Practice Parameter: The Evaluation of Distal Symmetric Polyneuropathy: The Role ofLaboratory and Genetic Testing (An Evidence-Based Review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

Louisiana State University Health Sciences Center, New Orleans, USA.
PM&R (Impact Factor: 1.53). 02/2009; 1(1):5-13. DOI: 10.1016/j.pmrj.2008.11.010
Source: PubMed


Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP.
A literature review using MEDLINE, EMBASE, Science Citation Index and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence.
1. Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine) and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). 2. Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic (EDX) features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation 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).

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    • "The second tier should be based on interdisciplinary investigation of patients at neuromuscular centres. Several excellent algorithms exist for this purpose [11,12]. Powerful tools, like next generation sequencing (NGS), are nowadays implemented in clinical practice and provide possibilities for more efficient genetic diagnostic service to patients with hereditary polyneuropathies [26]. "
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    ABSTRACT: Current genetic test algorithms for Charcot Marie Tooth (CMT) disease are based on family details and comprehensive clinical and neurophysiological data gathered under ideal conditions for clinical assessment. However, in a diagnostic laboratory setting relying on external test requisitions and patient samples, such conditions are not always met. Our objective was therefore to perform a retrospective evaluation of the data given in laboratory request forms and to assess their quality and applicability with regard to the recommended algorithms for CMT diagnostics. As we are the main test centre for CMT in Norway our results also provide an overview of the spectrum of gene defects in the Norwegian CMT population. Genetic testing was performed according to polyneuropathy type; demyelinating/mixed: PMP22 duplication, MPZ, EGR2, LITAF, NEFL, PMP22, GJB1, axonal: MFN2, MPZ, NEFL, and GJB1. Diagnostic testing of index patients was requested in 435 of the 549 cases. Seventy-two (16.6%) positive molecular genetic findings were made. The majority (94.6%) of mutation positive cases showed disease onset before 50 years of age. PMP22 (duplication), MPZ, GJB1 and MFN2 mutations constituted 95.8% of the positive findings. Within the nerve conduction study groups, mutation detection rates were; demyelinating 33.8%; mixed 29.0%; axonal 8.8%; unspecified 16.5%. We suggest a simplified algorithm intended for referral centres, dealing with DNA/blood samples, which involves the assessment of age at onset and neurophysiological data followed by testing of four genes; PMP22 (duplication), MPZ, GJB1 and MFN2. Patients negative for mutations in those four genes should be subjected to evaluation at an interdisciplinary inherited neuropathy clinic with the capacity for extended molecular genetic analysis by next generation sequencing.
    Full-text · Article · Sep 2013 · BMC Medical Genetics
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    • "The potential for genomics to contribute to clinical care has long been recognized, and many optimistic scenarios for clinical use of information about a patient's genome have been proposed.1,2,3 The pace of realizing this potential has appeared slow to some,4,5 although clinical adoption of scientific discoveries has been estimated to take up to 17 years6 and a recent genetic example7 required 18 years after the initial 1991 report.8 Indeed, relatively robust genotype–phenotype associations for common, complex diseases only began to become available around 2005.9 Yet several academic medical centers and integrated health systems have already begun programs for implementing genomic medicine, which we define here as using an individual patient's genotypic information in his or her clinical care. "
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    ABSTRACT: Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices. Genet Med 2013:15(4):258–267
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    • "The diagnostic protocol for demyelinating and dominant CMT (CMT1), which has been adapted from England et al. [14, 15], is summarized in Figure 2. Given that the data available suggest that duplication of PMP22 is the most frequent cause of CMT1 and that mutation of PMP22 is the most common cause of sporadic CMT1 [6, 16], it is proposed that the study of demyelinating CMT should begin by checking for duplication of the genomic fragment encompassing PMP22. Once this duplication has been ruled out, in sporadic cases or in cases where there is no male-to-male transmission, researchers should check for point mutations in the GJB1 gene (which can be used to diagnose up to 12% of cases). "
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    ABSTRACT: Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked), according to electrophysiological findings (demyelinating or axonal), or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data.
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