HMSN – Causes, Symptoms, Diagnosis, Treatment

HMSN/Hereditary Motor and Sensory Neuropathy/Charcot-Marie-Tooth disease (CMT) is slowly progressive neurodegenerative hereditary chronic motor and sensory neuropathy disease and one of a group of disorders that cause damage to the peripheral nerves, the nerves that transmit information and signals from the brain and spinal cord to and from the rest of the body, as well as sensory information such as touch back to the spinal cord and brain.  CMT can also directly affect the nerves that control the muscles.  Progressive muscle weakness typically becomes noticeable in adolescence or early adulthood, but the onset of disease can occur at any age.  Because longer nerves are affected first, symptoms usually begin in the feet and lower legs and then can affect the fingers, hands, and arms.  Most individuals with CMT have some amount of physical disability, although some people may never know they have the disease.

CMT, also known as hereditary motor and sensory neuropathy, slowly progressive inherited neurological disorders distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands is one of the most common neuropathy affecting an estimated. It is possible to have two or more types of CMT, which happens when the person has mutations in two or more genes, each of which causes a form of the disease.  CMT is a heterogeneous genetic disease, meaning mutations in different genes can produce similar clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity.

Types of Charcot-Marie-Tooth Disease

There are many different types of CMT disease, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

CMT1 – is caused by abnormalities in the myelin sheath.  The autosomal dominant disorder has six main subtypes.

• CMT1A – results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22).  The PMP22 protein is a critical component of the myelin sheath.  Overexpression of this gene causes the abnormal structure and function of the myelin sheath.  CMT1A is usually slowly progressive.  Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems.  A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes.  In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.
• CMT1B – is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath.  Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code.  To date, scientists have identified more than 120 different point mutations in the P0 gene.  CMT1B produces symptoms similar to those found in CMT1A.
• Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT2

• Results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1.  This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene.  Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1.  The onset of CMT2 is usually in childhood or adolescence.  Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease

• It is a particularly severe demyelinating neuropathy that begins in infancy.  Infants have severe muscle atrophy, weakness, delayed motor skills development, and sensory problems.  Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

• It comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4).  The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics.  People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk.  CMT4 is rare in the United States.

CMTX1 (also called CMT X, Type 1)

• It is the second most common form of CMT.  This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32.  The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath.  Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence.  Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Disease phenotypes

• Charcot–Marie–Tooth Disease  – As CMT1 and CMT2 present with similar clinical features, distinction on the basis of the neurological exam is often impossible. The onset of clinical symptoms is in the first or second decade of life. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes. With further progression the hands become weak. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature or vibration sensation in the legs is consistent with the phenotype. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome occurs in nearly 40% of patients with the axonal form.^[rx]
• Hereditary neuropathy with liability to pressure palsies (MIM 162500) – The clinical phenotype is characterized by recurrent nerve dysfunction at compression sites. Asymmetric palsies occur after relatively minor compression or trauma. Repeated attacks result in the inability of full reversal. Thus with ageing the patients with hereditary neuropathy with liability to pressure palsies (HNPP) can have significant clinical overlap with CMT1. Electrophysiological findings include mildly slowed NCV, increased distal motor latencies and conduction blocks.^[rx] The neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula).
• Dejerine–Sottas neuropathy (MIM 145900) – Dejerine–Sottas neuropathy (DSN) is a clinically distinct entity defined by delayed motor milestones. Signs of lower motor neuron-type lesion accompany the delayed motor milestones. Neurophysiological studies reveal severe slowing of NCV (<10 m/s). Neuropathology reveals pronounced demyelination, and a greater number of onion bulbs are present compared to CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.
• Congentital hypomyelinating neuropathy (MIM 605253) – Congentital hypomyelinating neuropathy (CHN) is usually present at birth, although frequently the delayed motor development draws the first attention to the peripheral neuropathy. The distinction between DSN and CHN is often difficult by clinical examination as they both may present as a hypotonic infant. The differentiation of CHN and DSN is based on pathology: the presence of onion bulbs suggest DSN whereas their absence indicate CHN. CHN may present as arthrogryposis multiplex congenita.^[rx]
• Roussy–Levy syndrome (MIM 180800) – Roussy–Levy syndrome (RLS) was originally described as demyelinating CMT associated with sensory ataxia and tremor. As molecular data became available, it was shown that these patients have the same molecular abnormalities as observed in patients clinically classified as demyelinating CMT. RLS represents the spectrum of CMT.

Causes Charcot-Marie-Tooth Disease

A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon.  The axon is surrounded by myelin, a covering that acts like the insulation on an electrical wire and aids the high-speed transmission of electrical signals.  Without an intact axon and myelin sheath, signals that run along the nerve and axon are either slow or have a weak signal, meaning that the peripheral nerve cells become unable to activate muscles or relay sensory information from the limbs back to the spinal cord and the brain.

CMT is caused by mutations in genes that support or produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. More than 40 genes have been identified in CMT, with each gene linked to one or more types of the disease.  In addition, multiple genes can be linked to one type of CMT.  More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17.

Although different proteins are abnormal in different forms of CMT disease, all of the mutations mainly affect the normal function of the peripheral nerves.  Gene defects in myelin cause dysfunction of the coating, which distorts or blocks nerve signals, while other mutations limit axon function and cause axonal loss.

CMTs may occur due to any one of the following molecular and cellular mechanisms

• 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)
• 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)
• 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)
• Proteasome and protein aggregation – genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
• Mitochondria – genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
• 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.[rx][rx] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[rx]

Symptoms of Charcot-Marie-Tooth Disease

CMT affects both sensory and motor nerves (nerves that trigger an impulse for a muscle to contract) in the arms, hands, legs, and feet.  The affected nerves slowly degenerate and lose the ability to communicate with their distant targets.  Motor nerve degeneration results in muscle weakness and a decrease in muscle bulk (atrophy) in the arms, legs, hands, or feet.

Typical early features include weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop) and a high-stepped gait with frequent tripping or falling.  Individuals also may notice balance problems.  Foot deformities, such as high arches and curled toes (hammertoes), are also common in CMT.  The lower legs may take on an “inverted champagne bottle” shape due to the loss of muscle bulk.  As the disease progresses, weakness and atrophy may occur in the hands, causing difficulty with fine motor skills.  Degeneration of sensory nerve axons may result in a reduced ability to feel heat, cold, and touch.  The senses of vibration and position (proprioception) are often decreased in individuals with CMT.  The disease also can cause curvature of the spine (scoliosis) and hip displacement.  Many people with CMT develop contractures—chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely.  Muscle cramping is common.  Nerve pain can range from mild to severe, and some individuals may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people with CMT experience tremors and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

The severity of symptoms can vary greatly among individuals and even among family members with the disease and gene mutation.  Progression of symptoms is gradual.

Signs and symptoms of Charcot-Marie-Tooth disease may include

• Weakness in your legs, ankles and feet
• Loss of muscle bulk in your legs and feet
• High foot arches
• Curled toes (hammertoes)
• Decreased ability to run
• Difficulty lifting your foot at the ankle (footdrop)
• Awkward or higher than normal step (gait)
• Frequent tripping or falling
• Decreased sensation or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Diagnosis of Charcot-Marie-Tooth disease

Diagnosis of CMT begins with a detailed medical history, family history, and neurological examination.

Family History

• A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Physical Exam

Treatment of Charcot-Marie-Tooth

Non Pharmacological

There is no cure for CMT, but physical and occupational therapies, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease.  In addition, pain-relief drugs can be prescribed for individuals who have severe nerve pain.

• Maintaining mobility, flexibility, and muscle strength – Beginning a treatment program early may delay or reduce nerve degeneration and muscle weakness before it progresses to the point of disability.  Physical therapy includes muscle strength training, muscle and ligament stretching, and moderate aerobic exercise.  A specialized exercise program approved by the person’s physician can help build stamina, increase endurance, and maintain overall health.
• Braces – Many individuals with CMT require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury.  Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs.  High-top shoes or boots also can give the person support for weak ankles.  Thumb splints can help with hand weakness and loss of fine motor skills.  Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some people with CMT may decide to have orthopedic surgery to treat severe foot and joint deformities, improve the ability to walk, and lessen pain.
• Occupational therapy –  involves learning new ways to cope with the activities of daily living.  For example, individuals with weakness in their arms and hands may learn to use Velcro closures or clasps instead of buttons on their clothes, or new ways of feeding themselves using assistive technology.
• Genetic counseling – Because CMT follows the principles of Mendelian inheritance, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history for an affected individual is defined. Because of intrafamilial variability in disease expression, definition of parental disease status requires either testing for a mutation defined in the propositus or, if the mutation is not identifiable, a thorough neurological exam with objective NCS.

Medications

Symptomatic treatment may have a substantial impact on the quality of life.

• NSAIDs – Nonsteroidal anti-inflammatory drugs may help to relieve lower back or leg pain.
• Antiepileptic drugs – Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).^{[rx, rx]}
• Beta-blockers – The tremor may respond to β-blockers or primidone.^[rx] Caffeine and nicotine can aggravate the fine intentional tremor, thus avoidance of these substances is recommended.
• Neurotoxic drugs – excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT, thus early detection of HMSN can avoid life-threatening vincristine neurotoxicity.^[rx]
• Vitamin C – Potential therapeutic approaches aiming at normalizing dosage by small molecules in the CMT1A duplication models include vitamin C and onapristone, a progesterone antagonist.^{[rx, rx, rx]} An alternate molecular mechanism, point mutations in Pmp22 in the Trembler and Trembler J mouse models cause peripheral neuropathy; the disease was modified by the administration of curcumin likely by alleviating the unfolded protein response.^[rx]
• 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.[rx] 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.[rx] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[rx]

Lifestyle and home remedies

Some habits may prevent complications caused by Charcot-Marie-Tooth disease and help you manage its effects.

Started early and followed regularly, at-home activities can provide protection and relief:

• Stretch regularly – Stretching can help improve or maintain the range of motion of your joints and reduce the risk of injury. It’s also helpful in improving your flexibility, balance and coordination. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.
• Exercise daily – Regular exercise keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.
• Improve your stability – Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, resulting in falls and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.

Here are some important points of which to take note

• CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
• 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.
• Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
• 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.
• There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
• 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.
• All patients should have genetic counseling before genetic testing.
• 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.
• 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.
• Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
• Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
• Patients should avoid using drugs that worsen neuropathy.
• Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Ongoing research on CMT includes efforts to identify more of the mutant genes and proteins that cause the various disease subtypes, discover the mechanisms of nerve degeneration and muscle atrophy with the goal of developing interventions to stop or slow down these debilitating processes, and develop therapies to reverse nerve degeneration and muscle atrophy.

The NINDS supports the NIH’s Rare Diseases Clinical Research Network, which is made up of different research consortia aimed at improving the availability of rare diseases information, clinical studies, and clinical research information.  The Network’s Inherited Neuropathies Consortium conducts studies that include a natural history analysis of CMT, the search for new genes and those that modify an individual’s symptoms, therapy development, and training programs to educate future investigators for the inherited neuropathies.  For more information on the Rare Diseases Clinical Research Network and its consortia, see Rare Diseases Info.

Scientists are studying PMP22 gene regulation to design and validate assays that measure the presence, amount, or activity of a target object.  Other studies examine the effects of small molecules on the biological system in order to develop novel treatments.  High-throughput screens (a way to quickly assess the biological activity of large numbers of compounds) may identify candidate medications that reduce PMP22 levels. Additional research focuses on how the mitochondria, the cell’s power plant, may play a role in the axonal degeneration seen in CMT, as well as other diseases.

An NIH longitudinal collaborative study hopes to determine the natural history of CMT and how the presence of a certain gene mutation may result in disease types and symptoms.  Also, a two-part study is looking for new genes that cause the disease as well as genes that do not cause the disease but may modify a person’s symptoms.  Other NIH-funded scientists are using next-generation sequencing (which can quickly identify the structure of millions of small fragments of DNA at the same time) to identify novel CMT genes.

Gene therapy is another promising area of research.  Experiments involving cell cultures and animal models of the disease have shown that it is possible to deliver genes to Schwann cells and muscles.  Other studies show trophic factors or nerve growth factors, such as the hormone androgen that prevent nerve degeneration.

References

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