A Family Harboring CMT1A Duplication and HNPP Deletion

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with duplication of chromosome 17p11.2-p12, whereas hereditary neuropathy with liability to pressure palsies (HNPP), which is an autosomal dominant neuropathy showing characteristics of recurrent pressure palsies, is associated with 17p11.2-p12 deletion. An altered gene dosage of PMP22 is believed to the main cause underlying the CMT1A and HNPP phenotypes. Although CMT1A and HNPP are associated with the same locus, there has been no report of these two mutations within a single family. We report a rare family harboring CMT1A duplication and HNPP deletion.     

Variable phenotypes are associated with PMP22 missense mutations

Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance.     

Screening for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsy in archival nerve biopsy samples by direct-double-differential PCR

Chromosomal imbalance of the peripheral myelin protein-22 gene (PMP22) is known to be the most frequent genetic abnormality in Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP). We applied a new quantitative PCR method, the direct-double-differential PCR (dddPCR), to the gene dosage determination of PMP22. The method allows the quantification of the PMP22 gene copy number independently from DNA fragmentation, even in highly degraded DNA from up to 12-year-old sural nerve biopsy samples. Chromosomal imbalance of the PMP22 gene, which had been detected by examination of four microsatellites located directly adjacent to the PMP22 gene, between the CMT1A-repetition (CMT1A-REP) elements was reliably confirmed by the dddPCR. Using this method we unexpectedly identified two cases with PMP22 imbalance, although morphologically the neuropathies were of a neuronal or axonal type and not of a demyelinating type as usual. One sural nerve biopsy was from a 58-year-old male diabetes mellitus patient with a disproportionately severe polyneuropathy showing a heterozygous duplication of PMP22. The second biopsy exhibiting a heterozygous deletion of PMP22 was from a 58-year-old female patient with a more axonal than demyelinating type of neuropathy without typical tomaculous changes seemingly altered by exogenous, possibly traumatic factors other than diabetes mellitus. Thus, the dddPCR provides a fast and reliable diagnostic tool for the screening and identification of CMT1A and HNPP cases, which is fast and may be essential even when nerve biopsies show morphologically atypical changes. Received: 10 April 2000 / Accepted: 7 June 2000     

Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22.

BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.     

Evidence for macrophage-mediated myelin disruption in an animal model for Charcot-Marie-Tooth neuropathy type 1A

Charcot-Marie-Tooth neuropathy type 1A (CMT 1 A) is the most common inherited neuropathy in humans and is mostly caused by a 1.5-Mb tandem duplication of chromosome 17 comprising the gene for the peripheral myelin protein 22-kDa (PMP 22). Although there are numerous studies on the functional role of PMP 22, the mechanisms of myelin degeneration under PMP 22-overexpression conditions have not yet been fully understood. We have shown previously that in mouse mutants hetero- or homozygously deficient for two other myelin components, P0 and C x 32, respectively, immune cells contribute to the demyelinating neuropathy. To test this possibility for PMP 22 overexpression, we investigated a putative mouse model for CMT 1 A, i.e., the mouse strain C 6 1 mildly overexpressing human PMP 22 in peripheral nerves. Electron microscopic and electrophysiologic investigations revealed that this mouse strain develops pathologic features similar to those found in CMT 1 A patients. A novel finding, however, was the upregulation of CD8- and F4/80-positive lymphocytes and macrophages, respectively, in peripheral nerves. The observation that macrophages enter endoneurial tubes of the mutants and obviously phagocytose morphologically normal myelin strongly suggests that the myelin degeneration is mediated at least partially by these phagocytic cells. By gene array technology and quantitative RT-PCR of peripheral nerve homogenates from PMP 22 mutants, monocyte chemoattractant protein-1 (MCP-1; cc l2) could be identified as a putative factor to attract or activate macrophages that attack myelin sheaths in this model of CMT 1 A.     

Myelin protein zero gene mutations in Taiwanese patients with Charcot-Marie-Tooth disease type 1

BACKGROUND: Charcot-Marie-Tooth disease type 1 (CMT1) is the most common inherited peripheral neuropathy and represents a genetically heterogeneous condition. In addition to the peripheral myelin protein 22 gene (PMP22) duplication (CMT1A), myelin protein zero gene (MPZ) mutations may account for a certain portion of CMT1 patients (CMT1B). OBJECTIVES: The authors analyzed the MPZ mutations in Taiwanese patients who do not have PMP22 duplication. Specifically, their clinical and molecular features were characterized. MATERIALS AND METHODS: Twenty-four of 57 unrelated Taiwanese patients with CMT1 were selected after excluding the CMT1A duplication. Subsequent analysis of the coding regions of the MPZ gene was performed with single-strand-conformation polymorphism (SSCP), which was then followed by nucleotide sequencing. RESULTS: Four missense mutations and one 4-base pair (bp) deletion, respectively, were identified in five patients, of which one mutation, c.173 T>A, has never been previously reported. Three missense mutations were located in exon 2, the other one in exon 3, and the deletion in exon 6. CONCLUSIONS: This study expands the number of CMT1 associated MPZ mutation and suggests that analysis of the coding sequence of MPZ should be performed in all CMT patients without CMT1A duplication to clarify their disease nature.     

A large family with Charcot-Marie-Tooth Type 1a and Type 2 diabetes mellitus

Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating peripheral neuropathy, and CMT Type 1A is the most common form. In most cases, CMT1A is usually caused by duplication at chromosome 17p11.2-12. Type 2 diabetes mellitus (Type 2 DM) is a common metabolic disorder, characterized by chronic hyperglycemia that can be associated with micro- and/or macrovascular complications. Only a few studies reported CMT1A duplication in association with Type 2 DM. This article explores the characteristics of a large family of 69 members with respect to CMT1A and Type 2 DM. CMT1A was detected in 28 of them. Molecular genetic study was performed in 22, and duplication was detected in all of them. Six of the 22 members with CMT1A also had Type 2 DM based on the American Diabetes Association diagnostic criteria. Association of these two conditions may be coincidental; however, the occurrence of these two diseases in this large family may also suggest a genetic basis. More extensive reports and further investigations of such families having this combination will certainly provide a better understanding of this link.     

A LARGE FAMILY WITH CHARCOT-MARIE-TOOTH TYPE 1A AND TYPE 2 DIABETES MELLITUS

Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating peripheral neuropathy, and CMT Type 1A is the most common form. In most cases, CMT1A is usually caused by duplication at chromosome 17p11.2–12. Type 2 diabetes mellitus (Type 2 DM) is a common metabolic disorder, characterized by chronic hyperglycemia that can be associated with micro- and/or macrovascular complications. Only a few studies reported CMT1A duplication in association with Type 2 DM. This article explores the characteristics of a large family of 69 members with respect to CMT1A and Type 2 DM. CMT1A was detected in 28 of them. Molecular genetic study was performed in 22, and duplication was detected in all of them. Six of the 22 members with CMT1A also had Type 2 DM based on the American Diabetes Association diagnostic criteria. Association of these two conditions may be coincidental; however, the occurence of these two diseases in this large family may also suggest a genetic basis. More extensive reports and further investigations of such families having this combination will certainly provide a better understanding of this link.     

Schwann cell differentiation in Charcot-Marie-Tooth disease type 1A (CMT1A): normal number of myelinating Schwann cells in young CMT1A patients and neural cell adhesion molecule expression in onion bulbs

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common hereditary demyelinating neuropathy caused by a duplication of the gene for the myelin protein PMP22, resulting in overexpression of PMP22 in young patients. Although genetically well defined, the pathogenesis of the hereditary demyelinating neuropathy CMT1A is still unclear. Homology of PMP22 cDNA to the growth arrest-specific gene gas3 and experiments in vitro showing decreased proliferation in PMP22-overexpressing Schwann cells suggest a role of PMP22 in Schwann cell differentiation. Furthermore, overexpression of PMP22 in fibroblasts induces programmed cell death. In this report we applied morphometrical methods using electron micrographs and immunohistochemistry to further characterise Schwann cells in CMT1A nerve biopsy samples from CMT1A patients. We show that the total number of PMP22-expressing Schwann cells, i.e. Schwann cells that are in a 1:1 relationship with axons, was not reduced in sural nerve biopsy samples from six young CMT1A patients. We excluded non-specific secondary Schwann cell proliferation. Thus, in young CMT1A patients with increased PMP22 overexpression there seems to be no evidence for altered initial Schwann cell proliferation in achieving a 1:1 relationship to axons prior to the process of de- and remyelination. Further, using electron microscopy we found no evidence for apoptosis of Schwann cells in CMT1A . However, we provide additional support for an abnormal Schwann cell phenotype in CMT1A by showing the expression of neural cell adhesion molecule immunoreactivity in onion bulbs. Thus, the role of PMP22 in cell growth and differentiation does not lead to an altered number of myelinating Schwann cells but to altered Schwann cell differentiation in CMT1A. Received: 23 September 1996 / Revised: 28 November 1996, 31 January 1997, 2 April 1997 / Accepted: 3 April 1997     

Duplication analysis in Turkish Charcot-Marie-Tooth type 1A patients using short tandem repeat markers

Charcot-Marie-Tooth (CMT) is a common inherited peripheral neuropathy with a prevalence of 1 in 2,500. CMT has two distinct forms (CMT1 and CMT2) that can be identified electrophysiologically. A 1.5 Mb tandem microduplication including peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2-12 causes CMT1A. The increased gene dosage effect of PMP22 is thought to be responsible for the pathogenesis of CMT1A. In this study, 39 Turkish CMT1A patients and 60 unrelated control samples had been examined for the duplication using polymorphic short tandem repeat (STR) markers. Seven STR marker sites (AC005838-4A-, AC0013248-9A-, AC0013248-9B-, D17S2218, D17S2220, D17S2227, and D17S2229) on the duplicated region were amplified via polymerase chain reaction, electrophoresed through 8% polyacrilamide gel and evaluated for the duplication. The rate of duplication was 92.3' (36/39) in the patients whereas it was zero in the control samples. Allele distributions, number of alleles and heterozygosity values of more informative markers (D17S2218, D17S2220, D17S2227, and D17S2229) were assessed. It is found that approximately 85% of duplications in Turkish CMT1A patients were depicted by using D17S2220 and D17S2229 markers together.     

Peripheral myelin protein-22 expression in charcot-marie-tooth disease type 1a sural nerve biopsies

Peripheral myelin protein-22 (PMP22) is expressed in myelinating Schwann cells and shows significant homology to murine growth arest-specific gene gas3. Charcot-Marie-Tooth disease type 1a (CMT1a) is a common hereditary demyelinating neuropathy. Recently it was demonstrated that the gene for PMP22 is duplicated in CMT1a patients. A gene dosage mechanism has been postulated to cause CMT1a. According to this hypothesis, the increase in copy number of PMP22 gene would lead to an elevated expression of PMP22 and thereby cause the demyelinating phenotype of CMT1a. In the present communication we analyzed PMP22 mRNA and protein expression in sural nerve biopsies from CMT1a patients and normal controls. We show that PMP22 mRNA expression in CMT1a is not uniform. We found both elevated as well as normal PMP22 mRNA levels in patients. Interestingly, the highest PMP22 mRNA level was found in the least affected patient. In contrast to the mRNA levels, PMP22 was clearly reduced in all CMT1a patients as shown by immunohistochemistry. Thus the CMT1a phenotype may not be strictly correlated with increased PMP22 mRNA and protein expression. Possible roles of PMP22 in the pathogenesis of CMT1a are discussed. © 1994 Wiley-Liss, Inc.     

Improved culture methods to expand schwann cells with altered growth behaviour from CMT1A patients

A duplication of the gene for myelin protein PMP22 is by far the most common cause of the hereditary demyelinating neuropathy CMT1A. A role for PMP22 in cell growth in addition to its function as a myelin protein has been suggested because PMP22 is homologous to a gene specifically upregulated during growth arrest. Furthermore, transfected rat Schwann cells overexpressing PMP22 show reduced growth. In addition, abnormal Schwann cell differentiation has been described in nerve biopsies from CMT1A patients. To analyse whether the duplication of the PMP22 gene in CMT1A neuropathy primarily alters Schwann cell differentiation and to exclude nonspecific secondary responses, we improved human Schwann cell culturing. This allowed us long-term passaging of human Schwann cells with unchanged phenotype, assessed by expression of different Schwann cell markers. Subsequently we established Schwann cell cultures from CMT1A nerve biopsies. We find decreased proliferation of Schwann cells from different CMT1A patients in all passages. We also demonstrate PMP22 mRNA overexpression in cultured CMT1A Schwann cells. We conclude that decreased proliferation in cultured Schwann cells that carry the CMT1A duplication indicates abnormal differentiation of CMT1A Schwann cells. The identification of an abnormal phenotype of CMT1A Schwann cells in culture could possibly lead to an in vitro disease model. GLIA 23:89–98, 1998. © 1998 Wiley-Liss, Inc.     

腓骨肌萎缩症1A型的临床、神经电生理和疾病基因突变分析

目的　观察腓骨肌萎缩症 (CMT) 1A型的临床、神经电生理特点和疾病基因的突变分析。方法对一CMT家系中 9个成员进行详尽的临床检查、疾病基因突变分析 ,对先证者进行神经电生理检查和神经肌肉活检。结果　本家系中 5人发病 ,符合常染色体显性遗传模式 ,除 1例患者无临床症状外 ,其余 4例均在2 0岁前起病。临床特点为进行性四肢远端肌无力、肌萎缩 ,末梢型感觉障碍 ,腱反射减弱或消失 ,足部畸形(高弓足 )。神经电生理检查示运动和感觉神经传导速度减慢。基因突变分析发现 17号染色体短臂 11 2区(17p11 2 )包含周围髓鞘蛋白 (PMP) 2 2基因的正向串联重复突变。结论　CMT1A型是CMT最常见类型 ,多于儿童期或青少年期起病 ,表现为进行性四肢远端肌无力、肌萎缩 ,腱反射减弱或消失。神经电生理特点为运动神经传导速度均一性减低 (<38m/s)。 17p 11 2区包含PMP 2 2基因在内的 1 5Mb(偶尔 <1 5Mb)的正向串联重复突变是CMT 1A最主要的突变型。     

Inherited peripheral neuropathy

Hereditary disorders of the peripheral nerves constitute a group of frequently encountered neurological diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is genetically heterogeneous and characterized by demyelination with moderately to severely reduced nerve conduction velocities, absent muscle stretch reflexes and onion bulb formation. Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1 B result from point mutations in the myelin protein zero (Po or MPZ) gene. The molecular defect in CMT1 C is unknown. Mutations in the early growth response 2 gene (EGR2) are also associated with demyelinating neuropathy. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q, and 11q. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is characterized by normal or mildly reduced nerve conduction velocity with decreased amplitude and axonal loss without hypertrophic features. One form of CMT2 maps to chromosome 1 p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the Po gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.     

周围髓鞘蛋白22基因重复突变致夏科-马里-图斯病1A亚型的临床变异性

目的 探讨夏科-马里-图斯病(CMT)患者周围髓鞘蛋白22(PMP22)基因重复突变特征及临床变异性.方法 联合应用改良的等位基因特异性PCR-双酶切和基于荧光标记毛细管电泳短串联重复序列(STR)分析对45例临床拟诊CMT患者进行PMP22基因重复突变的检测,详细分析其中阳性病例的临床特征.结果 在45例拟诊CMT患者中共检测出PMP22基因重复病例21例,包括10例临床特征符合四肢远端萎缩无力的典型CMT1型患者和11例不典型的CMT患者,后者具有特殊表型:1例仅以轻度头晕就诊;1例合并听力障碍;2例以反复发作性肢体无力起病;2例伴有上肢姿势性震颤;4例伴有小脑性共济失调;1例伴有癫(癎)发作.结论 PMP22基因重复突变为CMT病最常见的病因,改良的等位基因特异性PCR-双酶切提供了一种准确、可靠并易于操作的检测方法,有助于该病的诊断和鉴别.同时,通过综合分析PMP22重复突变阳性的CMT1A患者临床表现、电生理及病理特征,提示该组疾病具有高度的临床变异性.     

Effects of PMP22 duplication and deletions on the axonal cytoskeleton

Axonal loss in Charcot-Marie-Tooth type 1A (CMT1A) is an important feature correlated with the functional disability in affected individuals. It is not known, however, how the most common genetic defect in Schwann cells (PMP22 duplication) causes the CMT1A phenotype and results in axonal loss. In this study, sural nerve segments from individuals with PMP22 duplications or deletions, causing the reciprocal disorder hereditary neuropathy with pressure palsies (HNPP), were grafted into the cut ends of the sciatic nerve of nude mice. The xenografts and host segments were studied at 2, 4, 6, 8, 12, and 16 weeks after grafting and compared with the controls from healthy volunteers. Within the CMT1A xenografts, the nude mice axons in the proximal part of the graft showed a significant increase in axonal area with an increase in the neurofilament and membranous organelle (mitochondria) density, compared with distal graft and distal host segments. A preferential distal axonal loss, associated with a perpetual axonal atrophy, degeneration, and axonal sprouting was observed over time, with increasing intensity at 8 to 16 weeks. These alterations were seen to a lesser extent in HNPP xenografts and were not observed in controls. In addition, the onset of regeneration-associated myelination was delayed, more significantly in HNPP xenografts than those of CMT1A. Our findings indicate that the PMP22 duplication in Schwann cells results in an impairment in the normal axonal cytoskeletal organization, resulting in distal axonal degeneration and fiber loss, and the affect of PMP22 deletion on axonal cytoskeleton is less deleterious. Ann Neurol 1999;45:16–24     

Alterations in degradative pathways and protein aggregation in a neuropathy model based on PMP22 overexpression

Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly associated with duplication of the peripheral myelin protein 22 (PMP22) gene. Mice expressing seven copies of the human PMP22, termed C22, suffer from a demyelinating neuropathy and display phenotypic traits of CMT1A. In this article, we investigate whether protein aggregates play a role in the CMT1A-like pathology of C22 mice. Utilizing biochemical and immunochemical tools, we found slowed turnover rate of the newly-synthesized PMP22 and the presence of cytoplasmic protein aggregates in affected nerves. The formation of these aggregates correlates with reduced proteasome activity and the accumulation of detergent-insoluble ubiquitinated substrates. A fraction of the aggregates associates with autophagosomes and lysosomes. Together, these data indicate that as a result of missorting and inefficient proteasomal degradation, the aggregation of PMP22 and recruitment of autophagosomes and lysosomes are key factors in the subcellular pathogenesis of CMT1A neuropathies.     

Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients

We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 (PMP22) to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ’onion-like’ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ’mouse-nibbled’-like changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced.     

DUPLICATION ANALYSIS IN TURKISH CHARCOT-MARIE-TOOTH TYPE 1A PATIENTS USING SHORT TANDEM REPEAT MARKERS

Charcot-Marie-Tooth (CMT) is a common inherited peripheral neuropathy with a prevalence of 1 in 2,500. CMT has two distinct forms (CMT1 and CMT2) that can be identified electrophysiologically. A 1.5 Mb tandem microduplication including peripheral myelin protein 22 gene (PMP22) on chromosome 17p11.2-12 causes CMT1A. The increased gene dosage effect of PMP22 is thought to be responsible for the pathogenesis of CMT1A. In this study, 39 Turkish CMT1A patients and 60 unrelated control samples had been examined for the duplication using polymorphic short tandem repeat (STR) markers. Seven STR marker sites (AC005838-4A-, AC0013248-9A-, AC0013248-9B-, D17S2218, D17S2220, D17S2227, and D17S2229) on the duplicated region were amplified via polymerase chain reaction, electrophoresed through 8% polyacrilamide gel and evaluated for the duplication. The rate of duplication was 92.3′ (36/39) in the patients whereas it was zero in the control samples. Allele distributions, number of alleles and heterozygosity values of more informative markers (D17S2218, D17S2220, D17S2227, and D17S2229) were assessed. It is found that approximately 85% of duplications in Turkish CMT1A patients were depicted by using D17S2220 and D17S2229 markers together.     

Peripheral Myelin Protein 22 gene duplication with atypical presentations: A new example of the wide spectrum of Charcot-Marie-Tooth 1A disease

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype–phenotype correlations in Charcot-Marie-Tooth diseases.