CAM 299

Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies

Category:Laboratory   Last Reviewed:July 2021
Department(s):Medical Affairs   Next Review:July 2022
Original Date:August 2013    

Description 
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.

Policy

  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.  

Rationale
Peripheral neuropathies encompass the set of disorders that primarily lead to peripheral nerve dysfunction. Symptoms typically include weakness of muscles at extremities, spine curvature, and loss of sensation at extremities (Kang, 2019; UTD, 2021). Neuropathies may be caused by a variety of different factors, such as metabolic issues (including Fabry disease, Niemann-Pick disease, et al.) or present as a secondary symptom to another condition (such as Tangier disease) (Kang, 2019).

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, 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 within peripheral nerves. Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States (Kang, 2020a).

Symptoms
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 (Bird, 2020; 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 (NINDS, 2007)

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).

Causes
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 mutations affect the normal function of the peripheral nerves. There is little correlation between the genotype and phenotype of CMT; it is common to see differing mutations result in various clinical phenotypes all within the same gene (Kang, 2020a).

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 onto 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 onto 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 (Kang, 2020a).

CMT1
CMT1 is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slowed nerve conduction velocity (Bird, 2019). 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 CMT1 (Saporta et al., 2011)

Locus Name

Proportion of CMT1 (excluding CMTX)

Gene

Protein Product

CMT1A

70%-80%

PMP22

Peripheral myelin protein 22

CMT1B

10%-12%

MPZ

Myelin protein P0

CMT1C

~1%

LITAF

Lipopolysaccharide-induced tumor necrosis factor-alpha factor

CMT1D

Unknown

EGR2

Early growth response protein 2

CMT1E

~1%

PMP22

Peripheral myelin protein 22
(sequence changes)

CMT1F/2E

Unknown

NEFL

Neurofilament light polypeptide

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
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 (Bird, 2019).  In general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1 (Bird, 2019). 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 (Bird, 2019)

Locus

Proportion of CMT

Gene / Chromosome Locus

Protein Product

CMT2A1

Unknown

KIF1B

Kinesin-like protein KIF1B

CMT2A21

20%

MFN2

Mitofusin-2

CMT2B

Unknown

RAB7A

Ras-related protein Rab-7

CMT2B1

Unknown

LMNA

Lamin A/C

CMT2B2

Unknown

MED25

Mediator of RNA polymerase II transcription subunit 25

CMT2C2

Unknown

TRPV4

Transient receptor potential cation channel subfamily V member 4

CMT2D3

3%

GARS

Glycyl-tRNA synthetase

CMT2E/1F4

4%

NEFL

Neurofilament light polypeptide

CMT2F

Unknown

HSPB1

Heat-shock protein beta-1

CMT2G

Unknown

12q12-q13

Unknown

CMT2H/2K

5%

GDAP1

Ganglioside-induced differentiation-associated protein-1

CMT2I/2J

Unknown

MPZ

Myelin protein P0

CMT2L

Unknown

HSPB8

Heat-shock protein beta-8

CMT2N

Unknown

AARS

Alanine--tRNA ligase, cytoplasmic

CMT2O

Unknown

DYNC1H1

Cytoplasmic dynein 1 heavy chain 1

CMT2P

Unknown

LRSAM1

E3 ubiquitin-protein ligase LRSAM1

CMT2S

Unknown

IGHMBP2

DNA-binding protein SMUBP-2

CMT2T

Unknown

DNAJB2

DnaJ homolog subfamily B member 2

CMT2U

Unknown

MARS

Methionine--tRNA ligase, cytoplasmic

1. (Züchner, 2013). 2. (Schindler, 2014). 3. (Anthony Antonellis, 2018). 4. (Peter De Jonghe, 2011)

CMT3
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
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) (Kang, 2020a; NINDS, 2007).

Table 3: Molecular Genetics of CMT4 (Bird, 2019)

Locus Name

Proportion of CMT4

Gene

Protein Product

CMT4A1

Unknown

GDAP1

Ganglioside-induced differentiation-associated protein 1

CMT4B1

MTMR2

Myotubularin-related protein 2

CMT4B2

SBF2

Myotubularin-related protein 13

CMT4C2

SH3TC2

SH3 domain and tetratricopeptide repeats-containing protein 2

CMT4D

NDRG1

Protein NDRG1

CMT4E

EGR2

Early growth response protein 2

CMT4F

PRX

Periaxin

CMT4H3

FGD4

FYVE, RhoGEF and PH domain-containing protein 4

CMT4J4

FIG4

Phosphatidylinositol 3, 5 biphosphate

1. (Bird, 2017) 2. (Hamid Azzedine, 2015) 3. (Delague, 2013) 4. (Li, 2013)

CMTX
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, which wrap around nerve axons and make up a single segment of the myelin sheath (NINDS, 2007). CMTX type 1 is characterized by a moderate to severe motor and sensory neuropathy although symptoms tend to be less severe in women. Hearing loss and central nervous system symptoms may also occur in certain affected families (Abrams, 2020). 

Table 4: Molecular Genetics of CMTX

Disease Name

Proportion of X-Linked CMT

Gene / Chromosome Locus

Protein Product

CMTX11

90%

GJB1

Gap junction beta-1 protein (connexin 32)

CMTX22

Unknown

Xp22.2

 

CMTX31

 

Not applicable

CMTX41

AIFM1

Apoptosis-inducing factor 1

CMTX52

PRPS1

Ribose-phosphate pyrophosphokinase 1

CMTX61

PDK3

Pyruvate dehydrogenase kinase isoform 3

1.  (Bird, 2020) 2. (Kim, 2013).

Hereditary Brachial Plexopathy (Hereditary Neuralgic Amyotrophy)
This condition is primarily characterized by painful injuries to the brachial plexus nerves as well as episodic weakness of the shoulder and arm. Other symptoms such as winging of the scapula, short stature, neck folds, small face, and hypotelorism may be present. Nerve conduction velocity is typically normal, and the histopathology of this condition is non-specific. The septin 9 gene (SEPT9) on chromosome 17 has been associated with this condition (Bromberg, 2021).

Giant Axonal Neuropathy
This condition is characterized by disorganization of cytoskeletal intermediate filaments stemming from a mutated form of gigaxonin. Patients with this disorder often have a signature physical appearance; red and kinked hair, high foreheads, long eyelashes, and pale complexions are all hallmarks of this condition. The central nervous system may be affected as well with cerebellar dysfunction, spasticity, and potentially intellectual disability as possible symptoms. Nerve biopsy may show axonal loss or other axonal dysfunction. This diagnosis is confirmed by testing of the GAN gene (Kang, 2019).

Hereditary Sensory and Autonomic Neuropathies (HSANs)
This subsection of disorders primarily encompasses non-motor neuropathies and are characterized by major loss of myelinated and unmyelinated fibers. These conditions are not as common as hereditary motor neuropathies and primarily present with sensory dysfunction, although motor functions may be affected. There are five main types of HSAN, each caused by different genes. Genes are associated as shown below (Eichler, 2021):

Disease Name (subtype)

Gene(s) or Locus

Examples of symptoms

HSAN1 (A)

SPTLC1

Distal sensory loss, distal muscle wasting

HSAN1 (B)

3p24-p22

Axonal neuropathy with distal sensory impairment

HSAN1 (C)

SPTLC2

Distal sensory loss, distal muscle wasting

HSAN1 (D)

ATL1

Distal sensory loss, distal muscle wasting

HSAN1 (E)

DNMT1

Hearing loss, progressive dementia

HSAN1 (F)

ATL3

Distal sensory impairment

HSAN2 (A)

HSN2

Loss of pain, pressure, touch, and temperature sensation

HSAN2 (B)

FAM134B

Loss of pain, pressure, touch, and temperature sensation

HSAN2 (C)

KIF1A

Loss of pain, pressure, touch, and temperature sensation

HSAN2 (D)

SCN9A

Loss of pain and temperature sensation, hearing loss

HSAN3/Familial Dysautonomia

9q31

Dysautonomic crises, orthostatic hypotension

HSAN4/Congenital Insensitivity to Pain with Anhidrosis

NTRK1

Loss of pain sensation, thermoregulatory dysfunction

HSAN5

NGFB

Loss of pain and temperature sensation

HSAN6

DST

Lack of psychomotor development, respiratory difficulties

HSAN7

SCN11A

Inability to experience pain

Other unclassified HSANs exist, such as spastic paraplegia with ulcerations of the hands and feet (associated with CCT5) and sensory neuropathy with ichthyosis and anterior chamber syndrome (Eichler, 2021).

Genetic Testing
Charcot-Marie-Tooth disease is usually diagnosed by an extensive 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 most 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, including physical therapy. However, most therapies are only supportive (occupational, physical) and generally do not rely on the results of specific genetic testing (Kang, 2020a, 2020b).

Genetic testing for CMT is complicated by the extensive underlying genetic heterogeneity. The CMT spectrum of disorders can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The most commonly identified CMT subtypes are 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 account for 92 percent of genetically defined CMT cases. All other CMT subtypes and associated mutations each account for <1 percent of genetically defined CMT (CMTA; Kang, 2020a). 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 (Kang, 2020a). Numerous genetic panels are available for the assessment of peripheral neuropathies, such as GeneDx’s panel (64 genes) and Invitae’s panel (83 genes) (GeneDx, 2018; Invitae, 2020). Other pane’s include ones by Athena Diagnostics (23 genes) (Athena_Diagnostics, 2021), Claritas Genomics (PMP22 gene) (Claritas_Genomics, 2021), MNG Laboratories (139 genes) (MNG_Laboratories, 2021), and Prevention Genetics (44 genes) (Prevention_Genetics, 2021).   

Clinical Validity and Utility
DiVincenzo et al. (2014) performed an analysis of the genetic landscape of CMT. 14 genes associated with CMT (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) were evaluated out of 3312 individuals. Deletions and duplications in the PMP22 gene consisted of about 78% of positive findings, followed by mutations in the GJB1 (6.7%), MPZ (5.3%), and MFN2 (4.3%) genes. 71% of the pathogenic mutations found were missense mutations. Overall, 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 (DiVincenzo et al., 2014).

Pareyson (2017) reviewed the current literature on CMT diagnosis stating that data justifies a step-wise algorithm considering a variety of factors, such as phenotype, nerve conduction velocities, and ethnicity. The authors note that NGS is steadily replacing older methods of sequencing in this algorithm. The authors propose evaluating the first few common genes (PMP22, MPZ, et al) and then considering larger sequencing methods such as NGS. However, due to the growing number of genes associated with CMT, these larger sequencing methods may be considered first-line. Finally, the authors state that due to the growing number of associated genes, newer classifications need to be discussed and validated further (Pareyson et al., 2017).

Rudnik-Schöneborn and colleagues (2016) evaluated the clinical features and genetic results of 1,206 CMT patients and 124 affected relatives. Genetic detection rates were 56% in demyelinating CMT and 17% in axonal CMT. “Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%”. The authors concluded that “diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies” (Rudnik-Schoneborn et al., 2016).

Vaeth et al. (2019) evaluated the effect of implementing a targeted next-generation sequencing (NGS) approach for identifying CMT. The authors stated that from 1992-2012, a total of 1,442 CMT analyses were performed (through Sanger sequencing and other quantitative analyses) and a pathogenic variant was discovered in 21.6% of these cases. From this cohort, 195 samples that did not reach a definitive diagnosis were sequenced by a custom 63-gene panel. The authors identified a 5.6% increase in diagnostic yield using this targeted NGS approach (Vaeth et al., 2019).

Cortese et al. (2020) investigated the effectiveness of NGS panels in CMT. 220 patients were enrolled in the study and a targeted CMT NGS panel was performed. After NGS sequencing, a molecular diagnosis based on a pathogenic variant was found in 30% of the cases and variants of unknown significance were found in 33% of the cases. 39% of the cases held mutations in GJB1, MFN2, and MPZ while the others held mutations in SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS. Copy number changes were detected in PMP22, MPZ, MFN2, SH3TC2, and FDG4. The authors conclude that "NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT (Cortese et al., 2020)."

Rudnik-Schöneborn, Auer-Grumbach, and Senderek (2020) suggested a diagnostic algorithm for genetic testing of suspected hereditary neuropathy. Advanced genetic sequencing allows for comprehensive evaluation of the pathogenic relevance of identified variants. As shown in the chart above, “If PMP22 copy number analysis is negative, then clinical distinction of HNPP and CMT/dHMN will sort out patients for PMP22 mutation analysis only and those for broader multigene testing. If a pedigree is compatible with X-linked inheritance, it is recommended to analyze coding and non-coding regions of GBJ1. Patients who are tested negative for known neuropathy genes may be included in further whole exome or genome sequencing (WES/WGS) to detect mutations in rare and new genes (Rudnik-Schöneborn et al., 2020).” 

AAN, AANEM, and AAPM&R (2009, reaffirmed 2013, reaffirmed 2019)
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).

European Federation of Neurological Societies (EFNS, 2011)
The EFNS released recommendations on genetic testing for various types of peripheral neuropathies. Regarding CMT, they noted that “Given the rarity of AR CMT in the European population routine diagnostic screening of the many known genes is currently not feasible” but acknowledged that “Currently, molecular genetic testing can be offered for several of the more prevalent CMT genes”. EFNS stated that PMP22 duplication should be tested first in patients presenting with CMT1, followed by sequencing of GJB1 (in case no male-to-male transmission is present), MPZ, and PMP22. If a patient presents with CMT2, MFN2 should be screened first, followed by MPZ. If a patient presents with intermediate CMT, GJB1 and MPZ should be screened. EFNS notes that in patients with hereditary neuropathy with liability to pressure palsies will be investigated for a PMP22 deletion at the same time as a screening for a PMP22 duplication (Burgunder et al., 2011). 

However, routine diagnostic screenings for hereditary motor neuropathy (HMN) and hereditary sensory-autonomic neuropathy (HSAN) are not feasible due to low mutation frequencies. If screening is performed for these conditions, EFNS recommends BSCL2 as the first candidate for screening in HMN. NTRK1 may also be screened for in congenital insensitivity to pain with anhidrosis patients (CIPA, a sub-phenotype of HSAN) and RAB7 may be screened in CMT2B patients. Finally, SEPT9 may be screened in the context of hereditary neuralgic amyotrophy (HNA) (Burgunder et al., 2011). 

Regulatory Status 
A search on the FDA website for “neuropathy” on April 22, 2021 yielded no results pertaining to genetic testing (FDA, 2021). Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88).  As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

References 

  1. Abrams, C. (2020). GJB1 Disorders: Charcot Marie Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1374/
  2. Anthony Antonellis, P., Lev G Goldfarb, MD, and Kumaraswamy Sivakumar, MD. (2018). GARS-Associated Axonal Neuropathy. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1242/
  3. Athena_Diagnostics. (2021). CMT Advanced Evaluation - Comprehensive.
  4. Bird, T. (2017). GDAP1-Related Hereditary Motor and Sensory Neuropathy. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1539/
  5. Bird, T. (2019). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1358/
  6. Bird, T. (2020). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1358/
  7. Bromberg, M. (2021). Brachial plexus syndromes. Retrieved from https://www.uptodate.com/contents/brachial-plexus-syndromes?sectionName=Hereditary%20brachial%20plexopathy&search=Hereditary%20Neuropathy%20with%20liability%20to%20Pressure%20Palsies&topicRef=6207&anchor=H18&source=see_link#H18
  8. Burgunder, J. M., Schols, L., Baets, J., Andersen, P., Gasser, T., Szolnoki, Z., . . . Finsterer, J. (2011). EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. Eur J Neurol, 18(2), 207-217. doi:10.1111/j.1468-1331.2010.03069.x
  9. Claritas_Genomics. (2021). PMP22 Deletion/Duplication. Retrieved from http://www.claritasgenomics.com/test/pmp22-deletionduplication/index.html
  10. CMTA. Genetic Testing. Retrieved from https://www.cmtausa.org/resource-center/treatment-management/genetic-testing/
  11. Cortese, A., Wilcox, J. E., Polke, J. M., Poh, R., Skorupinska, M., Rossor, A. M., . . . Reilly, M. M. (2020). Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology, 94(1), e51-e61. doi:10.1212/wnl.0000000000008672
  12. Delague, V. (2013). Charcot-Marie-Tooth Neuropathy Type 4H. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK153601/
  13. DiVincenzo, C., Elzinga, C. D., Medeiros, A. C., Karbassi, I., Jones, J. R., Evans, M. C., . . . Higgins, J. J. (2014). The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med, 2(6), 522-529. doi:10.1002/mgg3.106
  14. Eichler, F. (2021). Hereditary sensory and autonomic neuropathies. Retrieved from https://www.uptodate.com/contents/hereditary-sensory-and-autonomic-neuropathies?search=Hereditary%20Neuropathy%20with%20liability%20to%20Pressure%20Palsies&topicRef=6207&source=see_link
  15. England, J. D., Gronseth, G. S., Franklin, G., Carter, G. T., Kinsella, L. J., Cohen, J. A., . . . Sumner, A. J. (2009). Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review). Neurology, 72(2), 185. doi:10.1212/01.wnl.0000336370.51010.a1
  16. FDA. (2021). Devices@FDA. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm
  17. GeneDx. (2018). Hereditary Neuropathy Panel. Retrieved from https://www.genedx.com/test-catalog/available-tests/hereditary-neuropathy-panel/
  18. Hamid Azzedine, E. L., and Mustafa A Salih. (2015). Charcot-Marie-Tooth Neuropathy Type 4C. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1340/
  19. Invitae. (2020). Invitae Comprehensive Neuropathies Panel. Retrieved from https://www.invitae.com/en/physician/tests/03200/#info-panel-assay_information
  20. Kang, P. (2019). Overview of hereditary neuropathies. Retrieved from https://www.uptodate.com/contents/overview-of-hereditary-neuropathies?search=Hereditary%20Neuropathy%20with%20liability%20to%20Pressure%20Palsies&source=search_result&selectedTitle=1~16&usage_type=default&display_rank=1
  21. Kang, P. (2020a). Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis. Retrieved from https://www.uptodate.com/contents/charcot-marie-tooth-disease-genetics-clinical-features-and-diagnosis
  22. Kang, P. (2020b). Charcot-Marie-Tooth disease: Management and prognosis. Retrieved from https://www.uptodate.com/contents/charcot-marie-tooth-disease-management-and-prognosis?topicRef=6220&source=see_link
  23. Kim, J.-W., Kim, Hee-Jin. (2013). Charcot-Marie-Tooth Neuropathy X Type 5. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1876/
  24. Li, J. (2013). Charcot-Marie-Tooth Neuropathy Type 4J. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK169431/
  25. MNG_Laboratories. (2021). Charcot-Marie-Tooth Disease, Axonal (NGS Panel and Copy Number Analysis + mtDNA). Retrieved from https://mnglabs.com/tests/NGS345A/charcot-marie-tooth-disease-axonal-ngs-panel-and-copy-number-analysis-mtdna
  26. NINDS. (2007). Charcot-Marie-Tooth Disease Fact Sheet. Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Charcot-Marie-Tooth-Disease-Fact-Sheet#3092_5
  27. Pareyson, D., Saveri, P., & Pisciotta, C. (2017). New developments in Charcot-Marie-Tooth neuropathy and related diseases. Curr Opin Neurol, 30(5), 471-480. doi:10.1097/wco.0000000000000474
  28. Peter De Jonghe, M., PhD and Albena K Jordanova, PhD. (2011). Charcot-Marie-Tooth Neuropathy Type 2E/1F. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1187/
  29. Prevention_Genetics. (2021). Charcot-Marie-Tooth (CMT) - Comprehensive Panel. Retrieved from https://www.preventiongenetics.com/testInfo?val=Charcot-Marie-Tooth+%28CMT%29+-+Comprehensive+Panel
  30. Rudnik-Schöneborn, S., Auer-Grumbach, M., & Senderek, J. (2020). Charcot-Marie-Tooth disease and hereditary motor neuropathies – Update 2020. Medizinische Genetik, 32(3), 207-219. doi:doi:10.1515/medgen-2020-2038
  31. Rudnik-Schoneborn, S., Tolle, D., Senderek, J., Eggermann, K., Elbracht, M., Kornak, U., . . . Zerres, K. (2016). Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet, 89(1), 34-43. doi:10.1111/cge.12594
  32. Saporta, A. S., Sottile, S. L., Miller, L. J., Feely, S. M., Siskind, C. E., & Shy, M. E. (2011). Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol, 69(1), 22-33. doi:10.1002/ana.22166
  33. Schindler, A. (2014). TRPV4-Associated Disorders. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK201366/
  34. UTD. (2021). Patient education: Charcot-Marie-Tooth disease (The Basics). Retrieved from https://www.uptodate.com/contents/charcot-marie-tooth-disease-the-basics?search=Hereditary%20Neuropathy%20with%20liability%20to%20Pressure%20Palsies&topicRef=6207&source=see_link
  35. Vaeth, S., Christensen, R., Duno, M., Lildballe, D. L., Thorsen, K., Vissing, J., . . . Jensen, U. B. (2019). Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform. Eur J Med Genet, 62(1), 1-8. doi:10.1016/j.ejmg.2018.04.003
  36. Züchner, S. (2013). Charcot-Marie-Tooth Neuropathy Type 2A. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1511/

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
  81403

Mopath procedure level 4

Genes:

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

  81404

Mopath procedure level 5

Genes:

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

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

HSPB1

  81405

Mopath procedure level 6

Genes:

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

RAB7A, PRX

  81406

Mopath procedure level 7

Genes:

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

BSCL2, LMNA, FIG4

  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

  96040 

Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family 

  S0265 

Genetic counseling, under physician supervision, each 15 minutes 

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
  Z13.71

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     

07/20/2021 

Annual review, no change to policy intent. Updating coding, rationale and references. Removing regulatory status as that is now included in the rationale. 

07/21/2020 

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

07/22/2019 

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

06/19/2019 

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

11/15/2018 

 Corrected typo in policy section. No other changes.

07/18/2018 

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

12/7/2017 

Updating policy with 2018 coding. No other changes. 

06/23/2017 

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

04/25/2017

Updated category to Laboratory. No other changes.

08/02/2016 

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

08/19/2015 

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

08/04/2014

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


Go Back