Pmp22

children who manifest with these disorders might never ambulate or lose ambulation. Breathing and bulbar weaknesses might develop in some forms of these motor and sensory neuropathies.

Increasingly molecular diagnosis is providing for classification (Table 2). Molecular genetic studies, however, without consideration of the clinical features, natural history, mode of inheritance, electrophysiologic characteristics, and neuropatho-logical features are not as useful as desired. Specifically, genetic testing is not available in many forms and some patients, despite identical mutations, might have markedly different severity. Regardless, genetic testing is often essential, as many acquired inflammatory immune illnesses mimic these syndromes, leading to inappropriate treatment with immunosuppressants.

Beyond the scope of our discussion are those inherited neuropathies that selectively affect the sensory and autonomic fibers termed hereditary sensory and autonomic neuropathies (HSANs) (73). There are five varieties described, HSAN I-V. Patients might have painless or painful injuries because of loss of sensory abilities and might have prominent autonomic dysfunction. Distinction between the forms is based on age of presentation, mode of inheritance, specific histopathologic description, and, increasingly, identification of molecular abnormalities. The mutations found are typically missense mutations. The disorders (and genes) are (1) HSAN 1 (SPTLC1), (2) HSAN II (unknown), (3) HSAN type III (IKBKAP), (4) HSAN IV (trKa), and (5) HSAN V (possibly trKa).

7.1. GENETICS The HMSN disorders are classified by whether the molecular genetic abnormality is primarily Schwann cell (myelin) or neuronal (axonal) and by the specific molecular derangements. Some disorders have unique clinical features and the classification has provided for these as separate forms. The demyelinating forms include (1) HMSN1A-C and HMSN4A-F, (2) Dejerine-Sottas syndrome (DSS also known as HMSN3A-C), (3) congenital hypomyelinating neuropathies (CHNs), and (4) hereditary neuropathy with pressure palsies (HNPPs), which is typically caused by deletions at 17p11.2, whereas HMSN1A is caused by duplications. The identified molecular defects are in structural and regulatory proteins of compact myelin, including peripheral myelin protein 22 (PMP22) (74) and myelin protein zero (MPZ) (75). Mutations affecting noncompact myelin via gap junction protein B1 (i.e., connexin 32) (GJB1) (76) and the cytoskeletal-associated protein, periaxin (PRX) (77), have also been identified. Proteins involved in transcription are causative and include transcription factors for late myelin genes [i.e., early growth response gene 2 {EGR2} (78)] and signal transduction proteins [i.e., myotubularin-related protein 2 gene {MTMR2} (79) and N-myc downstream-regulated gene 1 {NDRG1} (80)]. Finally, one gene potentially involved in regulation of apoptosis has been identified, lipopolysaccharide-induced tumor necrosis factor -a factor (LITAF) (81).

Within the described genes, various micromutations could similar or dissimilar phenotypes with varied patterns of inheritance, including both dominant (PMP22, MPZ, GJB1, EGR2) and recessively (PMP22, MTMR2, NDRG1, EGR2, PRX) inherited diseases (82). Of additional note is that mutations of PMP22, MPZ, and GJB1 can produce axonal diseases, implicating the critical interaction between Schwann cell elements and axonal components.

The axonal forms, HMSN 2A-E, are not as well understood as the demyelinating forms primarily because the axonal forms are not easily detected by electrophysiologic testing. The range of severity within this group of axonal disorders is broad. Abnormalities of structural proteins have been most commonly implicated, including neurofilament light chain gene (NFL) (83), kinesin 1b (K1F1B) (84), and gigaxonin gene (GAN1) (85).

The most common mutations in the HMSN varieties are likely within PMP22. Duplication mutations of PMP22 result in HMSN 1A phenotype (86), whereas deletions produce the phenotype of HNPPs (87). Homologous repeat sequences (CMT1A-REP) flank the region at 17p11.2 and are thought, in part, contributory by promoting misalignment and unequal DNA recombination (88). Alternate sex-linked mechanisms exist for deletions and duplication at PMP22. De novo macromutations from paternal origin appear to be duplications alone. Maternal origin mutations, however, produce both duplications and deletions. The specific mutation mechanisms at PMP22 during oogenesis include unequal sister chromatid exchange and intrachromatidal loop excision (89). These sex-dependent mechanisms might in part, explain the relative infrequency of HNPP compared to HMSN1A. Rare missense mutations resulting in the HMSN 1A phenotype exist (90). The existence of autosomal recessive PMP22 point mutation has also been proposed, but questions about the biological significance of these basepair changes have been raised (91).

PMP-22 heterozygous micromutations (typically missense mutations) can produce the severe dysmyelinating phenotype of Dejerine-Sottas syndrome (DSS) (92,93). These mutations occur exclusively within the transmembrane domains and are predicted to destabilize the wild-type protein (94). Factors external to PMP22 might alter clinical expression because identical mutations between and within families have been noted to produce phenotypic variability. Gene dosage has been proposed as a possible explanation for the clinical difference between HNPP (deletions) and HMSN1A (duplication) pheno-types. PMP-22 mRNA and protein levels are increased in HMSN1A and decreased in HNPP (95,96). Rare exceptions are noted; for example, patients homozygous for PMP22 duplications are noted for both severe and mild phenotypes, suggesting that gene dosage alone is not sufficient to explain clinical variability (86). Among the other varieties of HMSN, multiple micromutations, in connexin 32 are described, making X-linked CMT likely the second most common form of hereditary peripheral neuropathy identified to date.

7.2. MOLECULAR DIAGNOSIS One method of detecting the duplication within PMP22 is by using MspI-digested DNA hybridized with the probe VAW409R3a, which maps to 17p11.2 (D17S122). This probe/enzyme combination detects three polymorphic restriction fragments and has a heterozygos-ity of 70%. It is interesting to note that approx 8% of CMT1A duplication patients have all three fragments (97). Duplication is detected as a dosage difference between restriction fragments. A second method that offers definitive detection of CMT1A duplications is pulse-field gel electrophoresis (PFGE) of SacII-digested DNA, followed by hybridization with the VAW409R3a probe. This method is likely superior, as it detects the previously described 500-kb fragment in all CMT1A duplication patients and is preferred over Southern analysis. PCR analysis utilizing simple sequence repeats in the CMT1A region is a third method for the detection of duplications. This method is informative in 80% of duplication cases, and 46% of these patients are fully informative, having three detectable alleles (97). However, because it is difficult to detect duplications by PCR analysis, PCR is not the preferred method for the duplication analysis of CMT1A. Another method for the detection of duplications of the CMT1A locus is by fluorescence in situ hybridization (FISH) analysis with the VAW409R3a probe in combination with a control probe. Currently, the most commonly used testing strategy for detection of CMT1A duplications is Southern blot analysis, followed by PFGE in those cases in which restriction fragment length polymorphism (RFLP)

analysis is uninformative (98). FISH analysis, on the other hand, is recommended for the molecular diagnosis of HNPP, although an interphase FISH strategy for the detection of CMT1A duplications has recently been shown to be rapid and reliable as an alternative diagnostic approach (87,99). Molecular diagnosis of CMT1A and HNPP patients with alterations other than duplication or deletion typically requires amplification and sequencing of the expressed regions by standard PCR and sequencing techniques. Such techniques are employed to identify those mutations in the remaining forms of HMSN. Commercial testing is available for connexin 32, MPZ (Po), EGR2, and NF-L, with others likely to follow.

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