Peripheral Neuropathy

Peripheral neuropathy (PN) affects two million people in the U.S.,¹⁴ typically middle-aged and elderly individuals. It is a neurological disorder that affects the sensory, motor and/or autonomic nerves, and is caused by abnormal function of these nerves due to various etiologies.

These disorders can originate from numerous causes, such as diabetes, alcoholism, HIV, toxin exposure, metabolic abnormalities, vitamin deficiency, or adverse effects of certain drugs. However, after evaluations for the etiologies of these PNs are performed, 32-70% of all peripheral neuropathies remain idiopathic.¹ With the development of autoimumme and genetic tests, these idiopathic peripheral neuropathies can often be diagnosed.

Autoimmune Peripheral Neuropathy
Symptoms of an autoimmune peripheral neuropathy may include weakness, cramping, decreased tendon reflexes, numbness, tingling, and pain affecting the arms and/or legs. Clinically, peripheral neuropathies are classified according to various characteristics: symmetric or asymmetric, proximal or distal, acute or chronic, slowly progressive or rapid onset, affecting one (mononeuropathy) or many nerves (polyneuropathy).^2,14 Upon electrophysiological examination, assessment of a neuropathy can be further classified, depending on which part of the peripheral nervous system is affected, such as the axon or myelin sheath. Peripheral neuropathy can be demyelinating, axonal, or both, as determined by electromyography (EMG) and nerve conduction studies (NCS).

EMG/NCS Evaluation
Assessment of the peripheral neuropathy using EMG/NCS can direct a physician toward the appropriate autoimmune disorder. Typically, demyelinating neuropathies demonstrate slow nerve conduction velocities (NCV), often with reduced amplitudes of sensory/motor nerve conduction and prolonged distal latencies. By contrast, axonal neuropathies typically demonstrate normal NCVs with low amplitudes of sensory/motor nerve conduction. Neuropathies may also have mixed EMG/NCS results and exhibit features of both demyelination and axonal loss.

Autoantibody Testing
When a diagnosis cannot be made based on clinical workup and electrophysiological studies, autoantibody testing can be used to help identify the specific cause of an autoimmune peripheral neuropathy. Autoantibody tests can help identify the etiology of sensory, sensorimotor, and motor neuropathies. It is important to classify the etiology of a patient's peripheral neuropathy because each of these neuropathies responds differently to various treatment options. Several types of therapy are used to treat autoimmune PN: steroids,⁹ IVIg, cyclophosphamide, and plasma exchange.² Autoimmune peripheral neuropathies can be identified as anti-MAG, anti-GM1, anti-Sulfatide, or anti-GALOP. The following table compares these autoimmune peripheral neuropathies:

Table 1

Type of Autoimmune Peripheral Neuropathy		Anti-MAG		Anti-GM1 (MMN*)		Anti-Sulfatide		Anti-GALOP
Clinical Features		Sensory>Motor2		Motor weakness9		Sensory>Motor2		Sensory>Motor9
				Usually begins in distal arms2				Gait ataxia9
Anatomy		Distal9		Distal>proximal9		Distal9		Distal2
		Symmetric9		Asymmetric9		Symmetric9		Symmetric9
Nerve Physiology		Demyelinating> Axonal2		Demyelinating or Axonal9		Demyelinating or Axonal9		Demyelinating or Axonal9
EMG/NCS		Slow NCV9		Motor nerve conduction block, can be focal9		Slow NCV9		Variable, Demyelinating cases show slow NCV2
		No conduction block9		No conduction block in DLMN*2		No conduction block2		No conduction block2
		Prolonged distal latency9				Prolonged distal latency9		Prolonged distal latency2
		Axonal loss (low CMAPs*, SNAPs*)9		Motor nerve axonal loss (low CMAPs)9		Axonal loss (low CMAPs, SNAPs)9		Axonal loss (low CMAPs, SNAPs)2
Typical Sensory Symptoms or Signs		Weakness, sensory loss9		Minimal9 or absent2		Pain, paresthesias9		Mild to moderate2
								Positive Romberg sign9
Typical Motor Symptoms or Signs		Mild to severe10		Variable2		Variable16		Variable3
Evolution		Slow, progressive9		Slow, progressive9		Slow, progressive9		Variable3
Common Therapeutic Options		Cyclophosphamide, plasma exchange9		IVIg, cyclophosphamide9		IVIg, cyclophosphamide9		IVIg, cyclophosphamide9
Typical Onset		Adulthood9		Adulthood2		Adulthood10		Late adulthood9
* MMN = Multifocal Motor Neuropathy DLMN = Distal Lower Motor Neuron disease CMAP = Compound muscle action potential SNAP = Sensory nerve action potential

HMSNs are a group of progressive disorders affecting the motor and sensory components of the peripheral nervous system. The molecular basis of inherited neuropathies has allowed identification of these disorders. HMSNs encompass the following disorders:^4,5,8

• HMSN Type I hypertrophic form of Charcot-Marie-Tooth disease (CMT)
• HMSN Type II neuronal form of CMT
• HMSN Type III (Dejerine-Sottas disease)
• Hereditary neuropathy with liability to pressure palsies (HNPP)
• Congenital hypomyelinating neuropathy (CHN)
• Refsum's disease
• Familial amyloidotic polyneuropathy (FAP)

Charcot-Marie Tooth (CMT) presents as a chronically demyelinating motor-sensory neuropathy with decreased nerve conduction velocity (NCV<40m/s) in some types.⁷ It causes slowly progressive distal muscle atrophy and weakness, often with gait disturbance and deformity of the feet and hands.^5,7

• CMT1A is an autosomal dominant peripheral neuropathy originating from duplications or point mutations in the peripheral myelin protein-22 (PMP-22) gene on chromosome 17.⁸
• CMTX is an X-linked dominant peripheral neuropathy originating from point mutations in the connexin-32 gene on the X chromosome.⁸
• CMT1B is an autosomal dominant peripheral neuropathy originating from point mutations in the myelin protein zero (MPZ or P₀) gene on chromosome 1.⁸

Hereditary neuropathy with liability to pressure palsies (HNPP) is a demyelinating motor-sensory neuropathy which is autosomal dominant and which originates from a deletion, frameshift, or point mutation of the PMP-22 gene on chromosome 17.¹¹ It typically presents as a recurrent, focal compression in adolescence4 similar to carpal tunnel syndrome.¹¹ Nerve conduction may be slow at the site of compression.¹¹

Dejerine-Sottas Disease (DSD), also known as CMT3, is a motor-sensory neuropathy that typically can exhibit an autosomal recessive or autosomal dominant inheritance pattern, with onset of symptoms in childhood.¹² It presents with delayed motor development, abnormal gait, nerve hypertrophy,⁵ and generally results in individuals eventually becoming wheelchair- bound.¹² DSD can be caused by point mutations or a homozygous duplication in the PMP-22 or MPZ (P0) genes,⁸ or by point mutations in the EGR2 gene.¹³

Congenital hypomyelinating neuropathy (CHN) is an early-onset motor-sensory neuropathy associated with abnormal myelination of peripheral nerves and a variable inheritance pattern.¹³ It presents at birth, typically with hypotonia and limb weakness, neuropathy, and arthrogyrposis.⁵ Some severely affected newborns require ventilation and do not survive.¹² CHN results from a mutation in the MPZ gene and may present similarly to spinal muscular atrophy (SMA).¹²

Refsum's Disease is a demyelinating, motor-sensory neuropathy with an autosomal recessive⁶ inheritance pattern affecting children and adults. Common clinical features include motor and sensory neuropathy, retinitis pigmentosa, night blindness, ataxia, ichthyosis, and sensorineural hearing loss.⁵ Refsum's disease is associated with abnormally high levels of phytanic acid in the blood or plasma.⁵

Familial Amyloidotic Polyneuropathy (FAP) is a group of autosomal dominant disorders in which the majority are caused by point mutations in the transthyretin (TTR) gene on chromosome 18, resulting in abnormal deposition of amyloid in the peripheral nerves and in other organs, including the heart, kidneys, and eyes.⁸ It often presents in adulthood as a generalized sensorimotor and/or autonomic neuropathy, sometimes accompanied by gastrointestinal symptoms.⁸ At least 55 disease-causing mutations have been identified in the transthyretin gene.¹⁵ In addition, carpal tunnel syndrome, vitreous opacities, and other systemic abnormalities may be part of the presentation for some of the TTR gene mutations.⁸

Learn More about Peripheral Neuropathy.

Download the clinical presentation chart.

1. Dyck, P.J. et al., Intensive Evaluation of Referred Unclassified Neuropathies Yields Improved Diagnosis. Annals of Neurology 1981; 10:222-226.
2. Pestronk, A. Chronic Immune Polyneuropathies and Serum Autoantibodies. In Neuroimmunology for the Clinician, ed. L.A. Rolak and Y. Harati, 237-251. 1997. Boston: Butterworth-Heinemann.
3. Pestronk, A. et al., Treatable gait disorder and polyneuropathy associated with high titer serum IgM binding to antigens that copurify with myelin-associated glycoprotien. Muscle & Nerve 1994; 17:1293-1300.
4. Tyson, J. et al., Deletions of Chromosome 17p11.2 in Multifocal Neuropathies. Annals of Neurology 1996; 39(2): 180-186.
5. Sarnat, H.B. Hereditary Motor Sensory Neuropathies. In Textbook of Pediatrics, ed. W.E. Nelson, et al., 1758-1759. 1996. Philadelphia: W.B. Saunders Company.
6. Evans, O. et al., Inborn Errors of Metabolism of the Nervous System. In Neurology in Clinical Practice, 3rd ed., ed. W.G. Bradley et al., 1625-1634. 2000. Boston: Butterworth-Heinemann.
7. Bird, T. Charcot-Marie-Tooth Hereditary Neuropathy Overview. www.geneclinics.org/profiles/cmt/details.html 2000.
8. Bosch, E.P. and Smith, B.E. Disorders of Peripheral Nerves. In Neurology in Clinical Practice, 2nd ed., ed. W.G. Bradley et al., 2064-2067. 2000. Boston: Butterworth-Heinemann.
9. Pestronk, A. Chronic Immune Polyneuropathies. www.neuro.wustl.edu/neuromuscular/antibody/pnimdem.html. 2000.
10. Pestronk, A. et al., Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein. Neurology 1991; 41:357-362.
11. Bird, T.D. Hereditary Neuropathy with Liability to Pressure Palsies. www.geneclinics.org/profiles/hnpp/details.html. 2000.
12. Lyon, G. et al., Neurology of Hereditary Metabolic Diseases of Children, 2nd ed., 177-281. 1996. New York: McGraw-Hill, Inc.
13. Warner, L.E. et al., Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nature Genetics 1998; 18:382-384.
14. Donovan, M.A. and Latov, N. Explaining Peripheral Neuropathy. The Peripheral Neuropathy Association 1997.
15. The Human Gene Mutation Database, Cardiff. http://www.uwcm.ac.uk/uwcm/mg/search/119471.html. 2000.
16. Lopate, G. et al., Polyneuropathies associated with high titre antisulphatide antibodies: characteristics of patients with and without serum monoclonal proteins. Journal of Neurology, Neurosurgery, & Psychiatry 1997; 62:581-585.