CAM 20489

Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:August 2013    

The inherited peripheral neuropathies are a heterogeneous group of diseases that may be inherited in an autosomal dominant, autosomal recessive or X-linked dominant manner. The inherited peripheral neuropathies can be divided into hereditary motor and sensory neuropathies (Charcot-Marie-Tooth disease), hereditary neuropathy with liability to pressure palsies, hereditary sensory and autonomic neuropathies and other miscellaneous types (e.g., hereditary brachial plexopathy, giant axonal neuropathy). In addition to clinical presentation, nerve conduction studies and family history, genetic testing can be used to diagnose specific inherited peripheral neuropathies.

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy and peroneal muscular atrophy, is a group of progressive disorders that affect the peripheral nerves. CMT is caused by a mutation in one of several myelin genes that result in defects in myelin structure, maintenance or function. Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States.  

The neuropathy of CMT affects both motor and sensory nerves. Symptoms usually start in childhood and have a gradual progression. The severity of symptoms varies greatly among individuals and even among family members with the disease (NINDS, 2007). Typical symptoms include the following: 

  • Weakness of the foot and lower leg muscles, which may result in foot drop and a high-stepped gait with frequent ankle sprains, tripping or falls
  • Foot deformities, such as pes cavus and hammertoes
  • Distal calf muscle atrophy often occurs, causing the stork leg deformity or inverted champagne bottle appearance
  • Weakness and muscle atrophy may occur in the hands, resulting in difficulty with carrying out fine motor skills.
  • Sensory loss is gradual and mainly involves proprioception and vibration.
  • Spinal deformities like kyphosis and scoliosis can often develop 

Pain can range from mild to severe, and some people may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Although in rare cases, individuals may have respiratory muscle weakness, CMT is not considered a fatal disease and people with most forms of CMT have a normal life expectancy (NINDS, 2007). 

CMT is caused by mutations in genes that produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. Although different proteins are abnormal in different forms of CMT disease, all of the mutations affect the normal function of the peripheral nerves. 

Pattern of Inheritance
The pattern of inheritance varies with the type of CMT disease. CMT1, most cases of CMT2 and most intermediate forms are inherited in an autosomal dominant pattern. CMT4, a few CMT2 subtypes and some intermediate forms are inherited in an autosomal recessive pattern. CMTX is inherited in an X-linked pattern. In the X-linked recessive patterns, only males develop the disease, although females who inherit the defective gene can pass the disease on to their sons. In the X-linked dominant pattern, an affected mother can pass on the disorder to both sons and daughters, while an affected father can only pass it on to his daughters. 

Some cases of CMT disease result from a new mutation and occur in people with no history of the disorder in their family. In rare cases the gene mutation causing CMT disease is a new mutation which occurs spontaneously in the individual's genetic material and has not been passed down through the family. 

Types of Charcot-Marie-Tooth disease
There are many forms of CMT disease, including CMT1, CMT2, CMT3, CMT4 and CMTX. 

CMT1 is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss and slow nerve conduction velocity (typically 5-30 m/sec) (Bird, 2016). The six subtypes of CMT1 shown in Table 1 are clinically indistinguishable and are designated solely on molecular findings (Saporta et al., 2011)  

Table 1: Molecular Genetics of CMT Variants (adapted from Bird et al., 20155) 

Locus Name Proportion of CMT1 (exluding CMTX))  Gene Protein Product




Peripheral myelin protein 22




Myelin P0 protein




Lipopolysaccharide-induced tumor necrosis factor-α factor




Early growth response protein 2




Peripheral myelin protein 22 (sequence changes)




Neurofilament light polyeptide 

CMT1A is an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). Overexpression of this gene causes the structure and function of the myelin sheath to be abnormal. A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy (NINDS, 2007). 

CMT1B is an autosomal dominant disease caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (P0), which is another critical component of the myelin sheath. Most of these mutations are point mutations. As a result of abnormalities in P0, CMT1B produces symptoms similar to those found in CMT1A (NINDS, 2007). 

The less common CMT1C, CMT1D and CMT1E, which also have symptoms similar to those found in CMT1A, are caused by mutations in the LITAF, EGR2 and NEFL genes, respectively (NINDS, 2007). 

CMT2 is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Nerve conduction velocities are usually within the normal range; however, occasionally they fall in the low-normal or mildly abnormal range (35-48 m/sec) (Bird, 2016). In general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1. A threshold of 38 m/sec for median motor nerve conduction is often used clinically to distinguish CMT1 from CMT2 (Bird, 2016). It is less common than CMT1. CMT2A, the most common axonal form of CMT, is caused by mutations in Mitofusin 2, a protein associated with mitochondrial fusion. CMT2A has also been linked to mutations in the gene that codes for the kinesin family member 1B-beta protein, but this has not been replicated in other cases. Other less common forms of CMT2 are associated with various genes: CMT2B (associated with RAB7), CMT2D (GARS), CMT2E (NEFL), CMT2H (HSP27) and CMT2l (HSP22) (NINDS, 2007). 

Table 2: Molecular Genetics of CMT2 (Saporta et al., 2011) 


 Proportion of CMT

Gene/Chromosome Locus 

Protein Product 




Kinesin-like protein KIF1B








Ras-related protein Rab-7 




Lamin A/C 




Mediator of RNA polymerase II transcription subunit 25




Transient receptor potential cation channel subfamily V member 4 




Glycyl-tRNA synthetase 




Neurofilament light polypeptide 




Heat-shock protein beta-1 








Ganglioside-induced differentiation-associated protein-1 




Myelin P0 protein 




Heat-shock protein beta-8 




Alanyl-tRNA synthetase, cytoplasmic 




Cytoplasmic dynein 1 heavy chain 1 




E3 ubiquitin-protein ligase LRSAM1 




DNA-binding protein SMUBP-2 




DnaJ homolog subfamily B member 2 




Methionine--tRNA ligase, cytoplasmic 

CMT3 or Dejerine-Sottas disease is a severe demyelinating neuropathy that begins in infancy. Infants have severe muscle atrophy, weakness and sensory problems. This rare disorder can be caused by a specific point mutation in the P0 gene or a point mutation in the PMP-22 gene (NINDS, 2007). 

CMT4 comprises several different subtypes of autosomal recessive demyelinating motor and sensory axonal neuropathies. Each neuropathy subtype is caused by a different genetic mutation, may affect a particular ethnic population and produces distinct physiologic or clinical characteristics. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. Several genes have been identified as causing CMT4, including GDAP1 (CMT4A), MTMR13 (CMT4B1), MTMR2 (CMT4B2), SH3TC2 (CMT4C), NDG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FDG4 (CMT4H) and FIG4 (CMT4J) (NINDS, 2007). 

Table 3: Molecular Genetics of CMT4 (Bird, 2016) 

Locus Name 

Proportion of CMT4 


Protein Product 





Ganglioside-induced differentiation-associated protein 1 



Myotubularin-related protein 2 



Myotubularin-related protein 13 



SH3 domain and tetratricopeptide repeats-containing protein 2 



Protein NDRG1 



Early growth response protein 2






FYVE, RhoGEF and PH domain-containing protein 4 



Phosphatidylinositol 3, 5-biphosphate 

CMTX is caused by a point mutation in the connexin-32 gene on the X chromosome. The connexin-32 protein is expressed in Schwann cells -- cells that wrap around nerve axons, making up a single segment of the myelin sheath (NINDS, 2007). CMTX type 1 is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families (Bird, 2016).

Table 4: Molecular Genetics of CMTX  

Disease Name 

Proportion of X-Linked CMT 

Gene/Chromosome Locus 

Protein Product 




Gap junction beta-1 protein (connexin 32)







Not Applicable

CMTX4/Cowchock syndrome 


Apoptosis-inducing factor 1 



Ribose-phosphate pyrophosphokinase 1 



 Pyruvate dehydrogenase kinase isoform 3

Genetic Testing
Charcot-Marie-Tooth disease is usually diagnosed by an extensive medical history, family history and physical examination. The clinical diagnosis is then confirmed by electrodiagnostic tests like electromyography and nerve conduction velocity tests, and sometimes by nerve biopsy. Genetic testing is available for some types of CMT and results are usually enough to confirm a diagnosis. Genetic testing can simplify the diagnosis of CMT by avoiding invasive procedures such as nerve biopsy. In addition, early diagnosis can facilitate early interventions, such as physical therapy. However, genetic testing often will not affect the management for individual patients with CMT. 

Genetic testing for CMT is complicated by the extensive underlying genetic heterogeneity (Cruse, 2017). The CMT spectrum of disorders can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. The most commonly identified CMT subtypes were CMT1A (PMP22 duplication), CMTX1 (GJB1 mutation), hereditary neuropathy with liability to pressure palsies (PMP22 deletion), CMT1B (MPZ mutation) and CMT2A (MFN2 mutation). Together, these five subtypes accounted for 92 percent of genetically defined CMT cases. All other CMT subtypes and associated mutations each accounted for <1 percent of genetically defined CMT (Cruse, 2017).  

Genetic screening for relatives of a patient diagnosed with CMT is an option, but risk assessment depends on several factors, including accuracy of the diagnosis, determination of the mode of inheritance for the individual family and results of molecular genetic testing (Cruse, 2017).

Regulatory Status
No U.S. Food and Drug Administration-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service. Such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.


  1. Genetic counseling is considered MEDICALLY NECESSARY and recommended for genetic testing of CMT disease or other inherited peripheral neuropathies. 
  2. Genetic testing for CMT disease is considered MEDICALLY NECESSARY when the patient displays clinical features of CMT and a definitive diagnosis remains uncertain after history, physical examination, genetic counseling, and completion of conventional diagnostic studies (i.e., nerve conduction studies and/or electromyography). If results indicate a demyelinating neuropathy, then first test for the most commonly identified CMT subtype, CMT1A (PMP22 duplication)..
  3. Genetic testing for CMT in asymptomatic at-risk individuals is considered MEDICALLY NECESSARY if there is a close relative (i.e., first-, second-, or third-degree relative) with a known CMT mutation. 
  4. Genetic testing for CMT is considered MEDICALLY NECESSARY for prenatal diagnosis of known familial mutation(s) in at-risk pregnancies. 
  5. Peripheral nerve biopsy is considered MEDICALLY NECESSARY to diagnose CMT when clinical features are significantly suggestive of CMT and the genetic tests are negative.
  6. Genetic testing for hereditary neuropathy with liability to pressure palsies (PMP22 deletion) is considered MEDICALLY NECESSARY when the patient displays clinical features of HNPP and a definitive diagnosis remains uncertain after history, physical examination, genetic counseling, and completion of electrophysiologic studies. 
  7. Genetic testing for hereditary motor neuropathy (HMN) (BSCL2 gene) is considered MEDICALLY NECESSARY when the patient displays clinical features of HMN and a definitive diagnosis remains uncertain after history, physical examination, genetic counseling, and completion of electrophysiologic studies.

IV. Reimbursement

  1. If five or more genes are being tested, use appropriate genetic procedure sequencing panel code.

According to Cruse (2017), genetic testing to diagnose CMT can help patients avoid invasive procedures and facilitate early interventions such as physical therapy. Genetic screening in asymptomatic at-risk relatives of a patient diagnosed with CMT can be considered, but risk assessment depends on several factors, including accuracy of the diagnosis, determination of the mode of inheritance for the individual family and results of molecular genetic testing. Genetic counseling is recommended prior to prenatal testing for pregnancies at increased risk for CMT. Prenatal testing should be done only if the pathogenic variant in the family is already known (Cruse, 2017).

Bird (1998; updated 2016) recommended testing of asymptomatic adult relatives who are at risk of developing CMT if the specific pathogenic variant has been identified in an affected relative. Genetic counseling should be performed prior to testing. Testing of at-risk asymptomatic children was not recommended. The author also stated that prenatal testing and preimplantation genetic diagnosis for some forms of CMT should be performed only if the disease-causing variant has been already identified in the family.

One potential genetic testing strategy is use of a multi-gene panel that includes genes associated with CMT (Rossor et al., 2013). Panels exist for dominantly and recessively inherited CMTs as well as demyelination and axonal forms. Larger, all-inclusive panels are also available. The genes included and the methods used in multi-gene panels vary by laboratory and over time (Bird, 1998).

Another potential testing approach is to first test for pathogenic variant(s) in the single most likely gene that best fits the phenotype. If such testing does not identify the pathogenic variant, then proceed to genetic neuropathy panel testing (Rossor et al., 2015).

According to DiVincenzo et al. (2014), 95% of the positive results involved one of four genes (PMP22, GJB1, MPZ, MFN2). The authors conclude that these four genes should be screened first before proceeding with further genetic testing. Manganelli et al. (2014) essentially confirm the findings of DiVincenzo et al., except for finding a larger number of GDAP1 pathogenic variants (4%).

For inherited peripheral neuropathies other than CMT and HNPP, the clinical utility of genetic testing to confirm a clinical diagnosis of an inherited peripheral neuropathy is unknown. No evidence was found that use of genetic testing resulted in changes to patient monitoring and patient management and led to improvement in clinical outcomes. Genetic testing for other inherited peripheral neuropathies is, therefore, considered experimental and investigational.

Practice Guidelines and Position Statements
National Institute of Neurological Disorders and Stroke (NINDS)
NINDS states that "genetic testing is available for some types of CMT and results are usually enough to confirm a diagnosis. In addition, genetic counseling is available to assist individuals in understanding their condition and plan for the future" (NINDS, 2007).

The Polyneuropathy Task Force that included 19 physicians with representatives from the American Academy of Neurology (AAN), the American Academy of Neuromuscular and Electrodiagnostic Medicine (AANEM) and the American Academy of Physical Medicine and Rehabilitation (AAPM&R) concluded that "genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies (Class I)" (England et al, 2009). The Task Force stated that "for patients with a cryptogenic polyneuropathy who exhibit a classic hereditary neuropathy phenotype, routine genetic screening may be useful for CMT1A duplication/deletion and Cx32 mutations in the appropriate phenotype (Class III). Further genetic testing may be considered guided by the clinical question." The task force recommended that "genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies (Level A)". The task force further recommended that "Genetic testing may be considered in patients with a cryptogenic polyneuropathy and classic hereditary neuropathy phenotype (Level C). There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classic hereditary phenotype (Level U)" (England et al., 2009).

No guidelines or recommendations for genetic testing for inherited peripheral neuropathies other than CMT and HNPP were found from any professional association and regulatory agencies.


  1. Bird, T. (1998). Charcot-Marie-Tooth hereditary neuropathy overview, updated 2016. Retrieved January, 2017, from
  2. Charcot-Marie-Tooth Association. (2016). Diagnosing CMT. Retrieved January 28, 2017 from
  3. Cruse, R. (2016). Hereditary primary motor sensory neuropathies, including Charcot-Marie-Tooth disease. Retrieved January, 2017, from
  4. DiVincenzo, C., et al. (2014). The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Molecular Genetics and Genomic Medicine; 2(6); 522-529
  5. England, J, Gronseth, G.S., … and Sumner, A.J. (2009). Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Neurology, 72(2):185-192.
  6. Genetic Homes Reference – NIH (2017). Charcot-Marie-Tooth disease. Accessed online on January 30, 2017 from
  7. Manganelli F, Tozza S, Pisciotta C, Bellone E, Iodice R, Nolano M, Geroldi A, Capponi S, Mandich P, Santoro L. (2014). Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population. J Peripher Nerv Syst. 19:292–8.
  8. Muscular Dystrophy Association (2017). Charcot-Marie-Tooth Disease. Accessed online on January 29, 2017 from
  9. National Institute of Neurological Disorders and Stroke (2007) Charcot-Marie-Tooth Disease Fact Sheet. Accessed online on November 15, 2016 from
  10. Rossor, A.M., Polke, J.M., Houlden, H., Reilly, M.M. (2013). Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 9:562–71.
  11. Rossor, A.M., Evans, M.R.B., and Reilly, M.M. (2015). A practical approach to genetic neuropathies. Pract Neurol; 15: 187-198
  12. Saporta, A., Sottile, S., Miller, L., Feely, S., Siskind, C., & Shy, M. (2011). Charcot Marie Tooth (CMT) subtypes and genetic testing strategies. Ann Neurol., 69: 22–33. doi:10.1002/ana.22166

Coding Section

Codes Number Description
CPT 81324  Pmp22 (peripheral myelin protein 22) (eg, charcot-marie-tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis
  81325 Pmp22 (peripheral myelin protein 22) (eg, charcot-marie-tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis
  81326 Pmp22 (peripheral myelin protein 22) (eg, charcot-marie-tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant

Mopath procedure level 4


GJB1 (gap junction protein, beta 1) (eg, Charcot-Marie-Tooth X-linked), full gene sequence


Mopath procedure level 5


EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence

LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence



Mopath procedure level 6


GDAP1(ganglioside-induced differentiation-associated protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence

MPZ(myelin protein zero) (eg, Charcot-Marie-Tooth), full gene sequence

NEFL(neurofilament, light polypeptide) (eg, Charcot-Marie-Tooth), full gene sequence



Mopath procedure level 7


GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence

MFN2 (mitofusin 2) (eg, Charcot-Marie-Tooth disease), full gene sequence

SH3TC2 (SH3 domain and tetratricopeptide repeats 2) (eg, Charcot-Marie-Tooth disease), full gene sequence


  81448 (effective 1/1/2018) 

Hereditary peripheral neuropathies panel (eg, Charcot-Marie-Tooth, spastic paraplegia), genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy-related genes (eg, BSCL2, GJB1, MFN2, MPZ, REEP1, SPAST, SPG11, and SPTLC1) 

ICD-9-CM Diagnosis V26.31

Testing of female genetic disease carrier status


Testing of male for genetic disease carrier status

ICD-10-CM G62.89  Other specified polyneuropathies 
  M21.37 codes  Foot drop 

M62.551-M62.579 codes 

Muscle wasting and atrophy, not elsewhere classified 
  M62.81 Muscle weakness (generalized)
  009 codes Supervision of High risk pregnancy 
  R26.0, R26.2, R26.81, R26.89  Abnormalities of gait and mobility

Encounter for nonprocreative screening for genetic disease carrier status

  Z13.79 Encounter for other screening for genetic and chromosomal anomalies
  Z33.1 Pregnancy state, incidental
ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     


Annual review, rewording criteria #2 for clarity, adding medical necessity language related to hereditary motor neuropathy testing and adding a reimbursement statement. Updating coding. 


Interim review. Genetic counseling is recommended is replacing Genetic counseling is Medically necessary. No other changes made. 


Corrected typo in policy section. No other changes. 


Annual review, removing "ulnar/median" nerve in criteria #2, neutral to specific nerve. No other changes made. 


Updating policy with 2018 coding. No other changes. 


Interim review, updating background, description, policy, rationale, references and coding. 


Updated category to Laboratory. No other changes 


Annual review, no change to policy intent. Updating background, description, rationale and references. 


Annual review, no change to policy intent. Updated background, description, rationale and references. Added appendix 1, coding and guidelines.


Annual review. Updated description, background, rationale and references. No change to policy intent.

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