CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, WITH FOCALLY FOLDED MYELIN SHEATHS, TYPE 1A
HEREDITARY MOTOR AND SENSORY NEUROPATHY IA
HMSN IA
CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 1A
HMSN1A
CMT1A
Microduplication 17p12
Charcot-Marie-Tooth disease type 1
-Rare genetic disease
-Rare neurologic disease
Partial duplication of the short arm of chromosome 17
-Rare developmental defect during embryogenesis
-Rare genetic disease
For a general phenotypic description and a discussion of genetic heterogeneity of Charcot-Marie-Tooth disease type 1, see CMT1B (118200).
CMT1A is the most common form of CMT. The average age of onset of clinical symptoms is ... For a general phenotypic description and a discussion of genetic heterogeneity of Charcot-Marie-Tooth disease type 1, see CMT1B (118200). CMT1A is the most common form of CMT. The average age of onset of clinical symptoms is 12.2 +/- 7.3 years. Slow nerve conduction velocity (NCV) less than 38 m/s is highly diagnostic and is a 100% penetrant phenotype independent of age (Lupski et al., 1991, 1992).
Matise et al. (1994) referred to the tandem duplication underlying CMT1A as resulting in segmental trisomy. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A ... Matise et al. (1994) referred to the tandem duplication underlying CMT1A as resulting in segmental trisomy. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A lie within the duplication. Matise et al. (1994) demonstrated that the undetected presence of a duplication distorts transmission ratios, hampers fine localization of the disease gene, and increases false evidence of linkage heterogeneity. They devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. Schiavon et al. (1994) devised a rapid, informative, economical, and easily interpretable nonradioactive test for detection of the CMT1A duplication based on a microsatellite polymorphism. They found the CMT1A duplication in 76% of 56 unrelated patients. King et al. (1998) described a patient with CMT1A caused by duplication of the PMP22 gene through an unusual mechanism: unbalanced translocation of 17p to the X chromosome. This finding further supported the hypothesis of gene dosage as the basis of CMT1A. The case highlighted the importance of fluorescence in situ hybridization as an alternative molecular technique in the diagnosis of CMT1A. The duplication would not have been detected by standard commercial methods based on identification of a novel junction fragment by pulsed field gel electrophoresis. Aarskog and Vedeler (2000) described a quantitative PCR method for detecting both duplication and deletion of the PMP22 gene in CMT1A and HNPP, respectively. Their method of real-time quantitative PCR is a sensitive, specific, and reproducible method allowing 13 patients to be diagnosed in 2 hours. It involves no radioisotopes and requires no post-PCR handling. Saporta et al. (2011) were able to find a molecular basis for 527 (67%) of 787 patients with a clinical diagnosis of CMT. The most common CMT subtypes were CMT1A in 55%, CMT1X (302800) in 15.2%, HNPP (162500) in 9.1%, CMT1B (118200) in 8.5%, and CMT2A2 (609260) in 4.0%. All other subtypes accounted for less than 1% each. Eleven patients had more than 1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Saporta et al. (2011) concluded that combining features of the phenotype and physiology allowed for identification of patients with specific subtypes of CMT, and proposed a strategy of focused genetic testing for CMT.
Bird et al. (1983) and Dyck et al. (1983) reported families of typical CMT1 except that linkage to the Duffy blood group locus (Fy) on chromosome 1, where CMT1B maps, was excluded. Whereas Dyck et al. (1983) could ... Bird et al. (1983) and Dyck et al. (1983) reported families of typical CMT1 except that linkage to the Duffy blood group locus (Fy) on chromosome 1, where CMT1B maps, was excluded. Whereas Dyck et al. (1983) could discern no phenotypic differences between the linked and unlinked forms, Bird et al. (1983) suggested that slowing of nerve conduction is less marked and onion bulb formation on sural nerve biopsy less conspicuous in the Duffy-unlinked form. Berciano et al. (1994) observed that clinically normal adult CMT1A patients are rare, but do exist. They referred to 1 duplication-positive woman who had normal neurologic examinations at least up to the age of 31 even though her motor nerve conduction velocities were 30 meters per second in the median nerve. This patient had a clinically affected 4-year-old son. Berciano et al. (1994) stressed the importance of doing not only neurologic examinations but also electrophysiologic studies or DNA studies to exclude the diagnosis of CMT1A. Hoogendijk et al. (1994) reviewed the clinical and neurographic features of 44 affected individuals, aged 8 to 68 years (mean 34 years), from 6 families with chromosome 17p duplication. Motor nerve conduction velocity and, to a lesser extent, compound muscle action potential amplitude were inversely related to clinical severity. Neither clinical severity nor NCV was significantly related to age. They interpreted the findings as suggesting that the primary pathologic process is not active, or only slightly active, after childhood. Garcia et al. (1995) found remarkable concordance of nerve conduction velocities in each of 2 pairs of male homozygotic twins with a type 1A duplication. There was also congruity between the left and right side of each twin as well as between twin brothers. However, there was marked dissimilarity in the clinical severity in each of the twin pairs, as well as asymmetric clinical involvement of each affected individual. Palpable nerve enlargement was greater in the less affected twins than in their more severely affected brothers. The marked discrepancy between nerve conduction velocities and clinical weakness suggested that other factors must be responsible. Lupski et al. (1993) studied 2 unrelated patients with both CMT1 and neurofibromatosis type I (NF1; 162200). Since both of these disorders map to the pericentric region of chromosome 17, they investigated whether this might be a contiguous gene syndrome. In both patients, however, the CMT1A was inherited from the father, who did not have NF1. Furthermore, molecular analysis showed that the CMT1A duplication was stable in the 2 patients. One patient transmitted both disorders to her daughter. Thus, this was a chance concurrence of 2 common disorders. Bosch et al. (1981) had also reported the concurrence of these 2 conditions. Pyramidal dysfunction due to compression of the cervical spinal cord by hypertrophied nerve roots, resembling radicular neurofibromas, had been reported in several individuals with type 1 Charcot-Marie-Tooth disease by Rosen et al. (1989). Butefisch et al. (1999) reported an individual with compression of the cervical spine and the cauda equina, similar to the cases described by Rosen et al. (1989). By demonstrating a duplication of the PMP22 gene, they confirmed that this individual had CMT1A. Liehr et al. (1996) identified mosaicism for the CMT1A duplication by 3 different and independent techniques. Mosaicism was supported by the clinical features of the patient. The 25-year-old woman reported painful sensations in the shoulders, which increased after exercise. She had markedly reduced motor and sensory nerve conduction velocities and showed bilateral pes cavus. She showed a mild distally pronounced muscular weakness of the arms and legs. Muscle stretch reflexes were absent. Sensory disturbances of the limbs were located distal to the elbow and knees. Vibration sense was reduced at the malleolus internus. Sural nerve biopsy showed a marked reduction of myelinated fibers with signs of demyelination and onion bulb formation. Four different tissues were investigated successfully, yielding different patterns of mosaicism. Dematteis et al. (2001) diagnosed sleep apnea (107650) and CMT1A in 1 family member and prospectively investigated 13 further members not previously suspected of having neuropathy or sleep apnea. Eleven of the 14 family members had the autosomal dominant demyelinating form of CMT with PMP22 gene duplication. In addition, all 11 individuals had sleep apnea syndrome with a mean apnea-hypopnea index of 46.6 per hour (28.5) of sleep (normal value less than 15 per hour). The remaining 3 family members were free from neuropathy and sleep apnea syndrome. Sleep apnea and neuropathy severity were highly correlated; the compound muscle action potential amplitude of the median nerve was inversely correlated with the apnea-hypopnea index. The severity of neuropathy and of sleep apnea was higher in male CMT individuals and correlated with age and body mass index. No wake or sleep diaphragmatic dysfunction was shown. Dematteis et al. (2001) concluded that sleep apnea syndrome is related to a pharyngeal neuropathy. Patients with CMT disease are particularly susceptible to vincristine neurotoxicity (Weiden and Wright, 1972; Griffiths et al., 1985). Naumann et al. (2001) reported a 31-year-old woman with recurrent Hodgkin lymphoma (236000) and unrecognized HMSN I who developed severe motor neuropathy 3 weeks after the first cycle of treatment including 2 mg of vincristine. After the fact, the patient was found to have bilateral pes cavus deformity since early childhood, contractions of ankle joints, and shortened Achilles tendons. Her brother and mother had areflexia and moderate foot deformity. The diagnosis of HMSN IA was confirmed by molecular analysis. Swan et al. (2007) found no differences in disability, as measured by a CMT neuropathy score, between 44 previously pregnant women with CMT1A compared to both 47 affected men or 15 affected women who had never been pregnant. Statistical analysis revealed no difference in severity between men and woman overall. Approximately 50% of women who had been pregnant noted a worsening of symptoms during pregnancy, mainly weakness, changes in balance, and alterations in sensation. Nine of these women reported a permanent worsening, and 13 felt it was temporary, lasting about 2.5 months after giving birth. However, symptom scores between these 2 groups were not significant. Swan et al. (2007) concluded that men and women are equally disabled by CMT1A and that neither gender, pregnancy, nor plasma progesterone levels significantly contribute to the severity of neuropathy in women with CMT1A.
Suter and Patel (1994) reviewed and discussed the curious finding that gene dosage and point mutations affecting the same gene can lead to a similar phenotype. They pointed to a possibly identical situation with Pelizaeus-Merzbacher disease (312080) in ... Suter and Patel (1994) reviewed and discussed the curious finding that gene dosage and point mutations affecting the same gene can lead to a similar phenotype. They pointed to a possibly identical situation with Pelizaeus-Merzbacher disease (312080) in which either deletion of the entire locus encoding proteolipid protein (PLP1) (Raskind et al., 1991), as described in 300401.0006, or duplication of the PLP1 locus (Cremers et al., 1987) can cause Pelizaeus-Merzbacher disease. Gabreels-Festen et al. (1995) compared the histology of peripheral nerve in patients with duplication of the PMP22 gene to those with point mutations. In the duplication cases, onion bulbs developed gradually in the first years of life, and the ratio of the axon diameter versus the fiber diameter was significantly lower than normal. In contrast, in patients with point mutations in PMP22, nearly all myelinated fibers had a high ratio of axon diameter versus fiber diameter, and onion bulbs were abundant from an early age. Pellegrino et al. (1996) illustrated how it is possible in some instances to determine the genetic basis of clinical features in chromosomal rearrangements. They reported a child with monosomy 10q and dup(17p) resulting from an apparently balanced maternal translocation t(10;17)(q26.3;p11.2). Manifestations of both the duplication and the monosomy were present; however, the overall development was better than that previously reported in either syndrome. The patient's motor development was significantly more impaired than cognitive development, and signs of a peripheral neuropathy were found and attributed to duplication of 17p. Indeed, the patient was found to be trisomic for the PMP22 gene resulting in demyelinating neuropathy. An elevated serum alpha-fetoprotein had been detected at 16 weeks of gestation. The infant showed bilateral inguinal hernias and hydroceles at birth, and echocardiogram demonstrated ventriculoseptal defect (VSD) and bicuspid aortic valve. There was gastroesophageal reflux requiring Nissen fundoplication with gastrostomy tube. The VSD closed spontaneously. Hypoplastic corpus callosum was demonstrated by MRI. Terminal deletions of 10q had been reported in 26 patients, resulting in a definite phenotype (Wulfsberg et al., 1989). The manifestations included postnatal growth retardation, microcephaly, downslanting palpebral fissures, clinodactyly, syndactyly, congenital heart disease, and urogenital anomalies, all of which were present in the patient reported by Pellegrino et al. (1996). Gouvea et al. (2010) reported an unusual case of a father and daughter with CMT who had 2 mutations in the PMP22 gene: the common 1.4-Mb duplication and S72L (601097.0007). Restriction analysis indicated that the S72L mutation was only present in 1 of the 3 PMP22 genes for both father and daughter. Both patients had a relatively mild form of the disease, manifest mainly as generalized pain without significant motor or sensory defects. The findings suggested that presence of 2 mutations in the PMP22 gene results in an attenuated form of the disease rather than a more severe form. Gouvea et al. (2010) hypothesized that the increased dosage resulting from the 1.4-Mb duplication offset the toxic gain-of-function effects of the S72L mutation on intracellular trafficking.
- Common 1.5-Mb Duplication on Chromosome 17p12-p11
See 601097.0001 for discussion of the work of Lupski et al. (1991) and others indicating that a DNA duplication on chromosome 17 in the p12-p11.2 region is frequently the ... - Common 1.5-Mb Duplication on Chromosome 17p12-p11 See 601097.0001 for discussion of the work of Lupski et al. (1991) and others indicating that a DNA duplication on chromosome 17 in the p12-p11.2 region is frequently the basis of CMT1A. Hoogendijk et al. (1992) found that 9 of 10 sporadic patients had the duplication in chromosome 17 as a de novo change. Hertz et al. (1994) also demonstrated that a sporadic case of CMT1A was due to de novo duplication of the 17p12-p11.2 region. In all 12 de novo CMT1A duplications reported to that time, the duplication was of paternal origin. Sorour et al. (1995) described a case of CMT1A with molecular duplication of 17p12-p11.2 and inheritance of the duplication from a mosaic father. Whereas the patient had typical clinical features, the father had minimal findings of CMT1A. To investigate the frequency of de novo CMT1A duplications, Blair et al. (1996) examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. They estimated that 10% or more of autosomal dominant CMT1 families are due to de novo duplications. Using polymorphic markers from within the duplicated region, they showed that 7 of the duplications were of paternal and 1 of maternal origin. This was the first report of a de novo duplication of maternal origin. Bort et al. (1997) reported that the prevalence of de novo mutation in duplication-positive CMTA1 families was 18.3%. They reported that the ratio of maternal to paternal origin of the duplication was 1:8 in their study. Weterman et al. (2010) identified a heterozygous 186-kb deletion on chromosome 17p12 with breakpoints within the common 1.5-Mb duplication but not involving the PMP22 gene in 6 probands with CMT1A. The duplication segregated with the disorder in 2 families and was absent in more than 2,000 control chromosomes. Haplotype analysis of 2 families suggested a founder effect. The junction breakpoints were located in a repeat-rich region, located 90-kb from the proximal CMT repeat region on 1 side and 3-kb upstream of PMP22 between PMP22 and TEKT3 (612683) on the other side. The junctions created by this duplication were located outside of any known genes or open reading frames, and there was no indication for the involvement of genes located within the duplication. Weterman et al. (2010) postulated that this duplication affects PMP22 expression levels through an as yet unidentified mechanism. Weterman et al. (2010) noted that the 186-kb duplication would not be detected in most diagnostic assays. - Point Mutations in the PMP22 Gene In a Dutch kindred with CMT1A, Valentijn et al. (1992) identified a point mutation in the PMP22 gene (601097.0002). Thus, either duplication or point mutation in the PMP22 gene can result in CMT1A. Fabrizi et al. (1999) reported a family in which 4 individuals over 4 generations had severe CMT1A with focal myelin thickenings with a regular fusiform contour (tomacula) or a coarsely granular appearance. Ultrastructural examination disclosed uncompacted myelin and redundant irregular myelin loops. All affected patients had a heterozygous mutation in the PMP22 gene (601097.0016). Fabrizi et al. (2000) noted that myelin outfoldings have been described in other autosomal dominant CMT patients with mutations in MPZ (159440.0023), EGR2 (129010.0004), and PMP22, and that the finding is not restricted to CMT4B (see CMT4B1; 601382). Kleopa et al. (2004) reported a family from Cyprus in which 4 affected individuals had features of HNPP and/or CMT1A. One patient presented with typical HNPP, which later progressed to severe CMT1, 2 patients had HNPP with features of CMT1, and 1 patient had a chronic asymptomatic CMT1 phenotype. All 4 patients had the same heterozygous point mutation in the PMP22 gene (601457.0019). Kleopa et al. (2004) emphasized the broad phenotypic spectrum resulting from mutations in the PMP22 gene, as well as the phenotypic overlap of HNPP and CMT1A.
Lupski et al. (1992) stated that CMT in all of its forms is the most common inherited peripheral neuropathy in humans, with a total prevalence rate of 1 in 2,500. In a series of 172 index cases of ... Lupski et al. (1992) stated that CMT in all of its forms is the most common inherited peripheral neuropathy in humans, with a total prevalence rate of 1 in 2,500. In a series of 172 index cases of Italian families in which there was at least 1 subject with CMT1, Mostacciuolo et al. (2001) found that among 170 informative unrelated patients, the frequency of the chromosome 17 duplication was 57.6%. A difference was observed between the duplication frequency in familial (71.6%) as opposed to nonfamilial cases (36.8%). Among the patients without the duplication, 2 had mutations in the PMP22 gene, 12 in the GJB1 gene (304040), 4 in the MPZ gene (159440), and none in the EGR2 gene (129010). Among 153 unrelated patients with CMT, Boerkoel et al. (2002) found that 79 had a PMP22 duplication. The 1.5-Mb duplication of PMP22 is the predominant cause of autosomal dominant CMT1, accounting for approximately 70% of all cases (Reilly, 2005). Among 227 Japanese patients with demyelinating CMT, Abe et al. (2011) found that 53 (23.3%) carried PMP22 duplications and 10 (4.4%) carried PMP22 mutations. These were the most common genetic causes of demyelinating CMT, but the frequency of duplications was less than that observed in Caucasian populations. A molecular basis for demyelinating CMT could not be identified in 111 Japanese patients.