Hereditary neuropathies may account for as many as 50% of previously undiagnosed peripheral neuropathies referred to large neuromuscular centers. Charcot–Marie–Tooth (CMT) disease is the most common type of hereditary neuropathy, but, rather than one disease, CMT is a syndrome of several genetically distinct disorders (Table 11-1). In this chapter, we discuss CMT and related neuropathies. In the subsequent chapters, we will review other less common hereditary neuropathies (Chapters 12, 16, and 30).
|CMT1A||AD||17p11.2||PMP22 (usually duplication of gene)|
|CMT1E (with deafness)||AD||17p11.2||Point mutations in PMP22|
|CMT2A2 (allelic to HMSN VI with optic atrophy)||AD||1p36.2||MFN2|
|CMT2B1 (allelic to LGMD1B)||AR||1q21.2||LMNA|
|CMT2C (with vocal cord and diaphragm paralysis)||AD||12q23–24||TRPV4|
|CMT2D (allelic to distal SMA5)||AD||7p14||GARS|
|CMT2E (allelic to CMT1F)||AD||8p21||NEFL|
|CMT2H (allelic to CMT2K and CMT4A)||AD||8q21.3||GDAP1|
|CMT2I and 2J (allelic to CMT1B)||AD||1q22||MPZ|
|CMT2K (allelic to CMT2H and CMT4A)||AD/AR||8q13–q21||GDAP1|
|CMT2L (allelic to distal hereditary motor neuropathy type 2)||AD||12q24||HSPB8|
|CMT3 (Dejerine–Sottas disease, congenital hypomyelinating neuropathy)||AD||17p11.2||PMP22|
|CMT4A (allelic to CMT2H and 2K)||AR||8q13–21.1||GDAP1|
|CMT4E (congenital hypomyelinating neuropathy)||AR||Probably includes PMP22, MPZ, and ERG2|
|CMT4G (CMT-Russe type)||AR||10q23.2||HK1|
|Other hereditary neuropathies|
The various subtypes of CMT are classified according to the nerve conduction velocities (NCVs), presumed pathology (e.g., demyelinating or axonal), mode of inheritance (autosomal-dominant, autosomal recessive, or X-linked), age of onset (e.g., infancy or childhood/adulthood), and the specific mutated gene (Table 11-1).1–8 Updated information including recent mutations causing CMT can be found on the Internet: www.molgen.ua.ac.be/CMTMutations/DataSource/MutByGene.cfm. Type 1 CMT or CMT1 refers to inherited demyelinating motor and sensory neuropathies, whereas the axonal motor and sensory neuropathies are classified as CMT2. Both CMT1 and CMT2 usually begin in childhood or early adult life; however, onset later in life can occur, particularly in CMT2. CMT1 is associated with autosomal-dominant or X-linked inheritance, while CMT2 can be autosomal-dominant, autosomal-recessive, or X-linked. Most patients with different subtypes of CMT1 looked phenotypically indistinguishable from each other and subtypes of CMT2 and X-linked CMT. Some authorities advocate for classifying as CMT1 (dominant, recessive, or X-linked) and CMT2 (dominant, recessive, or X-linked) along with dominant-intermediate and recessive intermediate subtypes. However, reports of CMT3 and CMT4 remain in the literature so we will still discuss these. CMT3 is an autosomal-dominant neuropathy that appears in infancy and is associated with severe demyelination or hypomyelination. CMT4 is an autosomal-recessive motor and sensory neuropathy that typically begins in childhood or early adult life. Unfortunately, classification of these neuropathies is not straightforward. Mutations of the same gene can lead to neuropathies associated with nerve conduction studies (NCS) and histopathology that may reflect either a primary demyelinating or an axonal process, an autosomal-dominant or recessive inheritance, and a clinical phenotype with overlap between CMT and hereditary sensory and autonomic neuropathy (HSAN), hereditary motor neuropathy (distal spinal muscular atrophy), and hereditary spastic paraplegia (HSP) (Fig. 11-1). The causal mutated genes have many different functions (Table 11-2,Fig. 11-2). There are no specific medical therapies for any of the CMTs, but physical and occupational therapy can be beneficial as can bracing (e.g., ankle–foot orthotics for foot drop) and other orthotic devices.
|Myelin structure and function (PMP22, MPZ, CX32, PRX, MMTR2, MMTR13/SBF2, IFN2)|
|Axonal structure (NGF, NEFL, FGD4)|
|Axonal transport (DYM2, DYNC1 H, NFL, RAB7, WNK1, KIF1B, NDRG1, SH3TC2)|
|Golgi body formation (FAM134B)|
|Endoplasmic reticulum formation (ATL1, ALT2, ATL3)|
|Sphingolipid metabolism (SPTLC1, SPTLC2)|
|Nuclear structure (LMNA)|
|DNA transcription (ERG2, LITAF, MED25)|
|RNA translation (GARS, YARS, AARS, BCL2)|
|DNA methylation (DNMT1)|
|Protein degradation chaperones and stress regulation (LITAF, BAG3, HSPB1, HSP27, HSJ1)|
|Mitochondrial DNA maintenance (see Chapter 30)|
|Mitochondrial fission or fusion (MFN2, GDAP1)|
|Ion channels (TRPV4, SCN9A, SCN10A, SCN11A, HINT1)|
The overlap of CMT, HSAN, dHMN, HSP, episodic pain syndrome, and related disorders. Diseases: CMT, Charcot–Marie–Tooth disease (CMT1, demyelinating, autosomal dominant; CMT2, axonal, autosomal dominant or recessive; CMT4, demyelinating, autosomal recessive; CMTX, X-linked; I-CMT, intermediate CMT); dHMN, distal hereditary motor neuropathies; HSN, hereditary sensory neuropathies; HSP, hereditary spastic paraplegia. Genes: AARS, alanyl-trRNA synthetase; ATL, atlastin; BSCL2, Berardinelli–Seip congenital lipodystrophy type 2; DNM2, dynamin 2; DNMT1, DNA methyltransferase 1; DYNCH1H1, cytoplasmic dynein 1 heavy chain 1; DYS, dystonin; EGR2, early-growth response 2; FAM134B, family with sequence similarity 134, member B; GARS, glycyl-tRNA synthetase; GDAP1, ganglioside-induced differentiation-associated protein 1; GJB1, gap junction B1/connexin-32; HSJ1 (or DNAJB2), heat-shock protein J1 (or DNAJ Hsp40); HSPB1 (or HSP27), heat-shock 27-kDa protein 1; HSPB8 (or HSP22), heat-shock 22-kDa protein 8; HK6, hexokinase 6; HINT1, histidine triad nucleotide binding protein 1; IFN2, inverted formin 2; LITAF, lipopolysaccharide-induced tumor necrosis factor-alpha factor; LMNA, lamin A/C nuclear envelope protein; LSRAM1, leucine-rich repeat and sterile alpha motif containing 1; MED25, mediator complex subunit; MFN2, mitofusin 2; MTMR2, myotubularin-related protein 2; SBF2, SET-binding factor 2; SH3TC2, SH3 domain and tetratricopeptide repeat domain 2; NDRG1, N-myc downstream-regulated gene 1; NEFL, neurofilament light chain; NGF, nerve growth factor; MPZ, myelin protein zero; PLEKHG5, pleckstrin homology domain-containing protein; PMP22, peripheral myelin protein 22; PDK3, pyruvate dehydrogenase kinase isoenzyme 3; PRSP1, phosphoribosyl pyrophosphate synthetase 1; PRX, periaxin; RAB7, small GTPase late endosomal protein RAB7; SPTLC1, serine palmitoyltransferase long chain base 1; TRPA1, transient receptor potential A 1; TRPV4, transient receptor potential cation channel subfamily V, member 4; YARS, tyrosyl-tRNA synthetase; WNK1, protein kinase, lysine-deficient 1.
CMT TYPE 1 (CMT1)
CMT1 is the most common form of hereditary neuropathy, with the ratio of CMT1:CMT2 being approximately 2:1. Individuals with CMT1 usually present in the first to third decades with distal leg weakness, although patients may remain asymptomatic even late in life. There is an early predilection for the anterior compartment (peroneal muscle group), resulting in progressive foot drop. This leads to poor clearance of the toes when walking particularly on uneven surfaces. People with CMT1 often present with frequent tripping, falling, and recurrent ankle sprains. Affected individuals generally do not complain numbness or tingling, which can be helpful in distinguishing CMT from acquired forms of neuropathy.
Although people with CMT1 usually do not complain of sensory loss, reduced sensation to all modalities is apparent on examination. Muscle stretch reflexes are unobtainable or reduced throughout. There is often atrophy of the muscles below the knee (particularly the anterior compartment), leading to the appearance of the so-called inverted champagne bottle legs. However, rare individuals have asymmetric pseudohypertrophy of the calves.9 Most will have pes cavus, equinovarus, or hammertoe deformities (Fig. 11-3), which lead to aching in the feet. Rather than having a heel strike while ambulating, affected people land flat-footed or on their toes and thus use a steppage gait to help prevent tripping. Approximately two-thirds of individuals with CMT1 also have distal weakness and atrophy of the arms. Claw–hand deformities of the hands may develop in the most severely affected. Mild-to-moderate proximal weakness can develop over time as well, which can lead to diagnostic confusion with chronic inflammatory demyelinating polyneuropathy (CIDP). In addition, some individuals manifest with phrenic nerve involvement leading to respiratory weakness.10 Rarely, patients with hypertrophy of nerve roots can be severe enough such that it leads to compression of the spinal cord or cauda equina (see Fig. 24-14 in Chapter 24). Hypertrophy of the nerves, especially posterior to the ear and arm regions, may be visualized and palpated. Approximately one-third of patients with CMT1 have an essential tremor (Roussy–Levy syndrome). Some individuals who are affected also develop deafness or Adie’s pupils. Further, one subtype, CMT1G, is associated with focal segmental glomerulosclerosis. It is important to examine family members of patients with possible CMT. Although there may be no family history of CMT, careful examination of the family may demonstrate other members with features of the neuropathy. This can be important in clarifying a diagnosis and in providing genetic counseling.
Cerebrospinal fluid (CSF) protein levels may be elevated. Besides genetic testing, NCS are the most important laboratory tests in the evaluation of people suspected of having CMT. The NCS are invaluable in determining if patients have a demyelinating or axonal neuropathy and, if demyelinating, if it is uniform or multifocal, which is useful in distinguishing CMT from CIDP.2,11,13 Uniform slowing of NCVs is suggestive of a hereditary demyelinating neuropathy, while multifocal slowing is more typical of CIDP. At birth and in infancy, NCVs may be normal or only minimally slowed in children with CMT1. However, the NCVs rapidly decline, and, by 3–5 years of age, the nadir in NCV slowing is achieved and remains stable throughout the rest of the person’s life. However, the compound muscle action potential (CMAP) amplitudes continue to diminish over time, reflecting ongoing loss of axons. Distal motor latencies at birth are commonly borderline abnormal. These latencies continue to increase until approximately the age of 10 years, at which time there is little further prolongation of the distal latencies. A detailed discussion of specific nerve conduction abnormalities in CMT1 follows.
Motor NCVs by definition are slowed to less than 38 m/s in the upper extremities, but in most cases the NCVs are in the 20–25 m/s range.2,7,11–13 Patients with point mutations in peripheral myelin protein 22 (PMP22) and myelin protein zero (MPZ) genes can have even slower conduction velocities (CVs) approaching that seen in CMT3 (10 m/s or less).14,15 As will be discussed in the subsequent section, some people with MPZ mutations have only slightly slow or normal NCVs and thus by NCV criteria can be classified as having CMT2.12,16 Demyelination is generally uniform; therefore, patients with CMT1 do not usually demonstrate conduction block or temporal dispersion on NCS.13,17 However, there are well-documented cases of genetically proven CMT1A with nonuniform slowing and CVs over 42 m/s and thus might mimic an acquired neuropathy.9 Temporal dispersion of nerve conduction and irregularity of conduction slowing have been reported in CMT1C.18 In addition, mutations in MPZ, ERG2, GJB1, FIG4, SH3TC2 also cause hereditary neuropathies with acquired demyelinating features.
Distal motor latencies are usually markedly prolonged. The CMAPs may be absent when recordings are attempted from severely atrophic muscles. It is useful in people with wasted foot intrinsics to perform motor NCS in the lower limb by recording from the tibialis anterior muscle. F-waves are usually absent but, when obtainable, the latencies are extremely prolonged.
There is no correlation between the NCVs and the clinical severity of the neuropathy.19 The NCVs are quite slow in childhood, even when there are minimal clinical deficits. Further, asymptomatic adults can have prolonged distal motor latencies and slow NCV. It is apparent that weakness and loss of function are more related to the degree of axon loss, rather than the extent of demyelination and slowing of nerve conduction.
Motor nerve unit estimates can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude in view of reinnervation which to a certain extent may camouflage the extent of axon loss.20
Somatosensory evoked potentials have demonstrated slowing of central conduction in CMT1. Visual-evoked potentials also reveal similar slowing in the optic pathways.
Electromyography (EMG) reveals positive sharp waves and fibrillation potentials along with reduced recruitment of long-duration, high-amplitude, and polyphasic motor unit action potentials (MUAPs) in the distal legs and lesser in the arms.24 Evidence of active denervation and reinnervation may also be found in some of the proximal muscles.
We do not perform nerve biopsies on people suspected of having CMT1, as the diagnosis can usually be made by less invasive testing (e.g., NCS and genetic studies). Nevertheless, nerve biopsies, when done are strikingly abnormal.7,12,25,26 The enlarged gross appearance of the peripheral nerves led to the early designation of CMT1 as a hypertrophic neuropathy. Light microscopy reveals reduction of myelinated nerve fibers with a predilection for the loss of the large-diameter fibers.24,25 The diameters of the axons are also decreased; on the whole there is an increase in the density of neurofilaments within these atrophic axons. Early in life, the peripheral nerves may appear normally myelinated, but over time axons become thinly myelinated. Recurrent demyelination and remyelination lead to reduced internodal length, while Schwann cell proliferation results in the formation of the so-called onion bulbs (Fig. 11-4). In patients with CMT1B, occasionally biopsies reveal tomacula, uncompacted myelin, and focally folded or widened myelin sheaths (Fig. 11-5).4,14,27 Demyelination, neuronal loss, and axonal atrophy are slightly more prominent distally. Autopsy studies demonstrate the loss of myelinated fibers in the posterior columns in the spinal cord.
CMT1. Nerve biopsy demonstrates a reduction of myelinated nerve fibers, thinly myelinated fibers, and onion-bulb formations (A, semithin section). Electron microscopy reveals proliferation of Schwann cell processes surrounding demyelinated fiber forming a so-called onion bulb (B). (Reproduced with permission from neuropathology-web.org/.)
CMT1B. Semithin section reveals rarefaction of myelinated fibers, foldings of myelin, and onion-bulb proliferations of Schwann cells (A). Note the alternate disposition of normal (stars) and uncompacted myelin lamellae (lines), Scale bar = 0.2 μm (B). (Reproduced with permission from Vallat JM, Magy L, Lagrange E, et al. Diagnostic value of ultrastructural nerve examination in Charcot–Marie–Tooth disease: Two CMT1B cases with pseudo-recessive inheritance, Acta Neuropathol. 2007;113(4):443–449.)
CMT1 is a genetically heterogeneous disorder (Tables 11-1 and 11-2 and Figs. 11-1 and 11-2).1–8 In addition, there is phenotypic heterogeneity associated with mutations in specific genes. CMT1A (PMP22 duplication) is by far the most common form of CMT1, representing 70% of cases, while 20% have CMT1B, and 10% have one of the other subtypes.
Approximately 85% of people with CMT1A have a 1.5-megabase (MB) duplication within chromosome 17p11.2–12 where the PMP22 gene lies.28,29 Thus, these individuals carry three copies of the PMP22 rather than two. In contrast, inheritance of the chromosome with the deleted segment results in affected individuals having only one copy of the PMP22 gene and leads to hereditary neuropathy with liability to pressure palsies (HNPP). Although these disorders are inherited in an autosomal-dominant fashion, de novo mutations do occur. Most de novo duplications are paternally inherited and are believed to arise due to unequal crossover during meiosis. De novo mutations of maternal origin are probably caused by intrachromosomal rearrangement.30 In keeping with this abnormal dosage effect of PMP22, people affected with trisomy 17p (thus, containing three copies of the PMP22) also have a demyelinating sensorimotor polyneuropathy.31
Some individuals with CMT1A have point mutations in PMP22.32 These individuals can more closely resemble Dejerine–Sottas (CMT3) phenotypically, in which they are more severely affected at an earlier age, demonstrate slower NCVs (<10 m/s), and have more prominent histopathology than those with the classic duplication.15 Other individuals present with a milder phenotype with pressure-induced palsies (e.g., HNPP as discussed in a subsequent section).
The pathogenic basis for CMT1A is likely due to a toxic gain of function of the PMP22 protein. This protein accounts for 2–5% of myelin protein and is expressed in compact portions of the peripheral myelin sheath. An increased expression of PMP22 mRNA and the protein itself in the myelin sheaths has been demonstrated on nerve biopsies in CMT1A; however, late in the course PMP22 expression actually decreases.33–36 The exact function of PMP22 in the peripheral nerves is not known, but it may be important in maintaining the structural integrity of myelin, acting as an adhesion molecule, or regulating the cell cycle. Regeneration-associated remyelination is delayed in nerve xenografts implanted from individuals with CMT1A into mice.37 Further, PMP22 must also be essential for maintaining the integrity of the axon itself, as there is evidence of axonal atrophy on nerve biopsies in people with CMT1A.
Approximately 20% of people with CMT1 have CMT1B, which is caused by mutations in the MPZ gene located on chromosome 1q22–23 that encodes for myelin protein zero.38–40 CMT1B is for the most part clinically, electrophysiologically, and histologically indistinguishable from CMT1A. However, patients with MPZ mutations are more likely to have more “axonal” physiology on NCS than those patients with PMP22 mutations. Also, CMT associated with Adies’ pupils is more common in patients with MPZ mutations. MPZ is an integral myelin protein and accounts for more than half of the myelin protein in peripheral nerves. It is a member of the immunoglobulin superfamily and consists of an extracellular immunoglobulin-like domain, a transmembrane domain, and a cytoplasmic domain.1 MPZ localizes to the tight compact regions of myelin, where it may play a role in maintaining tight compaction by forming links between adjacent myelin layers. Nerve biopsies in people with CMT1B reveal abnormalities similar to that noted in CMT1A. However, occasionally tomaculae and uncompacted myelin are apparent, which are not typically seen on nerve biopsy in CMT1A.4,14,41 Immunohistochemistry and ultrastructural studies on nerve biopsy specimens may demonstrate decreased expression of MPZ protein.42 Some mutations in the MPZ gene have been associated with a severe demyelinating CMT3 phenotype, while others are associated with NCS suggestive of an axonopathy or CMT2. The specific location of the mutations in the MPZ gene and how these affect the function of the myelin protein probably account for the phenotypic heterogeneity.
This rare neuropathy is caused by mutations in the LITAF gene (lipopolysaccharide-induced tumor necrosis factor-alpha factor) located on chromosome 16p13.1–p12.3.18,43,44 In a large study of 968 unrelated cases of CMT1, the percentage of patients with LITAF mutations was only 0.6%.44LITAF, also known as SIMPLE (small integral membrane protein of the lysosome/late endosome), encodes a protein that is expressed on Schwann cells and may play a role in protein degradation pathways.45
Mutations in the early growth response 2 (ERG2) gene on chromosome 10q21.1–q22.1 are responsible for CMT1D.46 ERG2 is believed to be a transcription factor that binds DNA through three zinc finger domains and likely has an important action in regulating myelin genes in Schwann cells. CMT1D accounts for <1% of molecular-defined cases of CMT1.
This refers to kinships with CMT1 associated with deafness. It has been demonstrated to be allelic to CMT1A and caused by point mutations in PMP22.5
CMT1F is caused by mutations in the neurofilament light chain (NEFL or NFL) gene located on chromosome 8p13–21.47,48 It is usually associated with low-amplitude CMAPs and normal or only slightly slow NCVs and thus is often categorized as an axonal form of CMT (CMT2E). However, some cases have been reported with motor NCVs in the mid-twenties and thus have been classified as a CMT1F.
CMT1G is associated with focal segmental glomerulosclerosis (FSGS) and is caused by mutations in the gene that codes for inverted formin 2 (INF2).49,50 Mutations in this gene are also a major cause of isolated FSGS. Approximately one-third of patients have sensorineural hearing loss as well. Some affected individuals have intellectual disabilities and abnormalities in the white matter and ventricular dilatation on brain MRI. Formin 2 interacts with Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) and is felt to be important in the essential steps of myelination and myelin maintenance.
HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES
Because HNPP is associated with mutations affecting PMP22 and less commonly MPZ, we discuss it here before moving on to CMT2.
HNPP or tomaculous neuropathy is inherited in an autosomal-dominant manner.21,51–61 The neuropathy usually manifests within the second or third decade, although some affected individuals present earlier and others remain asymptomatic their entire life. People usually describe painless numbness and weakness in the distribution of a single peripheral nerve, although multiple mononeuropathies and cranial neuropathies can occur. Symptomatic mononeuropathy or multiple mononeuropathies are often precipitated by trivial compression of nerve(s), as it can occur with wearing a backpack, leaning on the elbows, or crossing one’s legs for even a short period of time. These pressure-related mononeuropathies usually resolve, although it may take several weeks or months. The most commonly affected sites are the median nerve at the wrist (carpal tunnel syndrome), ulnar nerve at the elbow (cubital tunnel syndrome), radial nerve in the arm (spiral groove insult), and peroneal nerve at the fibular head. In addition, the brachial plexus can be involved after carrying a heavy shoulder bag or backpack. Further, some individuals who are affected manifest with a progressive or relapsing, generalized, and symmetric sensorimotor peripheral neuropathy that resembles CMT or even CIDP.21,51,54 On examination, there is decreased sensation to all modalities, particularly large fiber functions. Muscle stretch reflexes are usually reduced throughout, but these can be normal. Pes cavus deformities and hammertoes are often evident, as seen in CMT.
Although the clinical symptoms and signs are typically focal, NCS often reveal diffuse abnormalities.21,51–64 Sensory and motor NCS usually demonstrate moderately prolonged distal latencies and slightly slow NCVs with normal or reduced amplitudes. Slowing of NCVs, conduction block, and temporal dispersion are accentuated across typical sites of entrapment or compression (i.e., the carpal and cubital tunnel, Guyon’s canal, and across the fibular head). In addition, there also appears to be a distal accentuation of nerve conduction slowing, irrespective of possible compression.51,52,59 However, this length-dependent slowing has not been appreciated by all.60,61 NCS may also be abnormal in asymptomatic family members who carry the mutation. Findings of widespread conduction slowing superimposed on the focal demyelinating lesions that correlate with the mononeuropathies, whether clinically evident or not, are a clue to this disorder.
Nerve biopsies demonstrate focal globular thickening of the myelin sheath, which is best appreciated on teased fiber preparations.51,56,62,65 The thickened myelin resembles as a sausage, hence the name tomaculous neuropathy (Latin: sausage) (Fig. 11-6). These tomaculae represent redundant loops of myelin. In addition, nerve biopsies reveal a reduction in large myelinated fibers, segmental demyelination and remyelination, and axonal atrophy and degeneration similar to but not as severe as that seen in CMT1.
HNPP nerve biopsy. Transverse section of toluidine blue-stained epon-embedded sural nerve from a patient with HNPP reveals scattered thinly myelinated nerve fibers and fibers with redundant myelin swellings (A). Teased fiber preparation demonstrates a sausage-shaped myelin swelling or tomacula (B).
Approximately 85% of cases of HNPP are caused by an inverse of the mutation that is responsible for most cases of CMT1A.21,51,66 While CMT1A is usually associated with a 1.5-MB duplication in chromosome 17p11.2, an extra copy of the PMP22 gene, HNPP is caused by inheritance of the chromosome with the corresponding 1.5-MB deletion of this segment and thus have only one copy of the PMP22 gene. De novo deletions are usually paternally inherited and arise due to unequal crossing-over during meiosis, while rare de novo mutations are of female origin and the result of intrachromosomal rearrangements.30 In addition, as with CMT1A, mutations within the PMP22 gene itself can cause HNPP.67 Why some point mutations in the PMP22 gene result in a CMT1A clinical phenotype and other are associated with a HNPP phenotype is not known. It is speculated that mutations causing CMT1A produce a gain of function of the PMP22 protein, while mutations causing HNPP cause a loss of function of the PMP22 protein. Nerve biopsies demonstrate an underexpression of PMP22 mRNA and the protein33,35 that inversely correlate with the mean diameter of the axons and clinical severity.68 Normal expression of PMP22 protein appears important for proper axonal development.
CMT TYPE 2 (CMT2)
CMT2 refers to the “axonal” hereditary motor and sensory neuropathies. Most of these are associated with autosomal-dominant inheritance, but they can be inherited in an autosomal-recessive or X-linked manner. The prevalence of CMT2 is about half that of CMT1. There are many well-defined subtypes based on the clinical features and genetic localization (Table 11-1).7,23–25,69–125 CMT2A2 caused by mitofusin 2 mutations is the most common subtype accounting for approximately one-third of CMT2 cases overall.74–76 The different subtypes can be difficult to distinguish from one another and even from CMT1; however, there are clinical features that may be helpful. CMT2 tends to present later in life compared to CMT1. Individuals who are affected usually become symptomatic by the second decade but some remain asymptomatic into late adult life while others present in the first decade of life.73,78 People with CMT2 tend to have less severe involvement of the intrinsic hand muscles than that appreciated in CMT1. In contrast, CMT2 is more likely to have profound atrophy and weakness of the posterior compartments (gastrocnemius and soleus) of the distal legs in addition to the anterior compartment involvement (peroneal and anterior tibial) compared to CMT1. Generalized areflexia is rare in CMT2, while it is rather common in CMT1. Ankle reflexes are usually absent in both types. Individuals with CMT2 are less likely to have a tremor (Roussy–Levy syndrome) than people with CMT1. Although patients generally do not complain of sensory loss or paresthesia, 50–70% of those with CMT2 have significant reductions in light touch, pain, joint position, and vibration sense on examination. While pes cavus and hammertoe deformities may be seen in CMT2, these are less frequent than in CMT1.
There are some features that also help distinguish the different subtypes of CMT2. For example, optic atrophy, hearing loss, pyramidal tract, and subcortical white matter abnormalities on brain magnetic resonance imaging findings are sometimes seen in CMT2A2, which was previously reported as hereditary motor and sensory neuropathy type 6 (HMSN VI) and overlaps with the HSPs.79,80 Severe mutilating neuropathic ulcerations similar to those typically seen in HSAN type 1 (HSAN1) sometimes complicate CMT2B.81–84
CMT2B1 is actually inherited in an autosomal recessive fashion and early cases were reported in North Africa and the Middle East, where consanguineous marriages are not uncommon.85–88 The age of onset has ranged from 6 to 27 years in these small series, and the course of the neuropathy is variable. The neuropathy can progress rapidly with severe distal and proximal weakness of the arms and legs evolving in a few years, while other affected individuals have only mild weakness two decades after the onset of symptoms.
CMT2C is associated with vocal cord paralysis and diaphragmatic weakness, in addition to limb involvement.3,89–92 The age of onset and symptoms are variable, and it can begin in infancy when it may manifest with breathing difficulties and stridor. Laryngeal weakness is more often insidious in onset and presents as progressive hoarseness. In addition, the phrenic nerves may be affected, leading to diaphragm weakness, reduced ventilatory function, and orthopnea. Some people will require tracheostomy and mechanical ventilation. Severe atrophy of the distal limbs is common. Individuals who are affected can develop proximal weakness as well. There is mild sensory loss to all modalities and deep tendon reflexes are reduced. Pes cavus can be appreciated in some patients, but such foot deformities are not as common as seen in CMT1, CMT2A, or CMT2B. Similar cases have been reported in the literature as hereditary distal spinal muscular atrophy with vocal cord paralysis.90,93
CMT2D is another genetically distinct autosomal-dominant form of CMT2.94–98 The hands are more severely affected than the distal legs. Selected wasting of the first interosseus muscles is often appreciated. Onset of weakness is usually appreciated in the late teens (range between the ages of 12 and 36 years), and the neuropathy has a slowly progressive course. Distal hypesthesia to all sensory modalities and areflexia are appreciated. Pes cavus, hammertoes, and scoliosis are variably present. Enlarged palpable nerves are not appreciated. This disorder is allelic to distal spinal muscular atrophy type 5.95–97
CMT2E is a rare neuropathy usually manifested in the second or third decade of life with progressive distal leg weakness.47,48,99 Some patients develop deafness. Sensory loss, pes cavus, and areflexia are also often appreciated on examination.
CMT2G was described in a large Spanish kinship with typical CMT2 phenotype, with an age at onset being 9–76 (mean 29) years. Most patients developed symptoms in the second decade of life.102
CMT2H, CMT2K, and CMT4A are allelic disorders caused by mutations in GDAP1. Affected individuals may have vocal cord paralysis. They can have axonal or demyelinating abnormalities on NCS. We discuss this more in the CMT4A section.
CMT2I is associated with late-onset axonal neuropathy, Adie’s pupil, and hearing loss. It is caused by mutations in MPZ that are more typically associated with demyelinating neurophysiology (CMT1B).
CMT2J, a late-onset neuropathy (usually fifth or sixth decade) associated with hearing loss and pupillary abnormalities (Adie’s pupil), is also allelic to CMT1B and caused is by mutations in MPZ.
CMT2L was reported in a large Chinese family.103 Onset of the disease was between 15 and 33 years of age with symmetric weakness of the distal lower limbs, mild-to-moderate sensory impairment including pain and touch, and absent muscle stretch reflexes.
CMT2N is associated with an age of onset ranging from early childhood to sixth decade of variable severity.107–109 Sensorineural hearing loss may be seen in some individuals. NCVs are in the intermediate range.
CMT2O presents in childhood with delayed motor milestones and abnormal gait.110 Some affected individuals have paresthesia and neuropathic pain, while some have learning disabilities.
The similarities between the CMT1 and CMT2 make it difficult to definitely distinguish between these neuropathies on clinical grounds alone; thus, NCS are invaluable. It is usually not difficult to differentiate CMT2 from the more common chronic idiopathic axonal neuropathy. Although there is electrophysiological evidence of motor involvement in chronic idiopathic axonal neuropathy, sensory symptoms predominate the clinical picture in this neuropathy, while motor signs and symptoms are the major clinical features in CMT2.113
NCS can help distinguish CMT1 from CMT2 7,11,24,70,71; however, these do not help ascertain the various subtypes of CMT2. Sensory NCS reveal reduced or absent SNAP amplitudes in both the upper and lower limbs. CVs are normal or only slightly reduced. Likewise, the distal sensory latencies are either normal or only mildly prolonged. The motor NCS demonstrate reduced CMAP amplitudes, particularly in the legs, except in CMT2D in which the distal arms are affected more than the legs. Distal motor latencies are normal or only mildly prolonged. NCVs are normal or only slightly slow, usually greater than 37 m/s in the upper extremities. However, cases of CMT2E have been reported with motor NCVs in the mid-twenties and thus may be classified as a subtype of CMT1.48,114 Some have had slowing of NCVs in an intermediate range and are designated as having dominant intermediate CMT. Needle EMG reveals fasciculation and fibrillation potentials, particularly in distal extremity muscles. A few patients with CMT2 have been reported to have continuous MUAP firing resembling neuromyotonia; these discharges are abolished with peripheral neuromuscular blockade.115,116 The MUAPs can be increased in amplitude and duration with a higher-than-normal number of polyphasic potentials. Recruitment is reduced in weak muscles as well.
Nerve biopsies in CMT2 demonstrate a generalized reduction in myelinated fibers, particularly the large myelinated fibers.83,117 Axonal atrophy, wallerian degeneration, and small clusters of thinly myelinated fibers representing regenerating axons can be appreciated. As opposed to CMT1, onion bulbs are not a prominent feature in CMT2. Abnormal accumulations of mitochondria may be appreciated on electron microscopy (EM) in CMT2A2. Some forms such as CMT2E are associated with giant axons and accumulation of disorganized neurofilaments.47
CMT2A1 is caused by mutations in a microtubule motor kinesin-like protein gene, KIF1B, located on chromosome 1p36.2.118,119 The kinesin superfamily is involved in axonal transport and likely impairment of this function leads to axon degeneration. Subsequent to the discovery of mutations in the KIF1B gene, missense mutations in the mitochondrial fusion protein mitofusin 2 gene, MFN2, also located on chromosome 1p36.2, were found.120 The majority of patients with CMT2A have MFN2 mutations (CMT2A2), which account for one-third of CMT2 cases overall.75,77 Mitofusin 2 localizes to the outer mitochondrial membrane, where it regulates the mitochondrial network architecture by fusion of mitochondria. Mitochondria undergo a dynamically regulated balance between fusion and fission reactions of their tubular and branched membrane network in order to maximize cell functions, such as equilibrating mitochondrial gene products to overcome acquired somatic mutations of mitochondrial DNA and establishing a uniform membrane potential at the mitochondrial double membrane and regulation of apoptosis.120 Mutations in MFN2 lead to abnormal mitochondrial trafficking, which may explain the length-dependent severity of the associated neuropathy.77,121
CMT2B (3q13–q22) is caused by mutations in a small GTPase late endosomal protein encoded by the RAB7 gene.83,122 Mutations in this gene also cause a form of HSAN1 (see below). The encoded protein serves as a guanine-nucleotide exchange factor for the Rho family of GTPase enzymes (RhoGTPases). Rho guanine-nucleotide exchange factors regulate the activity of small RhoGTP-ase by catalyzing the exchange of bound GDP by GTP. In turn, RhoGTPases play a pivotal role in regulating the actin cytoskeleton by their ability to influence cell polarity, microtubule dynamics, membrane-transport pathways, and transcription-factor activity, as well as RhoGTPases in neuronal morphogenesis, including cell migration, axonal growth and guidance, dendrite elaboration and plasticity, and synapse formation.83
CMT2B1 is usually caused by homozygous mutations in the LMNA gene located on chromosome 1q21.85–88 This gene encodes for the nuclear envelop protein, lamin A/C. This gene is also mutated in patients with LGMD (limb girdle muscular dystrophy) 1B and EDMD2 (Emery Dreifuss 2) (see Chapter 24). CMT2B2 is caused by mutations in MED25 on chromosome 19q13 that encodes for mediator of RNA polymerase II transcription subunit 25. The encoded protein is essential in the assembly of a functional preinitiation complex with RNA polymerase II and other transcription factors. Both CMT2B1 and CMT2B2 are inherited in an autosomal-recessive rather than autosomal-dominant manner.
CMT2C is caused by mutations in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4).9–93 CMT2C is allelic to some forms of distal HMN and scapuloperoneal spinal muscular atrophy. How a mutation in this cation channel that mediates calcium influx causes neuropathy is not exactly known.
CMT2D and distal spinal muscular atrophy type 5 are allelic disorders caused by mutations in the glycyl-tRNA synthetase (GARS) gene on chromosome 7p14.94–98 Glycyl-tRNA synthetase is a member of the family of aminoacyl-tRNA synthetases, responsible for charging tRNAs with their cognate amino acids. The pathogenic mechanism by which mutations in this gene lead to CMT2D/distal spinal muscular atrophy type 5 is not completely understood.
CMT2E is allelic with CMT1F and is caused by mutations in the NEFL gene located on chromosome 8p13–21.47,48,99,114 Neurofilaments are important for proper organization, function, and regeneration of axons as well as for axonal transport. Furthermore, neurofilament light chain encoded by NEFL plays a major role in regulating the expression and function of other neurofilament proteins.
CMT2F is caused by mutations in the HSPB1 gene located on chromosome 7q11–q21 that encodes for 27-kDa small heat-shock or HSP27.100,101 Mutations in this gene are also responsible for some patients categorized as having distal spinal muscular atrophy.101
CMT2G has been localized to chromosome 12q12–q13, but the gene has not been identified.102
CMT2H is caused by mutations in the gene that encodes for ganglioside-induced differentiation-associated protein 1 (GDAP1) and is allelic to CMT2K and CMT4A, which is discussed in a separate section.
CMT2I refers to late-onset cases with mutations in MPZ gene (CMT1B) but in which the neurophysiology and nerve biopsies look more axonal and thus can be classified as a form of CMT2.16,124 Likewise, CMT2J, which is associated with hearing loss and Adie’s pupil, is also associated with mutations in MPZ gene.
CMT2K refers to early-onset neuropathy (usually before the age of 2 years), which is caused by mutations in GDAP1 gene located on chromosome 8q13–q21. This is allelic to CMT2K and CMT4A.88 Some individuals who are affected have vocal cord paralysis. The mechanism by which this causes axonal degeneration is not known.
CMT2L is caused by mutations in the HSPB8 gene located on chromosome 12q2 that encodes for small heat-shock protein 22-kDa protein 8 (HSP22).103,125 Mutations in this gene are also responsible for distal hereditary motor neuropathy type 2. HSP22 forms homodimers and larger oligomers with other HSPs. The mutation may lead to an increased tendency to form cytoplasmic protein aggregates.125
CMT2M is allelic to CMTDIB and is caused by mutations in the DNM2 gene on chromosome 19p13.2. This gene encodes for dynamin 2 that belongs to a subfamily of GTP-binding proteins.104–106 Dynamins are associated with microtubules and bind proteins that bind actin and other cytoskeletal proteins.
CMT2O is caused by heterozygous mutation in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene on chromosome 14q32.110 Dyneins are a group of microtubule-activated ATPases that have a role in retrograde axonal transport and organelle movement.
CMT2P is caused by mutations in the ubiquitin ligase LRSAM1 gene (leucine-rich repeat and sterile alpha motif containing 1) located on chromosome 9q33. Inheritance was autosomal recessive in one family 111 and autosomal dominant 112 in another. The encoded protein regulates cell adhesion molecules, has ubiquitin ligase activity, and plays a role in receptor endocytosis, but the exact mechanism by which it caused neuropathy is unknown.
Mutations in the gene that encodes DNAJB2 (HSJ1) is another rare cause of autosomal-recessive CMT2 and dHMN (no specific CMT2 or dHMN number have been assigned to this neuropathy as yet).126,127 Mutations in other genes (HSPB1, HSPB8, BSCL2, GARS, DYNC1H1, TRPV4, HINT1, PLEKHG5) can be associated with either dHMN or CMT phenotypes, and disparate phenotypes can be seen even within the same family.
DOMINANT INTERMEDIATE CMT
Dominant intermediate CMT (DI-CMT) disease refers to forms of CMT in which the CVs show only mild slowing (>38 m/s) in the upper extremities) and in which there are both demyelinating and axonal features on nerve biopsies. The clinical features are for the most part similar to what was described previously in CMT1 and CMT2 sections. Different chromosomal loci have been linked with three autosomal-dominant, “intermediate” types of CMT: DI-CMTA (10q24.1–q25.1), DI-CMTB (19p12–p13.2), and DI-CMTC (1p34–p35). The causal gene for DI-CMTA has not been found. Mutations in dynamin 2 (DYN2) gene have been found in DI-CMTB.104–106 Of note, mutations in the same gene have been found in adult-onset centronuclear myopathy. DYN2 mutations should be considered in those with a classical mild to moderately severe phenotype, particularly when seen in combination with neutropenia or cataracts.105 Dynamin 2 belongs to the family of large GTPases and is important in endocytosis, membrane trafficking, actin assembly, and centrosome cohesion.106 DI-CMTC is caused by mutations in the YARS gene that encodes for tyrosyl-tRNA synthetase.128,129 Tyrosyl-tRNA synthetase appears to be localized to axon terminals and probably plays a role in protein biosynthesis.
RECESSIVE INTERMEDIATE CMT
Mutations in the pleckstrin homology domain-containing protein, family G, member 5 (PLEKHG5) gene on chromosome 1p36.31 leads to an intermediate form of autosomal-recessive CMT disease.130–132 Mutations in this gene also cause autosomal-recessive distal spinal muscular atrophy type 4. The encoded protein activates the nuclear factor kappa B signaling pathway. Affected individuals developed distal weakness and atrophy that were worse in the legs and associated with foot deformities, areflexia, and moderately slow NCVs. The age at onset was variable. Nerve biopsies demonstrated a loss of large myelinated fibers and thinly myelinated fibers.
CMT TYPE 3 (DEJÉRINE–SOTTAS DISEASE, CONGENITAL HYPOMYELINATING NEUROPATHY)
CMT3 was originally described by Dejérine and Sottas as a hereditary demyelinating sensorimotor polyneuropathy presenting in infancy or early childhood.7,133–144 Although initially CMT3 was believed to be an autosomal-recessive disorder because of a lack of family history,11,134 most cases are due to spontaneous mutations in the PMP22, MPZ, or ERG2 genes. Further, most cases of the so-called congenital hypomyelination neuropathy138,139 also represent a severe form of CMT3.140
CMT3 usually manifests as generalized weakness at birth or in early childhood. Affected infants can be hypotonic and often have distal contractures (arthrogryposis multiplex). Ventilatory distress and swallowing difficulties can develop in severe cases, leading to death in several months. In less severe cases, infants may appear normal at birth, but motor milestones are delayed. Some children achieve independent ambulation, although it may take several years. Distal muscles are affected more than proximal muscles. Weakness can progress and render some ambulatory patients to a wheelchair.
The peripheral nerves may be visible or palpably enlarged. There is a reduction in all sensory modalities, particularly those conveyed by large myelinated fibers (i.e., vibration and proprioception) and generalized areflexia. Sensory ataxia of the limbs and trunk can be profound. Sensorineural hearing and abnormal pupillary reaction to light can be detected in some children. Skeletal deformities (e.g., pes cavus and kyphoscoliosis) are common.
CSF protein levels are usually elevated. Motor NCVs are markedly slow, typically 5–10 m/s or less; the distal motor latencies are markedly increased; and the amplitudes are reduced.2,23,138,141,142 Sensory responses are usually unobtainable. Needle EMG demonstrates increased insertional activity with variable degrees of positive sharp waves and fibrillation potentials, and reduced recruitment of MUAPs.144 In milder cases of CMT3 in which reinnervation can occur, large-amplitude, long-duration, polyphasic MUAPs are apparent. However, in severe cases, the MUAPs can appear small and almost “myopathic” in appearance.
Nerve biopsies in CMT3 are markedly abnormal.140,145–147 One can see hypomyelination with redundant basal lamina or classical onion bulbs as well as amyelination. There is an increase in the size of nerve fasciculi with a reduction in the numbers of myelinated fibers, while unmyelinated nerve fibers are less affected.
The most common histopathological abnormality is hypomyelination with basal lamina onion bulbs. There is marked loss of myelinated nerve fibers, with the remaining axons surrounded by onion bulbs composed of multiple layers of basement membranes, with only one or two thin Schwann cell lamella in the outer ring. These abnormalities are typically found in cases of infantile or early-onset neuropathy. Although some of the infants have respiratory and swallowing problems, nearly all survive. However, affected children rarely achieve independent ambulation and most are wheelchair dependent.
Occasionally, nerve biopsies reveal hypomyelination, with classical onion bulbs composed of concentrically arranged thin Schwann cell lamellae, enclosing nearly all the fibers. This histopathological appearance is associated with a more benign neuropathy. Affected children can appear normal at birth but subsequently fail to meet normal motor milestones. They usually are eventually able to ambulate but may require assistance over time.
Other cases are associated with a marked reduction of nerve fibers with the remaining fibers having minimal myelin. Onion bulbs are not apparent. These so-called congenital amyelinating neuropathies are the most severe form of CMT3 and are usually lethal.
CMT3 is a genetically heterogeneous disorder. As previously discussed, CMT3 was initially felt to be an autosomal-recessive disorder. However, de novo heterozygous point mutations have been discovered in the genes for PMP22, MPZ, and ERG2, which are also genes responsible for autosomal-dominant CMT1.2,7,46,136,148 Further, a CMT3 phenotype was described in a child with four copies of the PMP22 gene as a result of both parents having the typical CMT1A duplication of 17p22.28 Thus, there exists a wide spectrum of clinical, electrophysiolgical, and histological phenotypes associated with mutations in PMP22, MPZ, and the ERG2 genes. Some individuals who are affected have a mild CMT1 phenotype with only asymptomatic slowing of NCV, while others manifest with severe congenital amyelinating neuropathy, resulting in severe generalized weakness and death in infancy. The severity of CMT is probably related to the exact locations of the mutations in the PMP22, MPZ, and the ERG2 genes and how these mutations specifically affect the function of the myelin proteins or how these interact with one another and the axons.
CMT TYPE 4
This subgroup of CMT is characterized by a severe, childhood-onset, sensorimotor polyneuropathy that is usually inherited in an autosomal-recessive fashion. The electrophysiological and histological features can have demyelinating or axonal features.7,8,149
CMT4A was initially reported in Tunisian families but has subsequently been reported elsewhere.88,150–157 As previously mentioned it is allelic to CMT2H and CMT2K. Distal weakness is usually noted within the first 2 years of life. Motor development is generally delayed, and progressive weakness involving the proximal muscles is apparent by the end of the first decade. Some individuals who are affected become wheelchair dependent by the third decade of life. Vocal cord paresis and diaphragm paralysis can occur.151,158 Mild sensory loss and areflexia are evident on clinical examination, as are scoliosis, pes cavus, and other skeletal deformities.
CMT4B is characterized clinically by distal greater than proximal weakness affecting the legs more than the arms and histologically by the abundance of focally folded myelin sheaths on nerve biopsy.159–161 Weakness is usually apparent at birth or within the first year of life but may not be apparent until the third decade. Motor milestones are often delayed but children do generally become ambulatory. Weakness is slowly progressive and the ability to ambulate without a wheelchair may be lost over time. Sensation is reduced, particularly large fiber function, and muscle stretch reflexes are generally unobtainable. Some people develop scoliosis.
CMT4C was initially described in two Algerian kinships, but has been reported now elsewhere.162 The main clinical features are delay in walking until 18–24 months, deformities in the feet and spine by 5 years of age, and distal greater than proximal leg and arm weakness. Reduced sensation primarily affects large fiber modalities and is evident prominently in patients with severe motor weakness. Some patients develop sensorineural hearing loss. Muscle stretch reflexes are reduced or absent. Hypertrophy of the nerves may be appreciated.
CMT4D is probably allelic to hereditary motor and sensory neuropathy with deafness—Lom (HMSN-Lom) (discussed in a subsequent section).