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MP 2.04.89 Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies

Medical Policy    
Section
Medicine 
Subsection Last Review Status/Date
Reviewed with literature search/6:2014
Issue
6:2014
Original Policy Date
June:2013
Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

The inherited peripheral neuropathies are the most common inherited neuromuscular disease. Genetic testing has been suggested as a way to diagnose specific inherited peripheral neuropathies.

Background

The inherited peripheral neuropathies are a clinically and genetically heterogeneous group of disorders. The estimated prevalence in aggregate is estimated at roughly 1 in 2500 persons, making inherited peripheral neuropathies the most common inherited neuromuscular disease.(1)

Peripheral neuropathies can be subdivided into 2 major categories: primary axonopathies and primary myelinopathies, depending on which portion of the nerve fiber is affected. Further anatomic classification includes fiber type (eg, motor versus sensory, large versus small), and gross distribution of the nerves affected (eg, symmetry, length-dependency).

The inherited peripheral neuropathies are divided into the hereditary motor and sensory neuropathies, hereditary neuropathy with liability to pressure palsies, and other miscellaneous, rare types (eg, hereditary brachial plexopathy, hereditary sensory autonomic neuropathies). Other hereditary metabolic disorders, such as Friedreich ataxia, Refsum disease, and Krabbe disease, may be associated with motor and/or sensory neuropathies but typically have other predominating symptoms. This policy will focus on the hereditary motor and sensory neuropathies and hereditary neuropathy with liability to pressure palsies.

A genetic etiology of a peripheral neuropathy is generally suggested by generalized polyneuropathy, family history, lack of positive sensory symptoms, early age of onset, symmetry, associated skeletal abnormalities, and very slowly progressive clinical course.(2) A family history of at least 3 generations with details on health issues, cause of death, and age at death should be collected.

Hereditary motor and sensory neuropathies

Most inherited polyneuropathies are variants of Charcot-Marie-Tooth (CMT) disease. The clinical phenotype of CMT is highly variable, ranging from minimal neurologic findings to the classic picture with pes cavus and “stork legs” to a severe polyneuropathy with respiratory failure.(3) CMT disease is genetically heterogeneous, as well as clinically heterogeneous. Mutations in more than 30 genes and more than 44 different genetic loci have been associated with the inherited neuropathies.(4) Most cases of CMT are autosomal dominant, although autosomal recessive and X-linked dominant forms exist. Most cases are CMT type 1.

CMT 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 usually slowly progressive 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 people usually become symptomatic between age 5 and 25 years, and lifespan is not shortened. Less than 5% of people become wheelchair dependent. CMT1 is inherited in an autosomal dominant manner. The CMT1 subtypes (CMT 1A-E) are separated by molecular findings and are often clinically indistinguishable. CMT1A accounts for 70% to 80% of all CMT1, and about two thirds of probands with CMT1A have inherited the disease-causing mutation and about one-third have CMT1A as the result of a de novo mutation.

CMT1A involves duplication of the gene PMP22. PMP22 encodes an integral membrane protein, peripheral membrane protein 22, which is a major component of myelin in the peripheral nervous system. The phenotypes associated with this disease arise because of abnormal PMP22 gene dosage effects.(5) Two normal alleles represent the normal wild-type condition. Four normal alleles (as in the homozygous CMT1A duplication) results in the most severe phenotype, whereas 3 normal alleles (as in the heterozygous CMT1A duplication) causes a less severe phenotype. (6) CMT1B (6% to 10% of all CMT1) is associated with point mutations in MPZ, CMT1C (1% to 2% of all CMT1) is associated with mutations in LITAF, and CMT1D (<2% of all CMT1) is associated with mutations in EGR2. CMT1E (<5% of all CMT1) is associated with point mutations in PMP22. CMT2E/1F (<5% of all CMT1) is associated with mutations in NEFL. Molecular genetic testing is clinically available for all of these genes.(6)

CMT hereditary neuropathy type 2 (CMT2) is a nondemyelinating (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.(7) Unlike CMT1, peripheral nerves are not enlarged or hypertrophic. The subtypes of CMT2 are similar clinically and distinguished only by molecular genetic findings. CMT2B1, CMT2B2, and CMT2H/K are inherited in an autosomal recessive manner; all other subtypes of CMT2 are inherited in an autosomal dominant manner.

The 15 genes in which mutations are known to cause CMT2 subtypes are KIF1B (CMT2A1), MFN2 (CMT2A2), RAB7A (formerly RAB7) (CMT2B), LMNA (CMT2B1), MED25 (CMT2B2), TRPV4 (CMTC), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/J), GDAP1 (CMT2H/K), HSPB8 (CMT2L), AARS (CMT2N), DYNC1H1 (CMT2O), and LRSAM1 (CMT2P). Molecular genetic testing is clinically available for CMT subtypes 2A1, 2A2, 2B, 2B1, 2B2, 2C, 2D, 2E, 2F, 2I, 2J, 2H/K, 2L, 2N, 2O, and 2P.(7) The most common subtype of CMT2 is CMT2A, which accounts for approximately 20% of CMT2 cases and is associated with mutations in the MFN2 gene.

CMT 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.(8) Sensorineural deafness and central nervous system symptoms also occur in some families. CMTX1 is inherited in an X-linked dominant manner. Molecular genetic testing of GJB1 (Cx32) detects about 90% of cases of CMTX1, which is available on a clinical basis.(8)

CMT 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, including GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FGD4 (CMT4H), and FIG4 (CMT4J).

Hereditary neuropathy with liability to pressure palsies

In hereditary neuropathy with liability to pressure palsies (HNPP) (also called tomaculous neuropathy), inadequate production of PMP22 causes nerves to be more susceptible to trauma or minor compression/entrapment. HNPP patients rarely present symptoms before the second or third decade of life. However, some authors report presentation as early as birth or as late as the seventh decade of life.(9) The prevalence is estimated at 16 persons per 100,000 although some authors indicate a potential for underdiagnosis of the disease.(9) An estimated 50% of carriers are asymptomatic and do not display abnormal neurologic findings on clinical examination.(10) 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 due to minor compression or trauma to the peripheral nerves. The disease is benign with complete recovery occurring within a period of days to months in most cases, although an estimated 15% of patients have residual weakness following an episode.(10) Poor recovery usually involves a history of prolonged pressure on a nerve, but in these cases the remaining symptoms are typically mild.

PMP 22 is the only gene in which mutation is known to cause HNPP. A large deletion occurs in approximately 80% of patients, and the remaining 20% of patients have point mutations and small deletions in the PMP22 gene. One normal allele (due to a 17p11.2 deletion) results in HNPP and a mild phenotype. Point mutations in PMP22 have been associated with a variable spectrum of HNPP phenotypes ranging from mild symptoms to representing a more severe, CMT1-like syndrome.(11) Studies have also reported that the point mutation frequency may vary considerably by ethnicity.(12) About 10% to 15% of mutation carriers remain clinically asymptomatic, suggesting incomplete penetrance.(13)

Treatment

Currently there is no effective therapy for the inherited peripheral neuropathies. Supportive treatment, if necessary, is generally provided by a multidisciplinary team including neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment choices are limited to physical therapy, use of orthotics, surgical treatment for skeletal or soft tissue abnormalities, and drug treatment for pain.(14) Avoidance of obesity and high-risk drugs such as vincristine is recommended in CMT patients.

Supportive treatment for HNPP can include transient bracing (eg, wrist splint or ankle-foot orthosis) which may become permanent in some cases of foot drop.(15) Prevention of HNPP manifestations can be accomplished by wearing protective padding (eg, elbow or knee pads) to prevent trauma to nerves during activity. Some authors report that vincristine should also be avoided in HNPP patients.(6,15) Ascorbic acid has been investigated as a treatment for CMT1A based on animal models, but trials in humans have not demonstrated significant clinical benefit.(16)

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.


Policy

Genetic testing is considered investigational to confirm a clinical diagnosis of an inherited peripheral neuropathy.

Genetic testing for an inherited peripheral neuropathy is considered investigational for all other indications.


Policy Guidelines

Coding

Beginning in 2013, there is specific CPT coding for genetic testing for PMP22 deletions and duplications, full sequencing, and familial variant testing:

81324: PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis

81325: full sequence analysis

81326: known familial variant.

CPT Tier 2 code 81403 includes the following test mentioned above –

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

CPT Tier 2 code 81404 includes the following tests mentioned above –

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

HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence

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

CPT Tier 2 code 81405 includes the following tests mentioned above –

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

PRX (periaxin)(eg, Charcot-Marie-Tooth disease), full gene sequence

RAB7A (RAB7A, member RAS oncogene family) (eg, Charcot-Marie-Tooth disease), full gene sequence.

CPT Tier 2 code 81406 includes the following tests mentioned above –

FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae])(eg, Charcot-Marie-Tooth disease), full gene sequence

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

LMNA (lamin A/C)(eg, Emery-Dreifuss muscular dystrophy [EDMD1, 2 and 3] limb-girdle muscular dystrophy [LGMD] type 1B, dilated cardiomyopathy [CMD1A], familial partial lipodystrophy [FPLD2]), 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

For the other genes listed above, there is no specific CPT listing of the test and the unlisted molecular pathology code 81479 would be reported.


Benefit Application

BlueCard/National Account Issues

No applicable information.


Rationale

Literature Review

This policy was created in 2013 and updated periodically with literature reviews. The most recent review is based on a search of the MEDLINE database through May 13, 2014.

Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; (2) clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and (3) clinical utility of the test, ie, how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

Most of the published data available for analytic and clinical validity of genetic testing for the inherited peripheral neuropathies are for duplications and deletions in the PMP22 gene in the diagnosis of Charcot-Marie-Tooth (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively.

Analytic validity

A variety of methods, in addition to fluorescence in-situ hybridization (FISH), can be used for deletion/duplication analysis targeted specifically at PMP22, including quantitative polymerase chain reaction (qPCR), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA), with high agreement between testing methods (see Table 1).

Table 1. Agreement Between CMT1A and HNPP Genetic Tests

 

Reference

Disorders Tested

Test Method

Confirmation Method

% Agreement CMT1A; HNPP

Hung, 2007(17)

CMT1A; HNPP

CE PCR

RFLP-PCR

100%; 100%

Ravise, 2003(18)

CMT1A; HNPP

dFISH

Southern Blot

94%; 100%

Hung, 2008(19)

CMT1A; HNPP

MLPA

Competitive multiplex PCR

100%; 100%

Slater, 2004 (20)

CMT1A; HNPP

MLPA

FISH

90%; 100%

Stangler, 2009 (21)

CMT1A; HNPP

MLPA

FISH

100%; 100%

Hung, 2008 (19)

CMT1A; HNPP

MLPA

RFLP-PCR

78%; 86%

Stangler, 2009(21)

CMT1A; HNPP

MLPA

RFLP-PCRb

88%; NA

Lin, 2006 (22)

CMT1A; HNPP

DHPLC

Microsatellite analysis

100%; 100%

Aarskog, 2000(23)

CMT1A; HNPP

RT-qPCR

Clinical and EMG characteristics

89.6%; 100%

Thiel, 2003(24)

CMT1A; HNPP

RT-qPCR

Microsatellite analysis

100%; 100%

Chen, 2008(25)

CMT1A; HNPP

RT-qPCR

Microsatellite analysis

100%; 100%

Kim, 2003 (26)

CMT1A; HNPP

RT-qPCR

Microsatellite analysis

100%; 100%

Choi, 2005 (27)

CMT1A; HNPP

RT-qPCR

REP-PCR

100%a; 100%a

CE: capillary electrophoresis; RFLP: restriction fragment length polymorphism; d: direct; MLPA: multiplex ligation-dependent probe amplification; DHPLC: denaturing high-performance liquid chromatography; REP: repeat.

a RT-qPCR detected 4 of 13 suspected cases of HNPP and 2 of 16 suspected cases of CMT1A not discovered by REP-PCR.

b RFLP-PCR had 1 false-negative and 3 false-positive results.

Analytic performance of several molecular analytic methods was presented in a review by Aretz et al.(28) The reported analytic sensitivity and specificity were given as almost 100% (tests considered included MLPA, qPCR, FISH, and direct sequencing). Further evidence is provided by another review in which segregation studies followed by several prospective cohort studies have also documented that currently available genetic testing results for CMT are unequivocal for diagnosis of established pathogenic mutations, providing a specificity of 100% (ie, no false positives) and high sensitivity.(3)

Clinical validity

The clinical sensitivity of the diagnostic test for CMT and HNPP can be dependent on variable factors such as the age or family history of the patient. A general estimation of the clinical sensitivity was presented in a report by Aretz et al on hereditary motor and sensory neuropathy and HNPP with a variety of analytic methods (MLPA, multiplex amplicon quantification [MAQ], qPCR, Southern blot, FISH, PFGE, dHPLC, high-resolution melting, restriction analysis and direct sequencing).(28) The clinical sensitivity (ie, proportion of positive tests if the disease is present) for the detection of deletions/duplications to PMP22 was about 50% and 1% for point mutations. The clinical specificity (ie, proportion of negative tests if the disease is not present) was nearly 100%.

An evidence-based review by England et al on the role of laboratory and genetic tests in the evaluation of distal symmetric polyneuropathies concluded that genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies in patients with a cryptogenic polyneuropathy who exhibit a classical hereditary neuropathy phenotype.(3) Six studies included in the review showed that when the test for CMT1A duplication is restricted to patients with clinically probable CMT1 (ie, autosomal dominant, primary demyelinating polyneuropathy), the yield is 54% to 80%, compared to testing a cohort of patients suspected of having any variety of hereditary peripheral neuropathy where the yield is only 25% to 59% (average, 43%).

Saporta et al reported results from genetic testing of 1024 patients with clinically suspected CMT who were evaluated at a single institution’s CMT clinic from 1997 to 2009.(4) Patients who were included were considered to have CMT if they had a sensorimotor peripheral neuropathy and a family history of a similar condition. Patients without a family history of neuropathy were considered to have CMT if their medical history, neurophysiological testing, and neurologic examination were typical for CMT1, CMT2, CMTX, or CMT4. Seven hundred eighty-seven patients were diagnosed with CMT; of those, 527 (67%) had a specific genetic diagnosis as a result of their visit. Genetic testing decisions were left up to the treating clinician, and the authors note that decisions about which genes to test changed over the course of the period included in the study. Most (98.2%) of those with clinically-diagnosed CMT1 had a genetic diagnosis, and of all of the patients with a genetic diagnosis, most (80.8%) had clinically-diagnosed CMT1. The authors characterize several clinical phenotypes of CMT based on clinical presentation and physiologic testing.

Few genotype-phenotype correlations for CMT type 2 are known. Considerable variability of phenotype has been observed within families with CMT2A.(7)

Clinical utility

The clinical utility of genetic testing for the hereditary peripheral neuropathies depends on how the results can be used to improve patient management. Published data for the clinical utility of genetic testing for the inherited peripheral neuropathies is lacking.

In a discussion of the clinical utility of the molecular diagnostic methods for these neuropathies, Aretz et al suggest that the avoidance of any unnecessary therapy due to an undefined diagnosis, sparing other family members from testing, and avoidance of certain risk factors (eg, obesity or certain occupations and activities) are potential benefits.(28)

The likelihood that genetic testing for this condition will alter patient management is low. Because 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.

Summary

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. These diseases can generally be diagnosed based on clinical presentation, nerve conduction studies, and family history.

Genetic testing for most of the inherited peripheral neuropathies is commercially available. The analytic validity of mutation testing for these diseases is high. The specificity has also been reported to be high, with variable sensitivity.

However, the clinical utility of genetic testing to confirm a diagnosis in a patient with a clinical diagnosis of an inherited peripheral neuropathy is unknown, and therefore this is considered investigational.

Practice Guidelines and Position Statements

The American Academy of Neurology published an evidence-based, tiered approach(3) for the evaluation of distal symmetric polyneuropathy, and for suspected hereditary neuropathies, which concluded that:

  • Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (level A classification of recommendations- established as effective, ineffective, or harmful for the given condition in the specified population)
  • Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (level C- possibly effective, ineffective, or harmful for the given condition in the specified population)
  • Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1) and MFN2 screening
  • There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (level U-data inadequate or conflicting; given current knowledge)

The American Academy of Family Physicians recommends genetic testing in a patient with suspected peripheral neuropathy, if basic blood tests are negative, electrodiagnostic studies suggest an axonal etiology, and diseases such as diabetes, toxic medications, thyroid disease, and vasculitides can be ruled out.(29)

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

  1. Burgunder JM, Schols L, Baets J et al. EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. Eur J Neurol 2011; 18(2):207-17.
  2. Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn) 2012; 18(1):13-38.
  3. England JD, Gronseth GS, Franklin G et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009; 72(2):185-92.
  4. Saporta AS, Sottile SL, Miller LJ et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 2011; 69(1):22-33.
  5. Stankiewicz P, Lupski JR. The genomic basis of disease, mechanisms and assays for genomic disorders. Genome Dyn 2006; 1:1-16.
  6. Bird TD. Charcot-Marie-Tooth Neuropathy Type 1. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews . Seattle (WA)1993.
  7. Bird TD. Charcot-Marie-Tooth Neuropathy Type 2. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews . Seattle (WA)1993.
  8. Bird TD. Charcot-Marie-Tooth Neuropathy X Type 1. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews . Seattle (WA)1993.
  9. Meretoja P, Silander K, Kalimo H et al. Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland. Neuromuscul Disord 1997; 7(8):529-32.
  10. Celik Y, Kilincer C, Hamamcioglu MK et al. Hereditary neuropathy with liability to pressure palsies in a Turkish patient (HNPP): a rare cause of entrapment neuropathies in young adults. Turk Neurosurg 2008; 18(1):82-4.
  11. Taioli F, Cabrini I, Cavallaro T et al. Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene. Brain 2011; 134(Pt 2):608-17.
  12. Bissar-Tadmouri N, Parman Y, Boutrand L et al. Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth Type 1 and HNPP patients. Clin Genet 2000; 58(5):396-402.
  13. Dubourg O, Mouton P, Brice A et al. Guidelines for diagnosis of hereditary neuropathy with liability to pressure palsies. Neuromuscul Disord 2000; 10(3):206-8.
  14. Pareyson D, Marchesi C. Natural history and treatment of peripheral inherited neuropathies. Adv Exp Med Biol 2009; 652:207-24.
  15. Bird TD. Hereditary neuropathy with liability to pressure palsies. Gene Reviews 2005. Available online at: http://www.geneclinics.org/profiles/hnpp/details.html. Last accessed June, 2014.
  16. Lewis RA, McDermott MP, Herrmann DN et al. High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial. JAMA Neurol 2013; 70(8):981-7.
  17. Hung CC, Chien SC, Lin CY et al. Use of multiplex PCR and CE for gene dosage quantification and its biomedical applications for SMN, PMP22, and alpha-globin genes. Electrophoresis 2007; 28(16):2826-34.
  18. Ravise N, Dubourg O, Tardieu S et al. Rapid detection of 17p11.2 rearrangements by FISH without cell culture (direct FISH, DFISH): a prospective study of 130 patients with inherited peripheral neuropathies. Am J Med Genet A 2003; 118A(1):43-8.
  19. Hung CC, Lee CN, Lin CY et al. Identification of deletion and duplication genotypes of the PMP22 gene using PCR-RFLP, competitive multiplex PCR, and multiplex ligation-dependent probe amplification: a comparison. Electrophoresis 2008; 29(3):618-25.
  20. Slater H, Bruno D, Ren H et al. Improved testing for CMT1A and HNPP using multiplex ligation-dependent probe amplification (MLPA) with rapid DNA preparations: comparison with the interphase FISH method. Hum Mutat 2004; 24(2):164-71.
  21. Stangler Herodez S, Zagradisnik B, Erjavec Skerget A et al. Molecular diagnosis of PMP22 gene duplications and deletions: comparison of different methods. J Int Med Res 2009; 37(5):1626-31.
  22. Lin CY, Su YN, Lee CN et al. A rapid and reliable detection system for the analysis of PMP22 gene dosage by MP/DHPLC assay. J Hum Genet 2006; 51(3):227-35.
  23. Aarskog NK, Vedeler CA. Real-time quantitative polymerase chain reaction. A new method that detects both the peripheral myelin protein 22 duplication in Charcot-Marie-Tooth type 1A disease and the peripheral myelin protein 22 deletion in hereditary neuropathy with liability to pressure palsies. Hum Genet 2000; 107(5):494-8.
  24. Thiel CT, Kraus C, Rauch A et al. A new quantitative PCR multiplex assay for rapid analysis of chromosome 17p11.2-12 duplications and deletions leading to HMSN/HNPP. Eur J Hum Genet 2003; 11(2):170-8.
  25. Chen SR, Lin KP, Kuo HC et al. Comparison of two PCR-based molecular methods in the diagnosis of CMT 1A and HNPP diseases in Chinese. Clin Neurol Neurosurg 2008; 110(5):466-71.
  26. Kim SW, Lee KS, Jin HS et al. Rapid detection of duplication/deletion of the PMP22 gene in patients with Charcot-Marie-Tooth disease Type 1A and hereditary neuropathy with liability to pressure palsy by real-time quantitative PCR using SYBR Green I dye. J Korean Med Sci 2003; 18(5):727-32.
  27. Choi BO, Kim J, Lee KL et al. Rapid diagnosis of CMT1A duplications and HNPP deletions by multiplex microsatellite PCR. Mol Cells 2007; 23(1):39-48.
  28. Aretz S, Rautenstrauss B, Timmerman V. Clinical utility gene card for: HMSN/HNPP HMSN types 1, 2, 3, 6 (CMT1,2,4, DSN, CHN, GAN, CCFDN, HNA); HNPP. Eur J Hum Genet 2010; 18(9).
  29. Azhary H, Farooq MU, Bhanushali M et al. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician 2010; 81(7):887-92.

 

Codes

Number

Description

CPT    See Policy Guidelines
ICD-9 Diagnosis  V26.31   Testing of female for genetic disease carrier status
  V26.34 Testing of male for genetic disease carrier status
ICD-10-CM (effective 10/1/15) Z31.430 Encounter of female for testing for genetic disease carrier status for procreative management
  Z31.440 Encounter of male for testing for genetic disease carrier status for procreative management
ICD-10-PCS (effective 10/1/15)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.


Index

Genetic Testing, PMP22
Genetic Testing, Peripheral Neuropathies


Policy History
Date Action Reason
6/13/13 Add to Medicine: Pathology/Laboratory Policy created with literature search through May 13, 2013. Investigational to confirm a clinical diagnosis of an inherited peripheral neuropathy and investigational for all other indications.
6/12/14 Replace policy Policy updated with literature review through May 13, 2014. References 4 and 16 added. No change to policy statements