Charcot-Marie-Tooth Disease

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Article initiated by:

Chaow Charoenkijkajorn, M.D.

All contributors:

Andrew Go Lee, MD, Manasi Joshi, Mohammad Pakravan, Nicole Weber, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS, Nagham Al-Zubidi, MD, Chaow Charoenkijkajorn, M.D.

Assigned editor:

Osama Al Deyabat, MBBS

Review:

Assigned status Update Pending

 by Osama Al Deyabat, MBBS on December 21, 2021.

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Disease Entity

Disease

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy (HMSN), encompasses a spectrum of genetically heterogeneous disorders. While CMT can be caused by multiple genetic variants, the common presenting clinical picture is distinctive, with decreased bulk and strength of distal extremity muscles, bony deformities and loss of deep tendon reflexes.

CMT can be classified into three forms. First, demyelinating CMT is called CMT1 if the familial inheritance is autosomal dominant and CMT4 if it is passed in an autosomal recessive manner. This type of CMT shows decreased conduction time on electrophysiology testing and myelin sheath anomalies on nerve biopsy. Next, the axonal form of CMT is characterized by normal nerve conduction speeds with evidence of chronic degenerative changes in axons. Third, CMT3, more often referred to as Dejerine-Sottas disease, refers to the rare recessive form with severe penetrance that appears in early childhood.

Further subtyping of CMT within these main categories is based on specific causative genetic mutations. For example, nearly half of CMT cases are CMT1A, which is associated with the overexpression of the PMP22 gene due to a regional duplication on chromosome 17p11.2.

Epidemiology

Affecting an estimated 126,000 Americans and 2.6 million individuals across the world, CMT is the most common genetically transmissible neuromuscular disorder. In the European Union, CMT has a prevalence of 1 in 2,500 individuals, though prevalence varies between populations and geographical regions. The inconsistencies in CMT prevalence can be explained by difficulties identifying, subtyping and assessing CMT due to its varying clinical presentation. The majority of studies employ genetic testing to detect a duplicated chromosome 17p11.2.

Etiology

CMT neuropathies result from inherited mutations in genes coding for myelin or axonal proteins that maintain the function of peripheral nerves. These mutations result in axonal degeneration, primarily affecting the longest nerves. Over 80 genes have been linked to CMT, most commonly PMP22, MPZ, GDAP1, MFN2, GJB1, HSPB1 and HSPB8. Studies have revealed that approximately 90% of individuals confirmed to have CMT via molecular testing had a genetic variant in PMP22, MPZ, GDAP1, MFN2 or GJB1.

Recent advances in technology, such as next generation sequencing (NGS), have revealed novel mutations in 7 genes associated with CMT.

Pathophysiology

Some genetic anomalies responsible for the CMT result in defective production and maintenance of the peripheral myelin sheath, causing slowed nerve conduction velocities on electrophysiology testing with demyelinating CMT. Mutations in genes that encode other structural proteins important for metabolism and axonal transport have normal nerve conduction speeds but decreased amplitudes, as with axonal CMT.

Diagnosis

Diagnosis of CMT is stepwise. First, a thorough history and physical examination are fundamental in evaluation for CMT. Describing the phenotype based on clinical presentation can lead to classification of the CMT subtype. Asking about other affected family members will shed light on mode of inheritance and potentially help identify ophthalmic manifestations early. Electrophysiological analysis further guides diagnosis and assesses the degree of decreased nerve conduction. Finally, molecular testing is key to ascertain the mutation responsible and allow for proper genetic counseling of family planning. Nerve biopsy is not necessary in most cases.

Fundus examination may help assess ophthalmic manifestations. It may reveal optic atrophy, attenuation of peripapillary vessels, pigmented retinopathy or retinal nerve fiber layer thinning.

Signs

Ophthalmic manifestations of CMT include optic neuropathy, impaired oculomotility, pupillary abnormalities, retinitis pigmentosa and premature presbyopia, color-vision abnormalities in the red-green axis.

The major form of ocular involvement in CMT is optic nerve atrophy. Optic nerve atrophy develops in a proportion of patients who have CMT2A, and these patients are then classified as having hereditary motor and sensory neuropathy type VI (HMSN-VI). Associated signs of optic nerve atrophy include bilateral, symmetric, gradual loss in visual acuity with defects in color vision and pale optic nerves. These signs present similarly to that of Leber hereditary optic neuropathy (LHON). Optic neuropathy has been documented as the first sign of CMT2A While optic atrophy occurs in rare patients with CMT2A, most have no involvement of the optic nerve, suggesting that optic neuropathy is linked to specific mutations within the larger category of CMT2A. Milder visual complications have been reported in patients with CMT1A, though optic nerve involvement in this subtype is still poorly defined.

The demyelinating effects of CMT on cranial nerves that would affect ocular movements are often subclinical. However, in one case, asymmetric oculomotor nerve palsy involvement was the first sign leading to an eventual diagnosis of CMT1A. In another case, a patient with early CMT portrayed clinically significant ophthalmoplegia. The disruption in ocular motility of this patient was intermittent and remitting in nature, progressing very slowly over time.

Pupillary anomalies associated with CMT include anisocoria and miosis unresponsive light and pharmacologic dilating drops. A lesion to the sympathetic, postganglionic neurons innervating the dilator muscle of the iris could cause persistent miosis of the pupils. Argyll-Robertson-like pupils, have also been described in patients with axonal CMT.

Retinal manifestations of CMT include thinning of the retinal layer, macular pigmentary changes and pigmentary retinopathy that does not typically involve the outer retina. These patients may present with a central or paracentral scotoma. Tapeto-retinal degeneration is associated with CMT and may be present in several family members due to its autosomal dominant inheritance. Visual evoked potentials and electroretinogram are typically normal. In CMT1A, painful neuropathic symptoms are linked to reduced corneal sensitivity, corneal nerve fiber density, corneal nerve fiber length. CMT has been linked to vitritis in one case.

Symptoms

Typically CMT presents with muscle wasting, weakness and decreased sensation of the distal limbs, progressing proximally with time. Motor manifestations begin in the foot with the development of hammer toes, high arches (pes cavus) and deterioration of intrinsic muscle groups. As CMT gradually advances it also affects the legs, lower thighs, hands and forearms. Sensory loss and decreased deep-tendon reflexes follow this same pattern of progression.

Differential Diagnosis

The top differential diagnoses include the different types of CMT itself, as there is substantial overlap between multiple forms. CMT should also be discerned from other diagnoses including inherited neuropathies, neuromuscular disorders such as distal myopathies and lower motor neuron disorders, and genetic disorders with CNS involvement such as spastic paraplegias, hereditary ataxias and mitochondrial encephalopathies.

Management

Currently, treatment for CMT is supportive and there is no disease-modifying drug therapy available. Supportive management includes physical rehabilitation therapy and surgical correction of bony deformities. No best practices have been defined. Currently, progesterone antagonists, neurotrophic factors, ascorbic acid and curcumin have been investigated in experimental models and ascorbic acid has been investigated in randomized control trials but has not shown to have significant effects A multidisciplinary approach is ideal to ensure the best possible quality of life. This involves coordination of care between the primary physician, surgeons, orthotists, physical therapists and genetic counselors.

Prognosis

The manifestations of CMT usually surface within the first two decades of life and progress slowly. The rate and clinical severity varies depending on CMT subtype. While gait stability is compromised, most patients maintain the ability to ambulate. Overall, CMT does not shorten life expectancy.