuals and families with information on the nature, inheritance,and implications of genetic disorders to help them make informed medical andpersonal decisions. The following section deals with genetic risk assessment andthe use of family history and genetic testing to clarify genetic status forfamily members. This section is not meant to address all personal, cultural, orethical issues that individuals may face or to substitute for consultation witha genetics professional. —ED.
遗传模式Mode of Inheritance
CMT4H是按常染色体隐性遗传方式遗传的。Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is inherited in an 常染色体隐性遗传 manner.
家庭成员的风险Risk to Family Members
先证者的后代。Offspring of a 先证者. 患CMT4H的个体的后代必然是杂合子（携带者），在FGD4基因上有一个致病性变异。The offspring of an individual with CMT4H are obligate heterozygotes (carriers) for a 致病性变异 in FGD4.其他家庭成员。
Other family members. 每个先证者父母的同胞有50%的概率为一个携带者。Each sib of the 先证者’s parents is at a 50% risk of being a 携带者.
携带者（杂合子）检测Carrier (Heterozygote) Detection
如果家系中的致病性突变被确定，对有风险的家庭成员进行携带者检测是可能的。Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
相关的遗传咨询问题Related Genetic Counseling Issues
计划生育Family planning
DNA银行DNA banking 是以后可能会用到的DNA（主要是从白血球中提取的）的存储处。因为很可能测试方法和我们对基因、等位基因变异体和疾病的理解在将来会有所改善，应当考虑将受累的个体的DNA放入DNA银行。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.
产前检查和着床前胚胎遗传学诊断Prenatal Testing and Preimplantation Genetic Diagnosis
一旦一个受累的家庭成员的致病性变异被确定，那么对于有增加风险的怀孕进行产前检查和对CMT4H的植入前遗传诊断是可能的。要求在产前检查不影响智力和有一些可获得的治疗方法的条件（像CMT4H）下进行检查，这些要求是很少的。在医疗专业人员和家庭中，产前检查的使用可能存在差异，特别是如果正在考虑终止妊娠而不是早期诊断。即使关于产前检测的决定是父母的选择，但关于这些问题的讨论是合理的。Once the 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 CMT4H are possible.
Requests for prenatal testing for conditions which (like CMT4H) do not affect intellect and have some treatment available are rare. 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 decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.
来源Resources
GeneReviews的员工已经选择下列特定的疾病和/或支持组织的保护者和/或注册者，为患有这个疾病的个体及他们的家庭提供好处。GeneReviews对其他组织提供的信息不负有责任。在信息的选择标准上，点击这里。GeneReviews staff has selected the following disease-specific and/orumbrella support organizations and/or registries for the benefit of individualswith this disorder and their families. GeneReviews is not responsible for theinformation provided by other organizations. For information on selectioncriteria, click here.
- Association CMT FranceFrancePhone: 820 077 540; 2 47 27 96 41
- Charcot-Marie-Tooth Association (CMTA)PO Box 105Glenolden PA 19036Phone: 800-606-2682 (toll-free); 610-499-9264Fax: 610-499-9267Email: info@cmtausa.org
- European Charcot-Marie-Tooth ConsortiumDepartment of Molecular GeneticsUniversity of AntwerpAntwerp Antwerpen B-2610BelgiumFax: 03 2651002Email: gisele.smeyers@ua.ac.be
- Hereditary Neuropathy Foundation, Inc.432 Park Avenue South4th FloorNew York NY 10016Phone: 855-435-7268 (toll-free); 212-722-8396Fax: 917-591-2758Email: info@hnf-cure.org
- My46 Trait Profile
- National Library of Medicine Genetics Home Reference
- NCBI Genes and Disease
- TREAT-NMDInstitute of Genetic MedicineUniversity of Newcastle upon TyneInternational Centre for LifeNewcastle upon Tyne NE1 3BZUnited KingdomPhone: 44 (0)191 241 8617Fax: 44 (0)191 241 8770Email: info@treat-nmd.eu
- Association Francaise contre les Myopathies (AFM)1 Rue de l'InternationalBP59Evry cedex 91002FrancePhone: +33 01 69 47 28 28Email: dmc@afm.genethon.fr
- European Neuromuscular Centre (ENMC)Lt Gen van Heutszlaan 63743 JN BaarnNetherlandsPhone: 31 35 5480481Fax: 31 35 5480499Email: enmc@enmc.org
- Muscular Dystrophy Association - USA (MDA)222 South Riverside PlazaSuite 1500Chicago IL 60606Phone: 800-572-1717Email: mda@mdausa.org
- Muscular Dystrophy UK61A Great Suffolk StreetLondon SE1 0BUUnited KingdomPhone: 0800 652 6352 (toll-free); 020 7803 4800Email: info@musculardystrophyuk.org
- RDCRN Patient Contact Registry: Inherited Neuropathies Consortium
分子遗传学Molecular Genetics
在分子遗传学和OMIM表格中的信息可能与在GeneReview的信息不同：GeneReview的表格可能包含更多最新的信息。——ED。Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. -ED.
表A.Table A.
4H型神经病变型腓骨肌萎缩：基因和数据Charcot-Marie-Tooth Neuropathy Type 4H: Genes and Databases
| 位点名称Locus Name | 基因Gene | 染色体位置Chromosome Locus | 蛋白质Protein | 特定位点的数据Locus-Specific Databases | 人基因突变数据库HGMD | ClinVar |
|---|---|---|---|---|---|---|
| CMT4H | FGD4 | 12p11-.21 | FYVE, RhoGEF and PH domain-containing protein 4 | IPN Mutations, FGD4 FGD4 homepage - Leiden Muscular Dystrophy pages | FGD4 | FGD4 |
数据是从以下标准引用编译的：来自GHNC的基因；染色体位置，位点名称，临界区，来自OMIM的互补群；来自UniProt的蛋白质。用于描述数据库（位点特异性，HGMD，ClinVar）所提供的链接，点击这里。Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt.For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.
表B.Table B.
关于4H型神经病变型腓骨肌萎缩的OMIM条目（在OMIM中见所有条目）OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4H (View All in OMIM)
基因结构。Gene structure.FGD4包含17个外显子，其中14个编码外显子。这个基因包含了一个大约14kb的基因组的区域。有几个异型体，但是最主要的转录本(NM_139241.2)是长2931bp（编码序列为2301bp）。见表A，以获得基因和蛋白质信息的详细总结，FGD4 comprises 17 exons, of which 14 are coding exons. The 基因 covers a 基因组的 region of about 14 kb. There are several 异型体, but the major transcript (NM_139241.2) is 2931 bp long (2301 bp of coding sequence). For a detailed summary of gene and protein information, see Table A, 基因。致病性变异。Gene.
Pathogenic variants. 14个FGD4致病性变异在13个家庭中已被描述。FGD4单核苷酸变异已经被描述（通过这个基因来发生），包括错义，无义，移码，剪接位点，和剪接变异。见表5获得FGD4的等位基因变异。14 FGD4 pathogenic variants have been described in 13 families. FGD4 single-nucleotide variants have been described (occurring throughout the 基因), including 错义, nonsense, frameshift, 剪接位点, and 剪接 variants.
See Table 5 for FGD4 allelic variants.
表5.Table 5.
13个被报道家庭中已确认的FGD4变异 Variants Identified in the 13 Reported Families
| 家系Family | 国家Origin | 血缘关系Consanguinity | DNA核苷酸改变（别名 1）DNA Nucleotide Change (Alias 1) | 在基因中的位置Location in the Gene | 预测的蛋白质改变Predicted Protein Change | 参考Reference |
|---|---|---|---|---|---|---|
| Ia, Ib 2 | 黎巴嫩Lebanon | 有Yes | c.893T>G 3 | 外显子 7 Exon 7 | p.Met298ArgfsTer8 3 | Delague et al [2007] |
| Ic 2 | 黎巴嫩Lebanon | 有Yes | c.893T>G 3 | 外显子 7 Exon 7 | p.Met298Arg 3 | Stendel et al [2007] |
| II | 阿尔及利亚Algeria | 有Yes | c.893T>C | 外显子 7 Exon 7 | p.Met298Thr | Delague et al [2007] |
| III | 土耳其Turkey | 有Yes | c.670C>T | p.Arg224Ter | Stendel et al [2007] | |
| IV | 土耳其Turkey | 有Yes | c.1628_1629delGA (1627_1628delGA or 1626_1627delAG) | 外显子 13 Exon 13 | p.Glu543GlyfsTer5 | |
| V | 泰米尔Tamil | 散发性Sporadic | c.1756G>T | 外显子 14 Exon 14 | p.Gly586Ter | |
| VI | 北爱尔兰Northern Ireland | 有Yes | c.823C>T | 外显子 6 Exon 6 | p.Arg275Ter | Houlden et al [2009] |
| VII | 意大利Italy | 有Yes | c.1762-2A>G | 内含子 14 Intron 14 | p.Tyr587fsTer14 | Fabrizi et al [2009] |
| VII | 黎巴嫩Lebanon | 有Yes | c.1698G>A | 外显子 14 Exon 14 | p.Met566Ile | Baudot et al [2012] |
| IX | 阿尔及利亚Algeria | 有Yes | c.1325G>A | 外显子 10 Exon 10 | p.Arg442His | |
| X | 突尼斯Tunisia | 有Yes | c.514_515dupG (514_515insG) | 外显子 4 Exon 4 | p.Ala172GlyfsTer27 | Boubaker et al [2013] |
| XI | 日本Japan | 有/无Yes/no | c.1888_1892delAAAGG (1890_1894del) | 外显子 15 Exon 15 | p.Lys630AsnfsTer5 | Hayashi et al [2013] |
| XII | 日本Japan | 有/无Yes/no | c.[837-2A>G + 1132+1G>A] | 内含子6/内含子 8 Intron 6/内含子 8 | p.[Trp279fsTer + Tyr355fsTer2] | |
| XIII | 日本Japan | 无/未知No/unknown | c.837-1G>A | 内含子 6Intron 6 | p.Glu280LysfsTer23 |
参考序列：NM_139241-.2 和 NP_640334-.2Reference sequences: NM_139241-.2 and NP_640334-.2
1.
不符合当前命名约定的变体名称Variant designation that does not conform to current naming conventions
2.
两个来自同一黎巴嫩家庭不同分支的人Two individuals from different branches of the same Lebanese family
3.
Stendel et al [2007] 描述了第893位上的碱基T变为了G，是一个错义变异，导致298位上的甲硫氨酸变为了精氨酸，但Delague et al [2007]同时描述了来自相同黎巴嫩家庭的不同分支的两个人的相同的致病性变异，实际上，显示了一个剪接突变，预测可能会导致一个含305个氨基酸的截短蛋白替换了全长766的氨基酸残基（p.298MetfsTer8），或者缺失整个蛋白质。Stendel et al [2007] described c.893T>G as a 错义 variant leading to p.Met298Arg substitution, but Delague et al [2007] simultaneously described the same 致病性变异 in two other branches from the same Lebanese family and demonstrated that it is, in fact, a 剪接 variant predicted to result in a truncated protein of 305 amino acids instead of the full-length 766 residues (p.298MetfsTer8), or in total absence of the protein.
正常的基因产物。Normal 基因产物.FGD4编码FRABIN（FGD1相关F肌动蛋白结合蛋白），一个含766个氨基酸的蛋白质(NP_640334.2)(105 kd),含5个功能域：一个N端F肌动蛋白结合结构域，一个DH（Dbl 同源）结构域，两个PH（血小板-白细胞C激酶底物同源）结构域，和一个富含半胱氨酸的FYVE结构域[Delague et al 2007]。FGD4 encodes FRABIN (FGD1-related F-actin binding protein), a 766-amino acid protein (NP_640334.2) (105 kd), with five functional domains: a N-terminal F-actin binding 结构域, one DH (Dbl homology) domain, two PH (pleckstrin homology) domains, and one cysteine-rich FYVE domain [Delague et al 2007].DH结构域是在Db1蛋白质中第一个被确定的结构域（并且出现在许多蛋白质中，它们在GDP到GTP的转化中起着关键作用）；而PH和FYVE结构域主要参与与不同形式肌醇磷脂的相互作用。
DH domains were first identified in the Dbl protein (and are present in many proteins where they play a key role in the catalysis of GDP to GTP exchange); while PH and FYVE domains are mainly involved in interactions with different forms of phosphoinositides.FRABIN是一个Rho GDP/GTP核苷酸的转化因子（RhoGEF），与Cdc42特定地结合，是小GTP结合蛋白（Rho GTPases）Rho家族的一个成员[Obaishi et al 1998, Umikawa et al 1999]。Rho GTP酶在调控真核生物的信号传导通路中起着关键作用。尤其是，它们在细胞迁移、形态发生、分化和分裂过程中，调节肌动蛋白细胞骨架变化中起着关键作用[Jaffe & Hall 2005, Etienne-Manneville & Hall 2002]。
FRABIN is a Rho GDP/GTP nucleotide exchange factor (RhoGEF), specific for Cdc42, a member of the Rho family of small GTP binding proteins (Rho GTPases) [Obaishi et al 1998, Umikawa et al 1999]. Rho GTPases play a key role in regulating signal transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division [Jaffe & Hall 2005, Etienne-Manneville & Hall 2002].FRABIN在外周神经中的作用还不太清楚；然而，在胚胎大鼠脊髓运动神经元和大鼠神经鞘瘤RT4细胞中过表达Frabin表现出在轴突顶端和生长锥中Frabin和F-肌动蛋白共定位，并且会诱导丝状伪足样微刺的形成[Delague et al 2007, Stendel et al 2007]。
The role of FRABIN in peripheral nerve is not well known; however, overexpression of Frabin in embryonic rat spinal motoneurons and rat RT4 schwannoma cells showed that Frabin co-localizes with F-actin in neurite tips and growth cones, and induces the formation of filopodia-like microspikes [Delague et al 2007, Stendel et al 2007].同样，在一个CMT4H[Horn et al 2012]的小鼠模型中的最新的研究表明在Schwann细胞中，Frabin调控RhoGTPase Cdc42和内吞作用。
Also, a recent study in a mouse model of CMT4H [Horn et al 2012] has shown that Frabin regulates the RhoGTPase Cdc42 and endocytosis in Schwann cells.异常的基因产物。
Abnormal 基因产物. 至今大多数FGD4致病性变异被描述为是功能丧失性变异。尤其是，无义，移码，剪接位点和剪接变异预测的结果可能导致截短蛋白或完全丧失FRABIN。至今没有发表的数据描述在CMT4H患者中蛋白质水平的致病性变异的影响。Most FGD4 pathogenic variants described to date are predicted to be 功能丧失性 variants. In particular, nonsense, frameshift, 剪接位点 and 剪接 variants are predicted to lead to either a truncated protein or to complete absence of FRABIN. No data describing the effect of the pathogenic variants at the protein level in individuals with CMT4H have been published to date.
参考References
引用的文献Literature Cited
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建议阅读Suggested Reading
- Dubourg O, Azzedine H, Verny C, Durosier G, Birouk N, Gouider R, Salih M, Bouhouche A, Thiam A, Grid D, Mayer M, Ruberg M, Tazir M, Brice A, LeGuern E. Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:75-86. [PubMed: 16775368]
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章节注释Chapter Notes
作者注释Author Notes
作者的团队Author’s Team我的团队在遗传性周围神经病变领域领导转化性研究（大多研究神经病变型腓骨肌萎缩疾病），一组影响周围神经的神经肌肉疾病。我们的目标是更好地了解这类疾病的遗传和病理生理学。通过研究大的近亲婚配的家系，我们重点研究这些疾病的常染色体隐性遗传形式。利用传统的位置克隆策略，结合高通量二代测序技术，我们在遗传性周围神经病中确定了新的基因缺陷。为了确定这些疾病的潜在治疗策略，通过建立不同的模型，我们进一步研究这些疾病的病理生理学。我们特别研究了两种CMT亚型：CMT4H，由在FGD4/FRABIN的致病性变异所引起，AR-CMT2A，由在LMNA中的致病性变异所引起。通过与儿童医院“La Timone”的分子遗传学部门的密切的关系，我们发展出了创新的诊断策略。
My team leads translational research in the field of Inherited Peripheral Neuropathies (mostly Charcot-Marie-Tooth disease), a group of neuromuscular disorders affecting peripheral nerve. Our aim is to better understand the genetics and physiopathology of this group of diseases. We focus our research on 常染色体隐性遗传 forms of these diseases, by studying large 近亲婚配的 families. By using traditional positional cloning strategies, combined to high-throughput Next Generation Sequencing strategies, we identify new defective genes in Inherited Peripheral Neuropathies. We further study the physiopathology of these diseases, by developing different models, in order to identify potential therapeutic strategies for these diseases. We study in particular two CMT subtypes: CMT4H, caused by pathogenic variants in FGD4/FRABIN and AR-CMT2A, caused by pathogenic variants in LMNA.
In close relationship with the Molecular Genetics Department of The Children’s Hospital “La Timone,” we develop innovative diagnosis strategies.
修订记录Revision History
- 2013年8月8日（我）现场发表评论8 August 2013 (me) Review posted live
- 2013年4月1日（vd）原始提交1 April 2013 (vd) Original submission