Charcot-Marie-Tooth disease - Clinicals, Diagnosis, and Management

Neurology

Clinicals - History

Fact Explanation
Distal muscle weakness The main feature of charcot marie tooth disease (CMT) is sensory-motor neuropathy.. It results from involvement of peripheral nerves that can affect the motor system and/or the sensory system.Individuals with CMT experience symmetrical, slowly progressive distal motor neuropathy of the arms and legs. It usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands.. Distal muscle weakness
The main feature of charcot marie tooth disease (CMT) is sensory-motor neuropathy.. It results from involvement of peripheral nerves that can affect the motor system and/or the sensory system.Individuals with CMT experience symmetrical, slowly progressive distal motor neuropathy of the arms and legs. It usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands..
Pain Although Charcot-Marie-Tooth hereditary neuropathy usually described as "painless," the neuropathy of CMT can be painful. Considering CMT1, Pain occurring especially in the feet, is reported by 20%-30% of individuals. The pain is often musculoskeletal in origin but may be neuropathic in some cases.. Pain
Although Charcot-Marie-Tooth hereditary neuropathy usually described as "painless," the neuropathy of CMT can be painful. Considering CMT1, Pain occurring especially in the feet, is reported by 20%-30% of individuals. The pain is often musculoskeletal in origin but may be neuropathic in some cases..
Hearing loss Early mild hearing loss may common in CMT1 phenotype. Hearing loss has been associated with point mutations in PMP22 and MPZ.Deafness has been occasionally reported in the CMT1.. Hearing impairment also has been reported in CMT2.. Hearing loss
Early mild hearing loss may common in CMT1 phenotype. Hearing loss has been associated with point mutations in PMP22 and MPZ.Deafness has been occasionally reported in the CMT1.. Hearing impairment also has been reported in CMT2..
Difficulty with phonation and breathing Seen in CMT2. A few individuals have vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing.. Difficulty with phonation and breathing
Seen in CMT2. A few individuals have vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing..
Intellectual disability Seen in CMTX 2, a type of X linked CMT. Deafness and intellectual disability is seen in CMTX 4 (Cowchock syndrome). There they have identified a missense mutation. Intellectual disability
Seen in CMTX 2, a type of X linked CMT. Deafness and intellectual disability is seen in CMTX 4 (Cowchock syndrome). There they have identified a missense mutation.

Clinicals - Examination

Fact Explanation
Depressed tendon reflexes CMT results from mutations in more than 40 genes expressed in Schwann cells and neurons causing overlapping phenotypes. The classic CMT phenotype reflects length-dependent axonal degeneration characterized by distal sensory loss and weakness with deep tendon reflex abnormalities.. The initial physical findings of CMT1 are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle.. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. But a subset of patients will retain deep tendon reflexes, especially in the axonal forms.. Depressed tendon reflexes
CMT results from mutations in more than 40 genes expressed in Schwann cells and neurons causing overlapping phenotypes. The classic CMT phenotype reflects length-dependent axonal degeneration characterized by distal sensory loss and weakness with deep tendon reflex abnormalities.. The initial physical findings of CMT1 are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle.. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. But a subset of patients will retain deep tendon reflexes, especially in the axonal forms..
Foot deformity The chronic nature of the motor neuropathy will result in foot deformity. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes.. CMT can be separated into autosomal-dominant demyelinating (CMT1) and axonal (CMT2), X-linked (CMT1X), and autosomal-recessive neuropathies.. From them, CMT1 is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Fewer than 5% of CMT1 individuals become wheelchair dependent Foot deformity
The chronic nature of the motor neuropathy will result in foot deformity. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes.. CMT can be separated into autosomal-dominant demyelinating (CMT1) and axonal (CMT2), X-linked (CMT1X), and autosomal-recessive neuropathies.. From them, CMT1 is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Fewer than 5% of CMT1 individuals become wheelchair dependent
Sensory deficits Vary from mild to moderate.. Signs of sensory system dysfunction are common (70%). It includes loss of vibration and joint position sense followed by decreased pain and temperature sensation in stocking and glove distribution. Clinical features do not distinguish between the demyelinating or axonal forms.. Sensory deficits
Vary from mild to moderate.. Signs of sensory system dysfunction are common (70%). It includes loss of vibration and joint position sense followed by decreased pain and temperature sensation in stocking and glove distribution. Clinical features do not distinguish between the demyelinating or axonal forms..
Restless leg syndrome This occurs in nearly 40% of patients with the axonal form.. Restless leg syndrome
This occurs in nearly 40% of patients with the axonal form..
Stork leg appearance Seen in CMT2. Occurs due to symmetrical atrophy of the muscles below the knee.. Stork leg appearance
Seen in CMT2. Occurs due to symmetrical atrophy of the muscles below the knee..
Dejerine-Sottas syndrome The term Dejerine-Sottas syndrome (DSS) was originally used to describe a severe demyelinating neuropathy of infancy and childhood associated with very slow NCVs (Nerve Conduction Velocity ), elevated CSF protein, marked clinical weakness, and hypertrophic nerves with onion bulb formation. Inheritance of DSS was assumed to be autosomal recessive.. Dejerine-Sottas syndrome
The term Dejerine-Sottas syndrome (DSS) was originally used to describe a severe demyelinating neuropathy of infancy and childhood associated with very slow NCVs (Nerve Conduction Velocity ), elevated CSF protein, marked clinical weakness, and hypertrophic nerves with onion bulb formation. Inheritance of DSS was assumed to be autosomal recessive..
Thenar muscle wasting Seen in Charcot Marie Tooth Neuropathy X Type 1. Atrophy of intrinsic hand muscles can be seen, especially the thenar muscles of the thumb.. Thenar muscle wasting
Seen in Charcot Marie Tooth Neuropathy X Type 1. Atrophy of intrinsic hand muscles can be seen, especially the thenar muscles of the thumb..
Enlarged palpable peripheral nerves. In CMT1, the most common CMT subtype, NCVs are very slow and peripheral nerves may be palpably enlarged. This is not true of CMT2. . Enlarged palpable peripheral nerves.
In CMT1, the most common CMT subtype, NCVs are very slow and peripheral nerves may be palpably enlarged. This is not true of CMT2. .
Ataxia and dysarthria Identified in X-Linked CMT1. Central nervous system (CNS) involvement is rare. But occasionally can be transiently debilitating, and is characterized by ataxia and dysarthria.. Persistent dysarthria and ataxia also have been reported.. Ataxia and dysarthria
Identified in X-Linked CMT1. Central nervous system (CNS) involvement is rare. But occasionally can be transiently debilitating, and is characterized by ataxia and dysarthria.. Persistent dysarthria and ataxia also have been reported..
Tremors Several neuropathies are accompanied by action tremors.Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of familial neuropathies in which tremor is reported to be common. But the tremor is not well defined.. Tremors
Several neuropathies are accompanied by action tremors.Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of familial neuropathies in which tremor is reported to be common. But the tremor is not well defined..

Investigations - Diagnosis

Fact Explanation
Genetic testing The genetic complexity of CMT necessitates a rational approach for clinical genetic testing. Factors to consider when initiating genetic testing should include careful evaluation of the availability of clinical testing, the yield of a specific molecular test, the aim of establishing a molecular diagnosis and the frequency of de novo mutations. .Testing is possible for mutations in numerous genes associated with similar phenotypes.Failure to identify a disease-causing mutation in a proband does not rule out a diagnosis of CMT since undetected mutations in other genes may be causative. . Genetic testing
The genetic complexity of CMT necessitates a rational approach for clinical genetic testing. Factors to consider when initiating genetic testing should include careful evaluation of the availability of clinical testing, the yield of a specific molecular test, the aim of establishing a molecular diagnosis and the frequency of de novo mutations. .Testing is possible for mutations in numerous genes associated with similar phenotypes.Failure to identify a disease-causing mutation in a proband does not rule out a diagnosis of CMT since undetected mutations in other genes may be causative. .
EMG and NCS (nerve conduction studies) EMG and nerve conduction studies (NCS) are extremely helpful in the clinical classification of hereditary peripheral neuropathies and in guiding genetic testing. Electrophysiological studies distinguish two major types including the demyelinating form, which is characterized by symmetrically slowed nerve conduction velocity (NCV; usually <38 m/s), and the axonal form, which is associated with normal or subnormal NCV and reduced compound muscle action potential.. EMG and NCS (nerve conduction studies)
EMG and nerve conduction studies (NCS) are extremely helpful in the clinical classification of hereditary peripheral neuropathies and in guiding genetic testing. Electrophysiological studies distinguish two major types including the demyelinating form, which is characterized by symmetrically slowed nerve conduction velocity (NCV; usually <38 m/s), and the axonal form, which is associated with normal or subnormal NCV and reduced compound muscle action potential..
Sural nerve biopsy Occasionally performed.. Sural nerve biopsies from patients with the demyelinating type reveal segmental demyelination and onion bulb formation.Nerve biopsies from patients with the axonal form show axonal loss, absent or few onion bulbs With no evidence of demyelination. Invasive diagnostic tests such as nerve biopsy are reserved for patients in whom genetic testing does not yield to a molecular diagnosis, patients with atypical presentation or patients in who are suspected to have inflammatory neuropathy.. Sural nerve biopsy
Occasionally performed.. Sural nerve biopsies from patients with the demyelinating type reveal segmental demyelination and onion bulb formation.Nerve biopsies from patients with the axonal form show axonal loss, absent or few onion bulbs With no evidence of demyelination. Invasive diagnostic tests such as nerve biopsy are reserved for patients in whom genetic testing does not yield to a molecular diagnosis, patients with atypical presentation or patients in who are suspected to have inflammatory neuropathy..

Management - Supportive

Fact Explanation
Administration of pain killers. Symptomatic treatment may have a substantial impact on the quality of life. Nonsteroidal anti-inflammatory drugs (NSAID) may help to relieve lower back or leg pain. Neuropathic pain can be treated with antiepileptic drugs such as gabapentin, pregabalin, topiramate or tricyclic antidepressants like amitriptyline.. Administration of pain killers.
Symptomatic treatment may have a substantial impact on the quality of life. Nonsteroidal anti-inflammatory drugs (NSAID) may help to relieve lower back or leg pain. Neuropathic pain can be treated with antiepileptic drugs such as gabapentin, pregabalin, topiramate or tricyclic antidepressants like amitriptyline..
β-blockers The tremor may respond to β-blockers or primidone. Caffeine and nicotine can aggravate the fine intentional tremors. So avoidance of these substances is recommended.. β-blockers
The tremor may respond to β-blockers or primidone. Caffeine and nicotine can aggravate the fine intentional tremors. So avoidance of these substances is recommended..
Avoid neurotoxic drugs Neurotoxic drugs and excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT.. Avoid neurotoxic drugs
Neurotoxic drugs and excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT..
Physiotherapy and occupational therapy Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.. Physiotherapy and occupational therapy aid in maintaining range of motion and thus help in functioning appropriately.. Physiotherapy and occupational therapy
Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.. Physiotherapy and occupational therapy aid in maintaining range of motion and thus help in functioning appropriately..
Application of orthotic devices The application of orthotic devices and assistive equipment can be made if safety or function requires them..Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking.Some individuals require forearm crutches or canes for gait stability. Fewer than 5% of individuals need wheelchairs. Application of orthotic devices
The application of orthotic devices and assistive equipment can be made if safety or function requires them..Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking.Some individuals require forearm crutches or canes for gait stability. Fewer than 5% of individuals need wheelchairs.
Exercise Exercise is encouraged within the individual's capability and many individuals remain physically active.And also daily heel cord stretching exercises to prevent Achilles' tendon shortening , as well as gripping exercises for hand weakness.. Exercise
Exercise is encouraged within the individual's capability and many individuals remain physically active.And also daily heel cord stretching exercises to prevent Achilles' tendon shortening , as well as gripping exercises for hand weakness..

Management - Specific

Fact Explanation
Genetic counseling Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions..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 this 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.. Charcot-Marie-Tooth (CMT) hereditary neuropathy may be transmitted in an autosomal dominant, autosomal recessive, or X-linked dominant manner depending on the genetic subtype in a family.. Genetic counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions..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 this 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.. Charcot-Marie-Tooth (CMT) hereditary neuropathy may be transmitted in an autosomal dominant, autosomal recessive, or X-linked dominant manner depending on the genetic subtype in a family..
Orthopedic surgery Orthopedic surgery may be required to correct severe pes cavus deformity.Surgery is sometimes required for hip dysplasia.. Surgical interventions for the hands and feet are sometimes necessary.. Orthopedic surgery
Orthopedic surgery may be required to correct severe pes cavus deformity.Surgery is sometimes required for hip dysplasia.. Surgical interventions for the hands and feet are sometimes necessary..

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  1. BIRD TD, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Charcot-Marie-Tooth Hereditary Neuropathy Overview [online] 1993 [viewed 07 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301532
  2. BIRD TD, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Charcot-Marie-Tooth Neuropathy Type 1 [online] 1993 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301384
  3. BIRD TD, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Charcot-Marie-Tooth Neuropathy Type 2 [online] 1993 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301462
  4. BIRD TD, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Charcot-Marie-Tooth Neuropathy X Type 1 [online] 1993 [viewed 07 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301548
  5. LOUIS ED, HERNANDEZ N, OTTMAN R, IONITA-LAZA I, CLARK LN. Essential Tremor in a Charcot-Marie-Tooth Type 2C Kindred Does Not Segregate with the TRPV4 R269H Mutation Case Rep Neurol [online] , 6(1):1-6 [viewed 07 August 2014] Available from: doi:10.1159/000357665
  6. PATZKó Á, SHY ME. Update on Charcot-Marie-Tooth Disease Curr Neurol Neurosci Rep [online] 2011 Feb, 11(1):78-88 [viewed 06 August 2014] Available from: doi:10.1007/s11910-010-0158-7
  7. SZIGETI K, LUPSKI JR. Charcot-Marie-Tooth disease Eur J Hum Genet [online] 2009 Jun, 17(6):703-710 [viewed 07 August 2014] Available from: doi:10.1038/ejhg.2009.31