Inherited Peripheral Neuropathies

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

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

Inherited peripheral neuropathies are divided into the hereditary motor and sensory neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP), 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 focuses on the hereditary motor and sensory neuropathies and HNPP.

A genetic etiology of peripheral neuropathy is typically 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 three generations with details on health issues, the cause of death, and age at death should be collected.

Charcot-Marie-Tooth Disease

Hereditary Motor and Sensory Neuropathies

Most inherited polyneuropathies were originally described clinically as variants of 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 and clinically heterogeneous. Variants in more than 30 genes and more than 44 different genetic loci have been associated with the inherited neuropathies.^4,Also, different pathogenic variants in a single gene can lead to different inherited neuropathy phenotypes and inheritance patterns. A 2016 cross-sectional study of 520 children and adolescents with CMT found variability in CMT-related symptoms across the 5 most commonly represented subtypes.^5,

CMT subtypes are characterized by variants in one of several myelin genes, which lead to abnormalities in myelin structure, function, or upkeep. There are seven subtypes of CMT, with type 1 and 2 representing the most common hereditary peripheral neuropathies.

Most cases of CMT are autosomal dominant, although autosomal recessive and X-linked dominant forms exist. Most cases are CMT type 1 (approximately 40%-50% of all CMT cases, with 78%-80% of those due to PMP22 variants).^6, CMT type 2 is associated with 10% to 15% of CMT cases, with 20% of those due to MFN2 variants.

A summary of the molecular genetics of CMT is outlined in Table 1.

Table 1. Molecular Genetics of CMT Variants

Locus	Gene	Protein Product	Prevalence (if known)
CMT type 1
CMT1A	PMP22	Peripheral myelin protein 22	70%-80% of CMT1
CMT1B	MPZ	Myelin P0 protein	10%-12% of CMT1
CMT1C	LITAF	Lipopolysaccharide-induced tumor necrosis factor-a factor	»1% of CMT1
CMT1D	EGR2	Early growth response protein 2
CMT1E	PMP22	Peripheral myelin protein 22 (sequence changes)	»1% of CMT1
CMT1F/2E	NEFL	Neurofilament light polypeptide
CMT type 2
CMT2A1	KIF1B	Kinesin-like protein KIF1B
CMT2A2	MFN2	Mitofusin-2	20% of CMT2
CMT2B	RAB7A	Ras-related protein Rab-7
CMT2B1	LMNA	Lamin A/C
CMT2B2	MED25	Mediator of RNA polymerase II transcription subunit 25
CMT2C	TRPV4	Transient receptor potential cation channel subfamily V member 4
CMT2D	GARS	Glycyl-tRNA synthetase
CMT2E/1F	NEFL	Neurofilament light polypeptide
CMT2F	HSPB1	Heat-shock protein beta-1
CMT2G	12q12-q13	Unknown
CMT2H/2K	GDAP1	Ganglioside-induced differentiation-associated protein 1
CMT2I/2J	MPZ	Myelin P0 protein
CMT2L	HSPB8	Heat-shock protein beta-8
CMT2N	AARS	Alanyl-tRNA synthetase, cytoplasmic
CMT2O	DYNC1H1	Cytoplasmic dynein 1 heavy chain 1
CMT2P	LRSAM1	E3 ubiquitin-protein ligase LRSAM1
CMT2S	IGHMBP2	DNA-binding protein SMUBP-2
CMT2T	DNAJB2	DnaJ homolog subfamily B member 2
CMT2U	MARS	Methionine-tRNA ligase, cytoplasmic
CMT type 4
CMT4A	GDAP1	Ganglioside-induced differentiation-associated protein 1
CMT4B1	MTMR2	Myotubularin-related protein 2
CMT4B2	SBF2	Myotubularin-related protein 13
CMT4C	SH3TC2	SH3 domain and tetratricopeptide repeats-containing protein 2
CMT4D	NDRG1	Protein NDRG1
CMT4E	EGR2	Early growth response protein 2
CMT4F	PRX	Periaxin
CMT4H	FGD4	FYVE, RhoGEF and PH domain-containing protein 4
CMT4J	FIG4	Phosphatidylinositol 3, 5-biphosphate
X-linked CMT
CMTX1	GJB1	Gap junction beta-1 protein (connexin 32)	90% of X-linked CMT
CMTX2	Xp22.2	Unknown
CMTX3	Xq26	Unknown
CMTX4	AIFM1	Apoptosis-inducing factor 1
CMTX5	PRPS1	Ribose-phosphate pyrophosphokinase 1
CMTX6	PDK3	Pyruvate dehydrogenase kinase isoform 3

Adapted from Bird (2016).^6,

CMT: Charcot-Marie-Tooth.

The clinical features of CMT are briefly summarized.

CMT Type 1

CMT1 is an autosomal dominant, 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 ages 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 variant, and about one-third have CMT1A as the result of a de novo variant.

CMT1A involves duplication of the PMP22 gene. 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.^7, Two normal alleles represent the normal wild-type condition. Four normal alleles (as in the homozygous CMT1A duplication) result in the most severe phenotype, whereas three normal alleles (as in the heterozygous CMT1A duplication) cause a less severe phenotype.^8,

CMT Type 2

CMT2 is a non‒demyelinating (axonal) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. Clinically, CMT2 is similar to CMT1, although typically less severe.^9, 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 most common subtype of CMT2 is CMT2A, which accounts for approximately 20% of CMT2 cases and is associated with variants in the MFN2 gene.

X-Linked CMT

CMT X type 1is characterized by a moderate-to-severe motor and sensory neuropathy in affected males and mild to no symptoms in carrier females.^10, Sensorineural deafness and central nervous system symptoms also occur in some families. CMT X type 1 is inherited in an X-linked dominant manner. Molecular genetic testing of GJB1 (Cx32), which is available on a clinical basis, detects about 90% of cases of CMT X type 1.^10,

CMT Type 4

CMT type 4 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, but some forms may be rapidly progressive and/or associated with severe weakness.

Hereditary Neuropathy with Liability to Pressure Palsies

The largest proportion of CMT1 cases are due to variants in PMP22. In HNPP (also called tomaculous neuropathy), inadequate production of PMP22 causes nerves to be more susceptible to trauma or minor compression or entrapment. HNPP patients rarely present symptoms before the second or third decade of life. However, some have reported presentation as early as birth or as late as the seventh decade of life.^11, The prevalence is estimated at 16 persons per 100000, although some authors have indicated a potential for underdiagnosis of the disease.^11, An estimated 50% of carriers are asymptomatic and do not display abnormal neurologic findings on clinical examination.^12, 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.^12, Poor recovery usually involves a history of prolonged pressure on a nerve, but, in these cases, the remaining symptoms are typically mild.

PMP22 is the only gene for which a variant is known to cause HNPP. A large deletion occurs in approximately 80% of patients, and the remaining 20% of patients have single nucleotide variants (SNVs) and small deletions in the PMP22 gene. One normal allele (due to a 17p11.2 deletion) results in HNPP and a mild phenotype. SNVs in PMP22 have been associated with a variable spectrum of HNPP phenotypes ranging from mild symptoms to representing a more severe, CMT1-like syndrome.^13, Studies have also reported that the SNV frequency may vary considerably by ethnicity.^14, About 10% to 15% of variant carriers remain clinically asymptomatic, suggesting incomplete penetrance.^15,

Treatment

Currently, there is no therapy to slow the progression of neuropathy for the inherited peripheral neuropathies. A 2015 systematic review of exercise therapies for CMT including 9 studies described in 11 articles reported significant improvements with functional activities and physiological adaptations with exercise.^16, 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.^17,Avoidance of obesity and drugs associated with nerve damage (eg, vincristine, paclitaxel, cisplatin, isoniazid, nitrofurantoin) is recommended in CMT patients.^6,

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.^18, Prevention of HNPP manifestations can be accomplishedby wearing protective padding (eg, elbow or knee pads) to prevent trauma to nerves during activity. Some have reported that vincristine should also be avoided in HNPP patients.^8,18, Ascorbic acid has been investigated as a treatment for CMT1A based on animal models, but a 2013 trial in humans did not demonstrate significant clinical benefit.^19, Attarian et al (2014) reported results of an exploratory phase 2 randomized, double-blind, placebo-controlled trial of PXT3003, a low-dose combination of 3 approved compounds (baclofen, naltrexone, sorbitol) in 80 adults with CMT1A.^20, The trial demonstrated the safety and tolerability of the drug. Mandel et al (2015) included this randomized controlled trial and 3 other trials (1 of ascorbic acid, 2 of PXT3003) in a meta-analysis.^21,

Molecular Genetic Testing

Multiple laboratories offer individual variant testing for genes involved in hereditary sensory and motor neuropathies, which would typically involve sequencing analysis via Sanger sequencing or next-generation sequencing followed by deletion/duplication analysis (ie, with array comparative genomic hybridization) to detect large deletions or duplications. For the detection of variants in MFN2, whole gene or select exome sequence analysis is typically used to identify SNVs, in addition to or followed by deletion or duplication analysis for the detection of large deletions or duplications.

A number of genetic panel tests for the assessment of peripheral neuropathies are commercially available. For example, GeneDx (Gaithersburg, MD) offers an Axonal CMT panel, which uses next-generation sequencing and exon array comparative genomic hybridization. The genes tested include: AARS, BSCL2, DNM2, DYNC1H1, GARS, GDAP1, GJB1, HSPB1, HSPB8, LMNA, LRSAM1, MED25, MFN2, MPZ, NEFL, PRPS1, RAB7A, and TRPV4.²² InterGenetics (Athens, Greece) offers a next-generation sequencing panel for neuropathy that includes 42 genes involved in CMT, along with other hereditary neuropathies. Fulgent Clinical Diagnostics Lab offers a broader NGS panel for CMT that includes 48 genes associated with CMT and other neuropathies and myopathies.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic testing for the diagnosis of inherited peripheral neuropathies is available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Related Policies

• None

Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.


[RATIONALE: This policy was created in 2012 and has been updated with searches of the MEDLINE database. The most recent literature update was performed through December 6, 2018.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Testing for Genes Associated with Inherited Peripheral Neuropathies

Clinical Context and Test Purpose

The purpose of testing for variants associated with hereditary motor and sensory neuropathies in patients with suspected inherited peripheral neuropathy is to make a diagnosis of an inherited peripheral neuropathy or to inform the prognosis of an inherited peripheral neuropathy.

The question addressed in this policy is whether and how the use of genetic testing would improve health outcomes compared with a management strategy without testing.

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with suspected inherited peripheral neuropathy who present with sensory, motor, or mixed findings, and sometimes with other findings. Charcot-Marie-Tooth (CMT) disease is clinically heterogeneous.

Interventions

The relevant intervention of interest is testing for variants associated with CMT, by deletion or duplication analysis, usually by multiplex ligation-dependent probe amplification, and gene sequencing, usually by next-generation sequencing.

Comparators

The relevant comparator of interest is a clinical diagnosis of an inherited peripheral neuropathy made using a combination of clinical features, family pedigree, and characteristic nerve conduction velocity/electromyography studies. However, subtypes of CMT are defined based on their genotype.

Outcomes

The general outcomes of interest are test validity, symptoms, and change in disease status. Beneficial outcomes resulting from a true test include avoiding potentially harmful therapies. Harmful outcomes resulting from a false-positive test include potentially unneeded treatments due to misidentified patients.

Timing

Years.

Setting

The setting of interest is outpatient, with testing ordered by a specialist. Genetic counseling is particularly important for CMT given the extreme genetic heterogeneity of the disorder.

Simplifying Test Terms

There are three core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:

·         Technically reliable

·         Clinically valid

·         Clinically useful.

Because different specialties may use different terms for the same concept, we are highlighting the core characteristics. The core characteristics also apply to different uses of tests, such as diagnosis, prognosis, and monitoring treatment.

Diagnostic tests detect the presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops, or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.

Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to the response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or to predictresponse to therapy.

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

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A general estimation of the clinical sensitivity of CMT variant testing was presented by Aretz et al (2010) who assessed hereditary motor and sensory neuropathy and HNPP using a variety of analytic methods (multiplex ligation-dependent probe amplification, multiplex amplicon quantification, quantitative polymerase chain reaction, Southern blot, fluorescence in-situ hybridization, pulsed-field gel electrophoresis, denaturing high-performance liquid chromatography, high-resolution melting, restriction analysis, direct sequencing).^23, The clinical sensitivity (ie, the proportion of positive tests if the disease is present) for the detection of deletions and duplications to PMP22 was about 50% and 1% for single nucleotide variants. The clinical specificity (ie, the proportion of negative tests if the disease is not present) was nearly 100%.

An evidence-based review by England et al(2009) 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 with testing a cohort of patients suspected of having any variety of hereditary peripheral neuropathies, where the yield is only 25% to 59% (average, 43%).

Sequential Testing

Given the genetic complexity of CMT, many commercial and private laboratories evaluate CMT with a testing algorithm based on patients’ presenting characteristics. For the evaluation of the clinical validity of genetic testing for CMT, we included studies that evaluated patients with clinically suspected CMT who were evaluated with a genetic testing algorithm that was described in the study.

Saporta et al(2011) 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, neurophysiologic 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 noted that decisions about which genes to test changed during the study. Most (98.2%) of those with clinically diagnosed CMT1 had a genetic diagnosis, and of all patients with a genetic diagnosis, most (80.8%) had clinically diagnosed CMT1. The authors characterized several clinical phenotypes of CMT based on clinical presentation and physiologic testing.

Rudnik-Schoneborn et al (2016) reported on results from genetic testing of 1206 index patients and 124 affected relatives who underwent genetic testing at a single reference laboratory from 2001 to 2012.^24, Patients were referred by neurologic or genetic centers throughout Germany, and were grouped by age at onset (early infantile <2 years], childhood [2-10 years], juvenile [10-20 years], adult [20-50 years], late adult [>50 years]), and by electroneurographic findings. Molecular genetic methods changed over the course of the study, and testing was tiered by patient features and family history. Of the 674 index patients with a demyelinating CMT phenotype on nerve conduction studies, 343 (51%) had a genetic diagnosis; of the 340 index patients with an axonal CMT phenotype, 45 (13%) had a genetic diagnosis; and of the 192 with HNPP, 67 (35%) had a genetic diagnosis. The most common genetic diagnoses differed by nerve conduction phenotype: of the 429 patients genetically identified with demyelinating CMT (index and secondary), 89.3% were detected with PMP22 deletion or duplication (74.8%), GJB1/Cx32(8.9%), or MPZ/P0 (5.6%) variant analysis. In contrast, of the 57 patients genetically identified with axonal CMT (index and secondary), 84.3% were detected with GJB1/Cx32(42.1%), MFN2 (33.3%), or MPZ/P0 (8.8%) variant analysis. In an earlier study, Gess et al (2013) reported on sequential genetic testing for CMT-related genes from 776 patients at a single center for suspected inherited peripheral neuropathies from 2004 to 2012.25, Most patients (n=624) were treated in the same center. The test strategy varied based on electrophysiologic data and family history. The testing yield was 66% (233/355) in patients with CMT1, 35% (53/151) in patients with CMT2, and 64% (53/83) in patients with HNPP. Duplications on chromosome 17 were the most common variants in CMT1 (77%), followed by GJB1 (13%) and MPZ (8%) variants among those with positive genetic tests. For CMT2 patients, GJB2 (30%) and MFN2 (23%) variants were most common among those with positive genetic tests. Ostern et al (2013) reported on a retrospective analysis of cases of CMT diagnostic testing referred to a single reference laboratory in Norway from 2004 to 2010.26 Genetic testing was stratified based on clinical information supplied on patient requisition forms based on age of onset of symptoms, prior testing, results from motor nerve conduction velocity, and patterns of inheritance. The study sample included 435 index cases of a total of 549 CMT cases tested (other tests were for at-risk family members or other reasons). Patients were grouped based on whether they had symptoms of polyneuropathy, classical CMT, with or without additional symptoms or changes in imaging or had atypical features or the physician suspected an alternative diagnosis. Among the cases tested, 72 (16.6%) were found to be variant-positive, all of whom had symptoms of CMT. Most (69/72 [95.8%]) of the positive molecular genetic findings were PMP22 region duplications or sequence variants in MPZ, GJB1, or MFN2 genes. Murphy et al (2012) reported on the yield of sequential testing for CMT-related gene variants from 1607 patients with testing sent to a single-center.27, Of the 916 patients seen in the authors’ clinic, 601 (65.6%) had a primary inherited neuropathy, including 425 with CMT and 46 with HNPP. Of the 425 with a clinical diagnosis of CMT, 240 had CMT1 (56.5%), and 115 (27.1%) had CMT2. Of those with CMT, 266 (62.6%) of 425 received a genetic diagnosis, most frequently (92%) with a variant in 1 of 4 genes (PMP22 duplication, and GJB1, MPZ,and MFN2). Panel Testing In addition to sequential testing algorithms, some studies were reported on the yield of multigene testing panels, most often using next-generation sequencing methods. Studies with populations of suspected inherited motor or sensory neuropathy that have reported on next-generation sequencing panel test results are summarized in Table 2. Table 2. Summary of Genetic Panel Tests in Charcot-Marie-Tooth

Study	N	Population	Test	Diagnostic Yield (NGS Panel)	VUS (NGS Panel)
Antoniadi et al (2015)28,	448	Suspected inherited peripheral neuropathy, with supportive NCV, some with negative testing for PMP2	56-gene NGS panel	137 (31%) patients (31 genes)	NR
DiVincenzo et al (2014)29,	17,377,503 with NGS	Suspected peripheral neuropathy, referred to a central laboratory	14-gene NGS panel and PMP22del/dup by MLPA	95 (18.9%) patients (8 genes)	38 (7.5%) patients (11 genes)

del/dup: deletion/duplication; MLPA: multiplex ligation-dependent amplification; NCV: nerve conduction velocity; NGS: next-generation sequencing; NR: not reported; VUS: variant of uncertain significance. Genotype-Phenotype Correlations There is significant clinical variability within and across subtypes of CMT. Therefore, some studies have evaluated genotype-phenotype correlations within CMT cases. For example, Sanmaneechai et al (2015) characterized genotype-phenotype correlations in patients with CMT1B regardingMPZ variants in a cohort of 103 patients from 71 families.30, Patients underwent standardized clinical assessments and clinical electrophysiology. There were 47 different MPZ variants and 3 characteristic ages of onset: infantile (age range, 0-5 years), childhood (age range, 6-20 years), and adult (age range, ≥21 years). Specific variants clustered by age group, with only two variants found in more than one age group. Karadima et al (2015) investigated the association between PMP22 variants and clinical phenotype in 100 Greek patients referred for genetic testing for HNPP.31, In the 92 index cases, the frequency of PMP22 deletions was 47.8%, and the frequency of PMP22 micro-variants was 2.2%. Variant-negative patients were more likely to have an atypical phenotype (41%), absent family history (96%), and nerve conduction study findings not fulfilling HNPP criteria (80.5%). Section Summary: Clinically Valid A relatively large body of literature, primarily from retrospective, single-center reference labs in which patients with suspected CMT have been tested, addressed clinical validity. The testing yield is reasonably high, particularly when patients are selected based on clinical phenotype. Clinically Useful 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. The diagnosis of an inherited peripheral neuropathy can generally be made clinically. However, when the diagnosis cannot be made clinically, a genetic diagnosis may add incremental value. A diagnosis of an inherited peripheral neuropathy is important to direct therapy, regarding early referrals to physical therapy and avoidance of potentially toxic medications. Some specific medications for CMT are under investigation, but their use is not well-established. There are significant differences in prognosis for different forms of CMT, although whether different prognosis leads to choices in therapy that lead to different outcomes is uncertain. In some cases, genetic diagnosis of an inherited peripheral neuropathy may have the potential to avoid other diagnostic tests. Summary of Evidence For individuals with suspected inherited motor and sensory peripheral neuropathy who receive testing for genes associated with inherited peripheral neuropathies, the evidence includes case-control and genome-wide association studies. The relevant outcomes are test validity, symptoms, and change in disease status. For the evaluation of hereditary motor and sensory peripheral neuropathies and hereditary neuropathy with liability to pressure palsies, the diagnostic testing yield is likely to be high, particularly when sequential testing is used based on patient phenotype. 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. No direct evidence for improved outcomes with the use of genetic testing for hereditary motor and sensory peripheral neuropathies and hereditary neuropathy with liability to pressure palsies was identified.However, a chain of evidence supports the use of genetic testing to establish a diagnosis in cases of suspected inherited motor or sensory neuropathy, when a diagnosis cannot be made by other methods, to initiate supportive therapies. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. SUPPLEMENTAL INFORMATION Practice Guidelines and Position Statements American Academy of Neurology et al The American Academy of Neurology and 2 other specialty societies (2009) published an evidence-based, tiered approach for the evaluation of distal symmetric polyneuropathy and suspected hereditary neuropathies, which concluded the following (see Table 3).3, Table 3. Recommendations on Distal Symmetric Polyneuropathy and Suspected Hereditary Neuropathies

Recommendation	LOEa
“Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies”	A
“Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype”	C
“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”	U

LOE: level of evidence. a Grade A: established as effective, ineffective, or harmful for the given condition in the specified population; grade C: possibly effective, ineffective, or harmful for the given condition in the specified population; grade U: data inadequate or conflicting; given current knowledge. The American Academy of Neurology website indicates the recommendations were reaffirmed in 2013 and in November 2017 indicated an update is in progress. American Academy of Family Physicians The American Academy of Family Physicians (2010) recommended genetic testing for 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.32, U.S. Preventive Services Task Force Recommendations Not applicable. Ongoing and Unpublished Clinical Trials Some currently unpublished trials that might influence this review are listed in Table 4. Table 4. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01193075	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Type (CMT1B), 2A (CMT2A), 4A (CMT4A), 4C (CMT4C), and Others	5000	Dec 2019
NCT01193088	Genetics of Charcot Marie Tooth Disease (CMT) - Modifiers of CMT1A, New Causes of CMT	1050	Dec 2019

NCT: national clinical trial.] ________________________________________________________________________________________ Horizon BCBSNJ Medical Policy Development Process: This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations. ___________________________________________________________________________________________________________________________ Index: Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies Inherited Peripheral Neuropathies, Genetic Testing for the diagnosis of Peripheral Neuropathies, Inherited, Genetic Testing for Neuropathies, Inherited, Peripheral, Genetic Testing for PMP22, Genetic Testing Charcot-Marie-Tooth Neuropathy, Genetic Testing for Axonal CMT Panel (GeneDx) NGS Panel for Neuropathy (InterGenetics) NGS Panel for CMT (Fulgent Clinical Diagnostics Lab) GeneDx (Axonal CMT) InterGenetics (NGS Panel for Neuropathy) Fulgent Clinical Diagnostics Lab (NGS Panel for CMT) 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. Feb 2011;18(2):207-217. PMID 20500522 2. Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn). Feb 2012;18(1):13-38. PMID 22810068 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. Jan 13 2009;72(2):185-192. PMID 19056666 4. Saporta AS, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. Jan 2011;69(1):22-33. PMID 21280073 5. Cornett KM, Menezes MP, Bray P, et al. Phenotypic variability of childhood Charcot-Marie-Tooth disease. JAMA Neurol. Jun 01 2016;73(6):645-651. PMID 27043305 6. Bird TD. Charcot-Marie-Tooth Hereditary Neuropathy Overview. In: Pagon RA, Bird TD, Dolan CR, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2016. 7. Stankiewicz P, Lupski JR. The genomic basis of disease, mechanisms and assays for genomic disorders. Genome Dyn. Aug 2006;1:1-16. PMID 18724050 8. Bird TD. Charcot-Marie-Tooth Neuropathy Type 1. In: Adams M, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2015. 9. Bird TD. Charcot-Marie-Tooth Neuropathy Type 2. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2016. 10. Bird TD. Charcot-Marie-Tooth Neuropathy X Type 1. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2016. 11. Meretoja P, Silander K, Kalimo H, et al. Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland. Neuromuscul Disord. Dec 1997;7(8):529-532. PMID 9447611 12. 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. Jan 2008;18(1):82-84. PMID 18382985 13. Taioli F, Cabrini I, Cavallaro T, et al. Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene. Brain. Feb 2011;134(Pt 2):608-617. PMID 21252112 14. 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. Nov 2000;58(5):396-402. PMID 11140841 15. Dubourg O, Mouton P, Brice A, et al. Guidelines for diagnosis of hereditary neuropathy with liability to pressure palsies. Neuromuscul Disord. Mar 2000;10(3):206-208. PMID 10734269 16. Sman AD, Hackett D, Fiatarone Singh M, et al. Systematic review of exercise for Charcot-Marie-Tooth disease. J Peripher Nerv Syst. Dec 2015;20(4):347-362. PMID 26010435 17. Pareyson D, Marchesi C. Natural history and treatment of peripheral inherited neuropathies. Adv Exp Med Biol. Jan 2009;652:207-224. PMID 20225028 18. Bird TD. Hereditary neuropathy with liability to pressure palsies. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. Gene Reviews. Seattle, WA: University of Washington; 2014. 19. 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. Aug 2013;70(8):981-987. PMID 23797954 20. Attarian S, Vallat JM, Magy L, et al. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. Dec 18 2014;9:199. PMID 25519680 21. Mandel J, Bertrand V, Lehert P, et al. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis. Jun 13 2015;10:74. PMID 26070802 22. GeneDx. Axonal CMT Panel. https://www.genedx.com/test-catalog/available-tests/axonal-cmt-panel-1/. Accessed November 15, 2017. 23. 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. Sep 2010;18(9). PMID 20512157 24. Rudnik-Schoneborn S, Tolle D, Senderek J, et al. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet. Jan 2016;89(1):34-43. PMID 25850958 25. Gess B, Schirmacher A, Boentert M, et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord. Aug 2013;23(8):647-651. PMID 23743332 26. Ostern R, Fagerheim T, Hjellnes H, et al. Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies. BMC Med Genet. 2013;14:94. PMID 24053775 27. Murphy SM, Laura M, Fawcett K, et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry. Jul 2012;83(7):706-710. PMID 22577229 28. Antoniadi T, Buxton C, Dennis G, et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. Sep 21 2015;16:84. PMID 26392352 29. DiVincenzo C, Elzinga CD, Medeiros AC, et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. Nov 2014;2(6):522-529. PMID 25614874 30. Sanmaneechai O, Feely S, Scherer SS, et al. Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain. Nov 2015;138(Pt 11):3180-3192. PMID 26310628 31. Karadima G, Koutsis G, Raftopoulou M, et al. Mutational analysis of Greek patients with suspected hereditary neuropathy with liability to pressure palsies (HNPP): a 15-year experience. J Peripher Nerv Syst. Jun 2015;20(2):79-85. PMID 26110377 32. Azhary H, Farooq MU, Bhanushali M, et al. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician. Apr 1 2010;81(7):887-892. PMID 20353146 Codes: (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.) CPT* 81324 81325 81326 81403 81404 81405 81406 81438 81479 HCPCS * CPT copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association. _________________________________________________________________________________________ Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage. The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy ____________________________________________________________________________________________________________________________