Charcot Marie Tooth Disease Essay
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Charcot-Marie-Tooth Disorder
Charcot-Marie-Tooth Disorder (CMT) is the most common type of hereditary motor and sensory neuropathy (HMSN), occurring in one of every 2500 births. The mean age of onset of clinical symptoms is 12.2 7.3 years. Severity of the disorder varies among the individual and among the subtypes of CMT. Subtypes are distinguishable by testing the nerve conduction velocity (NCV), muscle biopsies, and protein levels in cerebrospinal fluid. Three different subtypes have been identified, fittingly called CMT I, CMT II, and CMT III (or Dejerine-Sottas disease). (Epstein 1993)
CMT I shows a fully penetrant phenotype. The onset of clinical symptoms is usually seen by the age of two. Common features of this disorder include pes cavus, a deformity of the foot characterized by an abnormally high arch and hyperextension of the toes, which gives the foot a claw-like appearance, and hammer toes. As CMT progresses, weakness and atrophy of leg muscles occur. Areflexia occurs in the Achilles and patellar areas (absence of reflex), and later muscle degradation affects the intrinsic muscles in the hands. CMT II has a similar clinical phenotype to CMT I, but with a wider range of the age of onset and later appearance of symptoms. There is also less involvement of hand muscles. Dejerine-Sottas Syndrome (DSS or CMT III) is the rarest form of CMT. This syndrome shares clinical, electrophysiological, and pathological findings of CMT I. However, the onset of DSS is generally during infancy and the symptoms are typically more severe.
The causes of CMT have been linked to autosomal dominant, autosomal recessive, x-linked, and environmental means. The largest number studies have been done on CMT-IA (an autosomal dominant form), the most common form of CMT. It is often associated with a 1.5 megabase tandem duplication of the short arm of chromosome 17 (17p12) found in approximately seventy percent of unrelated CMT I patients. It is thought that this duplication is a result of unequal crossing-over between two chromosome 17 s during meiosis. (King 1998) Studies of CMT-IA have indicated that it is a demyelinating neuropathy. The tandem duplication of chromosome 17 includes the PMP22 gene. This gene is responsible for encoding a protein expressed in the compact myelin of a peripheral nerve. The exact physical size of the duplication is unknown, but the DNA markers found within the duplication spans a distance of fourteen centimorgans on the female meiotic map and four centimorgans on the male meiotic map. (Lupski et al. 1992)
It has been suggested that increased gene dosage of PMP22 is the mechanism by which DNA duplication gives rise to the CMT-IA phenotype. A study was done to test the following hypothesis: if the region duplicated in CMT-IA patients was contained entirely within the large duplication in the partial 17p trisomy patients, and the patients met electrophysiological diagnoses of CMT-IA, the gene dosage model would be supported. Cytogenetic and molecular analyses indicate that a gene dosage effect is indeed responsible for the electrophysiological phenotype associated with CMT-IA. The model of interruption of a candidate CMT-IA gene at the duplication junction can be refuted because the DNA markers are both proximal and distal to the duplication. Linkage analysis of CMT families is not consistent with two chromosome 17p loci so this rules out the possibility of two genes causing the phenotypes. (Lupski et al. 1992) This study indicates that a gene dosage effect may be responsible for other Mendelian disease phenotypes. This may allow scientists to develop therapeutic interventions targeting the gene products.
PMP22 is not the only gene that has been linked to CMT. Mutations in the mpz (myelin protein zero) gene have been linked to over forty mutations that have resulted in either CMT-IB or DSS. The gene Cx32 explains the mixed CMTI/CMTII and CMTX variations of CMT. Cx32 mutations are the second most prevalent mutation found in CMT-I. Over 150 mutations have been described, including deletions, missense, nonsense, and frameshift mutations. Unlike PMP22 and mpz, the range of clinical severity is much less in males. (Warner et al. 1999) This makes genotype and phenotype correlation very difficult. With a variety of genes thought to be responsible for CMT, clinicians must rely on complex molecular methods to determine which gene is playing a role.
The DNA duplication associated with CMT-IA requires FISH (fluorescence in situ hybridization) analysis of interphase nuclei. Molecular analysis using DNA markers is also used to map within the duplicated region. (Roa et al. 1996) Cytogenetic analysis of metaphase chromosomes is not enough to detect this mutation, primarily because the p arm of chromosome 17 is very short. It is for this reason that most cases of CMT are not detected until after the child is born.
A case study of four patients with de novo partial duplications of 17p was investigated for neuropathological signs of CMT-IA. Two showed telltale signs of the disorder (a decreased nerve conduction velocity), while the other two had normal NCVs. Cytogenetic and FISH analysis was performed, along with molecular studies to determine whether a duplication of the PMP22 gene was present. One patient (#621) had a reduced NCV and showed an inverted duplication of 17p13.3 p11.2. In addition to patient 621, three others were studied. These individuals also had the 17p partial trisomy, a direct duplication of bands 17p11.2 p12. However, only one of these three showed a decreased NCV.
Southern analyses were performed using DNA markers to identify and map the duplicated region. These studies found the PMP22 gene duplicated in those patients with a decreased nerve conduction velocity. However, patients that had the 17p trisomy with a normal NCV did not show duplication for the gene. Using RFLP analysis, it was determined that this gene was maternal in origin. (Roa et al. 1996)
FISH analysis showed patients with the duplicated PMP 22 gene displaying four red signals. In contrast, patients that did not have the duplicated gene only showed two red signals. Another probe was used to provide confirmation of 17p patients that did not show the duplication of the PMP22 gene. The results showed that the FLI gene, a gene linked to Smith-Magenis syndrome, was duplicated in these patients. The results of this study confirm that the duplication of the PMP22 gene is associated with CMT-IA in cases of cytogenetic duplication of 17p. Combined cytogenetic and molecular analysis indicates the PMP22 gene maps to band 17p12.
Chromosome 17 is not the only chromosome locus that has been shown to play a role in CMT. Loci can differ based on the symptoms, subtypes, and mode of inheritance. Autosomal dominant inheritance is seen in CMT I, CMT II, and CMT X. CMT X is an X-linked form of CMT occurring more often in males than females, but is considered to show a dominant inheritance pattern. CMT I can also show an autosomal recessive pattern. Below is a chart indicating inheritance pattern and chromosome location of each of the subtypes of CMT. (Warner et al. 1999)
Inheritance Pattern Chromosome locus
CMTI Autosomal dominant
Type IA 17p11.2-p12
Type IB 1q21.1-q23q
Type IC does not mark to either
CMT I Autosomal Recessive 5q23-q33, 8q24,...
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