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Charcot-Marie-Tooth Disease
Introduction
Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathies, is a group of inherited motor and sensory peripheral neuropathies and the most common inherited neuromuscular disorder. CMT was first described as a clinical entity in 1886 by physicians Jean-Marie Charcot, Pierre Marie, and Howard Henry Tooth, who referred to it as "progressive muscular atrophy."[1] CMT is heterogeneous in its clinical, electrophysiological, genetic, and pathological features. Based on neurophysiological findings, CMT was previously classified into the demyelinating form, CMT type 1 (CMT1), and the axonal form, CMT type 2 (CMT2). However, the increasing use of next-generation gene sequencing (NGS) technologies has altered the classification and diagnosis of CMT.[2][3][4]
CMT is a nerve-length-dependent disorder characterized by slowly progressive foot deformities (most often pes cavus), sensory loss, weakness in the lower extremities, and reduced or absent deep tendon reflexes. Most individuals with CMT exhibit symptoms in the first or second decade of life, with an insidious onset of weakness that begins in the lower extremities and later involves the upper extremities.[5][6] The presentation of CMT can overlap with other neurodegenerative disorders.
Etiology
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Etiology
CMT and related disorders are genetically determined, involving more than 100 genes. About 80% to 90% of the genetic abnormalities are due to copy number variations (CNVs) in peripheral myelin protein 22 (PMP22) and mutations in GJB1, MPZ, and MFN2 genes. Only a few families are affected by mutations in other genes, and 18% to 50% of cases remain unsolved, possibly due to mutations in noncoding DNA or structural variations. Structural variations describe genomic rearrangements that disrupt chromosomal organization and architecture, including duplications and deletions (also referred to as CNV), insertions, inversions, and translocations.[7][8][9][10]
Autosomal dominant CMT is the most common genetic subtype, followed by X-linked CMT, while autosomal recessive forms are rare.
About 90% of mutations in individuals with CMT type 1 are caused by 3 genetic defects—PMP22 duplication, GJB1 point mutations, and MPZ point mutations—which cause damage to Schwann cells and the myelin sheath of the axon. CMT type 1A, the most common CMT neuropathy, is caused by a 1.5-Mb duplication of chromosome 17p11.2, resulting in trisomy of PMP22. Due to its large size, this region is susceptible to frequent genomic rearrangements. Duplication or deletion in PMP22 leads to disease via a gene dosage effect, given the sensitivity of nervous tissue to the gain or loss of a copy of the PMP22 gene.[10]
Duplication in the heterozygous state results in 1.5-fold overexpression of PMP22 in Schwann cells, while homozygous duplication causes 2-fold overexpression. This genomic duplication results from an unequal meiotic crossover facilitated in the male germline by flanking homologous repeat sequences. In laboratory models, this overexpression overloads the proteasome system, leading to cytoplasmic aggregation of the ubiquitinated PMP22 protein, recruitment of autophagosomes and lysosomes, and increased autophagy.[11][12][13][14]
Frameshift mutations in MPZ lead to mutant proteins aggregating in the endoplasmic reticulum of the neuron and consequent apoptosis. Other variations of CMT are usually the result of loss-of-function mutations in different genes and are uncommonly due to a toxic gain of function.[15]
Epidemiology
CMT is a clinically and genetically heterogeneous neuropathic disorder that occurs worldwide and affects individuals from all ethnic groups. Overall, CMT has an estimated frequency of 1 in 2500 people.[16] Epidemiological data from adult neuropathy clinics indicate that CMT is more common than inflammatory or paraneoplastic neuropathies.[17][18] The prevalence of CMT ranges from 9.7 per 100,000 population in Serbia to 82.3 per 100,000 population in Norway.[19] Published studies vary in quality and methodology, making it challenging to accurately assess the true prevalence of CMT due to the diverse clinical symptoms and presentations of the disease. This variability is evident in older population-based surveys, which reported a wide range of CMT frequencies, from 8 per 100,000 individuals in Libya to 28 per 100,000 individuals in northern Spain.[20]
Based on median motor nerve conduction velocity (NCV), CMT is broadly categorized into demyelinating (CMT1) and axonal (CMT2) types. The frequency ranges from 37.5% to 84% for CMT1 and 12% to 35.9% for CMT2. However, prevalence studies focusing solely on CMT2 are rare, making the identification of affected individuals and families more challenging.[19]
Pathophysiology
The normal structure and functions of peripheral nerves depend upon the close anatomical and physiological interaction between Schwann cells and axons. Axons regulate the survival, proliferation, and differentiation of Schwann cells, which in turn have a crucial role in regulating ion channels and their maintenance, supporting survival, and facilitating regeneration of axons. Abnormalities in genes involved in myelin assembly and axonal transport can lead to primary demyelination and axonopathy.
Some of the molecular and cellular mechanisms thought to be involved in inducing CMT are mentioned below.[21]
- Myelin assembly: Genes such as MPZ (involved in myelin compaction), GJB1 (gap junction formation), and PMP22 (synthesis and maintenance of myelin) lead to impaired myelin sheath formation, the primary cause of demyelinating CMT.
- Cytoskeletal structure: These genes are involved in actin polymerization (INF2), stabilization of the myelin sheath through membrane-protein interactions (PRX), intermediate filaments (NEFL), cell signaling (FGD4), and axonal transport (DYNC1H1).
- Myelin-specific transcription factor: EGR2 is part of gene expression of myelin component proteins and Schwann cell differentiation.
- Nuclear-related genes: These genes include those encoding nuclear envelope proteins (LMNA), nucleotide biosynthesis enzymes, DNA repair factors, and proteins involved in cell survival.
- Endosomal sorting and cell signaling: These genes regulate vesicular transport, membrane trafficking, transport of intracellular organelles, and cell signaling. They include LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7, TFG, DNM2, and SIMPLE.
- Proteasome and protein aggregation: These genes regulate microtubules (HSPB1 and HSPB8), cell adhesion (LRSAM1), and ubiquitin ligase (TRIM2).
- Mitochondria: These genes are related to energy metabolism, mitochondrial dynamics, and ATP synthesis. MFN2 and GDAP1 are major contributors to CMT.
- Gene mutations: These genes are responsible for motor proteins and axonal transport, tRNA synthetases, RNA metabolism, and ion channel-related abnormalities.
Due to the close functional interaction between Schwann cells and axons, demyelinating neuropathies in CMT often progress to functional axonopathies, leading to secondary axonal degeneration.[22][23] Common secondary phenomena include axonal loss, secondary Schwann cell proliferation, and accelerated pathology due to immune-mediated mechanisms.[24]
Evolving Classifications of Charcot-Marie-Tooth Disease
CMT is categorized based on the age of onset into early infantile (age less than 2), childhood (age 2-10), juvenile (age 10-20), adult (age 20-50), and late adult (age 50 or older) forms.[8] Additionally, based on electrophysiological findings, CMT is classified as either a demyelinating or axonal neuropathy. CMT exhibits autosomal dominant, autosomal recessive, or X-linked patterns of inheritance, with autosomal dominant being the most common.[25] In the 1990s, reflecting evolving electrophysiological and pathological findings alongside key clinical features, CMT was renamed hereditary motor and sensory neuropathy.
With the wider availability of genetic testing, the classification of CMT has evolved, as listed below.
- CMT1: CMT1 accounts for 50% of cases and is characterized by demyelinating pathology, an autosomal dominant mode of inheritance, early onset, distal motor weakness, and moderate slowing of NCVs (>15 to ≤35 m/s). The most common subtype, CMT1A, results from a mutation in the PMP22 gene, while CMT1B is caused by mutations in MPZ.
- CMT2: CMT2 represents 15% to 30% of cases and is characterized by axonal pathology, an autosomal dominant mode of inheritance, onset typically in the second or third decade, distal motor weakness, and normal or slightly slowed NCVs (>40 m/s). The most common gene mutation associated with CMT2 is in MFN2.
- CMTX: CMTX accounts for 10% to 15% of cases and is characterized by both demyelinating and axonal pathology. CMTX follows an X-linked mode of inheritance with onset typically in the first or second decade. Symptoms are generally more severe in males than females, featuring gait impairment and mild slowing of NCVs (>35 to ≤45 m/s). CMT1X is caused by mutations in the Cx32 gene.
- CMT3: CMT3 is uncommon and characterized by demyelinating pathology with autosomal dominant inheritance. CMT3 has its onset in infancy with symptoms such as hypotonia, feeding difficulties, severe sensory and motor impairments, and profound slowing of NCVs (≤15 m/s). Most cases of CMT3 are caused by point mutations in the genes encoding PMP22, MPZ, or ERG2.
- CMT4: CMT4 accounts for less than 10% of cases and is characterized by demyelinating pathology with an autosomal recessive mode of inheritance. CMT4 presents with progressively severe sensory and motor symptoms and moderate slowing of NCVs (>15 to ≤35 m/s). CMT4 is genetically heterogeneous.
Significant phenotypic heterogeneity exists with mutations that can cause both demyelinating and axonal forms of CMT. Similarly, mutations in MFN2, MPZ, GDAP1, and EGR2 may have CMTs with autosomal dominant or recessive inheritance patterns.[26][27][2]
Histopathology
After obtaining informed consent, a nerve biopsy can help identify the underlying genetic etiology in sporadic cases and also help distinguish CMT from acquired disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Nerve biopsy may also provide a functional association when genetic tests detect "variants of uncertain significance" or a novel variant. Morphological and ultrastructural changes in axons, myelin, nodes of Ranvier, and mitochondria provide insights into the functions of mutated genes and the pathways contributing to disease pathogenesis.
Nonspecific histological changes may include axonal loss, demyelination or remyelination, and features indicative of inflammation. Chronic demyelination and remyelination can lead to concentric Schwann cell cytoplasm or basal lamina proliferation, forming multilayered "onion bulbs."[28] In CMT1, demyelination remains stable while axonal loss progresses over time. Occasionally, nerve biopsy in CMT1A may reveal "tomacula"—a characteristic feature of hereditary neuropathy with liability to pressure palsies (HNPP).[28] Tomacula are multifocal hypermyelinating processes that appear longitudinally like a "chain of sausages."[29] The presence of infiltration by inflammatory cells (lymphocytes and macrophages) may lead to a misdiagnosis of CIDP, particularly in cases associated with PMP22, MPZ, GJB1, and GDAP1 neuropathies. Some hypotheses explaining these inflammatory infiltrates include greater susceptibility to inflammation in CMT1A, the involvement of immune cells in genetically mediated demyelination, and superimposed CIDP.[30][31][32]
MPZ-associated neuropathy shows loss of compaction of myelin sheath layers, dissociation of the paired intra-period lines, regular widening between major dense lines, and irregularly uncompacted myelin sheaths.[29][33] Mutations in MPZ, MTMR2, MTMR12, MTMR5, SBF2, FGD4, SH3TC2, PRX, and NEFL can cause unusually thickened and folded myelin with redundant myelin loops.[29][34][35][36][37][38] These foldings differ from typical tomacula, characterized by focal hypermyelination and smooth external contours.[39][40][37][41]
SH3TC2-associated neuropathy exhibits abnormal extensions of Schwann cell cytoplasm and the formation of onion bulbs characterized by concentric proliferations of the basal lamina around both myelinated and unmyelinated fibers.[42][38] INF2-neuropathy shows unusual whorl-like proliferation and supernumerary elongated extensions of Schwann cell cytoplasm resembling filopodia, along with prominent axoplasmic reticulum and nodal widening.[43][28] Disruption of Cajal bands with focal hypermyelination is noted in PRX mutations.[44][45]
Mitochondria in MFN2 and GDAP1 mutations exhibit abnormal swelling, rounding, and vacuolation, often with accumulation of amorphous material and loss of cristae.[29] Uncommonly, ultrastructural observations may show an absence of transverse bands and the widening of the paranodal junctional gap between myelin loops and axolemma in CNTNAP1 mutations.[46][47][48] In NDRG1-associated neuropathy (CMT4D), a characteristic feature is the presence of pleomorphic granular deposits, sometimes containing filaments or vesicles filled with glycogen, in the adaxonal space of myelinated fibers. NEFL-associated neuropathies exhibit abnormally condensed unmyelinated fibers with aggregates containing glycogen granules and dense microtubules. Mutations in SH3TC2 and NEFL may lead to the formation of "giant axons."[29] In congenital amyelinating neuropathy due to EGR2 mutations, there is a total absence of myelin with normal axons.[49]
History and Physical
History of Present Illness
The history of the current illness includes assessments of pain, weakness, loss of sensation, foot deformities, and muscle cramps. Symptoms include difficulty walking fast or running, tripping, falls, and twisting or spraining ankles. Young patients with CMT may experience delayed motor milestones. During childhood, these patients may appear clumsy and struggle with athletic activities.
Since the onset of CMT is insidious and progression is usually slow, determining the exact age of onset is sometimes difficult. Affected patients may have foot deformities, delayed motor milestones, difficulty walking, and impaired sensation.[50][51] Severe phenotypes such as Dejerine-Sottas syndrome may manifest with neonatal hypotonia, difficulty in feeding, hip dysplasia, and respiratory compromise.[52][53]
Patients have varying severities of CMT, spanning a spectrum from minimally symptomatic to severe.[54] Concomitant illnesses such as hypothyroidism, diabetes, obesity, and toxin exposure increase impairment in these patients.[55] Early or infantile-onset CMT usually correlates with worse disability.[56]
Family History
The family history should include inquiries about symptoms of neuropathy in relatives. Patients exhibit intra-familial and interfamilial phenotypic heterogeneity in age at onset, motor deficits, and sensory loss. This variability is observed even in families sharing the same genetic abnormalities.[57] For example, point mutations in PMP22 may manifest as classical CMT1A, HNPP, Dejerine-Sottas syndrome, or congenital hypomyelinating neuropathy. Alternatively, they may remain asymptomatic, with only minor abnormalities detected on electrophysiological testing.[58][59]
Physical Examination
The physical examination must include a complete neurological assessment. Common clinical features across all variations of CMT are distal symmetrical weakness of the feet and legs, atrophy of weak muscles, reduction or loss of tendon reflexes, and skeletal deformities. Assessing gait is crucial, as weakness progression in CMT patients may lead to foot drop and a high-stepping gait. Onset in the upper limbs with proximal muscle weakness is rare. Hand weakness manifests as difficulty in buttoning, zipping, and writing. About 20% to 30% of patients with CMT complain of musculoskeletal pain rather than neuropathic pain. Paresthesias and positive sensory symptoms are infrequent.
Physical examination may reveal foot deformities such as pes cavus (high arches) or hammer toes and subtle wasting of hypothenar muscles in patients with long-standing disease due to the weakness of the intrinsic muscles of the hand. Atrophy of the lower legs and distal thighs may cause the "stork leg deformity." Spinal deformities (scoliosis) may also occur. Early and severe scoliosis is suggestive of, but is not an exclusive feature of, SH3TC2 mutations.[38] Abnormal gait and instability occur due to weakness, proprioceptive loss, and skeletal deformities such as pes cavus and hammer toes.[25] These clinical manifestations result from axonal loss, even in demyelinating CMT, as these patients have slowed NCVs before the onset of clinical manifestations.[60][61][62][54] Pyramidal signs may occur, which is associated with MFN2 mutations.[63]
In a study involving 49 patients with genetically confirmed CMT, 88% had at least 1 additional feature, and 65% had 2 or more additional symptoms. This may provide clues for underlying genetic variations.[64] Patients with CNVs in PMP22 and mutations in MPZ and GJB1 may exhibit pupillary abnormalities, including tonic pupils, miosis, mydriasis, anisocoria, and impaired pupillary reaction.[65][66][64]
Additional ocular manifestations of CMT include ptosis, optic atrophy, early cataract, glaucoma, and age-related macular degeneration. Cranial neuropathies, such as deafness, vocal cord palsy, facial or bulbar weakness, and tongue atrophy, can also occur in CMT, although rarely. Patients with PMP22 and MPZ-associated neuropathies may report pain and paresthesias. Patients with Thr124Met mutations in MPZ may present with a late-onset phenotype with pupillary abnormalities, shooting pains, disturbing paresthesias, and sometimes rapid progression.[65] In Hungarian patients, deafness and autoimmune disorders were often associated with PMP22 duplication.[9]
Features of dysautonomia, including urinary urgency and incontinence, orthostatic hypotension, and hyperhidrosis, have also been reported in CMT.[64] Patients with mutations in INF2 may develop focal segmental glomerulosclerosis, which can progress rapidly to end-stage renal disease.[67][68] Restless legs syndrome is more prevalent in patients with CMT as compared to the general population.[69][64] Axonal loss, irrespective of the CMT subtype, increases axonal excitability in the primary sensory units of leg muscles and leads to creeping sensations.[70] Other rare features include hyperkeratosis, skin hyperlaxity, arthrogryposis, impaired cognition, learning disability, lip or chin myokymia, respiratory insufficiency, tremor, nystagmus, ataxia, fasciculations, cold-induced cramps, hip dysplasia, and Ehlers-Danlos syndrome.[66][64][71] An occasional patient with genetically confirmed CMT may have acute worsening resembling inflammatory polyradiculoneuropathies.[72]
Evaluation
The evaluation of CMT has advanced with the development of more sophisticated tests. However, this is tempered by the fact that not all tests are uniformly available and may be expensive. In the past, diagnosis was solely based on the patient's clinical presentation. Presently, diagnosis involves a combination of clinical presentation, electrodiagnostic features, and genetic testing. Most experts in CMT advocate a stepwise process of testing when the disorder is suspected, starting with motor nerve conduction studies and then proceeding to sequential gene testing based on motor NCVs.
Electrophysiology
Electromyography (EMG) and NCV testing are crucial for confirming the diagnosis of neuropathy and distinguishing between demyelinating and axonal types of CMT. These minimally invasive tests offer rapid results and aid in excluding alternative causes of neuropathy. Additionally, EMG and NCV are valuable for screening asymptomatic relatives of the index patient.
The key parameters measured are distal latencies, amplitudes, and velocities of motor and sensory nerves. Slowing of conduction velocities is an indirect measure of myelin dysfunction. Reduced amplitude of compound muscle action potential with preserved conduction velocity indicates axonopathy. In some cases, both demyelinating and axonal neuropathies may coexist. Evidence of denervation detected on concentric needle EMG helps establish axonal pathology.
The median NCV of 38 m/s is commonly used to differentiate demyelinating from axonal types of CMT. However, an intermediate form of CMT exists where NCV ranges from 25 to 45 m/s.[25] Based on NCVs, CMT is categorized as very slow (<15 m/s), slow (15-35 m/s), and intermediate (35-45 m/s), aiding in the selection of genetic testing for patients with inherited neuropathies.[73]
Slowing is usually uniform and diffuse in inherited neuropathies. However, in GJB1-associated CMT, motor conduction slowing is nonuniform and heterogeneous within a single nerve and between multiple nerves, with greater velocity reduction in the median compared to the ulnar nerve. This inter-nerve variability is particularly prominent in females.[74][75] Demyelination is more severe and uniform in affected males, leading to a more pronounced reduction in conduction velocities.[74]
Temporal dispersion and conduction blocks are distinguishing features of acquired demyelinating neuropathies compared to inherited ones.[76] The absence of dispersion and conduction blocks, along with slowed conduction velocities typically ranging from 20 to 30 m/s, are indicative of an underlying hereditary neuropathy. However, in cases involving GJB1 mutations, temporal dispersion can still occur despite the genetic association.[77][78][74][79]
Reduction in the amplitude of evoked motor responses and sensory potentials indicates the extent of axonal loss, which correlates with clinical disability, especially in patients presenting late with demyelinating CMTs.[76] Distinguishing primary axonal from demyelinating forms of CMT becomes challenging when the motor and sensory potentials are unrecordable. Proximal nerve studies, including the musculocutaneous and radial nerves, provide valuable insights in such cases.[79]
Genetic Testing
Genetic testing is the standard for establishing a conclusive diagnosis, providing medical counseling, aiding reproductive planning, and selecting patients for therapeutic trials and research.[80] All patients suspected of having CMT should have phenotypic characterization, detailed and accurate pedigree analysis, and proper pretest counseling.
If there is a family history of CMT with a known variant, genetic testing should be performed for that variant. If the results are not diagnostic and NGS is available and affordable, CMT large-panel genetic testing should be performed. If not, sequential genetic testing based on motor NCVs should be done.
The most common genetic abnormality in CMT is CNV in PMP22. Molecular techniques that are available to detect CNVs in PMP22 include polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), denaturing gradient gel electrophoresis (DGGE), single-strand conformational polymorphism (SSCP), array comparative genomic hybridization (aCGH), and fluorescence in-situ hybridization (FISH). These techniques are time-consuming, labor-intensive, expensive, and have limited sensitivity. The multiplex ligation-dependant probe amplification (MLPA) follows the principle of comparative quantification of specifically bound probes amplified by PCR using universal primers.[81] This test is simple, quick, sequence-specific, sensitive, and efficient, and thus MLPAt is the recommended analytical platform.[82]
Sanger sequencing is the standard in molecular genetic diagnosis. However, it has limitations in diagnosing CMT due to the large number of possible genetic variations. Mutations in genes other than PMP22, MPZ, GJB1, and MFN2 are rare, making it challenging to prioritize and conduct sequential analysis of all the possible CMT genes by Sanger sequencing. This approach is both time-consuming and expensive.
Genetic testing has evolved with the development of NGS technology, which is capable of sequencing the entire human genome, its protein-coding sequences, or specific genes of interest in parallel.[83] The yield of NGS depends on the gene panel used. The exome refers to the complete set of protein-coding regions in the human genome. Although it constitutes only 1% of the total genomic content, it contains more than 85% of the functional variations. Whole-exome sequencing evaluates the entire protein-coding region in an unselected or unbiased manner. Whole-genome sequencing evaluates both coding and noncoding regions. Some laboratories distinguish between clinical exome and whole-exome sequencing; the former refers to a set of genes implicated in most human diseases.[84]
NGS of the entire exome may find the majority of the disease-causing genes. Targeted panel gene testing typically includes a limited number of genes based on the patient's phenotype. It has better technical performance, easier data analysis, fewer incidental findings, lower cost, and is easier to adopt in small laboratories. However, targeted panels may fail to identify novel gene associations.[85] NGS is the preferred technique for establishing the genetic diagnosis in CMT once CNVs or mutations in common genes are excluded. Even with whole-exome sequencing, about 40% of patients remain without a genetic diagnosis. NGS is negative in cases of mutations in genes that are unidentified or not described in the setting of CMT. NGS may miss mutations in the untranslated region (UTR), promoter, and other non-exonic regions. NGS is not sensitive to identifying CNVs or epigenetic, posttranscriptional, and posttranslational changes. Functional analysis is essential to ascribe pathogenicity when NGS identifies novel variants.[86]
Radiographic Imaging
Advances in imaging have enabled visualization of peripheral nerves along their entire length. Nerve ultrasound and magnetic resonance neurography are increasingly used to evaluate neuropathies. In CMT, diffuse enlargement of nerves exists, including roots, plexuses, and peripheral nerves, without variation between entrapment and nonentrapment sites.[87] Enlarged cranial nerves have also been described. The enlargement is more pronounced in upper limbs and CMT1A compared to other forms of CMT. In CMT2, there is no significant increase in the cross-sectional area (CSA) of peripheral nerves. An increase in CSA correlates with disability and disease progression.[88] Postcontrast enhancement, vascularity, altered signal characteristics within the nerve, and fascicular architecture differentiate CMT from other diagnoses, such as CIDP and leprosy.[89]
In children and adolescents with CMT, magnetic resonance imaging (MRI) can be used to evaluate the relationship between muscle volume and intramuscular fat accumulation (IMFA) in the lower legs and impaired gait, weakness, and disability.[90]
Evaluation of Systemic Involvement
Patients with CMT need evaluation for concomitant illnesses, including diabetes mellitus, thyroid dysfunction, and nutritional deficiencies that affect peripheral nerve function. They may also need slit-lamp examination (for cataracts), intraocular tension recording (for glaucoma), laryngoscopy (for vocal cord mobility), and audiometry (for hearing loss). Additionally, spirometry and polysomnography may be necessary for evaluating restrictive lung disease, obstructive sleep apnea, and restless leg syndrome. Patients with CMT and INF2 mutations need evaluation for proteinuria and nephrotic syndrome due to the risk of focal segmental glomerulosclerosis, as these patients are often asymptomatic and their renal function may worsen rapidly, necessitating a renal transplant.[67]
Treatment / Management
Treatment of CMT is predominantly rehabilitative and symptomatic, as there are currently no effective disease-modifying therapies to alter its natural progression. Management typically involves a multidisciplinary healthcare team comprising neurologists, physiatrists, orthopedic surgeons, podiatrists, and physical and occupational therapists.
Pharmacotherapy
Treatment remains largely symptomatic. Musculoskeletal pain may be alleviated with acetaminophen or nonsteroidal anti-inflammatory drugs. Neuropathic pain may respond to tricyclic antidepressants, carbamazepine, or gabapentin. Fatigue can be managed with modafinil.[91] Additional modalities rest on the current understanding of the underlying genetic abnormalities and pathophysiology of CMT, coupled with newer drug development techniques such as systemic biology-based modeling, anti-sense oligonucleotides, adenoviral vector-based drug delivery, and RNA interference technology. In CMT1A, efforts to target PMP22 overexpression—using agents such as ascorbic acid, onapristone, geldanamycin, and rapamycin—showed promise in animal and cell studies, but have not demonstrated effectiveness in human clinical trials.[92] (B3)
PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has demonstrated efficacy in reducing the toxic effects of PMP22 overexpression in both mice and humans. Subjects treated with PXT3003 showed no deterioration or improvement in CMT Neuropathy score (CMTNS), Overall Neuropathy Limitations Scale (ONLS), the 10-m walk test, and conduction velocities compared to placebo. PXT3003 was well tolerated and safe.[93] Additionally, curcumin has shown promise in alleviating endoplasmic reticulum stress and improving MPZ-associated neuropathy in murine models.[94](A1)
Other agents investigated for their therapeutic potential in CMTs, albeit with limited success, include promoters of axonal regeneration (neurotrophin-3 and neuregulins), gene expression regulators (histone deacetylases), chaperones and heat shock protein inducers (arimoclomol and celastrol), calcium homeostasis modulators (P2X7 antagonists-adenosine homodinucleotide P18), neuroprotective and antioxidant drugs (purified polyols-resveratrol), and potassium channel blockers (3,4-diaminopyridine).[92] Supplementation with essential fatty acids, phospholipids, vitamin E, creatine, and bovine-derived ganglioside mixture has not been effective.[95](B3)
Rehabilitation
An interprofessional healthcare team is crucial for treating patients with CMT who are at risk of developing reduced range of motion, contractures, and musculoskeletal deformities. The important components of physical therapy include stretching, gripping exercises, aerobics, resistance training, and timely use of orthotic devices such as special shoes with good ankle support to correct foot drop and facilitate walking. Some individuals may require canes or forearm crutches for gait stability. Physical therapy improves and maintains muscle strength and function, enhances joint flexibility and range of movement, and helps improve balance and cardiorespiratory fitness. Physical therapy also addresses fatigue and pain and prevents stiffness and deformities.[92][96] (A1)
Patients with CMT may face challenges participating in exercise programs due to heightened energy demands and altered gait kinetics. The concept of "overuse weakness," where exercise potentially exacerbates muscle loss and weakness, remains debated in CMT.[97] Orthoses improve posture and walking balance, particularly in cases of ankle weakness and deformity. Supervised exercise programs are necessary for managing hand muscle weakness, complemented by occupational therapy to aid daily activities. Splinting is effective in enhancing hand dexterity.[96](A1)
Additional Treatment Measures
Symptomatic treatment of fatigue, depression, neuropathic pain, and restless legs syndrome is similar to other neuropathies. Foot deformities, scoliosis, and hip dysplasia may need corrective surgeries and tendon transfers. Restrictive lung disease, sleep apnea, and vocal cord palsy need suitable intervention in collaboration with surgeons, pulmonologists, otorhinolaryngologists, physiatrists, and related specialties.[92] Close monitoring and management are recommended for pregnant women with CMT.[98](A1)
Pediatrics
Progressive resistance exercise of the ankle dorsiflexors is recommended to improve muscle strength and slow the progression of weakness. Strength training of core muscles is encouraged, as are joint stretching, balance training, and the use of ankle-foot orthoses. Referral to an orthopedic surgeon may be necessary for addressing progressive pes cavus, ankle contractures, hip dysplasia, and scoliosis. Adaptive equipment should be utilized to improve daily living activities. Respiratory deficits should be assessed, and a referral to a pulmonologist or sleep physician is advised for recurrent lower respiratory tract infections or sleep-disordered breathing.[99] (A1)
Differential Diagnosis
CMT must be differentiated from other conditions characterized by predominant distal weakness, muscle wasting, foot deformities, and a progressive course. The most critical differential diagnosis involves distinguishing between acquired dysimmune neuropathies and demyelinating CMT.[100]
Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene is an important differential diagnosis, as motor NCVs are very low in this condition. However, patients with SMARD1 have normal sensory nerve action potentials.[101] Distal myopathies can manifest with foot drop, but the pattern of weakness and electrophysiological studies (nerve conduction studies and concentric needle EMG) can distinguish them from CMT. In children, distinguishing CIDP from CMT can be challenging. Genetic testing, along with clinical and electrophysiological examinations of asymptomatic family members, and nerve biopsies, may assist in making an accurate diagnosis.[100]
Other differential diagnoses include acquired neuropathies due to diabetes mellitus, nutritional deficiencies, vasculitis, and heavy metal intoxication. Inherited conditions where neuropathy is part of a complex multisystem disorder, such as autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), Friedreich’s ataxia, metachromatic leukodystrophy, the syndrome of neurogenic weakness, ataxia, and retinitis pigmentosa (NARP), or Refsum’s disease, should also be considered.[100][102]
Staging
Patients with CMT have a progressive clinical course and need periodic monitoring. Composite scoring systems are available to assess longitudinal changes in function and disability, including natural history and outcome. The CMTNS is a reliable composite of 9 items that incorporates motor and sensory signs and symptoms, as well as electrophysiological parameters. The CMTNS score ranges from 0 (best) to 36 (worst) and is used for classifying patients as having mild (≤10), moderate (11-20), or severe (≥20) disability.[103]
A similar score exists for use in the pediatric population (CMTPedS).[104] However, the annual change in this score is insufficient to assess therapeutic response in clinical trials. Other clinical and functional outcome measures include handgrip myometry, ankle dorsiflexion myometry, the overall neuropathy limitations scale, and the 9-hole peg test.[105]
Alternate sensitive, reliable, reproducible, and clinically relevant markers that reflect degeneration of Schwann cells or axons and act as measures of disease burden and progression have been developed. These markers include IMFA in calf muscles, serum neurofilament light chain, transmembrane protease serine 5 (TMPRSS5), and cutaneous mRNA profiling.[105][106][107]
Prognosis
CMT is a group of insidiously progressive disorders characterized by increasing weakness and wasting of the extremities, which interfere with mobility and activities of daily living. The rate of progression varies among different forms of CMT. Although life expectancy is usually unaffected, the condition can be severe if early onset occurs. Periodic evaluation and interventions by an interprofessional rehabilitation team are essential for maintaining independence, safe ambulation, and functional activities.
Complications
Foot deformities are a major source of disability in CMT. These deformities develop over time and may worsen despite physiotherapy and the use of orthoses. Early surgical intervention to correct muscle imbalance and establish a plantigrade foot position may prevent further deformity and reduce the need for future joint fusions.[108][109] Corns and calluses may develop at sites of increased pressure and lead to skin ulceration. Respiratory insufficiency may arise due to severe neuropathy, diaphragmatic palsy, or concomitant spinal deformity.[64]
Worsening of CMT-related symptoms may occur during pregnancy, increasing the risk of abnormal fetal lie, postpartum hemorrhage, and the need for emergency intervention during delivery. Therefore, regular maternal-fetal prenatal care is recommended. Additionally, neurotoxic drugs, chemotherapeutic agents, and comorbid neuropathic diseases can exacerbate neuropathy in CMT.[80]
Deterrence and Patient Education
Individuals with CMT and their families should be educated about the disease and its symptoms, such as weakness and foot problems. Additional information should be provided about the available treatments and the overall progression of the disease. The likely mode of inheritance should be explained to the patient based on pedigree chart analysis and genetic testing. Patients with CMT are encouraged to remain active, maintain a healthy weight, follow up with the interprofessional team, and avoid neurotoxic agents and drugs that can worsen neuropathy. Referral to genetic counseling is essential to address questions about family planning.
Pearls and Other Issues
- CMT refers to a group of inherited neuropathies characterized by progressive weakness, muscle wasting, and foot deformities.
- Electrophysiological tests help confirm the diagnosis of neuropathy and exclude alternative conditions such as distal myopathies, muscular dystrophies, and idiopathic pes cavus that also present with foot drop and foot deformities.
- Electrophysiological tests are valuable for screening family members for asymptomatic neuropathy.
- Patients with demyelinating CMT typically exhibit slowed NCVs in early childhood. Over time, distal axonal loss leads to weakness, muscle wasting, and foot deformities.
- All patients suspected of having CMT should undergo genetic counseling before undergoing genetic testing.
- In demyelinating neuropathies, patients should first undergo testing for PMP22 duplication, as it is the most common genetic abnormality in CMT. Following the exclusion of CNVs in PMP22, targeted gene sequencing or whole-exome sequencing should be considered.
- In axonal neuropathies, the patient should first be tested for mutations in MFN2. Alternatively, they can undergo targeted gene sequencing or whole-exome sequencing.
- Establishing the genetic diagnosis is crucial for ongoing genetic counseling, reproductive planning, and considering the patient for potential new therapies in research.
- Patients with CMT should undergo monitoring for comorbid conditions.
- Patients with CMT should avoid using drugs that worsen neuropathy.
- The interprofessional healthcare team should offer patient education and counseling, regular follow-up, emphasize rehabilitation measures, and provide access to therapeutic trials.
Enhancing Healthcare Team Outcomes
Patients benefit most from an interprofessional healthcare team with a patient-centric approach to comprehensive care. The interprofessional healthcare team should include specialists in the fields of neurology, primary care, physiatry, physiotherapy, nursing, occupational therapy, social work, and neurogenetic counseling. Having experts in orthopedics, pulmonology, speech therapy, sleep medicine, and nephrology on the team is also essential. Healthcare providers should coordinate with these team members to optimize the patient's function, prevent injuries and complications, and improve the overall quality of life for individuals with CMT.
The team should include expertise in recognizing the varied clinical presentations of CMT and understanding the nuances of diagnostic techniques such as EMG, NCV testing, and genetic testing.
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