Continuing Education Activity

Charcot-Marie-Tooth disease (CMT) is the commonest inherited neuromuscular disorder. It affects the peripheral nerves and leads to progressive weakness of extremities. Occasionally it involves cranial nerves, other sites of the neuraxis, and other organ systems. Diagnosis of CMT is important for patient education and counseling as also for initiating appropriate rehabilitation measures and consideration for therapeutic trials. This activity reviews the clinical and electrophysiological evaluation of patients with CMT and provides a comprehensive update on the pathophysiology, genetics, and imaging findings. This activity also highlights the need for interprofessional care and trial of upcoming potential therapies.

Objectives:

• Review the pathophysiological mechanisms in Charcot-Marie-Tooth disease.
• Describe the evaluation of patients with Charcot-Marie-Tooth disease.
• Summarise the management in Charcot-Marie-Tooth disease.

Introduction

Inherited peripheral neuropathies are a group of disorders that include the hereditary motor and sensory neuropathies (HMSN), hereditary motor neuropathies (HMN), and hereditary sensory neuropathies (HSN) or hereditary sensory, and autonomic neuropathies (HSAN). The commonest entity, HMSN is also known as Charcot-Marie-Tooth disease (CMT).

This entity was first described in 1886 by Jean Marie Charcot and Pierre Marie from France and Howard Henry Tooth from England. Subsequently, Hoffman described thickened nerves in a patient of ‘peroneal muscular atrophy’. The CMTs are heterogeneous in clinical, electrophysiological, genetic, and pathological features. However, the majority of these patients manifest in the first or second decade with insidious onset and slowly progressive weakness that starts in lower extremities and later involves upper extremities.[1][2]

Etiology

The CMTs are genetically determined disorders with implications of nearly 100 genes. Over 80% to 90% of the genetic abnormalities are due to copy number variation in PMP22 and mutations in GJB1, MPZ, and MFN2 genes. The frequency of abnormalities in other genes individually is rare.[3][4][5] Copy number variation in PMP22 is the commonest cause of CMT. PMP22 is a large gene that is located in the middle of the 1.4 Mb regions in chromosome17p.12. This region is susceptible to frequent genomic rearrangements. Duplication or deletion in PMP22 leads to disease via a gene dosage effect.[6] 

Duplication in heterozygous state results in 1.5-fold overexpression, while homozygous duplication causes two-fold overexpression of PMP22 in Schwann cells. This genomic duplication results from an unequal meiotic crossover that is facilitated in the male germline by the flanking homologous repeat sequences. This overexpression overloads the proteasome system and leads to cytoplasmic aggregation of the ubiquitinated PMP22 protein. This, in turn, causes the recruitment of auto-phagosomes and lysosomes and increased autophagy.[7][8][9][10] 

Frameshift mutations in MPZ lead to mutant proteins aggregating in the endoplasmic reticulum (ER) and consequent apoptosis. Other CMTs are usually the result of the loss of function mutations in other genes and uncommonly due to a toxic gain of function.[11]

Epidemiology

CMTs are a group of clinically and genetically heterogeneous neuropathic disorders. They occur the world over and involve all ethnic groups. CMTs as a group form the commonest inherited neuromuscular disorder with an estimated frequency of 1 in 2500 people.[12] Epidemiological data from adult neuropathy clinics reveals that CMTs are more frequent than inflammatory or paraneoplastic neuropathies.[13][14] Its prevalence ranges from 9.7/100,000 in Serbia to 82.3 per 100,000 in Norway.[15] Population-based surveys have revealed a varied frequency of CMT in different countries; Libya: 8 per 100,000, Nigeria: 10 per 100,000, South Wales: 17 per 100,000, Northern Sweden: 20 per 100,000, and Northern Spain: 28 per 100,000.[16] CMTs are broadly categorized as demyelinating (CMT1) and axonal (CMT2) subtypes. The frequency ranges from 37.5% to 84% for CMT1 and from 12% to 35.9% for CMT2.[15] In western Norway, the estimated prevalence for autosomal dominant, X-linked, and autosomal recessive CMT was 36 in 100,000, 3.6 in 100,000, and 1.4 in 100,000, respectively.[15]

Pathophysiology

The normal structure and functions of peripheral nerves depend upon the close anatomical and physiological interaction between Schwann cells and axons. Axons determine survival, proliferation, and differentiation of Schwann cells. These cells in turn play an important role in regulating ion channels and maintenance, survival, and regeneration of axons. Abnormalities in genes that regulate myelin assembly and axonal transport lead to primary demyelination and axonopathy respectively. CMTs may occur due to any one of the following molecular and cellular mechanisms:

1. Myelin assembly: genes involved in myelin compaction (MPZ), gap junctions formation (GJB1), the interaction of Schwann cells with the extracellular matrix as well as in regulating cell spreading, cell migration and apoptosis (PMP22)
2. Cytoskeletal structure: genes involved in actin polymerization (INF2), membrane-protein interactions to stabilize the myelin sheath (PRX), intermediate filaments (NEFL), cell signaling (FGD4), axonal transport (DYNC1H1)
3. Endosomal sorting and cell signaling: genes regulating vesicular transport, membrane trafficking, transport of intracellular organelles and cell signaling (LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7A, TFG, DNM2, SIMPLE)
4. Proteasome and protein aggregation: genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
5. Mitochondria: genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
6. Others: genes regulating cell fusion-fission apparatus (DNM2), calcium homeostasis (TRPV4) glucose metabolism (HK1), transcription (EGR2, HINT1, PRPS1, AARS, GARS, MARS, KARS, YARS)

Because of the close functional interaction, demyelinating neuropathies eventually lead to functional axonopathies and clinically manifest secondary axonal degeneration.[17][18] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[19]

Classification of CMTs

CMTs have varied ages at onset: neonatal or ‘congenital’, infantile, or late-onset.[20] They are categorized as early infantile (<2 years), childhood (2 to 10 years), juvenile (10 to 20 years), adult (20 to 50 years), and late adult (>50 years) onset.[4] The CMTs are also classified based on the electrophysiological findings as demyelinating and axonal neuropathies. CMTs have autosomal dominant, autosomal recessive or X-linked patterns of inheritance. The autosomal dominant pattern of inheritance is the commonest.[21] Based on the electrophysiological and pathological findings, and key clinical features, CMTs were initially named as hereditary motor and sensory neuropathies (HMSN) and classified as;

1. HMSN I: demyelinating subtype
2. HMSN II: axonal subtype
3. HMSN III: Dejerine Sottas disease
4. HMSN IV: Refsum disease
5. HMSN V: with pyramidal signs
6. HMSN VI: with optic atrophy
7. HMSN VII: with retinitis pigmentosa

Later the classification was changed based on the mode of inheritance and clinical features as CMT1 (A, B, C...), CMT2 (A, B, C.. ), CMT3, CMTX (1,2,3..) and CMT4, etc. However, due to overlapping phenotype and genotype and advances in molecular testing, the classification has undergone changes over the years e.g. demyelinating CMT or CMT1 is autosomal dominantly inherited, recessively inherited demyelinating CMTs are named as CMT4, while recessively inherited axonal CMTs are designated as AR-CMT2. There exists a lack of consensus in the nosological terms provided by different experts.[22] 

There is significant phenotypic heterogeneity with certain mutations e.g. variations in MPZ, GDAP1, and NEFL can cause both the demyelinating and axonal CMTs. Similarly, patients with mutations in MFN2, MPZ, GDAP1, and EGR2 may have CMTs with autosomal dominant or recessive inheritance. Thus with expanding knowledge, it is proper to classify CMTs based on the molecular genetic abnormality and not by electrophysiological or pathological observations. A revised classification that incorporates the phenotype, electrophysiology, mode of inheritance, and the causal gene is gaining ground.[20]

History and Physical

The clinical features common to all CMTs are distal symmetrical weakness, wasting, hypo/areflexia, and skeletal deformities. These are more pronounced in lower limbs as compared to upper limbs. Commonly reported symptoms are difficulty in walking fast or running, tripping, falls, and twisting or spraining of ankles. Patients may have delayed motor milestones. During childhood, these patients are clumsy and ‘slow’ in sports, and not athletic. As the weakness progresses, patients develop foot drop and high-stepping gait. The weakness of hands manifests as difficulty in buttoning, zipping, and writing. Onset in upper limbs and weakness of proximal muscles may also occur, but uncommonly. Sensory symptoms and signs are relatively less prominent. About 20% to 30% of patients complain of pain, which is often musculoskeletal and rarely neuropathic. Thus paresthesia and positive sensory symptoms are rather infrequent.

Examination reveals pes cavus, hammertoes, and clawed hands in patients with long-standing disease due to the weakness of intrinsic muscles. Wasting of legs and distal thighs may seem like an inverted champagne bottle. Spinal deformities (scoliosis) may also occur. Early and severe scoliosis is suggestive of, but not an exclusive feature of SH3TC2 mutations.[23] Abnormal gait and imbalance occur because of proprioceptive loss and skeletal deformities like pes cavus and hammertoes.[21] These clinical manifestations are the result of axonal loss, even in demyelinating CMTs, since these patients have slowed velocities even before the onset of clinical manifestations.[24][25][26][27] Demyelinating subtypes may have thickened nerves. Pyramidal signs may co-exist, designated as HMSN type V and this phenotype is commonly associated with MFN2 mutations.[28]

Age at onset ranges from infancy to the elderly, but the most have onset within the first two decades of life. Since the onset is insidious and progression is usually slow, it is sometimes difficult to find the exact age at onset. Congenital hypo-myelinating neuropathy and Dejerine Sottas disease may have onset in the neonatal period or infancy. Affected patients manifest with foot deformities, delayed motor milestones, difficulty in walking, and impaired sensation.[29][30] Severe phenotypes manifest with neonatal hypotonia, difficulty in feeding, and respiratory compromise.[31][32]

Patients have varying severity of the disability, spanning a spectrum from minimally symptomatic to severe.[27] Patients have intra-familial and interfamilial phenotypic heterogeneity in the age at onset, motor deficits, and sensory loss. This variability is observed even in families sharing the same genetic abnormalities.[33] For example, point mutations in PMP22 may manifest with classical CMT1A, hereditary neuropathy with liability to pressure palsies (HNPP), Dejerine-Sottas syndrome, or congenital hypo-myelinating neuropathy or may remain asymptomatic with only minor abnormalities detected on electrophysiological testing.[34][35] Concomitant illnesses like hypothyroidism, diabetes, obesity, and toxin exposure increase impairment in these patients.[36] Early or infantile-onset usually correlates with worse disability.[37]

In addition to the classical phenotype of distal wasting, weakness, and deformities, patients may have several other features. In a study of 49 patients with genetically established CMT, Werheid et al., reported that 88% of the patients had at least one added feature, with 65% having two or more other manifestations. This may give a clue for underlying genetic variations.[38] Patients with copy number variations in PMP22 and mutations in MPZ and GJB1 may have pupillary abnormalities. They include tonic pupils, miosis, mydriasis, anisocoria, and impaired pupillary reaction.[39][40][38] 

Other ocular manifestations include ptosis, optic atrophy, early cataract, glaucoma, and age-related macular degeneration. Cranial neuropathies like deafness, vocal cord palsy, facial/ bulbar weakness, and tongue atrophy can also occur. Patients with PMP22 and MPZ associated neuropathies may report pain and paresthesias, as noted in acquired neuropathies. Patients with specific mutations in MPZ viz Thr124Met and Gly123Ala present with late-onset phenotype with pupillary abnormalities, shooting pains, disturbing paresthesias, and sometimes with rapid progression.[39][38] Milley et al. reported that deafness and autoimmune disorders were often associated with PMP22 duplication.[5]

Features of dysautonomia, including urinary urgency and incontinence, orthostatic hypotension, and hyper-hidrosis, have also been reported.[38] Focal segmental glomerulosclerosis rapidly progressing to end-stage renal disease is seen in patients with mutations in INF2.[41][42] Restless Leg Syndrome (RLS) is more prevalent in patients with CMT as compared to the general population.[43][38] Axonal loss, irrespective of the CMT subtype, increases axonal excitability in the primary sensory units of leg muscles and leads to creeping sensations.[44] 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 among others.[40][38][45] An occasional patient with genetically established CMT may have acute worsening resembling inflammatory polyradiculoneuropathies.[46]

Evaluation

Electrophysiology

Nerve conduction studies help in confirming the diagnosis of neuropathy and categorizing patients broadly into demyelinating and axonal subtypes. They are also useful in 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. Some patients may have features of both demyelinating and axonal neuropathy. Evidence of denervation on concentric needle electromyography is useful in establishing axonal pathology.

The median nerve conduction velocity of 38 m/sec is the commonly used cut-off for differentiating demyelinating from axonal types of CMT. Besides, there is an intermediate form where the nerve conduction velocity ranges from 25 to 45 m/sec.[21] Further, based on nerve conduction velocities, CMTs are categorized into: (1) very slow (<15 m/s); (2) slow (15 to 35 m/s); (3) intermediate (35 to 45 m/s); and (4) normal (>45 m/s). Saporta et al. reported the usefulness of this subdivision in selecting genetic testing for patients with inherited neuropathies.[47]

Slowing is usually uniform and diffuse in inherited neuropathies, unlike acquired etiologies, wherein the changes may be segmental, non-homogeneous, and asymmetrical. However, in GJB1 associated neuropathy, motor conduction slowing is non-uniform and heterogeneous within a single nerve and between multiple nerves, with the velocity being more reduced in the median as compared to the ulnar nerve. This inter-nerve variability is prominent in females.[48][49] On the other hand, demyelination is more severe and uniform in affected males, as reflected by a more marked reduction in conduction velocities.[48]

Temporal dispersion and conduction blocks distinguish acquired demyelinating neuropathies from inherited ones.[50] Lack of dispersion and conduction blocks along with slowed conduction velocities in the range of 20 to 30 m/sec gives a clue for an underlying hereditary neuropathy. Exceptionally, temporal dispersion can occur in GJB1 mutations.[51][52][48][53]

Reduction in the amplitude of evoked motor responses and sensory potentials reflects the degree of axonal loss, and this correlates with the clinical disability even in subjects with demyelinating CMTs.[50] Sometimes patients present late in the course of their disease. In this situation, it is difficult to distinguish primary axonal from demyelinating forms of CMT due to the un-recordable motor and sensory potentials. Here, studies of proximal nerves such as musculocutaneous and radial nerves are helpful.[53]

Nerve Imaging

Advances in imaging have enabled visualization of peripheral nerves along their entire length with great clarity. Nerve ultrasound and Magnetic Resonance Neurography are increasingly used in the evaluation of neuropathies. In CMTs, there is diffuse enlargement, including roots, plexuses, and peripheral nerves, without any variation between entrapment and non-entrapment sites.[54] Enlarged cranial nerves have also been described. The enlargement is more pronounced in upper limbs and CMT1A as compared to other CMTs. 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.[55] Post-contrast enhancement, vascularity, altered signal characteristics within the nerve, and fascicular architecture differentiates CMTs from other differential diagnoses such as chronic inflammatory demyelinating polyneuropathy (CIDP) and leprosy, among others.[56] Besides, muscle volume and intramuscular fat accumulation (IMFA) in legs also correlate with disability.[57]

Genetics

Genetic testing is useful in establishing a conclusive diagnosis (particularly so in a sporadic patient), medical counseling, reproductive planning, and in selecting patients for participating in therapeutic trials and research.[58] All patients should have phenotypic characterization, detailed and accurate pedigree analysis, and proper pre-test counseling by an expert.  

The commonest genetic abnormality in CMT is copy number variation in PMP22. Molecular techniques that are available to detect copy number variations 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-intense, and expensive and have limited sensitivity. The multiplex ligation dependant probe amplification (MLPA) follows the principle of comparative quantification of specifically bound probes that are amplified by PCR using universal primers.[59] This test is simple, quick, sequence-specific, fairly sensitive, and efficient, and thus MLPAt is the most common recommended analytical platform.[60]

The 'gold-standard' in molecular genetic diagnosis is Sanger sequencing. However, it has limitations since the number of genetic variations implicated in CMT is huge, and the frequency of abnormalities in each gene is rare. There are no specific phenotypic distinguishing features between the different CMTs. Except for PMP22, MPZ, GJB1, and MFN2, mutations in other genes are rather rare. Hence it is difficult to prioritize and carry out sequential analysis of all these genes by Sanger sequencing as it is both time-consuming and expensive.

High-throughput or the Next Generation Sequencing (NGS) technology is capable of massively parallel sequencing of DNA in an efficient, precise, fast, and economical way with improved throughput and high read depth.[21] 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. Though it forms only 1% of the total genomic content, it has more than 85% of the functional variations. Whole-exome sequencing evaluates the entire protein-coding region in an unselected or unbiased way. Whole-genome sequencing evaluates coding as well as non-coding regions. Some laboratories distinguish between the 'clinical exome' and the 'whole exome' sequencing; the former referring to a set of genes that are implicated in the majority of human diseases.[61] NGS of the entire exome may find the majority of the disease-causing genes. 'Targeted' panel generally consists of a limited number of genes based on the phenotype. It has better technical performance, easier data analysis, fewer incidental findings, lower cost, and is easier to adopt in small laboratories.  However, it may fail to identify novel genes associations.[62]

Thus the NGS is the preferred technique for establishing the genetic diagnosis in CMT, once copy number variations or mutations in common genes are excluded. Nevertheless, even with whole-exome sequencing, a significant proportion of patients are left without a genetic diagnosis. NGS is negative in cases of mutations in genes that are yet unidentified or not described in the setting of CMT. NGS may miss mutations in the untranslated region (UTR), promoter, and other non-exonic regions. Besides, NGS is not a sensitive technique for identifying copy number variations or epigenetic, post-transcriptional, and post-translational changes. Functional analysis is essential to ascribe the pathogenicity when NGS identifies novel variants.[63]

Nerve Biopsy

Nerve biopsy has a role in identifying underlying genetic etiology in sporadic cases, and it helps to distinguish CMT from acquired disorders like CIDP. Nerve biopsy may also support a functional association when the genetic tests detect "variants of uncertain significance" or a novel variant. Morphological and ultrastructural changes in the axons, myelin, nodes of Ranvier, and mitochondria help in understanding the functions of the mutated genes, and to some extent, the pathways leading to disease.

Non-specific changes include axonal loss, demyelination/remyelination, and occasionally features suggestive of inflammation. Chronic demyelination and remyelination induces concentric proliferation of Schwann cell cytoplasm or basal lamina and causes the formation of 'onion bulbs.' In CMT1, demyelination remains stable while axonal loss progresses with time. In some instances, nerve biopsy in CMT1A may show 'tomaculae' that is the characteristic feature of HNPP.[64] Tomaculae is multifocal hyper-myelinating processes that appear in longitudinal sections like a chain of sausages.[65] The presence of infiltration by inflammatory cells viz lymphocytes and macrophages may sometime lead to a misdiagnosis of CIDP, particularly in PMP22, MPZ, GJB1, and GDAP1 associated neuropathies. Greater susceptibility to inflammation in CMT1A, the involvement of immune cells in genetically mediated demyelination, and superimposed CIDP are some of the hypotheses to explain these inflammatory infiltrates.[66][67][68]

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 un-compacted myelin sheaths.[65][69] Mutations in MPZ, MTMR2, MTMR12, MTMR5, SBF2, FGD4, SH3TC2, PRX, and NEFL can cause unusually thickened and folded myelin with redundant myelin loops.[65][70][71][72][73][23] These foldings are different from typical tomaculae, which are characterized by focal hypermyelination and 'smooth' external contours.[74][75][73][76] SH3TC2-associated neuropathy shows abnormal extensions of the cytoplasm of Schwann cells and 'onion bulbs' formed by concentric proliferations of the basal lamina of Schwann cells, both myelinated and unmyelinated fibers.[77][23] INF2-neuropathy shows unusual whorl-like proliferation and supernumerary elongated extensions of Schwann cell cytoplasm resembling filopodia, prominent axoplasmic reticulum, and nodal widening.[78][64] Disruption of Cajal bands with focal hypermyelination is noted in PRX mutations.[79][80]

Mitochondria are abnormally swollen, rounded, and vacuolated and may show accumulation of amorphous material with loss of cristae in MFN2 and GDAP1 mutations.[65] 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.[81][82][83] The pathological hallmark of NDRG1-associated neuropathy (CMT4D) is the pleomorphic granular deposits, sometimes with filaments or vesicles filled with glycogen, in the adaxonal space of myelinated fibers. In NEFL-associated neuropathies, unmyelinated fibers are abnormally condensed and show aggregates containing glycogen granules and dense microtubules. SH3TC2 and NEFL mutations may show "giant axons."[65] In congenital amyelinating neuropathy due to EGR2 mutations, there is a total absence of myelin with normal axons.[84]

Evaluation of Systemic Involvement

Patients need evaluation for concomitant illnesses like diabetes mellitus, thyroid dysfunction, and vitamins, and other nutritional deficiencies that impact peripheral nerve function. Patients may also need slit-lamp examination (for cataract), intra-ocular tension recording (for glaucoma), laryngoscopy (for vocal cord mobility), and audiometry (for deafness). Patients may undergo spirometry and polysomnography for the evaluation of restrictive lung disease, obstructive sleep apnea, and restless leg syndrome if required. Patients with INF2 mutation may need evaluation for proteinuria arising from nephrotic syndrome due to focal segmental glomerulosclerosis, as they are often asymptomatic or paucisymptomatic and their renal function may worsen rapidly necessitating a renal transplant.[41]

Treatment / Management

Treatment of CMTs is mostly rehabilitative and symptomatic since there is no definite and effective disease-modifying treatment to alter the natural progressive course of the disease.

Pharmacotherapy

Rests on the current understanding of the underlying genetic abnormality and pathophysiology of CMTs 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, agents target PMP22 overexpression such as ascorbic acid, onapristone, geldanamycin, and rapamycin have been beneficial in animal models and cell lines with improved muscle mass and weakness. However, these agents were not useful in human clinical trials.[85] PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has shown a reduction in the toxic effects of PMP22 over-expression in mice and humans. A significant number of subjects who received PXT3003 showed non-deterioration or improvement in CMT Neuropathy score(CMTNS), Overall Neuropathy Limitations Scale (ONLS), 10-meter walk test, and conduction velocities as compared to placebo. PXT3003 was well tolerated and safe.[86] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[87]

Other agents whose therapeutic role in CMTs have been explored with limited results include those that promote axonal regeneration (neurotrophin-3, neuregulins), regulators of gene expression (histone deacetylases), chaperones and inducers of heat shock proteins (arimoclomol and celastrol), calcium homeostasis (P2X7 antagonists-adenosine homodinucleotide P18), neuroprotective and antioxidant drugs (purified polyols-resveratrol) and potassium channel blockers (3,4-diaminopyridine).[85] Supplementation with essential fatty acids, phospholipids, vitamin E, creatine, and bovine-derived ganglioside mixture has not been useful.[88]

Rehabilitation

Involves a multi-disciplinary team and is the cornerstone of medical management. Patients are at risk of developing a reduced range of movement, contractures, and deformities. The important components of physical therapy are stretching exercises, aerobics, resistance training, and timely use of orthotic devices. They improve and keep-up muscle strength and function besides improving joint flexibility and range of movement, balance, and cardio-respiratory fitness. There is also a positive impact on fatigue and pain and in preventing stiffness and deformities.[85][89] Practically, patients have difficulty in participating in the exercise program because of increased energy demand and altered gait kinetics. The phenomenon of ‘overuse weakness’ wherein exercise increases muscle loss and worsens weakness is controversial in CMT [90] Overall, moderate or submaximal exercise is helpful. Orthosis improves posture and walking balance caused by ankle weakness and deformity. Hand muscle weakness requires a supervised exercise program and training for activities of daily living. Splinting improves hand dexterity.[89]

Others

Symptomatic treatment of fatigue, depression, neuropathic pain, and RLS is like that for other neuropathies. Foot deformities, scoliosis, and hip dysplasia may need corrective surgeries and tendon transfers depending on the merit of the case. Restrictive lung disease, sleep apnea, and vocal cord palsy need suitable intervention in collaboration with surgeons, pulmonologists, otorhinolaryngologists, physiatrists, and allied specialties.[85]

Differential Diagnosis

CMT needs to be differentiated from conditions that manifest with predominant distal weakness, wasting, and deformities of the foot and have a progressive course.

Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in IGHMBP2 is a close differential diagnosis since motor nerve conduction velocities are very low in this condition. However, these patients have normal sensory nerve action potentials.[91] Distal myopathies manifest with foot drop, but the pattern of weakness and electrophysiological studies (nerve conduction studies and concentric needle electromyography) can distinguish them from CMTs. It is particularly challenging to differentiate CIDP from CMT in children. Follow up for response to immunotherapy, and clinical and electrophysiological examination of ‘asymptomatic’ family members and genetic testing may aid in diagnosis.[92]

Other differential diagnoses include acquired neuropathies due to diabetes mellitus, nutritional deficiencies, vasculitis, and heavy metal intoxication and inherited conditions wherein neuropathy is a part of a complex multisystem disorder such as autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), Friedreich’s ataxia, metachromatic leucodystrophy, syndrome of neurogenic weakness, ataxia, and retinitis pigmentosa (NARP), Refsum’s disease, etc.[93]

Staging

Patients with CMT have a progressive clinical course and need periodic monitoring. Composite scoring systems are available to assess longitudinal changes in function/ disability, including natural history and outcome. The CMT Neuropathy Score (CMTNS) is a reliable composite of nine items that incorporate the motor and sensory symptoms and signs and electrophysiological parameters. The CMTNS score ranges from 0 (best) to 36 (worst) and is used for classifying patients as having mild (≤ 10), moderate (11 to 20), or severe (≥ 20) disability.[94] 

A similar score exists for use in the pediatric population (CMTPedS).[95] 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, overall neuropathy limitations scale, and the 9-hole peg test, among others.[96] 

Alternate sensitive, reliable, reproducible, and clinically relevant markers that reflect degeneration of Schwann cells and/or axons and thereby act as measures of disease burden and progression, as well as target engagement of specific therapies, have also been developed. They include intramuscular fat accumulation (IMFA) in calf muscles, serum neurofilament light chain, transmembrane protease serine 5 (TMPRSS5), and cutaneous mRNA profiling.[96][97][98]

Prognosis

CMTs are insidiously progressive disorders. Patients develop increasing weakness and wasting of extremities that interfere with mobility and activities of daily living. The rate of progression varies among various CMTs. Life expectancy is usually not affected, but the disease may be severe when the onset is very early.  Periodic evaluation and interventions by an interdisciplinary rehabilitation team are essential for the maintenance of independence, safe ambulation, and functional activities.

Complications

Foot deformities are a major source of disability in CMTs. They develop over time and may worsen despite physiotherapy and the use of orthosis. Such patients need surgery to establish plantigrade foot and correct muscle imbalance.[99] Corns and calluses may develop at the extremities corresponding to sites of increased pressure. Rarely respiratory insufficiency may rarely arise due to severe neuropathy, diaphragmatic palsy, or concomitant spinal deformity.[38] 

Worsening of CMT related symptoms may occur during pregnancy. There is an increased risk of an abnormal fetal lie, post-partum hemorrhage, and the need for emergency intervention during delivery, and therefore a regular ante-natal checkup is recommended. Neurotoxic drugs and chemotherapeutic agents and co-morbid neuropathic diseases also worsen neuropathy in CMT.[58]

Deterrence and Patient Education

The patients are informed about the insidiously progressive course as well as the inherited nature of the illness. Based on the pedigree chart analysis and genetic testing, the likely mode of inheritance is explained to the patient. The patients are encouraged to remain active, have a regular follow-up with health care providers, and carry out exercises as recommended. The patients are advised to avoid obesity and the use of agents and drugs that have the potential to worsen neuropathy.

Pearls and Other Issues

Here are some important points of which to take note:

1. CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
2. Electrophysiological tests are useful to confirm the diagnosis of neuropathy and exclude alternative conditions that present with foot drop and/or foot deformities such as distal myopathies, muscular dystrophies, and idiopathic pes cavus, among others.
3. Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
4. Patients of demyelinating CMTs have slowed conduction velocities within the first few years of life. Clinical manifestations of weakness, wasting, and deformities arise from axonal loss over the years.
5. There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
6. A detailed pedigree chart covering three or four generations is essential to find the pattern of inheritance. This is necessary before carrying out genetic studies.
7. All patients should have genetic counseling before genetic testing.
8. In the case of demyelinating neuropathies, the patient should first undergo testing for PMP22 duplication since it is the commonest genetic abnormality. After excluding copy number variations in PMP22, they need targeted gene sequencing or whole-exome sequencing.
9. In the case of axonal neuropathies, the patient is first tested for mutations in MFN2. Alternately, the patient can directly undergo target gene sequencing or whole-exome sequencing.
10. Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
11. Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
12. Patients should avoid using drugs that worsen neuropathy.
13. Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

Enhancing Healthcare Team Outcomes

Patients often need a multi-disciplinary team with a patient-centric approach for comprehensive care. This should include a neurologist/ physician, physiatrist, physiotherapist, nurse, occupational therapist, social worker, and geneticist. Depending on the need, experts in orthopedics, pulmonology, speech therapy, and nephrology give inputs as and when required. The health care provider should coordinate with the other team members to prevent injuries and complications, limit disability, optimize care, and improve the overall quality of life of these patients.