Charcot-Marie-Tooth disease: CMT2, CMT4, and others
Sep. 10, 2023
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X-linked Charcot-Marie-Tooth disease (CMTX1) is the third most common form of inherited neuropathy. Patients develop a progressive distal weakness and atrophy that results from length-dependent axonal loss. CMTX1 is caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32. More than 700 different GJB1 variants have been found, the majority of which result in defective function of the gap junctions formed by connexin32. In addition to the demyelinating neuropathy, many patients have subclinical CNS findings, and a few GJB1 mutations are associated with striking, transient CNS manifestations.
• Charcot-Marie-Tooth disease type X1 is the second most common form of Charcot-Marie-Tooth disease.
• Men are more affected than women; women are variably affected.
• Intermediate conduction slowing (25 to 40 m/sec) is characteristic for men; slowing is typically less pronounced in women.
• Charcot-Marie-Tooth disease type X is caused by mutations in GJB1, the gene that encodes connexin32.
Shortly after the first descriptions of autosomal dominant kindreds with inherited neuropathy by Charcot, Marie, and Tooth in 1886, Herringham described a family in which males were selectively affected (22). He noted the similarity of the affected men to the individuals described by Charcot, Marie, and Tooth, and was struck by the finding that the women who passed the trait of their fathers to their own sons were themselves unaffected. "This form makes one wonder what inheritance is. That the diseased tissues of a consumptive father should be so represented in his spermatozoon as to cause his child to fall into consumption is remarkable enough. But that the women of this family, themselves even uncommonly buxom and healthy, should be able to select their children, and transmit to the males alone tissues unlike their own, and endowed with a regular form of weakness that they do not themselves possess, is still more marvelous. It seems as if the daughter of a diseased father carried from the beginning of her life ova of 2 sexes, the female healthy, the male containing within it the representation of the father's disease." What makes Herringham's analysis so prescient is that in 1889, Mendel's discovery of autosomal inheritance was unheralded and Morgan's demonstration of X-linked inheritance did not appear until 1910.
Non-syndromic, inherited neuropathies are called Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy (50; 16). Most forms of Charcot-Marie-Tooth disease have slowly progressive, length-dependent weakness, atrophy, and sensory loss, including reduction of deep tendon reflexes. On the basis of the clinical features, nerve conduction velocities, and histopathology, Charcot-Marie-Tooth disease was subdivided into demyelinating (conduction velocities of the motor nerves in the arms less than 35 m/s) and axonal (conduction velocities of the motor nerves in the arms greater than 35 m/s); “intermediate” forms of Charcot-Marie-Tooth disease have also been recognized owing to their intermediate conduction velocities (conduction velocities of the motor nerves in the arms 30 to 40 m/s). Dominant mutations in PMP22, MPZ, LITAF/SIMPLE, EGR2, GJB1, and PMP2 cause CMT1; this list is mostly complete because a few CMT1 patients do not have mutations in these genes (15). All of these genes are expressed by myelinating Schwann cells and are thought to cause disease through their effects in myelinating Schwann cells (48). Although demyelination is the initial effect of these mutations, the severity of all of these neuropathies is directly related to the degree of axonal loss rather than demyelination per se (31).
In males, symptoms typically begin in childhood or adolescence. The initial symptoms include difficulty running and frequently sprained ankles; foot drop and sensory loss in the legs develop later. Depending on the tempo of the disease, the distal weakness may progress to involve the gastrocnemius and soleus muscles, even to the point where assistive devices are required for ambulation.
Weakness, atrophy, and sensory loss also develop in the hands, particularly in thenar muscles. These clinical manifestations are the result of a chronic, length-dependent axonal loss and are nearly indistinguishable from those seen in patients with CMT1A or CMT1B, although atrophy, particularly of intrinsic hand muscles, positive sensory phenomena, and sensory loss may be more prominent in CMTX1 patients (47). Neurologic examination also reveals diminished to absent reflexes and sensory impairment, all of which are length-dependent and worsen insidiously over time but to varying degrees in different patients. Pes cavus, varus deformities, and "hammer toes" are frequently present.
Female carriers may be asymptomatic; if affected, they usually have a later onset and are less affected than males of the same age (53; 40). The reason that female carriers are less affected probably owes to X-inactivation; only a fraction of their myelinating Schwann cells express the mutant GJB1 allele (49). A few kindreds have been reported to have recessive CMTX1, but even in these kindreds, most obligate carriers have electrophysiological evidence of peripheral neuropathy (20).
These clinical manifestations, including their age-related progression, are described in the clinical vignette.
CMT1X typically does not affect longevity. Regardless of the mutation, affected men have a similar degree of impairment, but one cannot predict the degree to which a presymptomatic woman will be affected (53).
There are a few potential complications. Ionasescu and colleagues reported "breathing difficulty due to phrenic nerve involvement" in severe cases of CMT1X, but no details were provided (26; 27). Scoliosis has been reported in patients with Charcot-Marie-Tooth disease, including CMT1X (23). Although skin breakdown and trophic ulcers do not appear to be as problematic as in other neuropathies, it is prudent to advise patients about foot care. Pain and autonomic involvement are not prominent features of CMT1X. Patients with CMT1X have not been reported to develop a superimposed inflammatory demyelinating neuropathy.
Patients with any inherited neuropathy may be at increased risk of developing neuropathy if they are exposed to agents that can cause neuropathy. This potential hazard is exemplified by patients with CMT1A who develop severe vincristine neuropathy. Thus, drugs that can cause neuropathy should be avoided if possible; these include vincristine, cisplatin, taxol, suramin, colchicine, metronidizole, amiodarone, disulfiram, nitrofurantoin, isoniazid, dapsone, perhexiline, thalidomide, and "mega-doses" of pyridoxine (vitamin B6). Cisplatin (12) and even vincristine (04), however, have been given to CMT1X patients without obvious complications, but there is a brief report that the combination of vincristine and voriconazole worsened the neuropathy in a 5-year-old girl with CMT1X (44).
The following 4 paragraphs are excerpted from a description of a CMT1X family by Hahn and colleagues (20); this family has a Tyr211stop mutation in GJB1.
Patient A. On examination, this 61-year-old male reported that the onset of his symptoms dated back to early childhood, when he noted awkwardness and difficulty in running. He always had highly arched feet. In his teens, the muscles in his lower legs became thin, and he frequently twisted his ankles. His penmanship was always poor, and his fingers and hands were clumsy, particularly in cold weather. Over the years, his symptoms progressed insidiously, and he developed pain and sensations of pins and needles in his feet and intermittently in his fingers. The hand muscles became progressively wasted, and his fingers became so clawed that he had poor use of his hands and could not even sign his name. A triple arthrodesis, performed in both feet at age 38 years, improved his walking, yet in the past 10 years, walking had become more difficult and he had to use 2 sticks. On examination there was marked wasting and weakness of the hand muscles, in particular the thenar muscles, and of all muscles below the knee. There was pes cavus and varus deformity. Tendon reflexes were depressed in the arms and at the knees, and ankle jerks were absent. There was a graded sensory loss to just above the wrist and to the knee. His gait was unsteady with bilateral foot drop.
Patient B. On examination, this 14-year-old male reported that he had difficulty running even when in kindergarten, when his feet were already highly arched. Between the ages of 8 and 10 years, his gait became increasingly awkward. He tripped easily and tended to walk on the lateral edge of the foot. He had difficulty using his hands in cold weather and needed help with shoelaces and buttons. On examination, there was mild wasting and weakness of the hand muscles, in particular the thenar muscles. His feet were highly arched with marked hammer toe formation and extensive callosities on the lateral foot borders. Peroneal and anterior tibial muscles, and to a lesser extent the gastrocnemius muscles, were wasted, and he was unable to dorsiflex his ankle. His tendon reflexes were depressed, and the ankle jerks were absent. All modalities of sensation were reduced to wrist and midcalf levels. Cutaneous nerves were not enlarged.
Patient C. On examination, this 37-year-old mother of Patient B reported that she was clumsy when running as a child and was never able to ice skate. In her late teens, her fingers felt awkward in cold weather and she had trouble buttoning her clothes. Her feet were always highly arched, but recently she had developed increasing hammer toes, and she had a tendency to sprain her ankles. Her feet became numb. The examination showed moderate wasting of the intrinsic hand muscles and the thenar eminences, and moderate wasting and weakness of the peroneal muscles and small foot muscles, with pes cavus and hammer toe formation. Ankle jerks were absent, and sensation was reduced to the wrists and ankles. She walked with a mild steppage gait.
Patient D. On examination, this 29-year-old female reported that she had highly arched feet since childhood, was unable to ice skate, and had slight difficulty walking on uneven ground with a tendency to trip. The examination showed slight wasting and weakness of intrinsic hand muscles, highly arched feet, and hammer toe formation but only a little weakness in ankle dorsiflexion and eversion. Ankle jerks were absent, and there was a mild impairment of sensation in her toes and soles. Her gait was normal.
Thus, the affected men and women developed symptoms and signs of a progressive, length-dependent neuropathy. Most males had clinical onset in the first decade, developed a significant gait disturbance in the second decade, with progression to the point of requiring aids, but did not become wheelchair bound. Women, by comparison, first noted symptoms toward the end of the second decade, and at every age, were much more mildly affected. Similarly, electrophysiological testing demonstrated that affected men had more axonal loss, including several who had an absent extensor digitorum brevis motor responses. Both men and women; however, had mild to moderate slowing of the peroneal motor response. Sensory nerve biopsies of 2 affected men (Patient A and Patient B) revealed evidence of demyelination and remyelination, as well as axonal degeneration and regeneration.
CMTX1 is caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32 (Cx32).
In the 100 years following Herringham's paper, many workers reported other CMTX1 kindreds from Europe and North America. Although the existence of X-linked kindreds with inherited neuropathy fell into dispute by 1980, their existence was confirmed by subsequent linkage studies. Early linkage studies excluded the distal short arm and the distal long arm of the X chromosome. Using restriction fragment length polymorphisms, many kindreds were linked to the proximal long arm of X chromosome. Further recombination analyses in several large families refined the localization of CMTX1 to an approximately 1.5 megabase interval in Xq13.1, where 3 genes previously had been mapped, including GJB1. Because mutations in genes expressed by myelinating Schwann cells were known to cause other inherited demyelinating neuropathies, Bergoffen and colleagues tested whether these candidate genes were expressed in normal rat peripheral nerves (09). GJB1 was the only one expressed, and direct sequencing of GJB1 in 8 families demonstrated 7 different mutations. Subsequent reports, largely from patients from Europe and North America, but also from Russia, Japan, China, Korea, Turkey, and China, confirmed these findings. More than 720 different variants have been described; most of them are listed on the following website:hihg.med.miami.edu.
It has become clear that not all GJB1 variants cause CMTX1. Most reported variants are missense mutations (amino acid substitutions) that collectively affect most of the 283 amino acids of Cx32 and are associated with a similar phenotype as nonsense mutations (premature stop codons), insertions and deletions (many of which lead to frameshifts), and deletion of the entire gene. Thus, we should accept variants that segregate with a “CMTX1 phenotype” in individual families, especially if they have been reported more than once. ClinVar has begun this analysis, but it is by no means complete. More information about ClinVar can be accessed at the following website:https://www.ncbi.nlm.nih.gov/clinvar/. Of the 421 GJB1 variants classified by ClinVar, 95 are considered “pathogenic” or “likely pathogenic,” 266 are considered “uncertain,” 17 are considered “conflicting,” and 20 are considered “benign” (and 18 out of 20 are synonymous).
This is a schematic of a Cx32 molecule, which consists of 4 transmembrane domains, 2 extracellular loops, 1 intracellular loop, as well as intracellular N- and C-termini. The 421 missense GJB1 variants classified by ClinVar are...
In my opinion, not all of the variants have not yet been properly classified by ClinVar: there are many “uncertain” variants that are “pathogenic”/“likely pathogenic” (they have been reported in people with CMTX1) or “benign” (GJB1 variants with allele counts greater than 2 are probably too common to cause CMTX1).
The large scale sequencing of DNA from cross-sections of people has now revealed many benign polymorphisms in GJB1 and even more variants of uncertain significance.
Most GJB1 variants found in gnomAD have an unknown or even doubtful association with CMTX1. This is a schematic of a Cx32 molecule, which consists of 4 transmembrane domains, 2 extracellular loops, 1 intracellular loop, as well...
Of the 70 missense variants found in gnomAD, 10 have an established relationship with CMTX1 (patients with these mutations have been seen by a CMT expert), 41 have an unknown relationship with CMTX1 (the variant is present in gnomAD, but a patient with this variant has not been reported to have CMTX1), and 19 have a doubtful/no association with CMTX1 because the variant is too common in gnomAD to be a cause of CMTX1 (it is more prevalent than the most common, disease-associated variant) (42). More information can be found on the following website:https://gnomad.broadinstitute.org/. In my opinion, the majority of the GJB1 variants that are currently of unknown relationship to CMTX1 in gnomAD will turn out to be benign.
Properly classifying as many GJB1 variants as possible remains an important matter in properly diagnosing patients and in providing accurate genetic counseling. To accomplish this goal, one must consider the phenotype of the patient, segregation of the variant in that family, whether the variant has previously been well documented to cause CMTX1, and the prevalence of the variant in the population. In addition, because Cx32 forms a channel with well-described electrophysiological characteristics, Cx32 mutants that do not form normal channels are almost certain to cause CMTX1 (01). In addition, because the mouse and human Cx32 proteins have a nearly identical amino acid sequence, one can make a given GJB1 variant in mice and determine whether this creates a neuropathy. Until a variant is conclusively classified, merely finding a GJB1 variant in a patient with neuropathy is insufficient evidence for concluding that the affected person has CMT1X.
Some CMTX1 kindreds do not have mutations in the open reading frame. In these families, mutations might affect the promoter, splice sites, or the untranslated portions of the mRNA. In mammals, GJB1 is composed of 2 exons and a large intron (6 to 8 kb). The second exon contains the entire open reading frame. Cx32 transcripts in peripheral nerves are initiated at an alternative promoter, termed P2, which is located close to the exon 2. Transcripts in the liver, brain, spinal cord, and pancreas, on the other hand, are initiated at the P1 and the P2 promoters. Several mutations are just proximal to the start site of transcription, likely affecting the EGR2 and SOX10 binding sites; these are important transcription factors for the development and maintenance of myelinating Schwann cells (56). Other mutations affect the splicing of exons 1A and 2 (37), or abolish an internal ribosome entry site (-459C> T) in the 5' UTR that is essential for the translation of Cx32 mRNA (25). Similar to what was described above, there are variants in the 5’ and 3’ UTR that cause CMTX, and others that are probably benign (57).
Gap junctions are intercellular channels, usually between adjacent cells, and are found in most tissues (10; 17). Intercellular gap junctions have been postulated to be involved in a number of processes, including metabolic cooperation, spatial buffering of potassium ions, intercellular synchronization, growth control, cellular differentiation, and pattern formation during development. The channels are composed of 2 apposed hemichannels (or connexons) that can form a contiguous pathway between the adjacent cells. Each connexon is composed of a hexamer of connexin molecules arranged around a central pore. All connexins are believed to have a similar structure (33). In the transmembrane domains are alpha helixes; the first transmembrane domain forms the central pore. The channel diameter is too small to allow transfer of proteins and nucleic acids but large enough to allow the diffusion of ions and other small molecules (less than 1000 Da). The N-terminal domain is involved in the insertion of the nascent polypeptide chain into the endoplasmic reticulum, and, along with the first transmembrane domain, determines voltage gating. The extracellular loops regulate the connexon to connexon interactions, including heterotypic channel formation; each loop contains 3 cysteine residues (conserved among all connexins) that form essential intramolecular disulfide bonds. The intracellular loop and C-terminal domain regulate pH gating.
In keeping with the diversity of tissues with gap junctions, 21 different connexins have been found in mammals (60). Most connexins are expressed in more than one tissue and most tissues express more than one connexin. All connexins are highly homologous, indicating that their structure and function were conserved as they evolved from a common ancestral gene. The possible interactions of different connexins are potentially complex, as connexons may be composed of a single connexin (homomeric connexons), or they may be heteromeric. Furthermore, homomeric connexons can couple with homomeric connexons composed of the same connexin (homotypic junctions), with connexons composed of a different connexin (heterotypic junctions), or even with different combinations of heteromeric connexons. Not all combinations of hemichannels, however, can form heterotypic junctions.
Cx32 was the first connexin to be cloned and was named according to the predicted molecular mass of the protein, 32 kDa. It is highly conserved; the amino acid sequence of human Cx32 protein is 98% identical to those of the mouse and rat. Despite the broad expression pattern of Cx32, peripheral neuropathy is usually the sole clinical manifestation of GJB1 mutations, although CNS abnormalities are associated with certain mutations. Why these other tissues are not affected is unclear. One reason may be the co-expression of other connexins, which could protect against the loss of Cx32. Myelinating Schwann cells in rodents express Cx29, whether human Schwann cells express Cx31.3, the human ortholog of Cx29, remains to be determined.
The GJB1 mutations that cause CMTX1 involve all portions of the Cx32 protein. Because mutations affect conserved regions, one might anticipate that they disrupt its function. The effects of some mutations can be inferred from the locations of the affected amino acids, as detailed above. For instance, there are naturally occurring mutations affecting all 6 cysteines of the extracellular loops; all of the corresponding mutants would be predicted to result in nonfunctional channels (13). Because the effects of individual mutations are difficult to predict, many mutations have been expressed in Xenopus oocytes. Many mutants do not form functional channels, although they probably do reach the cell membrane (01). In contrast, other mutants form gap junctions, but most of these have abnormal biophysical characteristics, including their incorporation into hemichannels. It is possible that some Cx32 mutants affect other connexins that are expressed by myelinating Schwann cells (Cx29) or oligodendrocytes (Cx29 and Cx47) (05; 35; 39). Dominant effects could result in a more severe phenotype, particularly in the central nervous system (see below).
In mammalian cells, many Cx32 mutants do not reach the cell surface (61); these mutants cannot form functional gap junctions. Other mutants reach the cell surface and form gap junctional plaques. One reason for the discrepancy in the cell surface localization of Cx32 mutants is the more stringent requirements in mammalian cells for protein trafficking; misfolded proteins are degraded in 2 distinct pathways, involving either proteasomes or lysosomes. Different Cx32 mutants exhibit different trafficking defects and differ in their sensitivity to drugs that block proteasomes and lysosomes (58). These findings fit the general theme that the molecular pathogenesis of intrinsic membrane proteins is related to abnormal trafficking of the mutant proteins. Finally, these results highlight the limitations of transfection analysis, which did not reveal any abnormality in trafficking or function of several mutants that cause CMT1X. Even expressing these mutants in myelinating Schwann cells has not revealed how some Cx32 mutants cause disease (24).
Until GJB1 mutations were found to cause CMTX1, little attention had been paid to the finding that myelin sheaths may contain gap junctions. Putative gap junctions were seen within paranodes and incisures by freeze fracture electron microscopy, exactly where Cx32-immunoreactivity is found (09; 34). Paranodes and incisures are regions of non-compact myelin in the myelin sheath and contain different intrinsic membrane proteins from those of compact myelin.
If Cx32 forms functional gap junctions in incisures and paranodes, then these could provide a direct pathway for the diffusion of ions and small molecules directly across the myelin sheath. For thick myelin sheaths, this direct radial pathway would be 1000 times shorter than the circumferential pathway through the Schwann cell cytoplasm. Thus, myelinating Schwann cells may use "reflexive" gap junctions (gap junctions of a cell onto itself) to compensate for long circumferential pathways for diffusion of small molecules and ions, inherent to their specialized geometry. If Cx32 mutants interrupt the function of these gap junctions, then this could damage myelinating Schwann cells and their axons, leading to demyelination as well as axonal loss.
Dye transfer studies, the standard way of demonstrating dye-coupling between cells, have demonstrated functional gap junctions in the myelin sheath (08). Living myelinated fibers were injected with dyes of differing molecular mass. Dyes of low molecular mass can pass from the outer (abaxonal) collar of Schwann cell cytoplasm to the inner (adaxonal) collar of cytoplasm, whereas high molecular mass dyes do not reach the adaxonal cytoplasm. Furthermore, pre-incubating the teased fibers in an agent known to uncouple gap junctions prevents low molecular mass dyes from diffusing into the cytoplasm adjacent to the axon. These results indicate that there is a gap junction-mediated pathway for diffusion of small molecules directly across the myelin sheath, probably located within incisures. This pathway did not appear to be disrupted in the myelinating Schwann cells from Gjb1-null mice, indicating that other connexins may compensate for the absence of Cx32. Cx31.3, the human ortholog of rodent Cx29, is a strong candidate, except that it does not appear to form functional channels (03; 46).
Given the large number and variety of GJB1 mutations, the question arises whether different mutations cause different degrees of clinical involvement. This is clearly the case for mutations in PMP22 and MPZ genes that encode other myelin proteins (48). Different PMP22 and MPZ mutations cause a wide range of phenotypes, ranging from mild (hereditary neuropathy with liability to pressure palsies) to severe (congenital hypomyelinating neuropathy or Dejerine-Sottas syndrome). In spite of earlier suggestions of a genotype-phenotype correlation (27), a more thorough investigation indicates that most GJB1 mutations cause a similar phenotype, equivalent to a null allele (51). Thus, if a GBJ1 variant is found in a person with the typical clinical and electrophysiological picture of CMTX1 and segregates within their family and has been reported to cause CMTX1 in another family, then it likely the cause of their neuropathy. As discussed above, all GJB1 variants cause CMTX1, and there are biological assays that inform the issue of whether a given GJB1 variant is pathogenic.
GJB1 mutations cause at least 3 kinds of CNS manifestations (02):
(1) Many mutations cause delayed brainstem auditory evoked responses, even in the absence of clinical involvement (38). Visual and motor pathways may also be affected too (07).
(2) Some mutations are associated with mild, fixed CNS findings such as extensor plantar responses or abnormal MRIs when asymptomatic (p.Trp3Gly, p.Trp24Cys, p.Met34Val, p.Ala39Val, p.Asn54His, p.Met93Val, p.Ser128Leu, p.Arg143Pro, p.Trp157Cys, p. Val170Phe, p.Asn175Ser). p.Asn54His is associated with persistent CNS dysfunction in one child who also had an abnormal brain MRI (52). p.Cys64Tyr was found in several members of a family who also had white matter changes on MRI, one of whom has an multiple sclerosis-like illness.
(3) Some mutations (p.Met1Ile, p.Arg22Gln, p.Val27Ala, p.Ile33Asn, p.Ala39Val, p.Phe51Leu, p.Asn54Ser, p.Thr55Ile, p.Cy60Tyr, p.Asp66Asn, p.Arg75Trp, p.Pro87Leu, p.Gln99_His100insGln, p.His100Gln, p.Glu102del, p.Trp132stop, p.Trp133fs, p.Val139Met, p.Arg142Trp, p.Arg142Gln, p.Leu156Arg, p.Arg164Trp, p.Arg164Gln, p.Cys168Tyr, p.Val177Ala, p.Arg183His, and p.Glu186stop) are associated dramatic, transient clinical and MRI abnormalities of CNS involvement, often initially diagnosed as ADEM or a stroke.
(4) One mutation, p.Pro58Ser, has been associated with spinocerebellar degeneration (54; 11).
(5) At least 4 different GJB1 mutations (p.Val38Ala, p.Thr55Arg, p.Arg142Gln, and p.Thr191frameshift) have been associated with hearing loss, some of these also were found to have prolonged brainstem auditory evoked responses (55; 30; 28); there may be others (38; 21). Males, and even females, can be affected in childhood.
Charcot-Marie-Tooth disease is a common genetic disease, with an estimated prevalence that ranges from 1 out of 2500 to 1 out of 8000 (14). CMTX1 is the third most common form of Charcot-Marie-Tooth disease, after CMT1A and hereditary neuropathy with liability to pressure palsies, accounting for 10% of all Charcot-Marie-Tooth disease patients (15).
The manifestations of CMTX1 cannot be prevented by any known measures. Prenatal and preimplantation testing can be done.
Inherited neuropathy should be considered in the differential diagnosis of every patient who has a chronic, length-dependent neuropathy of unknown etiology. A clear family history and electrophysiological evidence of a chronic, length-dependent neuropathy are the hallmarks of all inherited neuropathies. However, sporadic cases of CMTX1 have been described, including ones caused by new mutations; therefore, the absence of a family history does not exclude CMTX1 (or any other inherited neuropathy). The following genetic, clinical, electrophysiological, and pathological features differentiate CMTX1 from other forms of Charcot-Marie-Tooth disease.
A diagnosis of CMTX1 should be considered for patients who appear to have CMT1, especially if the family history indicates that men are more affected than women and no male-to-male transmission is documented. The degree of slowing in motor responses helps to distinguish CMT1 from CMTX1, as forearm motor velocities in CMT1 (10 to 40 m/sec) are often slower than in CMTX1 (30 to 40 m/sec). This so-called "intermediate slowing" is typical for affected men but is also seen in affected women (40). The nerve biopsies from CMTX1 patients show more axonal loss and “regenerated clusters” of myelinated axons and fewer "onion-bulbs" as opposed to CMT1A (45; 19; 59).
Distinguishing CMTX1 from CMT2 or "dominant intermediate" forms of Charcot-Marie-Tooth disease is more problematic, especially in small kindreds in which the lack of male-to-male transmission in not evident. Further, the clinical phenotypes of CMTX1 and CMT2 can be similar, and the ranges of motor nerve conduction velocities overlap. In spite of the difficulties separating the 2, the notion that GJB1 mutations can cause CMT2 is unfounded. Rather, GJB1 mutations cause demyelination that is compounded by axonal loss, whereas in CMT2 axonal loss is probably the fundamental pathological alteration.
Finally, it should be emphasized that atypical cases of CMTX1 have also been described, largely owing to availability of genetic testing. CMTX1 can affect young women and children of either sex. GJB1 mutations have been found in patients who are suspected inflammatory demyelinating neuropathies not responding to treatment (36). Hearing loss and abnormalities in the central nervous system have also been described. In particular, stroke-like episodes of CNS dysfunction that are accompanied by MRI abnormalities have been described (02). These episodes appear to be associated with a subset of GJB1 mutations and may be brought on physical exertion or a change in altitude.
A family history of neuropathy and a physical exam that reveals features of a length-dependent peripheral neuropathy are strongly suggestive of an inherited neuropathy. Electrophysiological evaluation of multiple peripheral nerves along with electromyography will confirm whether the patient has a length-dependent neuropathy, and should also establish whether this is associated with slow (less than 30 m/sec), intermediate (30 to 40 m/sec), or normal (greater than 45 m/sec) motor conduction velocities in the arms. Symmetrical slowing indicates an inherited demyelinating neuropathy; asymmetrical slowing is characteristic of an acquired, demyelinating neuropathy. In CMTX1, however, the nerve conduction velocities are less uniform than in other forms of CMT1 (18; 32), to the point that some patients were treated (unsuccessfully) for CIDP (36). The cerebrospinal fluid from CMTX1 patients has not been systematically characterized, but there are reports of mild elevations (less than 100 mg/dl), which may serve to distinguish CMTX1 from chronic, acquired demyelinating neuropathies.
Patients who are suspected of having a genetic neuropathy with slow or intermediate motor conduction velocities should be advised that this could be a genetic neuropathy and that genetic testing is available. It would be reasonable to refer the patient to a neurologist who specializes in neuromuscular diseases or a genetic counselor who is familiar with Charcot-Marie-Tooth disease. After the genetic testing is explained, blood samples can be sent for testing. For CMTX1, the entire open reading frame of the GJB1 gene should sequenced. If no mutations are found, and CMTX1 is strongly suspected, then the promoter and 5’ untranslated region could be sequenced. Updated information on the availability of genetic testing can be found on the following website:GeneTests Website.
A nerve biopsy is not required to diagnose CMTX1.
The National Institutes of Health Web site states, “There is no cure or specific treatment for CMT. Proper foot care including custom-made shoes and leg braces may minimize discomfort and increase function. Physical therapy and moderate activity are often recommended to maintain muscle strength and endurance. For some patients, surgery may be beneficial.” The management issues are chiefly related to the orthopedic complications of the disease (41). These include the well-known foot deformities common to all types of Charcot-Marie-Tooth disease: pes cavus, varus, callosities on the lateral foot borders, and "hammer toes," which can compromise ambulation and even require surgical intervention. Ankle instability can be treated with high-top shoes or boots or orthoses, and foot drop can be treated with braces. Scoliosis has been noted in more severely affected patients, but the literature does not indicate that CMTX1 patients typically need intervention (23). Physical therapy, especially stretching for contractures, is advocated, and splinting, specific exercises, adaptive devices, and surgery may help maintain hand function.
CMTX1 typically does not affect longevity. Regardless of the mutation, affected men have a similar degree of impairment, but one cannot predict the degree to which a presymptomatic woman will be affected (53).
There are a few potential complications of CMTX1. Ionasescu and colleagues reported "breathing difficulty due to phrenic nerve involvement" in severe cases of CMTX1, but no details were provided (26; 27). Scoliosis has been reported in Charcot-Marie-Tooth disease patients, including CMTX1 (23). Although skin breakdown and trophic ulcers do not appear to be as problematic as in other neuropathies, it is prudent to advise patients about foot care. Pain and autonomic involvement are not prominent features of CMTX1. Patients with CMTX1 have not been reported to develop a superimposed inflammatory demyelinating neuropathy.
Patients with any inherited neuropathy may be at increased risk of developing neuropathy if they are exposed to agents that can cause neuropathy. This potential hazard is exemplified by patients with CMT1A who develop severe vincristine neuropathy. Thus, drugs that can cause neuropathy should be avoided if possible; these include vincristine, cisplatin, taxol, suramin, colchicine, metronidizole, amiodarone, disulfiram, nitrofurantoin, isoniazid, dapsone, perhexiline, thalidomide, and "mega-doses" of pyridoxine (vitamin B6). Cisplatin and even vincristine have been given to CMTX1 patients without obvious complications, but there is a brief report that the combination of vincristine and voriconazole worsened the neuropathy in a 5-year-old girl CMTX1 (12; 04; 44).
Women with CMT1X are fertile. Pregnancy, labor, and delivery have not been reported to alter the disease.
There is no specific information available about anesthesia and CMT1X. Although there are theoretical reasons for avoiding depolarizing neuromuscular agents such as succinylcholine during anesthesia because denervated muscle fibers might release potassium, thereby causing hyperkalemia, this has not been observed in patients with CMT1 (06). Patients with CMT1 may have increased sensitivity to thiopental, a drug widely used during the induction of anesthesia (29), and vecuronium, a neuromuscular blocker (43).
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