Hereditary and Sensory Motor Neuropathy

Neurology

Clinicals - History

Fact Explanation
Family history As the disease is genetically determined, family history is important. CMT 1 and CMT 2 are inherited as autosomal dominant neuropathies (HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1) and genetic loci are identified as chromosomes 3q13-22 and 9q22.1-22.3, respectively. But there's a genetic heterogeneity. Also autosomal recessive, X-linked inherited conditions are identified. The HMSN classification of Dyck is used for classification. Family history
As the disease is genetically determined, family history is important. CMT 1 and CMT 2 are inherited as autosomal dominant neuropathies (HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1) and genetic loci are identified as chromosomes 3q13-22 and 9q22.1-22.3, respectively. But there's a genetic heterogeneity. Also autosomal recessive, X-linked inherited conditions are identified. The HMSN classification of Dyck is used for classification.
Gait disturbances Usually these symptoms start as early as 2nd year of life but can be delayed till 5th decade. The cause is due to demyelination and/or axonal loss of the peripheral nerves. As a result there is progressive weakness of the distal musculature particularly peroneal muscular atrophy which is accompanied by progressive weakness of dorsiflexion of the ankle and eventual foot drop. Pes cavus, Pes planus, and/or hammer toes deformities invariably develop as well further destabilizing the gait Gait disturbances
Usually these symptoms start as early as 2nd year of life but can be delayed till 5th decade. The cause is due to demyelination and/or axonal loss of the peripheral nerves. As a result there is progressive weakness of the distal musculature particularly peroneal muscular atrophy which is accompanied by progressive weakness of dorsiflexion of the ankle and eventual foot drop. Pes cavus, Pes planus, and/or hammer toes deformities invariably develop as well further destabilizing the gait
Proximal muscle weakness This is a late manifestation and axial muscles are usually spared. Proximal muscle weakness
This is a late manifestation and axial muscles are usually spared.
Tingling or burning sensations of the feet This is due to involvement of sensory nerves but some may complain of loss of pain and temperature sensation or loss of all sensory modalities at the onset of the disease. In the early stages of the disease, only toes are affected but later spread to the distal parts of the lower limbs, and can extend up to the knees. Tingling or burning sensations of the feet
This is due to involvement of sensory nerves but some may complain of loss of pain and temperature sensation or loss of all sensory modalities at the onset of the disease. In the early stages of the disease, only toes are affected but later spread to the distal parts of the lower limbs, and can extend up to the knees.
Spontaneous pain This usually occurs in the feet, legs, thighs, hands, or even shoulders. Spontaneous pain
This usually occurs in the feet, legs, thighs, hands, or even shoulders.
Easy traumatization, foot ulcers, painless burns Due to reduced muscle mass and sensory disturbance, the nerves are vulnerable to trauma and compression. Easy traumatization, foot ulcers, painless burns
Due to reduced muscle mass and sensory disturbance, the nerves are vulnerable to trauma and compression.
Disturbed sweating Hypohidrosis, hyperhidrosis, or anhidrosis occurs as the commonest feature of autonomic nervous system dysfunction. however hypotension, erectile dysfunction, and disturbed lacrimation rarely occur Disturbed sweating
Hypohidrosis, hyperhidrosis, or anhidrosis occurs as the commonest feature of autonomic nervous system dysfunction. however hypotension, erectile dysfunction, and disturbed lacrimation rarely occur
progressive deafness/ complete deafness This is due to a unique point mutation in PMP22 which causes progressive auditory nerve deafness in addition. progressive deafness/ complete deafness
This is due to a unique point mutation in PMP22 which causes progressive auditory nerve deafness in addition.

Clinicals - Examination

Fact Explanation
Palpably enlarged nerves Due to hypertrophy of affected nerves due to demyelination followed by attempts of remyelination Palpably enlarged nerves
Due to hypertrophy of affected nerves due to demyelination followed by attempts of remyelination
Wasting of the muscles in the anterior compartment of the lower legs Due to peroneal muscle atrophy Wasting of the muscles in the anterior compartment of the lower legs
Due to peroneal muscle atrophy
Weakness of dorsiflexion of the ankle and an ultimate foot drop Due to peroneal muscle atrophy Weakness of dorsiflexion of the ankle and an ultimate foot drop
Due to peroneal muscle atrophy
Ankle contractures and painful Pes cavus, planus, hammer toe deformities Due to denervation of intrinsic foot muscles Ankle contractures and painful Pes cavus, planus, hammer toe deformities
Due to denervation of intrinsic foot muscles
Contractures of the wrists and ultimately a claw hand Due to wasting of forearm and hand muscles Contractures of the wrists and ultimately a claw hand
Due to wasting of forearm and hand muscles
Lost tendon reflexes Due to demyelination and/or axonal loss of the peripheral nerves. Knee jerk is often preserved or even brisk but disappear with progression of the disease, however Achilles tendon reflexes are diminished or absent Lost tendon reflexes
Due to demyelination and/or axonal loss of the peripheral nerves. Knee jerk is often preserved or even brisk but disappear with progression of the disease, however Achilles tendon reflexes are diminished or absent
Reduced sensation in the feet Loss pain and temperature is prominenet but complete loss of touch-pressure sensation can occur with proprioception affected in some. Vibration sense maybe preserved for a long time Reduced sensation in the feet
Loss pain and temperature is prominenet but complete loss of touch-pressure sensation can occur with proprioception affected in some. Vibration sense maybe preserved for a long time
Spasticity of lower limbs This is not common but can occur in the form of HSN with spastic paraplegia. Spasticity of lower limbs
This is not common but can occur in the form of HSN with spastic paraplegia.

Investigations - Diagnosis

Fact Explanation
Full blood count and blood picture This is done to exclude anemia due to vitamin B12 deficiency and blood picture may show oval macrocytes in vitamin B12 deficiency and lead poisoning may show microcytic hypochromic anemia Full blood count and blood picture
This is done to exclude anemia due to vitamin B12 deficiency and blood picture may show oval macrocytes in vitamin B12 deficiency and lead poisoning may show microcytic hypochromic anemia
Erythrocyte sedimentation rate This is often elevated in connective tissue diseases Erythrocyte sedimentation rate
This is often elevated in connective tissue diseases
Fasting blood sugar This is done to exclude polyneuropathy due to diabetes mellitus Fasting blood sugar
This is done to exclude polyneuropathy due to diabetes mellitus
Thyroid function tests This is done to exclude polyneuropathy due to hypo or hyperthyrodism Thyroid function tests
This is done to exclude polyneuropathy due to hypo or hyperthyrodism
Renal function tests- Serum creatinine, Blood urea nitrogen This is done to exclude polyneuropathy due to uremia Renal function tests- Serum creatinine, Blood urea nitrogen
This is done to exclude polyneuropathy due to uremia
Serum Vitamin B12 level This is done to exclude vitamin B12 deficiency causing polyneuroapthy Serum Vitamin B12 level
This is done to exclude vitamin B12 deficiency causing polyneuroapthy
Serum Anti nuclear antobodies, Anti-DNA antibodies, Anti-Sm antibodies and Anti-phospholipid antibodies These tests are done mainly to exclude connective tissue disorders such as SLE, Polyarteritis nodosa Serum Anti nuclear antobodies, Anti-DNA antibodies, Anti-Sm antibodies and Anti-phospholipid antibodies
These tests are done mainly to exclude connective tissue disorders such as SLE, Polyarteritis nodosa
HIV screening To exclude HIV causing polyneuropathy HIV screening
To exclude HIV causing polyneuropathy
Nerve conduction studies Motor and sensory nerve conduction velocities are very much reduced and nerve Conduction Velocity (NCV) in the motor median nerve is used to divide autosomal dominant CMT into CMT1 (<38 m/s), CMT2 (>38 m/s) and dominant intermediate CMT (25–45 m/s). Autosomal recessive CMT is called CMT4 and X-linked CMT CMTX independent of the NCV Nerve conduction studies
Motor and sensory nerve conduction velocities are very much reduced and nerve Conduction Velocity (NCV) in the motor median nerve is used to divide autosomal dominant CMT into CMT1 (<38 m/s), CMT2 (>38 m/s) and dominant intermediate CMT (25–45 m/s). Autosomal recessive CMT is called CMT4 and X-linked CMT CMTX independent of the NCV
Electromyography (EMG) This can help to detect active axonal damage,
with spontaneous muscle fiber activity at rest
(denervation). In neuropathic conditions, reinnervation changes are also seen
Electromyography (EMG)
This can help to detect active axonal damage,
with spontaneous muscle fiber activity at rest
(denervation). In neuropathic conditions, reinnervation changes are also seen
Cerebrospinal fluid (CSF) for protein May be elevated, but no cells appear in the CSF. It also useful to distinguish immune mediated neuropathies such as CIDP or chronic immune mediated axonal neuropathies where the CSF protein
is raised.
Cerebrospinal fluid (CSF) for protein
May be elevated, but no cells appear in the CSF. It also useful to distinguish immune mediated neuropathies such as CIDP or chronic immune mediated axonal neuropathies where the CSF protein
is raised.
Sural nerve biopsy Characteristic onion bulb formations of proliferated Schwann cell cytoplasm surround axons is seen and this pathologic finding is called interstitial hypertrophic neuropathy. In addition large- and medium-sized myelinated fibers are reduced in number, collagen is increased, and extensive segmental demyelination and remyelination also occur Sural nerve biopsy
Characteristic onion bulb formations of proliferated Schwann cell cytoplasm surround axons is seen and this pathologic finding is called interstitial hypertrophic neuropathy. In addition large- and medium-sized myelinated fibers are reduced in number, collagen is increased, and extensive segmental demyelination and remyelination also occur
Genetic analysis CMT1A is predominantly caused by a 1.5 Mb duplication on chromosome 17p11.2 that includes the PMP22 gene. But due to the clinical and genetic heterogeneity, the low sensitivity of genetic testing for CMT2 and scarcity of clinical data, CMT can be difficult to be diagnosed by genetic testing always. Genetic analysis
CMT1A is predominantly caused by a 1.5 Mb duplication on chromosome 17p11.2 that includes the PMP22 gene. But due to the clinical and genetic heterogeneity, the low sensitivity of genetic testing for CMT2 and scarcity of clinical data, CMT can be difficult to be diagnosed by genetic testing always.

Investigations - Management

Fact Explanation
Foot care Foot ulcers in HSMN are similar to diabetic neuropathic ulcers therefore called "pseudodiabetic foot syndrome". Careful follow up similar to a diabetic foot is needed with treatment of foot ulcers and infections Foot care
Foot ulcers in HSMN are similar to diabetic neuropathic ulcers therefore called "pseudodiabetic foot syndrome". Careful follow up similar to a diabetic foot is needed with treatment of foot ulcers and infections
Full blood count To detect and correct any anemia prior to surgery Full blood count
To detect and correct any anemia prior to surgery
Coagulation studies To detect and correct any coagulopathy before surgical management Coagulation studies
To detect and correct any coagulopathy before surgical management
Renal function tests- Serum creatinine, Blood urea nitrogen To determine any renal dysfunction prior to anesthesia Renal function tests- Serum creatinine, Blood urea nitrogen
To determine any renal dysfunction prior to anesthesia

Management - Supportive

Fact Explanation
Patient education Education regarding the course of the disease, prognosis and the extent of exercise capacity should be explained. Patient education
Education regarding the course of the disease, prognosis and the extent of exercise capacity should be explained.
Psychological support Group and family counseling may be beneficial and patients should be referred to support groups for psychological support and problem solving. If necessary, a patient should be referred to a mental health professional Psychological support
Group and family counseling may be beneficial and patients should be referred to support groups for psychological support and problem solving. If necessary, a patient should be referred to a mental health professional
Genetic counseling As there's often a family history genetic counseling may help to prevent new cases Genetic counseling
As there's often a family history genetic counseling may help to prevent new cases
Prenatal diagnosis When the disease causing mutation is known, this maybe helpful. When a patient is male, artificial insemination with donor sperm can be discussed with the couple. Prenatal diagnosis
When the disease causing mutation is known, this maybe helpful. When a patient is male, artificial insemination with donor sperm can be discussed with the couple.
Physiotherapy Patients with CMT appeared to benefit significantly from a strengthening programme and help to reduce muscle wasting, and deformities and contractures Physiotherapy
Patients with CMT appeared to benefit significantly from a strengthening programme and help to reduce muscle wasting, and deformities and contractures
Occupational therapy This may help to carry out day to day activities Occupational therapy
This may help to carry out day to day activities
Avoidance of certain neurotoxic agents Especially vincristine, can have a devastating effect, even in low dose therefore should be avoided Avoidance of certain neurotoxic agents
Especially vincristine, can have a devastating effect, even in low dose therefore should be avoided
Optimal control of blood sugar level Because co-existence of diabetes mellitus in a CMT1A patient can exacerbate symptoms of the peripheral neuropathy Optimal control of blood sugar level
Because co-existence of diabetes mellitus in a CMT1A patient can exacerbate symptoms of the peripheral neuropathy
Medical treatment with Phenytoin or Carbamezapine For burning paresthesias of the feet Medical treatment with Phenytoin or Carbamezapine
For burning paresthesias of the feet
Protection of the leg from compression neuropathies Placement of soft pillows beneath or between the lower legs Protection of the leg from compression neuropathies
Placement of soft pillows beneath or between the lower legs
Supportive care for the legs with stabilization of the ankles This includes exercise training, shoe inlays, orthopaedic shoes and orthoses for stabilization of ankles. Wearing a thumb opposition splint may improve manual dexterity in CMT Supportive care for the legs with stabilization of the ankles
This includes exercise training, shoe inlays, orthopaedic shoes and orthoses for stabilization of ankles. Wearing a thumb opposition splint may improve manual dexterity in CMT
Foot care Proper foot care should be taken and patients should be educated on foot care, and early treatment of infections, ulcers should be done. Properly fitted foot wear should be worn Foot care
Proper foot care should be taken and patients should be educated on foot care, and early treatment of infections, ulcers should be done. Properly fitted foot wear should be worn

Management - Specific

Fact Explanation
Surgical interventions Flexor Digitorum Superficialis Opposition tendon transfer has showed improved hand function, reduce disability, and improve quality of life. Surgical fusion of the ankle can also be done Surgical interventions
Flexor Digitorum Superficialis Opposition tendon transfer has showed improved hand function, reduce disability, and improve quality of life. Surgical fusion of the ankle can also be done
Neurotrophin-3 (NT-3) Treatment with this led to slight improvement of sensory and reflex scores in CMT1A patients. NT-3 therapy resulted in measurable NT-3 secretion levels in blood and improvement in motor function, histopathology, and electrophysiology of the peripheral nerves Neurotrophin-3 (NT-3)
Treatment with this led to slight improvement of sensory and reflex scores in CMT1A patients. NT-3 therapy resulted in measurable NT-3 secretion levels in blood and improvement in motor function, histopathology, and electrophysiology of the peripheral nerves
Ultrasound guided nerve block for post operative pain These may help in hypertrophic peripheral neuropathy [Charcot–Marie–Tooth disease type 1 (CMTD1)] to alleviate the severe post operative pain Ultrasound guided nerve block for post operative pain
These may help in hypertrophic peripheral neuropathy [Charcot–Marie–Tooth disease type 1 (CMTD1)] to alleviate the severe post operative pain

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