临床特征.Clinical characteristics.

腓骨肌萎缩症神经病4型（Charcot-Marie-Tooth neuropathy type 4，CMT4）是一类进步运动和感觉轴突和神经脱髓鞘的疾病，并且与其他种类以 常染色体隐性遗传 方式遗传的CMT不同。受累的个体有典型的CMT 表型 包括远端肌肉无力和萎缩伴随有感觉丧失和经常性的弓形足畸形。Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by 常染色体隐性遗传 inheritance.Affected individuals have the typical CMT 表型 of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity.

诊断/检验.

CMT4子类型的诊断基于临床症状，神经生理学研究，和 分子遗传学检测。 在以下11个基因中的一个基因上的双等位基因的 致病突变检测建立了诊断的基础：GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2(CMT4E), PRX(CMT4F), HK1 (CMT4G), FGD4 (CMT4H), 和 FIG4 (CMT4J)。

Diagnosis/testing.

diagnosis of CMT4 subtypes is based on clinical findings, neurophysiologic studies, and 分子遗传学检测.Detection of 双等位基因的 pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J).

管理.Management.

治疗临床表现: 医疗治疗团队包括一个神经病医师，物理治疗医师，整形外科医师，职业理疗技师；特殊的鞋子和/或脚踝/足矫正器械以矫正足下垂并帮助走路；如需要可做手术以治疗严重的弓形足；如需要可用前臂拐杖，手杖，轮椅帮助移动；如可以忍受可进行运动；有症状的进行疼痛，抑郁，睡眠呼吸中止症，不宁腿综合症的治疗。Treatment of manifestations:treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; symptomatic treatment of pain, depression, sleep apnea, restless leg syndrome.

预防次级并发症: 每天进行跟线拉伸以防止跟腱缩短。Prevention of secondary complications:Daily heel cord stretching to prevent Achilles' tendon shortening.

监督: 监控步态和脚的状况以决定是否需要支撑，特殊的鞋子，手术。Surveillance:Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.

需要避免的药剂/环境:肥胖症（因其使得行动更加困难）；已知的可以引起神经损坏的药物（例如，长春新碱，异烟肼，呋喃妥英）Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage.

其他: 职业和就业咨询。Other:career and employment counseling.

遗传咨询.Genetic counseling.

CMT4子类型按常染色体隐性遗传方式遗传。受累的 个体的父母必然是在该家庭中存在的CMT4-相关致病性变异的携带者。 理论上，每个受累个体的同胞有25%的概率也受累，有50%的概率是一个无症状的 携带者，并有25%的概率既不受累也不是携带者。如果在受累家庭成员上的致病性变异已经，有患病风险的亲属的带菌体实验和怀孕的产前诊断是可行的。The CMT4 subtypes are inherited in an 常染色体隐性遗传 manner. Parents of an 受累的 individual are obligate carriers of the CMT4-related 致病性变异 present in their family.At conception, each sib of an affected 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 relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in an affected family member are known.

推测性结论Suggestive Findings

腓骨肌萎缩症神经病4型（Charcot-Marie-Tooth neuropathy type 4，CMT4）在有以下临床症状，神经传导速度和家族史的群体中可以被判断。Charcot-Marie-Tooth neuropathy type 4 (CMT4) should be suspected in individuals with the following clinical findings, nerve conduction velocities, and family history.

临床症状Clinical findings

• 在脚和/或手远端的肌肉逐渐无力Progressive weakness of the distal muscles in the feet and/or hands
• 高足弓脚High-arched feet
• 踝关节背曲能力弱Weak ankle dorsiflexion
• 远端肌肉萎缩Atrophic distal muscles
• 肌腱反射被抑制或缺失Depressed or absent tendon reflexes
• 远端感觉丧失Distal sensory loss

神经传导速度 (NCVs) 通常很慢 (<40 m/s)Nerve conduction velocities (NCVs) that are usually slow (<40 m/s)

家族史与 常染色体隐性遗传方式一致（也就是说，父母不是受累的除非存在几代的近亲婚配）Family history consistent with 常染色体隐性遗传 inheritance (i.e., parents not 受累的 unless multigenerational 近亲婚配 exists)

建立诊断Establishing the Diagnosis

CMT4的诊断建立在一个先证者有进步运动和感觉神经病，神经传导速度缓慢，和在11个已知与CMT4 表型相关的基因之一的双等位基因的 致病性变异(Table 1)。The diagnosis of CMT4 is established in a 先证者 with progressive motor and sensory neuropathy, slow nerve conduction velocities, and 双等位基因的 pathogenic variants in one of the 11 genes known to be associated with the CMT4 表型 (Table 1).分子检测方法可包括

系列单-基因 测试，表型靶向检测的使用，和更综合的基因组的测试。Molecular testing approaches can include serial single-基因 testing, use of a 表型靶向检测, and more comprehensive 基因组的 testing.

• 系列单-基因测试可能被考虑按致病性变异最可能发生的顺序或由种族如果先证者的突变被确认出来 (Table 1)。Serial single-基因 testing can be considered based on the order in which pathogenic variants most commonly occur or by ethnicity if founder variants have been identified (Table 1).
• 表型靶向检测包括一些（或所有）Table 1 中所列的11个基因和一些其他的感兴趣的基因（见Differential Diagnosis）也可能被考虑。注意：被包括的基因和多-基因面板的 敏感性随实验室和时间的不同而不同。A 表型靶向检测 that includes some (or all) of the 11 genes listed in Table 1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the 敏感性 of multi-gene panels vary by laboratory and over time.
• 更综合的基因组的测试（如果可行）包括外显子组测序，线粒体测序，并且基因组测序也可能要考虑如果系列单-基因测试（和/或使用包括一些或所有与CMT4基因相关的表型靶向检测）没能确认一个有CMT4症状的个体的诊断 [Schabhüttl et al 2014]。了解更多对基因检测结果的解释，点此处。More comprehensive 基因组的 testing (when available) including 外显子组测序, mitochondrial sequencing, 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 that includes some or all of the genes associated with CMT4) fails to confirm a diagnosis in an individual with features of CMT4 [Schabhüttl et al 2014]. For issues to consider in interpretation of genomic test results, click here.

临床描述Clinical Description

临床症状包括周围神经病，缓慢的神经传导速率，遗传模式，和特殊的基因上的双等位基因的致病性变异是CMT子类型分类的基础。The clinical findings of a peripheral neuropathy, slow NCV, 遗传模式, and 双等位基因的 pathogenic variants in a specific 基因 have been the basis for classification for the majority of CMT subtypes.CMT4患者通常有CMT表型的临床症状，包括远端肌肉无力萎缩，感觉丧失，并且经常伴有弓形足畸形。（见CMT Overview 可获得更多信息）

Individuals with CMT4 usually have the clinical characteristics of the CMT 表型, including distal muscle weakness and atrophy, sensory loss, and, often, pes cavus foot deformity. (See CMT Overview for more details.) 轴突和脱髓鞘神经病都包含在CMT4中。Both axonal and demyelinating neuropathies are included in CMT4. 常染色体隐性遗传神经病趋向于更早爆发（儿童早期）和更严重的进程比起常染色体显性遗传突变。

The 常染色体隐性遗传 neuropathies tend to have an earlier onset (early childhood) and more severe progression than the 常染色体显性遗传 varieties. 除了近亲婚配的情况，他们也只发生在同胞上或作为单发的的病例。Except in the case of 近亲婚配, they also appear only in sibs or as 单发的 cases.CMT4A在突尼斯的家庭中

第一次发现。CMT4A was first identified in families in Tunisia. 典型的，运动发育延迟在生命的第二年显著。Typically, delayed motor development is noted in the second year of life. 远端肌肉无力和脚萎缩逐渐发展到近端肌肉到第十年末。Distal muscle weakness and atrophy of feet progress to involve the proximal muscles by the end of the first decade. 手萎缩在之后可能发生。Hand atrophy may occur later. 受累的个体普遍变得依靠轮椅，经常是到30岁[Claramunt et al 2005]。It is common for 受累的 individuals to become wheelchair dependent, often by age 30 years [Claramunt et al 2005].一些有CMT4A的家庭有脱髓鞘神经病的特征，然而其他的有轴突神经病的特征[Nelis et al 2002b, Claramunt et al 2005, Kabzińska et al 2006b]。

Some families with CMT4A have features of a demyelinating neuropathy, whereas others have features of axonal neuropathy [Nelis et al 2002b, Claramunt et al 2005, Kabzińska et al 2006b]. 神经传导速率的范围从非常缓慢到正常 (from 18 to >50 m/s) [Ammar et al 2003, Senderek et al 2003a]。NCVs range from very slow to normal (from 18 to >50 m/s) [Ammar et al 2003, Senderek et al 2003a].轻微的感觉丧失，肌腱反射缺失，骨骼畸形，并且脊柱侧凸可以被观察到。

Mild sensory loss, absent tendon reflexes, skeletal deformities, and scoliosis can be observed. 声带麻痹可能会发生[Sevilla et al 2003, Stojkovic et al 2004, Sevilla et al 2008]。Vocal cord paresis may occur [Sevilla et al 2003, Stojkovic et al 2004, Sevilla et al 2008].神经活检显示髓鞘形成减少并有由基膜组成的洋葱皮样[Nelis et al 2002b, Kabzińska et al 2005, Kabzińska et al 2006b]。

Nerve biopsy reveals hypomyelination with onion bulbs composed of basal laminae [Nelis et al 2002b, Kabzińska et al 2005, Kabzińska et al 2006b].脑脊液蛋白浓度正常。

Cerebrospinal fluid protein concentration is normal.

杂合子表现.Manifesting heterozygotes. 一些个体有杂合的GDAP1致病性变异有温和的表现和神经病变的症状与常染色体显性遗传相容[Zimoń et al 2011, Kabzińska et al 2014]。Some individuals with a 杂合的GDAP1致病性变异 can have mild signs and symptoms of neuropathy compatible with 常染色体显性遗传 inheritance [Zimoń et al 2011, Kabzińska et al 2014].CMT4B1

在意大利家庭中第一次发现被Quattrone et al [1996]。CMT4B1 was first described in an Italian family by Quattrone et al [1996]. 5个意大利和沙特阿拉伯祖先的家庭被报道[Bolino et al 2000, Houlden 2001]。Five families of Italian and Saudi Arabian ancestry have been reported [Bolino et al 2000, Houlden 2001].   Nelis et al [2002a]和Parman et al [2004]报道了两个附加的家庭说明爆发年龄和严重性的变化。  Nelis et al [2002a] and Parman et al [2004] reported two additional families showing variability in age of onset and severity. 远端逐渐进展到近端的下肢肌肉无力在儿童早期显著（平均爆发年龄是34周）。Progressive distal and proximal weakness of the lower limbs is noted in early childhood (mean onset age 34 months). 弓形足畸形普遍并且一些患者发展到面部肌无力。Pes cavus foot deformity is common and a few individuals develop facial weakness. Nouioua et al [2011] 报道有关于声带麻痹，胸部畸形，和爪形手。Nouioua et al [2011] reported associated vocal cord paresis, chest deformities, and claw hands.受累的的成年有严重的残疾并且到了20岁通常需要轮椅。

Adults who are 受累的 are seriously handicapped and frequently require wheelchairs by age 20 years. 病期从27岁到39岁不等，通常在第40年或50年死亡。Duration of illness ranges from age 27 to 39 years and death occurs in the fourth or fifth decade.智力正常。 Intellect is normal.两个家庭被Parman et al [2004]报道。

Two families were reported by Parman et al [2004].在有MTMR2致病性变异和17p11.2 重复的家庭，表型 是在儿童早期爆发出严重的脱髓鞘神经病 [Verny et al 2004]。

In a family with an MTMR2致病性变异 and a 17p11.2 重复, the 表型 was severe early childhood-onset demyelinating neuropathy [Verny et al 2004].听觉诱发电位异常。

Auditory evoked potentials are abnormal.神经传导速率缓慢（15-17 m/s）并经常无法测量。

NCVs are very slow (15-17 m/s) and often undetectable.腓肠神经活性切片检查发现不规则的多余的局部髓鞘折叠环。

Sural nerve biopsy reveals irregular redundant loops of focally folded myelin.CMT4B2

在土耳其家庭中被检出有严重的感觉运动神经病并有低神经传导速率和局部折叠髓鞘 [Othmane et al 1999]。CMT4B2 was identified in a Turkish family with a severe sensorimotor neuropathy with slow nerve conduction and focally folded myelin [Othmane et al 1999]. Azzedine et al [2003] 检测出两个来自突尼斯和摩洛哥的家庭也有早期爆发的青光眼。Azzedine et al [2003]identified two families from Tunisia and Morocco who also had early-onset glaucoma. 附加的家庭被报道[Conforti et al 2004, Chen et al 2014]包括一个有青少年型青光眼 [Hirano et al 2004]。Additional families have been reported [Conforti et al 2004, Chen et al 2014] including one with juvenile glaucoma [Hirano et al 2004].一个患有神经病和神经病理的日本家庭有不规则的多余的环并且折叠的髓鞘与青少年爆发的青光眼有关[Kiwaki et al 2000]。

A Japanese family with neuropathy and nerve pathology showing irregular redundant loops and folding of the myelin sheath has been associated with juvenile onset of glaucoma [Kiwaki et al 2000]. 一个SBF2上的致病性变异随后在这个家庭中被发现[Hirano et al 2004]。A 致病性变异 in SBF2 was subsequently identified in this family [Hirano et al 2004].CMT4B3

在一个韩国的有脱髓鞘表型的家庭中被发现，并在神经活检中发现有局部的髓鞘折叠[Nakhro et al 2013]。CMT4B3 was identified in a single Korean family with demyelinating 表型 and focally folded myelin sheaths on nerve biopsy [Nakhro et al 2013].Bohlega et al [2011]报道了一个近亲婚配的沙特阿拉伯的患有感觉运动神经病的家庭并有明显的手部肌无力，头小畸形，和认知损害。Bohlega et al [2011] reported a Saudi family with sensory motor neuropathy with marked hand weakness, microcephaly, and cognitive impairment.CMT4C

一开始在一个近亲婚配的阿尔及利亚家庭中被报道，随后在其他北非和西欧国家中的家庭被发现[Gabreëls-Festen et al 1999, Senderek et al 2003b, Parman et al 2004]。CMT4C was initially reported in 近亲婚配的 Algerian families, and subsequently in families from other countries of North Africa and western Europe [Gabreëls-Festen et al 1999, Senderek et al 2003b, Parman et al 2004]. 在童年或青春期爆发，经常伴有弓形足畸形和微弱的行走困难并逐渐严重，经常在15年病期后变成严重的脊柱侧凸。Onset is in childhood or adolescence, often associated with pes cavus foot deformity and a mild walking disability with a progressive, often severe scoliosis after a 15-year disease duration. Houlden et al [2009b]注意到了大量的临床变化，从严重的童年时期爆发到温和的脊柱侧凸和足部畸形。Houlden et al [2009b] noted considerable clinical variability, ranging from severe childhood onset to mild scoliosis and foot deformity.严重的脊柱后侧凸和颅神经损伤有10例病例并被Ferrarini et al [2011]报道。

Severe kyphoscoliosis and cranial nerve involvement were found in ten cases reported by Ferrarini et al [2011].受累个体在下肢有运动和感觉神经病并且正中神经传导速率很慢（平均24m/s）。

Affected individuals have motor and sensory neuropathy in the lower limbs and slow median NCV (mean is 24 m/s).神经活检说明脱髓鞘和无髓鞘轴突周围的基膜增加，相对的经典的洋葱皮样很少，施万细胞胞质扩展多[Gabreëls-Festen et al 1999]。

Nerve biopsy shows an increase of basal membranes around demyelinated and unmyelinated axons, relatively few classic onion bulbs, and large cytoplasmic extensions of the Schwann cells [Gabreëls-Festen et al 1999].

杂合子表型.Manifesting heterozygotes.Lupski et al [2010]说明SH3TC2致病性变异p.Arg954Ter或p.Tyr169His杂合的的人可能有温和的晚爆发的神经病的风险。Lupski et al [2010] have suggested that persons 杂合的 for either the SH3TC2致病性变异p.Arg954Ter or p.Tyr169His may be at risk for a mild late-onset neuropathy.CMT4D已经在一个保加利亚吉普赛人群中被Kalaydjieva et al [1998]报道，他们起源于多瑙河洛姆河区有DRG1致病性变异 (p.Arg148Ter)的先证者。

CMT4D has been reported in Bulgarian Gypsies by Kalaydjieva et al [1998] originating from the community of Lom on the Danube caused by a founder NDRG1致病性变异 (p.Arg148Ter). 逐渐加深的运动感觉神经病并伴有缓慢的神经传导速率和足畸形是很常见的[Guergueltcheva et al 2006, Claramunt et al 2007, Ricard et al 2013, Okamoto et al 2014]。Progressive sensory motor neuropathy with slow NCVs is present and foot deformity is common [Guergueltcheva et al 2006, Claramunt et al 2007, Ricard et al 2013, Okamoto et al 2014].CMT4D有明显的临床症状包括感觉神经性耳聋，并且经常在第三十年爆发。

CMT4D has the distinguishing clinical characteristic of sensorineural deafness, with onset usually in the third decade. 舌萎缩也被发现了。Tongue atrophy has also been described.一个患有中枢神经系统白质病变的非吉普赛的家庭在[Echaniz-Laguna et al 2007]中被报道。

A non-Gypsy family with CNS white matter lesions has been reported [Echaniz-Laguna et al 2007].神经活检检测出肥大的洋葱皮样改变。

Nerve biopsy shows a hypertrophic onion bulb change.CMT4E

是先天的髓鞘形成不足神经病（hypomyelinating neuropathy，CHN）伴有早期爆发的神经传导速率缓慢和Déjérine-Sottas综合症-类似表现（见Nomenclature）[Boerkoel et al 2001a, Chung et al 2005]。CMT4E is a 先天的 hypomyelinating neuropathy (CHN) with early-onset slow NCVs and a Déjérine-Sottas syndrome-like presentation (see Nomenclature) [Boerkoel et al 2001a, Chung et al 2005]. 呼吸功能紊乱和颅神经畸形也可能会发生[Szigeti et al 2007]。Respiratory dysfunction and cranial nerve abnormalities may occur [Szigeti et al 2007].Funalot et al [2012]报道了一个患有严重的CHN的儿童。

Funalot et al [2012] have reported a child with severe CHN.CMT4F

被指定为严重的伴有神经传导速率缓慢的脱髓鞘神经病在三个家庭中被报道出来[Delague et al 2000, Boerkoel et al 2001b, Guilbot et al 2001, Kijima et al 2004, Parman et al 2004]。CMT4F is the designation for a severe demyelinating neuropathy with slow NCVs reported in three families [Delague et al 2000, Boerkoel et al 2001b, Guilbot et al 2001, Kijima et al 2004, Parman et al 2004].Takashima et al [2002]报道了同胞，其表型一开始是明显的感觉神经病并有明显的脱髓鞘特征。

Takashima et al [2002] described sibs in whom the 表型 was initially a marked sensory neuropathy with prominent demyelinating features.一个儿童有运动发育迟缓并有明显的肌无力。

A child had delayed motor milestones and marked weakness. 附加的家庭被Kabzińska et al [2006a]和Otagiri et al [2006]描述。Additional families are described by Kabzińska et al [2006a] and Otagiri et al [2006].一个更良性的表型是爆发时间晚（7-12岁）但是有明显的脊柱畸形在Nouioua et al [2011]中被报道。

A more benign 表型 with later age of onset (7-12 years) but with marked spine deformities was reported by Nouioua et al [2011]. Tokunaga et al [2012]也报道了更晚爆发的更良性的例子（包括在一个个体中的声带麻痹）。Tokunaga et al [2012] have also reported later onset and more benign course (including vocal cord paresis in one individual).明显的感觉丧失发生在一个家庭中[Auer-Grumbach et al 2008]。

Prominent sensory loss occurred in one family [Auer-Grumbach et al 2008]. 感觉丧失也在Marchesi et al [2010]中被强调。Sensory loss was also emphasized by Marchesi et al [2010].腓肠神经病理表现出脱髓鞘，洋葱皮状，和局部髓鞘变薄。

Sural nerve pathology showed demyelination, onion bulbs, and focal myelin thickening.CMT4G

是严重的畸形的周围神经病并伴随明显的感觉丧失和适当的运动神经传导速率减慢在巴尔干半岛（鲁塞）的吉卜赛人中与10q22联锁[Guergueltcheva et al 2006, Hantke et al 2009]。CMT4G is a severe disabling form of peripheral neuropathy with prominent sensory loss and moderately reduced motor NCVs in Balkan (Russe) Gypsies linked to 10q22 [Guergueltcheva et al 2006, Hantke et al 2009]. CMT4G不如CMT4D严重。CMT4G is less severe than CMT4D.CMT4H

在De Sandre-Giovannoli et al [2005]中被报道作为严重的脱髓鞘神经病联锁于12p11.2-p13.1。CMT4H was reported by De Sandre-Giovannoli et al [2005] as a severe demyelinating neuropathy linked to 12p11.2- p13.1. 相关研究结果是严重的脊柱侧凸，神经纤维髓鞘丧失，和髓鞘外折叠[Stendel et al 2007]。Associated findings are severe scoliosis, loss of myelinated nerve fibers, and outfoldings of the myelin sheath [Stendel et al 2007]. 早期的爆发和明显的脊柱后侧凸在突尼斯家庭中被确认并被Boubaker et al [2013]报道。The early onset and prominent kyphoscoliosis have been confirmed in a Tunisian family reported by Boubaker et al [2013].两个在爱尔兰的同胞一直能行走直到中年[Houlden et al 2009a]。

Two sibs in Ireland remained ambulatory into middle age [Houlden et al 2009a].一个阿尔及利亚和一个黎巴嫩受累的个体有明显的神经传导缓慢[Baudot et al 2012]。

An Algerian and a Lebanese 受累的 individual had marked slowing of nerve conductions [Baudot et al 2012].CMT4J

是严重的儿童-爆发的脱髓鞘神经病综合症[Chow et al 2007]。CMT4J is a syndrome of severe childhood-onset demyelinating neuropathy [Chow et al 2007]. 个体有迅速发展的麻痹并没有感觉障碍被报道[Zhang et al 2008]。An individual with rapidly progressive paralysis without sensory symptoms was reported [Zhang et al 2008]. Nicholson et al [2011]已经强调高度变异的爆发年龄和严重性，可能是不对称的近端和远端的肌无力，并频繁发展成严重的肌萎缩。Nicholson et al [2011] have emphasized the highly variable onset age and severity, proximal and distal weakness that may be asymmetric, and frequent progression to severe amyotrophy.Menezes et al [2014]

报道了一个两代的家庭有多种的复合杂合FIG4致病性变异，此变异类似于“常染色体显性遗传”。Menezes et al [2014] reported a two generation family with a variety of 复合杂合FIG4 pathogenic variants that masqueraded as “常染色体显性遗传” inheritance.

基因型-表型相关性Genotype-Phenotype Correlations

总体上，没有已知的特定一致的基因型-表型相关性。In general, no specific consistent 基因型-表型 correlations are known.

命名法Nomenclature

严重的神经病并有缓慢的神经传导速度且在儿童早期爆发也经常被叫做Déjérine-Sottas综合症（Déjérine-Sottas syndrome，DSS）。这是描述临床的命名并不涉及一个特定的疾病因为它是由多基因的致病性变异引起的 [Plante-Bordeneuve & Said 2002] (见 CMT Overview)。Severe neuropathy with slow NCVs and onset in early childhood is often called the Déjérine-Sottas syndrome (DSS). This is a descriptive clinical term that does not refer to a specific disease because it is caused by pathogenic variants in multiple genes [Plante-Bordeneuve & Said 2002] (see CMT Overview).

流行性Prevalence

遗传性神经病的流行性总体上在人群中大约为30:100,000。The overall prevalence of hereditary neuropathies is estimated to be approximately 30:100,000 population. 那些病例中超过一半的是CMT1型(15:100,000)。More than half of these cases are CMT type 1 (15:100,000).常染色体隐性遗传形式的CMT十分罕见且经常限制于特定的族群（比如说在北非），在该族群中则相对比较普遍。

The 常染色体隐性遗传 forms of CMT are quite rare and often limited to specific ethnic groups (e.g., in North Africa), where they may be relatively common.CMT4A是最普遍的常染色体隐性遗传CMT的原因，并在许多研究中被提到[Bouhouche et al 2007, Auer-Grumbach et al 2008, Moroni et al 2009, Moroni et al 2012]。

CMT4A is the most common cause of 常染色体隐性遗传 CMT as noted in several studies [Bouhouche et al 2007, Auer-Grumbach et al 2008, Moroni et al 2009, Moroni et al 2012]. 两个先证者的致病性变异被确认，在西班牙的先证者是GDAP1:p.Gln163Ter[Claramunt et al 2005] 且在意大利的先证者为 p.Met116Arg  [Di Maria et al 2004]。Two founder pathogenic variants have been identified GDAP1:p.Gln163Ter in Spain [Claramunt et al 2005] and p.Met116Arg in Italy [Di Maria et al 2004].三个在欧洲吉普赛人群的子群的先证者致病性变异在CMT4被发现[Gabrikova et al 2013, Sevilla et al 2013]：

Three founder pathogenic variants are found in CMT4 in subgroups of the European Gypsy population [Gabrikova et al 2013, Sevilla et al 2013]:

• CMT4C (SH3TC2: p.Arg1109Ter) [Claramunt et al 2007]
• CMT4D (NDRG1:p.Arg148Ter) [Kalaydjieva et al 1998]
• CMT4G (HK1: c.-249-3838G>C) [Sevilla et al 2013]

初步诊断后的评估Evaluations Following Initial Diagnosis

为了判断疾病严重程度和被诊断患有腓骨肌萎缩症神经病4型（Charcot-Marie-Tooth neuropathy type 4，CMT4）的患者的需求，推荐使用以下评估：To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4 (CMT4), the following evaluations are recommended:

• 体格检查以确定肌无力肌萎缩，弓形足，步态稳定性，感觉丧失的程度Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• 神经传导速率帮助判断疾病是否是轴突，脱髓鞘，或混合型NCV to help determine whether the disease is axonal, demyelinating, or mixed
• 详细的家庭史Detailed family history
• 咨询临床遗传学者和/或遗传咨询师Consultation with a clinical geneticist and/or genetic counselor

治疗症状Treatment of Manifestations

受累的的个体经常受多学科康复综合小组管理，包括神经学家，物理治疗医师，整形外科医生，和理疗技师[Pareyson & Marchesi 2009, Reilly & Shy 2009, Rossor et al 2015]。The 受累的 individual is often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [Pareyson & Marchesi 2009, Reilly & Shy 2009, Rossor et al 2015].治疗是有对症的可能包括以下：

Treatment is symptomatic and may include the following:

• 特殊的鞋子，包括那些有很好的脚踝支撑的Special shoes, including those with good ankle support
• 踝/足矫正器械以帮助矫正足下垂并帮助行走Ankle/foot orthoses to correct foot drop and aid walking
• 整形外科以矫正严重的弓形足畸形[Guyton & Mann 2000, Ward et al 2008]Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000, Ward et al 2008]
• 前臂拐杖或手杖以维持步态稳定性；少于5%的受累的个体需要轮椅。Forearm crutches or canes for gait stability; fewer than 5% of 受累的 individuals need wheelchairs.
• 在个人能力范围内的锻炼以保持身体活跃Exercise within the individual's capability to remain physically active

预防次级并发症Prevention of Secondary Complications

每天进行跟线伸展运动锻炼帮助防止跟腱缩短。Daily heel cord stretching exercises are helpful in preventing Achilles' tendon shortening.

监测Surveillance

儿童的脚应有规律的间期观察以提供合适的鞋子避免疡和皮肤皲裂。步态监测和脚的状况的监测是合适的以决定是否需要支架，特殊的鞋子，和/或手术。Children's feet should be watched at regular intervals to provide for properly fitting shoes and avoid sores and skin breakdown.

It is appropriate to monitor gait and condition of feet to determine need for bracing, special shoes, and/or surgery.

需要避免的药剂/环境Agents/Circumstances to Avoid

过度肥胖是需要避免的因为肥胖让走步变得更加困难。对患有CMT的人有毒或有潜在毒性的药物有一系列风险从明确的高风险到可忽略不计的风险。点此处 (pdf)获得最新列表。Obesity is to be avoided because it makes walking more difficult.

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

对有风险亲属的评估Evaluation of Relatives at Risk

若有遗传咨询目的，可见Genetic Counseling获得有关有风险亲属的测试的话题。See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 purposes.

怀孕管理Pregnancy Management

没有明确的怀孕管理建议被发表。然而在怀孕期间增重可能会产生额外的步态障碍。No specific pregnancy management recommendations have been published. However, weight gain during pregnancy may produce additional gait disability.

调查中的治疗方法Therapies Under Investigation

Ekins et al [2015] 和 Mathis et al [2015]已经总结了之前的和正在进行的对CMT的治疗性试验。查阅ClinicalTrials.gov可获得各式各样的疾病与状况的临床研究信息 Ekins et al [2015]and Mathis et al [2015] have reviewed prior and ongoing treatment trials for CMT.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

其他Other

职业和就业可能会被长久的手和/或脚的肌无力所影响。Career and employment may be influenced by the persistent weakness of hands and/or feet.

遗传方式Mode of Inheritance

所有的在此篇GeneReview讨论的腓骨肌萎缩症神经病4型（Charcot-Marie-Tooth neuropathy type 4，CMT4）的子型 (CMT4A, 4B1, 4B2, 4B3, 4C, 4D, 4E, 4F, 4G, 4H, and 4J)是常染色体隐性遗传方式遗传的。All of the Charcot-Marie-Tooth neuropathy type 4 (CMT4) subtypes discussed in this GeneReview (CMT4A, 4B1, 4B2, 4B3, 4C, 4D, 4E, 4F, 4G, 4H, and 4J) are inherited in an 常染色体隐性遗传 manner.

家庭成员的风险Risk to Family Members

先证者的父母Parents of a 先证者

• 受累的个体的父母必然是杂合子因此携带先证者中存在的CMT4子型-相关的致病性变异之一。Parents of an 受累的 individual are obligate heterozygotes and therefore carriers of one of the CMT4 subtype-related pathogenic variants present in the 先证者.
• 杂合子（携带者）是无症状的并没有发展成CMT的风险。Heterozygotes (carriers) are asymptomatic and are not at risk of developing CMT.

先证者的同胞Sibs of a 先证者

• 理论上，受累的的个体的每个同胞有25%的概率受累，有50%的概率不受累而是一个携带者，25%的概率既不受累也不是携带者。At conception, each sib of an 受累的 individual has a 25% chance of being affected, a 50% chance of being unaffected and a 携带者, and a 25% chance of being unaffected and not a carrier.
• 一旦有风险的同胞被确定不受累，他/她是先证者中存在的CMT4子型-相关致病性变异中的一个致病性变异的携带者的概率是2/3。Once an at-risk sib is known to be unaffected, the chance of his/her being a 携带者 of one of the CMT4 subtype-related pathogenic variants present in the 先证者 is 2/3.
• 杂合子（携带者）是无症状的且没有发病的风险。Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

先证者的子代Offspring of a 先证者. CMT4患者的子代必然是先证者中存在的CMT4子型-相关致病性变异中的一个变异的杂合子（携带者）The offspring of an individual with CMT4 are obligate heterozygotes (carriers) for one of the CMT4 subtype-related pathogenic variants present in the proband.先证者的其他家庭成员

Other family members of a 先证者. 先证者的父母的每个同胞都有50%的概率是一个携带者。Each sib of the proband's parents is at a 50% risk of being a 携带者.

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

有风险亲属的携带测试需要提前确认家庭中的PCD-相关致病突变。Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

相关的遗传咨询问题Related Genetic Counseling Issues

计划生育Family planning

• 测定基因风险, 确定 携带者 基因状态,并讨论产前诊断是否可行的最优时间是怀孕之前。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.
• 应该为 受累的，携带的，或有患病或携带风险的年轻成年人提供 遗传咨询 (包括讨论子代潜在的风险和生殖选择)。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 of being carriers.

DNA银行是一个储存 DNA (主要是从白细胞中提取的) 以便将来使用。因为测试方法和我们对基因的理解, 等位基因突变, 和疾病在将来很可能会增多, 应该考虑建设受累的 人群的DNA银行。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.

产前诊断和植入前遗传Prenatal Testing and Preimplantation Genetic Diagnosis

一旦受累的家庭成员的致病性变异被确认，高患病风险的妊娠的产前诊断和CMT4的植入前遗传诊断是可行的。医学专家和家庭内使用产前诊断的观点可能不同， 尤其是如果测试是出于终止妊娠的目的而不是早期诊断的目的。尽管大多数中心认为决定是否做产前诊断是父母选择，这些事情的考虑还是合适的。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 CMT4 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.

引用文献Literature Cited

• Ammar N, Nelis E, Merlini L, Barisic N, Amouri R, Ceuterick C, Martin JJ, Timmerman V, Hentati F, De Jonghe P. Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease. Neuromuscul Disord. 2003;13:720-8. [PubMed: 14561495]
• Auer-Grumbach M, Fischer C, Papić L, John E, Plecko B, Bittner RE, Bernert G, Pieber TR, Miltenberger G, Schwarz R, Windpassinger C, Grill F, Timmerman V, Speicher MR, Janecke AR. Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome. Neuropediatrics. 2008;39:33-8. [PMC free article: PMC3272394] [PubMed: 18504680]
• Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003;72:1141-53. [PMC free article: PMC1180267] [PubMed: 12687498]
• 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]
• Baloh RH, Strickland A, Ryu E, Le N, Fahrner T, Yang M, Nagarajan R, Milbrandt J. Congenital hypomyelinating neuropathy with lethal conduction failure in mice carrying the Egr2 I268N mutation. J Neurosci. 2009;29:2312-21. [PMC free article: PMC2679588] [PubMed: 19244508]
• Baudot C, Esteve C, Castro C, Poitelon Y, Mas C, Hamadouche T, El-Rajab M, Lévy N, Megarbané A, Delague V. Two novel missense mutations in FGD4/FRABIN cause Charcot-Marie-Tooth type 4H (CMT4H). J Peripher Nerv Syst. 2012;17:141-6. [PubMed: 22734899]
• Baulac S, Lenk GM, Dufresnois B, Ouled Amar Bencheikh B, Couarch P, Renard J, Larson PA, Ferguson CJ, Noé E, Poirier K, Hubans C, Ferreira S, Guerrini R, Ouazzani R, El Hachimi KH, Meisler MH, Leguern E. Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology. 2014;82:1068-75. [PMC free article: PMC3962989] [PubMed: 24598713]
• Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet. 2002;30:21-2. [PubMed: 11743579]
• Berger P, Bonneick S, Willi S, Wymann M, Suter U. Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet. 2002;11:1569-79. [PubMed: 12045210]
• Berghoff C, Berghoff M, Leal A, Morera B, Barrantes R, Reis A, Neundorfer B, Rautenstrauss B, Del Valle G, Heuss D. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3. Neuromuscul Disord. 2004;14:301-6. [PubMed: 15099588]
• Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR. EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics. 2001a;3:153-7. [PubMed: 11523566]
• Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, Lupski JR. Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet. 2001b;68:325-33. [PMC free article: PMC1235266] [PubMed: 11133365]
• Bohlega S, Alazami AM, Cupler E, Al-Hindi H, Ibrahim E, Alkuraya FS. A novel syndromic form of sensory-motor polyneuropathy is linked to chromosome 22q13.31-q13.33. Clin Genet. 2011;79:193-5. [PubMed: 21210780]
• Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, Christodoulou K, Hausmanowa-Petrusewicz I, Mandich P, Schenone A, Gambardella A, Bono F, Quattrone A, Devoto M, Monaco AP. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000;25:17-19. [PubMed: 10802647]
• Bolis A, Zordan P, Coviello S, Bolino A. Myotubularin-related (MTMR) phospholipid phosphatase proteins in the peripheral nervous system. Mol Neurobiol. 2007;35:308-16. [PubMed: 17917119]
• Bonneick S, Boentert M, Berger P, Atanasoski S, Mantei N, Wessig C, Toyka KV, Young P, Suter U. An animal model for Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet. 2005;14:3685-95. [PubMed: 16249189]
• Boubaker C, Hsairi-Guidara I, Castro C, Ayadi I, Boyer A, Kerkeni E, Courageot J, Abid I, Bernard R, Bonello-Palot N, Kamoun F, Cheikh HB, Lévy N, Triki C, Delague V. A novel mutation in FGD4/FRABIN causes Charcot Marie Tooth disease type 4H in patients from a consanguineous Tunisian family. Ann Hum Genet. 2013;77:336-43. [PubMed: 23550889]
• Bouhouche A, Birouk N, Azzedine H, Benomar A, Durosier G, Ente D, Muriel MP, Ruberg M, Slassi I, Yahyaoui M, Dubourg O, Ouazzani R, LeGuern E. Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. Brain. 2007;130:1062-75. [PubMed: 17347251]
• Burgunder JM, Schöls L, Baets J, Andersen P, Gasser T, Szolnoki Z, Fontaine B, Van Broeckhoven C, Di Donato S, De Jonghe P, Lynch T, Mariotti C, Spinazzola A, Tabrizi SJ, Tallaksen C, Zeviani M, Harbo HF, Finsterer J. EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. Eur J Neurol. 2011;18:207-17. [PubMed: 20500522]
• Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, Dubas F, Amati-Bonneau P, Reynier P, Bonneau D, Procaccio V. Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. Exp Neurol. 2011;227:31-41. [PubMed: 20849849]
• Chen M, Wu J, Liang N, Tang L, Chen Y, Chen H, Wei W, Wei T, Huang H, Yi X, Qi M. Identification of a novel SBF2 frameshift mutation in charcot-marie-tooth disease type 4B2 using whole-exome sequencing. Genomics Proteomics Bioinformatics. 2014;2014;12:221-7. [PMC free article: PMC4411414] [PubMed: 25462154]
• Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K, Szigeti K, Shy ME, Li J, Zhang X, Lupski JR, Weisman LS, Meisler MH. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007;448:68-72. [PMC free article: PMC2271033] [PubMed: 17572665]
• Chung KW, Sunwoo IN, Kim SM, Park KD, Kim WK, Kim TS, Koo H, Cho M, Lee J, Choi BO. Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family. Neurogenetics. 2005;6:159-63. [PubMed: 15947997]
• Claramunt R, Pedrola L, Sevilla T, Lopez de Munain A, Berciano J, Cuesta A, Sanchez-Navarro B, Millan JM, Saifi GM, Lupski JR, Vilchez JJ, Espinos C, Palau F. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet. 2005;42:358-65. [PMC free article: PMC1736030] [PubMed: 15805163]
• Claramunt R, Sevilla T, Lupo V, Cuesta A, Millán JM, Vílchez JJ, Palau F, Espinós C. The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clin Genet. 2007;71:343-9. [PubMed: 17470135]
• Conforti FL, Muglia M, Mazzei R, Patitucci A, Valentino P, Magariello A, Sprovieri T, Bono F, Bergmann C, Gabriele AL, Peluso G, Nistico R, Senderek J, Quattrone A. A new SBF2 mutation in a family with recessive demyelinating Charcot-Marie-Tooth (CMT4B2). Neurology. 2004;63:1327-8. [PubMed: 15477569]
• Cotter L, Özçelik M, Jacob C, Pereira JA, Locher V, Bauman R, Relvas JB, Suter U, Tricaud N. DIg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science. 2010;328:1415-8. [PubMed: 20448149]
• De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N, Szepetowski P, Hammadouche T, Vandenberghe A, Stewart CL, Grid D, Levy N. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot- Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002;70:726-36. [PMC free article: PMC384949] [PubMed: 11799477]
• De Sandre-Giovannoli A, Delague V, Hamadouche T, Chaouch M, Krahn M, Boccaccio I, Maisonobe T, Chouery E, Jabbour R, Atweh S, Grid D, Megarbane A, Levy N. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. J Med Genet. 2005;42:260-5. [PMC free article: PMC1736004] [PubMed: 15744041]
• Delague V, Bareil C, Tuffery S, Bouvagnet P, Chouery E, Koussa S, Maisonobe T, Loiselet J, Megarbane A, Claustres M. Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am J Hum Genet. 2000;67:236-43. [PMC free article: PMC1287083] [PubMed: 10848494]
• Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, Chouery E, Chaouch M, Kassouri N, Jabbour R, Grid D, Megarbane A, Haase G, Levy N. Mutations in FGD4 Encoding the Rho GDP/GTP Exchange Factor FRABIN Cause Autosomal Recessive Charcot-Marie-Tooth Type 4H. Am J Hum Genet. 2007;81:1-16. [PMC free article: PMC1950914] [PubMed: 17564959]
• Di Maria E, Gulli R, Balestra P, Cassandrini D, Pigullo S, Doria-Lamba L, Bado M, Schenone A, Ajmar F, Mandich P, Bellone E. A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect. J Neurol Neurosurg Psychiatry. 2004;75:1495-8. [PMC free article: PMC1738732] [PubMed: 15377708]
• DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, Braastad CD, Bishop CM, Jaremko M, Wang Z, Liaquat K, Hoffman CA, York MD, Batish SD, Lupski JR, Higgins JJ. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014;2:522-9. [PMC free article: PMC4303222] [PubMed: 25614874]
• Echaniz-Laguna A, Degos B, Bonnet C, Latour P, Hamadouche T, Levy N, Leheup B. NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement. Neuromuscul Disord. 2007;17:163-8. [PubMed: 17142040]
• Echaniz-Laguna A, Ghezzi D, Chassagne M, Mayençon M, Padet S, Melchionda L, Rouvet I, Lannes B, Bozon D, Latour P, Zeviani M, Mousson de Camaret B. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease. Neurology. 2013;81:1523-30. [PMC free article: PMC3888171] [PubMed: 24027061]
• Ekins S, Litterman NK, Arnold RJ, Burgess RW, Freundlich JS, Gray SJ, Higgins JJ, Langley B, Willis DE, Notterpek L, Pleasure D, Sereda MW, Moore A. A brief review of recent Charcot-Marie-Tooth research and priorities. F1000Res. 2015;4:53. [PMC free article: PMC4392824] [PubMed: 25901280]
• Ferrarini M, Cavallaro T, Taioli F, Tiziani E, Chiaramonte G, Polo A, Boffi P, Bellone E, Plasmati R, Fabrizi GM. Ten additional pedigrees with Charcot-Marie-Tooth type 4C. J Peripher Nerv Syst. 2011;16:S37.
• Funalot B, Topilko P, Arroyo MA, Sefiani A, Hedley-Whyte ET, Yoldi ME, Richard L, Touraille E, Laurichesse M, Khalifa E, Chauzeix J, Ouedraogo A, Cros D, Magdelaine C, Sturtz FG, Urtizberea JA, Charnay P, Bragado FG, Vallat JM. Homozygous deletion of an EGR2 enhancer in congenital amyelinating neuropathy. Ann Neurol. 2012;71:719-23. [PubMed: 22522483]
• Gabreëls-Festen A, van Beersum S, Eshuis L, LeGuern E, Gabreëls F, van Engelen B, Mariman E. Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie- Tooth disease) with a gene locus on chromosome 5q23-q33. J Neurol Neurosurg Psychiatry. 1999;66:569-74. [PMC free article: PMC1736348] [PubMed: 10209165]
• Gabrikova D, Mistrik M, Bernasovska J, Bozikova A, Behulova R, Tothova I, Macekova S. Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia. J Appl Genet. 2013;54:455-60. [PubMed: 23996628]
• Gillespie CS, Sherman DL, Fleetwood-Walker SM, Cottrell DF, Tait S, Garry EM, Wallace VC, Ure J, Griffiths IR, Smith A, Brophy PJ. Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron. 2000;26:523-31. [PubMed: 10839370]
• Gonzaga-Jauregui C, Lotze T, Jamal L, Penney S, Campbell IM, Pehlivan D, Hunter JV, Woodbury SL, Raymond G, Adesina AM, Jhangiani SN, Reid JG, Muzny DM, Boerwinkle E, Lupski JR, Gibbs RA, Wiszniewski W. Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. JAMA Neurol. 2013;70:1491-8. [PMC free article: PMC4039291] [PubMed: 24126608]
• Guergueltcheva V, Tournev I, Bojinova V, Hantke J, Litvinenko I, Ishpekova B, Shmarov A, Petrova J, Jordanova A, Kalaydjieva L. Early clinical and electrophysiologic features of the two most common autosomal recessive forms of Charcot-Marie-Tooth disease in the Roma (Gypsies). J Child Neurol. 2006;21:20-5. [PubMed: 16551448]
• Guilbot A, Williams A, Ravise N, Verny C, Brice A, Sherman DL, Brophy PJ, LeGuern E, Delague V, Bareil C, Megarbane A, Claustres M. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum Mol Genet. 2001;10:415-21. [PubMed: 11157804]
• 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]
• Hahn AF, Parkes AW, Bolton CF, Stewart SA. Neuromyotonia in hereditary motor neuropathy. J Neurol Neurosurg Psychiatry. 1991;54:230-5. [PMC free article: PMC1014391] [PubMed: 1851512]
• Hantke J, Chandler D, King R, Wanders RJ, Angelicheva D, Tournev I, McNamara E, Kwa M, Guergueltcheva V, Kaneva R, Baas F, Kalaydjieva L. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR). Eur J Hum Genet. 2009;17:1606-14. [PMC free article: PMC2987011] [PubMed: 19536174]
• Hirano R, Takashima H, Umehara F, Arimura H, Michizono K, Okamoto Y, Nakagawa M, Boerkoel CF, Lupski JR, Osame M, Arimura K. SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology. 2004;63:577-80. [PubMed: 15304601]
• Higuchi Y, Hashiguchi A, Yuan J, Yoshimura A, Mitsui J, Ishiura H, Tanaka M, Ishihara S, Tanabe H, Nozuma S, Okamoto Y, Matsuura E, Ohkubo R, Inamizu S, Shiraishi W, Yamasaki R, Ohyagi Y, Kira JI, Oya Y, Yabe H, Nishikawa N, Tobisawa S, Matsuda N, Masuda M, Kugimoto C, Fukushima K, Yano S, Yoshimura J, Doi K, Nakagawa M, Morishita S, Tsuji S, Takashima H. Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. Ann Neurol. 2016 Mar 17; [PMC free article: PMC5069600] [PubMed: 26991897]
• Houlden H. Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin. Brain. 2001;124:907-15. [PubMed: 11335693]
• Houlden H, Hammans S, Katifi H, Reilly MM. A novel Frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H. Neurology. 2009a;72:617-20. [PMC free article: PMC2677538] [PubMed: 19221294]
• Houlden H, Laura M, Ginsberg L, Jungbluth H, Robb SA, Blake J, Robinson S, King RH, Reilly MM. The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy. Neuromuscul Disord. 2009b;19:264-9. [PubMed: 19272779]
• Howard HC, Mount DB, Rochefort D, Byun N, Dupre N, Lu J, Fan X, Song L, Riviere JB, Prevost C, Horst J, Simonati A, Lemcke B, Welch R, England R, Zhan FQ, Mercado A, Siesser WB, George AL Jr, McDonald MP, Bouchard JP, Mathieu J, Delpire E, Rouleau GA. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002;32:384-92. [PubMed: 12368912]
• Kabzińska D, Drac H, Sherman DL, Kostera-Pruszczyk A, Brophy PJ, Kochanski A, Hausmanowa-Petrusewicz I. Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene. Neurology. 2006a;66:745-7. [PubMed: 16534116]
• Kabzińska D, Kochański A, Drac H, Rowińska-Marcińska K, Ryniewicz B, Pedrola L, Palau F, Hausmanowa-Petrusewicz I. A novel Met116Thr mutation in the GDAP1 gene in a Polish family with the axonal recessive Charcot-Marie-Tooth type 4 disease. J Neurol Sci. 2006b;241:7-11. [PubMed: 16343542]
• Kabzińska D, Kochański A, Drac H, Ryniewicz B, Rowińska-Marcińska K, Hausmanowa-Petrusewicz I. Autosomal recessive axonal form of Charcot-Marie-Tooth Disease caused by compound heterozygous 3'-splice site and Ser130Cys mutation in the GDAP1 gene. Neuropediatrics. 2005;36:206-9. [PubMed: 15944907]
• Kabzińska D, Kotruchow K, Cegielska J, Hausmanowa-Petrusewicz I, Kochański A. A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation. Acta Biochim Pol. 2014;61:739-44. [PubMed: 25337607]
• Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet. 2000;67:47-58. [PMC free article: PMC1287101] [PubMed: 10831399]
• Kalaydjieva L, Nikolova A, Turnev I, Petrova J, Hristova A, Ishpekova B, Petkova I, Shmarov A, Stancheva S, Middleton L, Merlini L, Trogu A, Muddle JR, King RH, Thomas PK. Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings. Brain. 1998;121:399-408. [PubMed: 9549516]
• Kijima K, Numakura C, Shirahata E, Sawaishi Y, Shimohata M, Igarashi S, Tanaka T, Hayasaka K. Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease. J Hum Genet. 2004;49:376-9. [PubMed: 15197604]
• Kiwaki T, Umehara F, Takashima H, Nakagawa M, Kamimura K, Kashio N, Sakamoto Y, Unoki K, Nobuhara Y, Michizono K, Watanabe O, Arimura H, Osame M. Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma. Neurology. 2000;55:392-7. [PubMed: 10932274]
• Leal A, Morera B, Del Valle G, Heuss D, Kayser C, Berghoff M, Villegas R, Hernandez E, Mendez M, Hennies HC, Neundorfer B, Barrantes R, Reis A, Rautenstrauss B. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3. Am J Hum Genet. 2001;68:269-74. [PMC free article: PMC1234926] [PubMed: 11112660]
• Lenk GM, Ferguson CJ, Chow CY, Jin N, Jones JM, Grant AE, Zolov SN, Winters JJ, Giger RJ, Dowling JJ, Weisman LS, Meisler MH. Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS Genet. 2011;7:e1002104. [PMC free article: PMC3107197] [PubMed: 21655088]
• Li X, Hu Z, Liu L, Xie Y, Zhan Y, Zi X, Wang J, Wu L, Xia K, Tang B, Zhang R. A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy. Neurology. 2015;84:2430-7. [PubMed: 26078401]
• Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, Bainbridge M, Dinh H, Jing C, Wheeler DA, McGuire AL, Zhang F, Stankiewicz P, Halperin JJ, Yang C, Gehman C, Guo D, Irikat RK, Tom W, Fantin NJ, Muzny DM, Gibbs RA. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010;362:1181-91. [PMC free article: PMC4036802] [PubMed: 20220177]
• Manganelli F, Tozza S, Pisciotta C, Bellone E, Iodice R, Nolano M, Geroldi A, Capponi S, Mandich P, Santoro L. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population. J Peripher Nerv Syst. 2014;19:292-8. [PubMed: 25429913]
• Marchesi C, Milani M, Morbin M, Cesani M, Lauria G, Scaioli V, Piccolo G, Fabrizi GM, Cavallaro T, Taroni F, Pareyson D. Four novel cases of periaxin-related neuropathy and review of the literature. Neurology. 2010;75:1830-8. [PubMed: 21079185]
• Mathis S, Magy L, Vallat JM. Therapeutic options in Charcot-Marie-Tooth diseases. Expert Rev Neurother. 2015;15:355-66. [PubMed: 25703094]
• Menezes MP, Waddell L, Lenk GM, Kaur S, MacArthur DG, Meisler MH, Clarke NF. Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease. Neuromuscul Disord. 2014;24:666-70. [PMC free article: PMC4096049] [PubMed: 24878229]
• Moroni I, Morbin M, Milani M, Ciano C, Bugiani M, Pagliano E, Cavallaro T, Pareyson D, Taroni F. Novel mutations in the GDAP1 gene in patients affected with early-onset axonal Charcot-Marie-Tooth type 4A. Neuromuscul Disord. 2009;19:476-80. [PubMed: 19500985]
• Moroni I, Milani M, Ardissone A, Gandioli C, Uziel G, Taroni F, Pareyson D. Clinical and genetic study in early-onset axonal charcot-marie-tooth disease. J Peripher Nerv Syst. 2012;17:S37.
• Murphy SM, Laura M, Fawcett K, Pandraud A, Liu YT, Davidson GL, Rossor AM, Polke JM, Castleman V, Manji H, Lunn MP, Bull K, Ramdharry G, Davis M, Blake JC, Houlden H, Reilly MM. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry. 2012;83:706-10. [PMC free article: PMC3736805] [PubMed: 22577229]
• Nakhro K, Park JM, Hong YB, Park JH, Nam SH, Yoon BR, Yoo JH, Koo H, Jung SC, Kim HL, Kim JY, Choi KG, Choi BO, Chung KW. SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology. 2013;81:165-73. [PubMed: 23749797]
• Nelis E, Erdem S, Tan E, Lofgren A, Ceuterick C, De Jonghe P, Van Broeckhoven C, Timmerman V, Topaloglu H. A novel homozygous missense mutation in the myotubularin-related protein 2 gene associated with recessive Charcot-Marie-Tooth disease with irregularly folded myelin sheaths. Neuromuscul Disord. 2002a;12:869-73. [PubMed: 12398840]
• Nelis E, Erdem S, Van Den Bergh PY, Belpaire-Dethiou MC, Ceuterick C, Van Gerwen V, Cuesta A, Pedrola L, Palau F, Gabreëls-Festen AA, Verellen C, Tan E, Demirci M, Van Broeckhoven C, De Jonghe P, Topaloglu H, Timmerman V. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology. 2002b;59:1865-72. [PubMed: 12499475]
• Nicholson G, Lenk GM, Reddel SW, Grant AE, Towne CF, Ferguson CJ, Simpson E, Scheuerle A, Yasick M, Hoffman S, Blouin R, Brandt C, Coppola G, Biesecker LG, Batish SD, Meisler MH. Distinctive genetic and clinical features of CMT4J: A severe neuropathy caused by mutations in the PI(3,5)P(2) phosphatase FIG4. Brain. 2011;134:1959-71. [PMC free article: PMC3122378] [PubMed: 21705420]
• Noack R, Frede S, Albrecht P, Henke N, Pfeiffer A, Knoll K, Dehmel T, Meyer Zu Hörste G, Stettner M, Kieseier BC, Summer H, Golz S, Kochanski A, Wiedau-Pazos M, Arnold S, Lewerenz J, Methner A. Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential. Hum Mol Genet. 2012;21:150-62. [PubMed: 21965300]
• Nouioua S, Hamadouche T, Funalot B, Bernard R, Bellatache N, Bouderba R, Grid D, Assami S, Benhassine T, Levy N, Vallat JM, Tazir M. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes. Neuromuscul Disord. 2011;21:543-50. [PubMed: 21741241]
• Numakura C, Lin C, Oka N, Akiguchi I, Hayasaka K. Hemizygous mutation of the peripheral myelin protein 22 gene associated with Charcot-Marie-Tooth disease type 1. Ann Neurol. 2000;47:101-3. [PubMed: 10632107]
• Okamoto Y, Goksungur MT, Pehlivan D, Beck CR, Gonzaga-Jauregui C, Muzny DM, Atik MM, Carvalho CM, Matur Z, Bayraktar S, Boone PM, Akyuz K, Gibbs RA, Battaloglu E, Parman Y, Lupski JR. Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D. Genet Med. 2014;16:386-94. [PMC free article: PMC4224029] [PubMed: 24136616]
• Otagiri T, Sugai K, Kijima K, Arai H, Sawaishi Y, Shimohata M, Hayasaka K. Periaxin mutation in Japanese patients with Charcot-Marie-Tooth disease. J Hum Genet. 2006;51:625-8. [PubMed: 16770524]
• Othmane KB, Johnson E, Menold M, Lennon-Graham F, Ben Hamida M, Hasegawa O, Rogala A, Ohnishi A, Pericak-Vance M, Hentati F, Vance JM. Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease with focally folded myelin on chromosome 11p15. Genomics. 1999;62:344-9. [PubMed: 10644431]
• Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8:654-67. [PubMed: 19539237]
• Parman Y, Battaloglu E, Baris I, Bilir B, Poyraz M, Bissar-Tadmouri N, Williams A, Ammar N, Nelis E, Timmerman V, De Jonghe P, Necefov A, Deymeer F, Serdaroglu P, Brophy PJ, Said G. Clinicopathological and genetic study of early-onset demyelinating neuropathy. Brain. 2004;127:2540-50. [PubMed: 15469949]
• Parman Y, Planté-Bordeneuve V, Guiochon-Mantel A, Eraksoy M, Said G. Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas disease. Ann Neurol. 1999;45:518-22. [PubMed: 10211478]
• Pedrola L, Espert A, Wu X, Claramunt R, Shy ME, Palau F. GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum Mol Genet. 2005;14:1087-94. [PubMed: 15772096]
• Pehlivan D, Coban Akdemir Z, Karaca E, Bayram Y, Jhangiani S, Yildiz EP, Muzny D, Uluc K, Gibbs RA. Baylor-Hopkins Center for Mendelian Genomics, Elcioglu N, Lupski JR, Harel T. Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis. Hum Genet. 2015;134:671-3. [PMC free article: PMC4426057] [PubMed: 25893792]
• Plante-Bordeneuve V, Said G. Dejerine-Sottas disease and hereditary demyelinating polyneuropathy of infancy. Muscle Nerve. 2002;26:608-21. [PubMed: 12402282]
• Quattrone A, Gambardella A, Bono F, Aguglia U, Bolino A, Bruni AC, Montesi MP, Oliveri RL, Sabatelli M, Tamburrini O, Valentino P, Van Broeckhoven C, Zappia M. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology. 1996;46:1318-24. [PubMed: 8628474]
• Rautenstrauss B, Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Ekici A, Pasutto F, Endele S, Saifi M, Lupski JR, Morera B, Del Valle G, Barrantes R, Huess D, Bergoff C, Bergoff M, Neudorfer B, Uhlmann T, Meisterernst M, Sereda MW, zu Horste GM, Nave K-A. Positional cloning of the CMT2B2 gene and its implications for CMT1A. J Peri Nerv Syst. 2005;10(S1):77.
• Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009;80:1304-14. [PubMed: 19917815]
• Ricard E, Mathis S, Magdelaine C, Delisle MB, Magy L, Funalot B, Vallat JM. CMT4D (NDRG1 mutation): genotype-phenotype correlations. J Peripher Nerv Syst. 2013;2013;18:261-5. [PubMed: 24028195]
• Robinson FL, Niesman IR, Beiswenger KK, Dixon JE. Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice. Proc Natl Acad Sci U S A. 2008;105:4916-21. [PMC free article: PMC2290800] [PubMed: 18349142]
• Rogers T, Chandler D, Angelicheva D, Thomas PK, Youl B, Tournev I, Gergelcheva V, Kalaydjieva L. A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23. Am J Hum Genet. 2000;67:664-71. [PMC free article: PMC1287526] [PubMed: 10915613]
• Rossor AM, Evans MR, Reilly MM. A practical approach to the genetic neuropathies. Pract Neurol. 2015;15:187-98. [PubMed: 25898997]
• Rudnik-Schöneborn S, Tölle D, Senderek J, Eggermann K, Elbracht M, Kornak U, von der Hagen M, Kirschner J, Leube B, Müller-Felber W, Schara U, von Au K, Wieczorek D, Bußmann C, Zerres K. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet. 2016;89:34-43. [PubMed: 25850958]
• Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies. J Investig Med. 2003;51:261-83. [PubMed: 14577517]
• Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. Charcot Marie Tooth (CMT) subtypes and genetic testing strategies. Ann Neurol. 2011;69:22-33. [PMC free article: PMC3058597] [PubMed: 21280073]
• Schabhüttl M, Wieland T, Senderek J, Baets J, Timmerman V, De Jonghe P, Reilly MM, Stieglbauer K, Laich E, Windhager R, Erwa W, Trajanoski S, Strom TM, Auer-Grumbach M. Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. J Neurol. 2014;261:970-82. [PubMed: 24627108]
• Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A, Zuchner S, De Jonghe P, Rudnik-Schöneborn S, Zerres K, Schroder JM. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain. 2003a;126:642-9. [PubMed: 12566285]
• Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, Timmerman V, Chrast R H G, Verheijen M, Lemke G, Battaloglu E, Parman Y, Erdem S, Tan E, Topaloglu H, Hahn A, Muller-Felber W, Rizzuto N, Fabrizi GM, Stuhrmann M, Rudnik-Schöneborn S, Zuchner S, Michael Schroder J, Buchheim E, Straub V, Klepper J, Huehne K, Rautenstrauss B, Buttner R, Nelis E, Zerres K. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet. 2003b;73:1106-19. [PMC free article: PMC1180490] [PubMed: 14574644]
• Senderek J, Bergmann C, Weber S, Ketelsen UP, Schorle H, Rudnik-Schoneborn S, Buttner R, Buchheim E, Zerres K. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet. 2003c;12:349-56. [PubMed: 12554688]
• Sevilla T, Cuesta A, Chumillas MJ, Mayordomo F, Pedrola L, Palau F, Vilchez JJ. Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene. Brain. 2003;126:2023-33. [PubMed: 12821518]
• Sevilla T, Jaijo T, Nauffal D, Collado D, Chumillas MJ, Vilchez JJ, Muelas N, Bataller L, Domenech R, Espinós C, Palau F. Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy. Brain. 2008;131:3051-61. [PubMed: 18812441]
• Sevilla T, Martínez-Rubio D, Márquez C, Paradas C, Colomer J, Jaijo T, Millán JM, Palau F, Espinós C. Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth. Clin Genet. 2013;83:565-70. [PubMed: 22978647]
• Stendel C, Roos A, Deconinck T, Pereira J, Castagner F, Niemann A, Kirschner J, Korinthenberg R, Ketelsen UP, Battaloglu E, Parman Y, Nicholson G, Ouvrier R, Seeger J, Jonghe PD, Weis J, Kruttgen A, Rudnik-Schöneborn S, Bergmann C, Suter U, Zerres K, Timmerman V, Relvas JB, Senderek J. Peripheral nerve demyelination caused by a mutant rho GTPase guanine nucleotide exchange factor, frabin/FGD4. Am J Hum Genet. 2007;81:158-64. [PMC free article: PMC1950925] [PubMed: 17564972]
• Stendel C, Roos A, Kleine H, Arnaud E, Ozçelik M, Sidiropoulos PN, Zenker J, Schüpfer F, Lehmann U, Sobota RM, Litchfield DW, Lüscher B, Chrast R, Suter U, Senderek J. SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling. Brain. 2010;133:2462-74. [PubMed: 20826437]
• Stojkovic T, Latour P, Viet G, de Seze J, Hurtevent JF, Vandenberghe A, Vermersch P. Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene. Neuromuscul Disord. 2004;14:261-4. [PubMed: 15019704]
• Szigeti K, Wiszniewski W, Saifi GM, Sherman DL, Sule N, Adesina AM, Mancias P, Papasozomenos SCh, Miller G, Keppen L, Daentl D, Brophy PJ, Lupski JR. Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations. Neurogenetics. 2007;8:257-62. [PubMed: 17717711]
• Takashima H, Boerkoel CF, De Jonghe P, Ceuterick C, Martin JJ, Voit T, Schroder JM, Williams A, Brophy PJ, Timmerman V, Lupski JR. Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann Neurol. 2002;51:709-15. [PubMed: 12112076]
• Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Am J Hum Genet. 2014;95:294-300. [PMC free article: PMC4157141] [PubMed: 25152455]
• Tazir M, Azzedine H, Assami S, Sindou P, Nouioua S, Zemmouri R, Hamadouche T, Chaouch M, Feingold J, Vallat JM, Leguern E, Grid D. Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain. 2004;127:154-63. [PubMed: 14607793]
• Thomas PK, Kalaydjieva L, Youl B, Rogers A, Angelicheva D, King RH, Guergueltcheva V, Colomer J, Lupu C, Corches A, Popa G, Merlini L, Shmarov A, Muddle JR, Nourallah M, Tournev I. Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies. Ann Neurol. 2001;50:452-7. [PubMed: 11601496]
• Tokunaga S, Hashiguchi A, Yoshimura A, Maeda K, Suzuki T, Haruki H, Nakamura T, Okamoto Y, Takashima H. Late-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation. Neurogenetics. 2012;13:359-65. [PubMed: 22847150]
• Vaccari I, Dina G, Tronchère H, Kaufman E, Chicanne G, Cerri F, Wrabetz L, Payrastre B, Quattrini A, Weisman LS, Meisler MH, Bolino A. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet. 2011;7:e1002319. [PMC free article: PMC3197679] [PubMed: 22028665]
• Verny C, Ravise N, Leutenegger AL, Pouplard F, Dubourg O, Tardieu S, Dubas F, Brice A, Genin E, LeGuern E. Coincidence of two genetic forms of Charcot-Marie-Tooth disease in a single family. Neurology. 2004;63:1527-9. [PubMed: 15505184]
• Ward CM, Dolan LA, Bennett DL, Morcuende JA, Cooper RR. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease. J Bone Joint Surg Am. 2008;90:2631-42. [PMC free article: PMC2663331] [PubMed: 19047708]
• Warner LE, Svaren J, Milbrandt J, Lupski JR. Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. Hum Mol Genet. 1999;8:1245-51. [PubMed: 10369870]
• Winters J, Lenk G, Giger-Mateeva V, Shrager P, Meisler M, Giger R. Oligodendrocyte maturation and proper CNS myelination require the lipid phosphatase Fig4. Glia. 2011;59:S65.
• Ylikallio E, Pöyhönen R, Zimoń M, De Vriendt E, Hilander T, Paetau A, Jordanova A, Lönnqvist T, Tyynismaa H. Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy. Hum Mol Genet. 2013;22:2975-83. [PubMed: 23562820]
• Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain. 2008;131:1990-2001. [PMC free article: PMC2724900] [PubMed: 18556664]
• Zimoń M, Baets J, Almeida-Souza L, De Vriendt E, Nikodinovic J, Parman Y, Battalo Gcaron Lu E, Matur Z, Guergueltcheva V, Tournev I, Auer-Grumbach M, De Rijk P, Petersen BS, Müller T, Fransen E, Van Damme P, Löscher WN, Barišić N, Mitrovic Z, Previtali SC, Topalo Gcaron Lu H, Bernert G, Beleza-Meireles A, Todorovic S, Savic-Pavicevic D, Ishpekova B, Lechner S, Peeters K, Ooms T, Hahn AF, Züchner S, Timmerman V, Van Dijck P, Rasic VM, Janecke AR, De Jonghe P, Jordanova A. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012;44:1080-3. [PubMed: 22961002]
• Zimoń M, Baets J, Fabrizi GM, Jaakkola E, Kabzińska D, Pilch J, Schindler AB, Cornblath DR, Fischbeck KH, Auer-Grumbach M, Guelly C, Huber N, De Vriendt E, Timmerman V, Suter U, Hausmanowa-Petrusewicz I, Niemann A, Kochański A, De Jonghe P, Jordanova A. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology. 2011;77:540-8. [PMC free article: PMC3272385] [PubMed: 21753178]

建议阅读Suggested Reading

• Bernard R, De Sandre-Giovannoli A, Delague V, Levy N. Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies. Neuromolecular Med. 2006;8:87-106. [PubMed: 16775369]
• Vallat JM, Tazir M, Magdelaine C, Sturtz F, Grid D. Autosomal-recessive Charcot-Marie-Tooth diseases. J Neuropathol Exp Neurol. 2005;64:363-70. [PubMed: 15892292]

修订历史Revision History

• 14 April 2016 (tb) Revision: MME and related reference added
• 20 August 2015 (me) Comprehensive update posted live
• 17 April 2014 (tb) Revision: edits to TRIM2
• 20 February 2014 (tb) Revision: Ylikallio et al 2013 reference added describing one person with an unclassified recessive neuropathy
• 26 September 2013 (tb) Revision: to Differential Diagnosis -- information on SURF1 deficiency [Echaniz-Laguna et al 2103]
• 8 August 2013 (tb) Revision: addition of add FIG4deletion/duplication analysis and CMT4B3 (SBF1)
• 11 October 2012 (tb) Revision: hereditary neuropathy with neuromyotonia (caused by mutations in HINT1) included as a type of CMT4
• 13 September 2012 (me) Comprehensive update posted live
• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 22 April 2010 (me) Comprehensive update posted live
• 30 April 2009 (cd) Revision: 序列分析 available clinically for CMT4H
• 12 June 2008 (cd) Revision: 序列分析 of entire NDRG1编码区 available clinically
• 6 September 2007 (me) Comprehensive update posted to live Web site
• 15 April 2005 (me) Comprehensive update posted to live Web site
• 19 December 2003 (tb) Author revisions
• 24 October 2003 (cd,tb) Revision: change in test availability
• 21 August 2003 (cd,tb) Revision: change in 基因 name
• 29 May 2003 (tb) Author revisions
• 4 April 2003 (me) Comprehensive update posted to live Web site
• 8 November 2001 (tb) Author revisions
• 27 June 2001 (tb) Author revisions
• 22 June 2001 (tb) Author revisions
• 11 April 2001 (tb) Author revisions
• 25 September 2000 (tb) Author revisions
• 25 August 2000 (me) Comprehensive update posted to live Web site
• 15 June 2000 (tb) Author revisions
• 15 May 2000 (tb) Author revisions
• 14 January 2000 (tb) Author revisions
• 24 September 1999 (tb) Author revisions
• 31 August 1999 (tb) Author revisions
• 18 June 1999 (tb) Author revisions
• 8 April 1999 (tb) Author revisions
• 24 September 1998 (tb) Review posted to live Web site
• April 1996 (tb) Original submission