Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
Peripheral neuropathies
1. Definition
Peripheral neuropathy, a result of damage to your peripheral nerves, often causes weakness, numbness
and pain affecting various areas of the body.
2. Classification
2.1. Etiology:
Hereditary forms
-
Charcot-Marie-Tooth neuropathy (CMT)
-
Hereditary Neuropathy with Pressure Palsy (HNPP)
-
Familiar amyloid polyneuropathy
Acquired forms
-
Diabetic neuropathy
-
Toxic neuropathy
-
Dysimmune neuropathy
-
Autoimmune disease
-
Vasculitis
-
Paraneoplastic syndrome
-
Metabolic cause
2.2. Involved nerves:
Number of involved nerves
-
Mononeuropathy (only one nerve)
-
Multiplex mononeuropathy (couple of nerves)
-
Polyneuropathy (many nerves)
Type of neuropathy
-
Motor neuropathy
-
Sensory neuropathy
-
Sensorimotor neuropathy
Regarding the distribution
-
Symmetric or asymmetric
-
Proximal or distal
2.3. Characteristic of neuropathy
Demyelinating
-
Uniform slowing
-
Non-uniform slowing with conduction blocks
1
Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
Axonal
Intermediate
2.4. Course of disease
Acute (hours, days)
Subacute (weeks, months)
Chronic (months, years)
3. Evaluation of neuropathy
3.1. Medical history
Age at onset, first symptoms, course of progression
Familial anamnesis
Exposition of toxic substances (alcohol, chemotherapeutics, medications, toxins)
Infectious diseases (Lyme disease – tick bites, HIV, HCV, HBV)
Other medical conditions, especially: malignant neoplasm, lymphoma, multiple myeloma,
amyloidosis, autoimmune disease, thyroid dysfunction, uremia
3.2. Clinical assessment
Symptoms occur primarily in the regions of nerve damage.
Motor symptoms
Paresis, atrophy and hypotonia (impaired tip toe and heel walking, paretic gait, problem with
but, difficulty using zippers and buttons, clumsiness in manipulating small objects)
Decreased or absent tendon reflexes
Fasciculation, cramps, pes cavus, shortening of Achilles tendon
Sensory symptoms
Paraesthesia, hypaesthesia, anaesthesia or pain (starts usually distal and progress proximal)
Impaired autonomic innervation (urine and/or stool incontinence and/or retention)
Spinal ataxia
To follow the progression, the weakness of muscles and affected regions should be given exactly
parallel with the distribution and the type of sensory impairment.
3.3 Nerve conduction study
Demyelinating neuropathy can be diagnosed if the distal latency and/or F-latency was prolonged
and/or the conduction velocity was reduced. Increased temporal dispersion shows demyelination as
well. Diffuse amplitude-reduction indicate axonal loss. Nerve lesion can be diagnosed as intermediate
or mixed type if both axonal and myelin loss was present. Normal ranges can
3.4 Lab tests
se. glucose (fasting glu., oral glucose tolerance test) HgbA1C
First round (family doctor)
sediment rate, Ca2+, CK, LDH, TSH, B12 vitamin levels
2
Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
ganglioside profile (GM1, GD1b, GQ1b) IgG and IgM,
Second round
postinfectious panel (B. burgerdorfii, HIV, HBV és HCV, C. jejuni)
Ig electrophoresis, ANA/ANCA, paraneoplastic s. markers
Third round / suspicion
3.5 Further investigations
Liqour punction: CIDP, GBS
Nerve biopsy: vasculitis
Rectum or skin biopsy: amyloidosis
Muscle biopsy: mitochondrial dysfunction (multiple organs are affected)
Bone marrow biopsy: multiple myeloma
CT or MRI: radiculopathia or myelolysis
Head MRI: CNS involvement or myelon lesio
Nerve ultrasound: mononeuropathy, CMT1
3
Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
4
Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
4. Hereditary motor and sensory neuropathy – classification and clinical evaluation
A Charcot-Marie-Tooth disease (CMT) is one type of hereditary motor and sensory polyneuropathy. It
is one of the most common hereditary neurological disorders.
4.1. CMT classification
According to the type of neuropathy, two main groups of CMT can be separated: (1) demyelinating
type or CMT1 (NCV <38 m/s) and (2) axonal type or CMT2 (NCS >38 m/s, decreased amplitudes).
Intermediate form (ICMT) both type are present and cannot be distinguished. CMT starts usually in
the first two decades. (CMT1: 10-20 ys; CMTII – 20-30 ys).
4.2 Genetic background
Hereditary neuropathy shows the following inheritance patterns: autosomal dominant (CMT1, CMT2,
ICMT), recessive (CMT4) or X-linked (CMTX).
There are more than 70 known genes causing CMT and this number increase permanently.
Abbreviation Gene
Distribution
CMT1A
PMP22
dupl
37.2%
CMTX1
Cx32
6.5%
CMT2A
MFN2
4.2%
CMT1B
MPZ
4.1%
CMT1E
PMP22
1.0%
CMT1D
EGR2
0.06%
CMT1C
LITAF
0.12%
Percentages of gene distribution [Fridman et al. 2014]
5
Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
Algorithm of CMT genetic evaluation [Friedman et al and own data]
4.3 Clinical appearance
The symptoms show distal symmetric neuropathy phenotype. CMT Neuropathy Score-t (CMTNS) is
recommended to evaluate the severity and to follow up (see p. 6). CMTNS is consisted by nine
different scores: symptoms (3), signs (4) and neurophysiology (2). Each score is rated from 0 to 4
regarding the severity (0 – normal, 4 – severe). Severity is ranked as follows: ≤10 mild, 11-20
moderate, >20 severe.
Certain
GJB1 mutations can cause CNS involvement (spasticity, corticospinal tract involvement,
cortical lesion, cerebellar ataxia) as well. Furthermore, early onset hearing impairment and acute florid
attacks can be also observed sometimes.
GJB1 mutations cause milder clinical signs and symptoms in
females compared to males.
MFN2 can appear with mitochondrial deletion or depletion, cerebellar
ataxia or CNS involvement. DNM2 mutations can be associated with mitochondrial deletion,
centronuclear myopathy (seen in muscle biopsy) or rarely with cardiomyopathy
Suspicion of hereditary neuropathy usually comes up if relatives are also affected and the disorders
starts in first decades. However, sporadic cases are also relatively common. Acquired neuropathies
must be ruled out.
6
Institute of Genomic Medicine and Rare
Disorders
Semmelweis University
Head of department: Prof. Dr. Mária Judit Molnár
25-29. Tömő str., Budapest, Hungary, H-1083
Tel:+36-1-459-1483
4.4 Management of CMT
There is no cure for CMT but symptoms and signs can be treated. These aim the improvement of life
quality and the slower progression.
-
vitamins – C-vitamin 1000 mg, Milgamma 1-3 pills
-
neuropathic pain – Lyrica 1-2x 75mg / Cymbalta 30-60mg/ Teperin-EP 25-50mg
-
musculosceletal pain – COX2 inhibitors (Xefo 8mg)
-
physiotherapy
-
Mobility aids – surgery, peroneus orthesis, Toe-OFF, wheel chair, crutches
-
depression – neuropsychological examination, antidepressants, psychotherapy
-
control and treat of diabetes mellitus
-
avoiding the neurotoxic agents (alcohol, industrial toxins, certain medications)
4.5 Differential diagnostic
Inherited disorders accompanied with polyneuropathy:
Mitochondrial disorders (systematic involvement, elevated lactate, muscle biopsy,
mitochondrial deletio, hotspot mutation);
Familiar amyloid polyneuropathy (heart, kidney, vascular involvement, V30M mutation)
Hereditary Neuropathy with Pressure Palsy (HNPP) if multifocal motor neuropathy is present
(PMP22 deletion)
References:
Harrison’s Neurology in Clinical Use 1st Edition
Murphy et al 2011; Journal of Peripheral Nervous System 16:191-198
Fridman V et al 2014; J Neurol Neurosurg Psychiatry 2014;0;1-6
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