Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018
Hereditary neuropathies are a heterogeneous group of disorders affecting the peripheral nervous system. They may be inherited in an autosomal dominant, autosomal recessive or X-linked dominant manner. The estimated prevalence is 1 in 2,500 individuals, making inherited peripheral neuropathies the most common inherited neuromuscular disease. These neuropathies are divided into hereditary motor and sensory neuropathies, hereditary neuropathy with liability to pressure palsies, and other miscellaneous rare types (e.g., hereditary brachial plexopathy, hereditary sensory autonomic neuropathies).
Currently a diagnosis for inherited peripheral neuropathies is based upon characteristic clinical findings and electrophysiologic studies (electromyography and nerve conduction velocity), nerve biopsy and family history. The development of genetic testing has been suggested as another way to diagnose specific inherited peripheral neuropathies.
This policy only addresses the hereditary motor and sensory neuropathies and hereditary neuropathy with liability to pressure palsies (HNPP).
Hereditary motor and sensory neuropathies
The most common type of hereditary motor and sensory neuropathy is Charcot-Marie-Tooth (CMT) disorder. Multiple subtypes have been identify (Type 1, Type 2, Type 4 and Type X) which are caused by a variety of mutations in genes that encode myelin, Schwann cells, and axons.
Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is a slow progressive type disorder and often associated with pes cavus foot deformity, bilateral foot drop and palpably enlarged nerves, especially the ulnar nerve at the olecranon groove and the greater auricular nerve. Affected individuals usually become symptomatic between the age of 5 and 25 years. The most common subtype (CMT1A) is caused by duplication of the PMP22 (i.e., peripheral myelin protein 22) gene.
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is a non-demyelinating (axonal) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. Clinically, CMT2 is similar to CMT1, although typically less severe and unlike CMT1, peripheral nerves are not enlarged or hypertrophic. CMT2 subtypes are caused by mutations in 15 genes.
Charcot-Marie-Tooth hereditary neuropathy type 4 (CMT4) is a form of hereditary motor and sensory neuropathy that is inherited in an autosomal recessive fashion and occurs secondary to myelinopathy or axonopathy. It occurs more rarely than the other forms of CMT neuropathy. There are 10 genes in which mutations are known to cause CMT4 subtypes.
Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families. CMTX1 is inherited in an X-linked dominant manner.
Hereditary Neuropathy with liability to Pressure Palsies (HNPP)
Hereditary neuropathy with liability to pressure palsies (HNPP) is a slow progressive, neuromuscular disorder. The inadequate production of PMP22 (i.e., peripheral myelin protein 22) gene causes an individual to be very susceptible to nerve injury from pressure, stretch or repetitive use. HNPP is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop and episodes of numbness, muscular weakness, atrophy, and palsies. Individuals rarely present symptoms before the second or third decade of life. This disorder is benign with recovery occurring within a period of days to months in most cases, although an estimated 15% of individuals have residual weakness following an episode.
There are no effective therapies for inherited peripheral neuropathies. The supportive treatment is generally provided by a multidisciplinary team including neurologists, orthopedic surgeons, physical and occupational therapists; with treatment choices limited to physical therapy, the use of orthotics, surgical treatment for skeletal or soft tissue abnormalities, and drug treatment for pain. The supportive treatment for HNPP can include transient bracing (e.g., a wrist splint or ankle-foot orthosis) which may become permanent in some cases of foot drop. The prevention of HNPP manifestations can be accomplished by wearing protective padding (e.g., elbow or knee pads) to prevent trauma to nerves during activity.
Genetic testing to confirm a clinical diagnosis of inherited peripheral neuropathy is considered investigational.
Genetic testing for all other indications of inherited peripheral neuropathy is considered investigational.
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The clinical utility of genetic testing for hereditary peripheral neuropathies depends on how the results can be used to improve an individual’s management; however, well-designed, evidence-based studies are lacking in peer review journals that address how the genetic testing would change the individual’s medical management. Since the diagnosis of an inherited peripheral neuropathy can generally be made clinically and the inherited peripheral neuropathies have no specific therapy, the incremental benefit of a genetic confirmation of these disorders is not known.
American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation (Published 2009, reaffirmed 2013) Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review).Retrieved May 31, 2013 from www.neurology.org.
Antoniadi, T., Buxton, C., Davis, G., Forrester, N., Smith, D., Lunt, P., & Burton-Jones, S. (2015). Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Medical Genetics, (2015), 16:84. (Level 4 evidence)
BlueCross BlueShield Association. Medical Policy Reference Manual. (1:2018). Genetic testing for the diagnosis of inherited peripheral neuropathies (2.04.89). Retrieved June 17, 2018 from BlueWeb. (32 articles and/or guidelines reviewed)
Burgunder, J. M., Schols, L., Baets, J., Andersen, P., Gasser, T., Szolnoki, Z., et al. (2011). EFNS guidelines for the molecular diagnosis of neurogenetic disorders: Motoneuron, peripheral nerve and muscle disorders. European Journal of Neurology, 18 (2), 207-217. (Level 2 evidence)
Cornett, K., Menezes, M., Bray, P., Halaki, M., Shy, R., Yum, S., et al. (2016). Phenotypic variability of childhood Charcot-Marie-Tooth disease. Journal of American Medical Association, 73 (6), 645-651. (Level 4 evidence)
DiVincenzo, C., Elzinga, C., Medeiros, A., Karbassi, I., Jones, J., Evans, M., et. al., (2014, July) The allelic spectrum of Charcot–Marie–Tooth disease in over 17,000 individuals with neuropathy. Molecular Genetics & Genomic Medicine. 2014; 2(6): 522–529.
Saporta, M., and Shy, M. (2013, May) Inherited peripheral neuropathies. Neurology Clinics, 31 (2), 597-619. (Level 5 evidence)
ORIGINAL EFFECTIVE DATE: 12/14/2013
MOST RECENT REVIEW DATE: 8/9/2018
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