|The majority of genetically determined polyneuropathies are variants of Charcot–Marie–Tooth (CMT) disease, and genetic testing is available for an increasing number of these neuropathies. The clinical phenotype of CMT is extremely variable, ranging from a severe polyneuropathy with respiratory failure through the classic picture with pes cavus and “stork legs” to minimal neurological findings.2,3 Since a substantial proportion of CMT patients have de novo mutations, a family history of neuropathy may be lacking.2,3,10 Additionally, different genetic mutations can cause a similar phenotype (genetic heterogeneity) and different phenotypes can result from the same genotype (phenotypic heterogeneity).
How Accurate Is Genetic Testing for Identifying Patients with Genetically Determined Neuropathies? The CMT phenotype has been linked to 36 loci and mutations have been identified in 28 different genes, several of which can be identified by commercially available genetic testing. Previous segregation studies followed by several prospective cohort studies have documented that the results of currently available genetic testing are unequivocal for diagnosis of established pathogenic mutations, providing a specificity of 100% (i.e., no false-positives) and high sensitivity (Class I and II).4,5,13,17,24–27,34,39 The interpretation of novel mutations may require further characterization available in specialized centers. Data from six Class I, six Class II, and one Class III study indicate that genetic testing is useful for the accurate classification of hereditary polyneuropathies.2,4,5,10,13,17,24–27,34,38,39
Which Patients with Polyneuropathy Should Be Screened for Hereditary Neuropathies? Genetic studies of hereditary neuropathies have tested the prevalence of various mutations in selected patients with the classic CMT phenotype with and without a family history of polyneuropathy.5,17,24–27,39 (Class III evidence for screening.) For these patients the yield of genetic tests has been relatively high.
Data from seven studies indicate that the demyelinating form of Charcot–Marie–Tooth (CMT1) is the most prevalent, and about 70% of these patients have a duplication of PMP22 gene (CMT1A).5,17,24– 27,39 CMT1A is also the most common variety of sporadic CMT1, accounting for 76%–90% of cases.10,26 Six studies showed that when the test for CMT1A duplication is restricted to patients with clinically probable CMT1 (i.e., autosomal dominant, primary demyelinating polyneuropathy), the yield is 54%–80% as compared to testing a cohort of patients suspected of having any variety of hereditary peripheral neuropathy where the yield is only 25%– 59% (average of 43%).5,13,24,26,34,39
Axonal forms of Charcot–Marie–Tooth (CMT2) are most commonly caused by MFN2 mutations, which account for 33% of the cases.38 MFN2 mutations have not occurred in the CMT1 group. Data from eight studies indicate that Cx32(GJB1) mutations cause an X-linked neuropathy (CMTX), which may present with either a predominantly demyelinating or axonal phenotype and account for 12% of all cases of CMT.4,5,13,24,25,27,34,39 If the pedigree is uninformative as to whether the inheritance is autosomal dominant or X-linked (lack of father to son transmission), Cx32(GJB1) mutation is in the differential diagnosis for both predominantly demyelinating and axonal neuropathies.
Data from seven studies has established average mutation frequencies of 2.5% for PMP22 point mutations, and 5% for MPZ mutations in the CMT population.4,5,13,24,25,39 CMT caused by other genes is much less frequent (see Fig. 1).
Given the relationships between pattern of inheritance, EDX results, and specific mutations, the efficiency of genetic testing can be improved by following a stepwise evaluation of patients with possible hereditary neuropathy. First, a clinical classification that includes EDX studies should be performed to determine whether the neuropathy is primarily demyelinating or primarily axonal in type. Since EDX studies are sometimes problematic in children, some physicians may opt to proceed directly to genetic testing of symptomatic children suspected of having CMT. Second, the inheritance pattern (autosomal dominant, autosomal recessive, or X-linked) should be ascertained. Based on this information, the most appropriate genetic profile testing can then be performed.
Figure 1 indicates an evidence-based, tiered approach for the evaluation of suspected hereditary neuropathies, and Table 3 shows the relative frequency of the most common genetic abnormalities accounting for the CMT phenotype from population studies.
Evaluation of Suspected Hereditary Neuropathies
FIGURE 1. Evaluation of suspected hereditary neuropathies. Decision algorithm for use in the diagnosis of suspected hereditary polyneuropathies using family history and NCSs. *PMP22 denotes peripheral myelin protein 22; MPZ myelin protein zero; PRX periaxin; GDAP1 ganglioside-induced differentiation-associated protein 1; GJB1 gap-junction beta-1 protein (connexin 32); MFN2 mitofusin 2; EGR2 early growth response 2; LITAF lipopolysaccharide-induced tumor necrosis factor ; RAB7 small guanosine triphosphatase late endosomal protein; GARS glycyltransfer RNA synthetase; NEFL neurofilament light chain; HSPB1 heat shock protein beta-1.
The previous discussion applies to patients with polyneuropathy and a classical hereditary neuropathy phenotype with or without a family history. The authors were not able to find studies of the yield of genetic screening in polyneuropathy patients without a classical hereditary neuropathy phenotype. Some patients with CMT genetic mutations have minimal neurological findings and do not have the classical CMT phenotype.2,3 Thus, some patients with cryptogenic polyneuropathies without the classical CMT phenotype may also have hereditary neuropathies. The prevalence of mutations in this population is unknown.
Conclusions. Genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies (Class I). For patients with a cryptogenic polyneuropathy who exhibit a classical 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. There is insufficient evidence to determine the usefulness of routine genetic screening in cryptogenic polyneuropathy patients without a classical hereditary neuropathy phenotype.
Recommendations. Genetic testing may be considered in patients with a cryptogenic polyneuropathy and classical hereditary neuropathy phenotype (Level C). To achieve the highest yield, the genetic testing profile should be guided by the clinical phenotype, inheritance pattern (if available), and EDX features (demyelinating versus axonal). (See Fig. 1 for guidance.)
There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classical hereditary phenotype (Level U). polyneuropathy and highlights opportunities for research.
RECOMMENDATIONS FOR FUTURE RESEARCH
This comprehensive review reveals several weaknesses in the current approach to the evaluation of polyneuropathy and highlights opportunities for research.
The finding of a laboratory abnormality does not necessarily mean that the abnormality is etiologically significant. For instance, there is a relatively high prevalence of impaired glucose tolerance in patients with distal symmetric polyneuropathy; however, whether this is etiologically diagnostic is not known. This and other such examples point to the need for more research into the basic pathobiology of the peripheral nervous system. As an extension of this area of research, there is a need to determine whether aggressive treatment or reversal of specific laboratory abnormalities improves or alters the course of polyneuropathy.
The genetic revolution has provided great insights into the mechanisms of hereditary neuropathies. Genetically determined neuropathies are more common and clinically diverse than previously appreciated. Further research to identify genotype–phenotype correlation is needed to improve the evaluation process for patients with suspected hereditary neuropathies. The issue of cost/ benefit ratio of genetic testing is important since an ever-increasing number of genetic tests are commercially available. More clearly defined guidelines for genetic testing are needed to maximize yield and to curtail the costs of such evaluations. Continued exploration into the genetic basis of neuropathies has tremendous potential for the understanding of basic pathophysiology and treatment of neuropathies.
The AAN, the AANEM, and the AAPM&R determined that there was a need for an evidence-based and clinically relevant practice parameter for the evaluation of polyneuropathy. As a prelude to this project, the three organizations developed a formal case definition of DSP.8
As outlined in this previous publication, the most accurate diagnosis of distal symmetric polyneuropathy is provided by a combination of neuropathic symptoms, signs, and EDX studies. Since EDX studies are sensitive, specific, and validated measures of the presence of polyneuropathy and can distinguish between demyelinating and axonal types of neuropathy, they should be included as an integral part of the diagnosis.8
This practice parameter assumes that a clinical diagnosis of polyneuropathy has been determined based on such criteria.
The diagnosis and evaluation of polyneuropathy is complex. The practice parameter is not intended to replace the clinical judgment of experienced physicians in the evaluation of polyneuropathy. The particular kinds of tests utilized by a physician in the evaluation of polyneuropathy depend on the specific clinical situation and the informed medical judgment of the treating physician.
This statement is provided as an educational service of the AAN, AANEM, and the AAPM&R. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific test or procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN, AANEM, and AAPM&R recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.
Conflict of Interest.
The AAN, AANEM, and AAPM&R are committed to producing independent, critical, and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN, AANEM, and AAPM&R keep separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN, AANEM, and AAPM&R limit the participation of authors with substantial conflicts of interest. The AAN, AANEM, and AAPM&R forbid commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least three AAN committees, AANEM and AAPM&R committees, a network of neurologists, Neurology
peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com.
Quality Standards Subcommittee Members.
Jacqueline French, MD, FAAN (co-chair); Gary S. Gronseth, MD (co-chair); Charles E. Argoff, MD; Eric Ashman, MD; Stephen Ashwal, MD, FAAN (ex-officio); Christopher Bever Jr., MD, MBA, FAAN; John D. England, MD, FAAN (QSS facilitator); Gary M. Franklin, MD, MPH, FAAN (ex-officio); Deborah Hirtz, MD (ex-officio); Robert G. Holloway, MD, MPH, FAAN; Donald J. Iverson, MD, FAAN; Steven R. Messe´, MD; Leslie A. Morrison, MD; Pushpa Narayanaswami, MD, MBBS; James C. Stevens, MD, FAAN (ex-officio) David J. Thurman, MD, MPH (exofficio); Samuel Wiebe, MD; Dean M. Wingerchuk, MD, MSc, FRCP(C); and Theresa A. Zesiewicz, MD, FAAN.
Practice Issues Review Panel (AANEM).
Yuen T. So, MD, PhD (chair); Michael T. Andary, MD; Atul Patel, MD; Carmel Armon, MD; David del Toro, MD; Earl J. Craig, MD; James F. Howard, MD; Joseph V. Campellone Jr., MD; Kenneth James Gaines, MD; Robert Werner, MD; Richard Dubinsky, MD.
Clinical Quality Improvement Committee (AAPM&R).
Dexanne B. Clohan, MD (chair); William L. Bockenek, MD; Lynn Gerber, MD; Edwin Hanada, MD; Ariz R. Mehta, MD; Frank J. Salvi, MD, MS; and Richard D. Zorowitz, MD.
Classification of Evidence for Studies of Diagnostic Accuracy.
Evidence provided by a prospective study in a broad spectrum of persons with the suspected condition, using a “gold standard” for case definition, where a test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.
Evidence provided by a prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by “gold standard”) compared to a broad spectrum of controls, where a test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.
Evidence provided by a retrospective study when either persons with the established condition or controls are of a narrow spectrum, and where a test is applied in a blinded evaluation.
Any design where a test is not applied in blinded evaluation or evidence provided by expert opinion alone or in descriptive case series (without controls).
Classification of Recommendations.
Approved by the AANEM Board of Directors on May 1, 2008. With regard to conflicts of interest, the authors disclose the following: (1) Holds financial interests in Pfizer. (2) Holds financial interests in Pfizer and GlaxoSmithKline and Boeheringer Ingelheim for speaker honoraria and Ortho-McNeil for serving on the IDMC Committee. (3) Nothing to disclose. (4) Nothing to disclose. (5) Received royalties from the American Medical Resources, Enduring Medical Materials (CD/DVD), has received honorarium from Medical Education Resources, CME LLC, Expert Witness testimony and record review, Peters Marketing Research, Delve Marketing Research, Cross Country Education and American Medical Seminars. Dr. Kinsella holds corporate appointments with Cross Country Education and Forest Park Hospital. (6) Nothing to disclose. (7) Receives residual royalties from Elsevier for editorial work done prior to 2005. He receives honoraria from the Dana Foundation, NY, and the International Society for Neuroimmunology. His wife is a consultant for the Dana Foundation. (8) Nothing to disclose. (9) Financial interests in Athena Diagnostics and has received research funding from NIH/NEI, NIH/NIDCR, Charcot-Marie-Tooth Association, and the March of Dimes. (10) Serves as a Scientific Advisor for Quest Diagnostics and is a member of a Steering Committee, Talecris Biotherapeutics. Dr. Latov receives royalties from Demos publications and has received research support from the NIH and Talecris Biotherapeutics. He holds stock options in Therapath LLC and is the beneficiary of license fee payments from Athena Diagnostics to Columbia University. He has given expert testimony in legal proceedings related to neuropathy and has prepared an affidavit with regarding to the legal proceeding related to neuropathy. (11) Financial interests in Talecris and has received research funding from MDA and CMTA. He estimates that approximately 33% of his clinical effort is spent on electromyography. He has received payment for expert testimony regarding the use of IVIg in CIDP; neuropathic pain after breast reduction. (12) Served as a consultant for WR Medical, Viatris, Eli Lilly and Company, Chelsea Therapeutics, and Quigley Corporation. (13) Financial interests in Astrazeneca, Photothera, Wyeth, Jalmarjone Sahron, Inarx, Boehringer-Ingelheim, Dullehi-Arubio, Axaron, U-Servicer, and PAION. (14) Estimates that approximately 15%–20% of his clinical effort is spent on skin biopsies. (15) Serves on a myasthenia gravis medical scientific board, has served as an Associate Editor, Journal of Clinical Neuromuscular Disease (1998–2006), receives honoraria from Duke University Medical Center, and Medical Educational Resources. He is the director of MEG laboratories and estimates that 75% of his time is spent there. He also holds stock options in GE, Pfizer, and Johnson & Johnson. In addition, he has provided an affidavit on two cases regarding myasthenia gravis. (16) Financial interests in GlaxoSmithKline and Formenti-Grunenthal. In addition he has received research funding from Pfitzer, FormentiGrunenthal, Foramenti-Grunenthal, Italian Ministry of Health, and Regione Lombardia. (17) Financial interests in Celgene and Pathologica. (18) Financial interests in DSMB, Pfizer, Johnson & Johnson, Mitsubishi Pharma, Merck, Xenoport, and GSK. He has received research funding from JDRF, NIH, Astellas Pharma, Mitsubishi Pharma, and Sanofi-Aventis. He estimates that 10% of his clinical effort is devoted to EMG, 5% to skin biopsy, and 1% on lumbar puncture. (19) Received payment for expert testimony in the possible neurotoxic injury of the peripheral nerve.
||Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires as least two consistent Class I studies.)
||Probably effective, ineffective, or harmful for the givencondition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)
||Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
||Data inadequate or conflicting; given current knowledge, treatment is unproven.
[Note. Strength of evidence is indicated for references used to formulate conclusions and recommendations.]
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