Charcot‐Marie‐Tooth disease: frequency of genetic subtypes in a Southern Italy population

The objective of this study is to assess the genetic distribution of Charcot‐Marie‐Tooth (CMT) disease in Campania, a region of Southern Italy. We analyzed a cohort of 197 index cases and reported the type and frequency of mutations for the whole CMT population and for each electrophysiological group (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]) and for familial and isolated CMT cases. Genetic diagnosis was achieved in 148 patients (75.1%) with a higher success rate in HNPP and CMT1 than CMT2. Only four genes (PMP22, GJB1, MPZ, and GDAP1) accounted for 92% of all genetically confirmed CMT cases. In CMT1, PMP22 duplication was the most common mutation while the second gene in order of frequency was MPZ in familial and SH3TC2 in isolated cases. In CMT2, GJB1 was the most frequent mutated gene and GJB1 with GDAP1 accounted for almost 3/4 of genetically defined CMT2 patients. The first gene in order of frequency was GJB1 in familial and GDAP1 in isolated cases. In HNPP, the majority of patients harbored the PMP22 gene deletion. The novelty of our data is the relatively high frequency of SH3TC2 and GDAP1 mutations in demyelinating and axonal forms, respectively. These epidemiological data can help in panel design for our patients' population.     

Two novel MPZ mutations in Chinese CMT patients

To investigate the myelin protein zero (MPZ) gene mutation and related clinical features in Chinese Charcot‐Marie‐Tooth (CMT) patients, we screened the coding sequence of MPZ in 70 unrelated CMT index patients after excluding the PMP22 duplication, Cx32 and MFN2 mutations. We found four different missense mutations: c.194C>T, c.242A>T, c.371C>T, and c.419C>G. The frequency of MPZ mutation was approximately 4.35% of the total, 3.08% of CMT1, and 6% of CMT2. Mutations c.242A>T and c.419C>G are novel. The mutation c.242A>T exhibited late onset and rapidly progressive CMT2 phenotype. The mutation c.419C>G exhibited relatively late onset and slowly progressive CMT1 phenotype.     

PMP22‐Related neuropathies and other clinical manifestations in Chinese han patients with charcot‐marie‐tooth disease type 1

Introduction: Most cases of Charcot‐Marie‐Tooth (CMT) disease are caused by mutations in the peripheral myelin protein 22 gene (PMP22), including heterozygous duplications (CMT1A), deletions (HNPP), and point mutations (CMT1E). Methods: Single‐nucleotide polymorphism (SNP) arrays were used to study PMP22 mutations based on the results of multiplex ligation‐dependent probe amplification (MLPA) and polymerase chain reaction–restriction fragment length polymorphism methods in 77 Chinese Han families with CMT1. PMP22 sequencing was performed in MLPA‐negative probands. Clinical characteristics were collected for all CMT1A/HNPP probands and their family members. Results: Twenty‐one of 77 CMT1 probands (27.3%) carried duplication/deletion (dup/del) copynumber variants. No point mutations were detected. SNP array and MLPA seem to have similar sensitivity. Fifty‐seven patients from 19 CMT1A families had the classical CMT phenotype, except for 1 with concomitant CIDP. Two HNPP probands presented with acute ulnar nerve palsy or recurrent sural nerve palsy, respectively. Conclusions: The SNP array has wide coverage, high sensitivity, and high resolution and can be used as a screening tool to detect PMP22 dup/del as shown in this Chinese Han population. Muscle Nerve 52 : 69–75, 2015     

PMP22 Mutations In DÉJÈRine-Sottas Disease: A Mutational "Hot Spot" On Codon 72

Increased dosage of the gene encoding the peripheral myelin protein PMP22 is the most common molecular mechanism underlying the demyelinating form of Charcot-Marie-Tooth disease (CMT1A). It results from the duplication of a 1.5-Mb tract on chr. 17p11.2 which encompasses the PMP22 gene. Mutations in this gene can also cause CMT1A and are often associated with more severe phenotypes such as Déjèrine-Sottas disease (DSD) and congenital hypomyelinating neuropathy (CHN). We have analyzed the PMP22 gene in 20 unrelated patients affected with a severe form of demyelinating motor and sensory neuropathy (severe CMT1 or DSD). All the patients had been found negative for the common CMT1A duplication and for mutations in the myelin protein P₀ gene (MPZ). Direct sequence analysis of PMP22 uncovered the presence of missense mutations in 3 patients diagnosed as having DSD. In each case, the mutation was heterozygous and was not carried by any of the nonaffected parents, thus indicating that it was a de novo dominant mutation. Patient #1, a 3-y-old boy, carried a C-to-T transition in PMP22 exon 4 which would result in the amino acid substitution of Leu-80 with Pro in the 2nd transmembrane domain of the protein. This mutation had been previously observed in another DSD patient (Tyson, 1997). Patient #2, a 3-y-old girl, and patient #3 carried the same mutation, the 215C-to-T transition in exon 4. Interestingly, patient #3 was a 35-y-old man born of consanguineous healthy parents. The disease had started during the first years of life and the patient had become wheelchair-bound at the age of 28 y. The 215C-to-T mutation eliminates a TaqI restriction site and results in the substitution of Ser-72 (TCG) with Leu (TTG) in the 2nd transmembrane domain of PMP22. Approx. 40 different PMP22 mutations are currently listed in the European CMT Consortium Database. In the majority of cases, the mutations have been identified in single or very few patients, with the only exception of the Ser72Leu substitution. Including the two unrelated patients reported here, this mutation has been thus far described in a total of 7 patients. The mutation, which occurs within a CpG dinucleotide, exhibits phenotypic heterogeneity and has been observed in both DSD (6) and CHN (1) cases. In conclusion, PMP22 mutations are rare causes of genetic neuropathies. Given the limited number of such mutations, the recurrence of substitutions at codon 72 would indicate that this may represent a mutational “hot spot”. We therefore suggest that sequence analysis of PMP22 exon 4 should routinely precede analysis of the remaining exons and intron/exon boundaries.     

A case of CMT 1B due to Val 102/fs null mutation of the MPZ gene presenting as hyperCKemia

Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2). The most common demyelinating form is CMT1A, due to a duplication in the gene encoding the peripheral myelin protein 22 (PMP22). Less frequently, mutations in the myelin protein zero gene (MPZ/P0) account for demyelinating CMT1B. Herein, we report a patient presenting with an isolated hyperCKemia in whom electrophysiological and pathological findings revealed a demyelinating and axonal neuropathy. Sequencing of the MPZ gene revealed a 306delA at codon 102 in the proband and in two relatives. This mutation has been already described in association with paucisymptomatic CMT without hyperCKemia.     

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.     

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.     

Mutation Analysis of MFN2, GJB1, MPZ and PMP22 in Italian Patients with Axonal Charcot–Marie–Tooth Disease

Charcot–Marie–Tooth (CMT) diseases include a group of clinically heterogeneous inherited neuropathies subdivided into demyelinating (CMT1), axonal (CMT2) and intermediate CMT forms. CMTs are associated with different genes, although mutations in some of these genes may cause both clinical pictures. To date, more than 50 CMT genes have been identified, but more than half of the cases are due to mutations in MFN2, MPZ, GJB1 and PMP22. The aim of this study was to estimate the frequency of disease mutations of these four genes in the axonal form of CMT in order to evaluate their effectiveness in the molecular diagnosis of CMT2 patients. A cohort of 38 CMT2 Italian subjects was screened for mutations in the MFN2, MPZ and GJB1 genes by direct sequencing and for PMP22 rearrangements using the MLPA technique. Overall, we identified 15 mutations, 8 of which were novel: 11 mutations (28.9 %) were in the MFN2 gene, 2 (5.3 %) in MPZ and 2 (5.3 %) in PMP22. No mutations were found in GJB1. Two patients showed rearrangements in the PMP22 gene, which is commonly associated with CMT1 or HNPP phenotypes thus usually not tested in CMT2 patients. By including this gene in the analysis, we reached a molecular diagnosis rate of 39.5 %, which is one of the highest reported in the literature. Our findings confirm the MFN2 gene as the most common cause of CMT2 and suggest that PMP22 rearrangements should be considered in the molecular diagnosis of CMT2 patients.     

Molecular diagnosis of PMP22-associated neuropathies using fluorescence in situ hybridization (FISH) on archival peripheral nerve tissue preparations

Charcot-Marie-Tooth (CMT) syndrome type 1 and tomaculous neuropathy, also called hereditary neuropathy with liability to pressure palsies (HNPP), represent two groups of neurological disorders with different subtypes, which can be distinguished at the molecular level. It is known that a 1.5-mb region on chromosome 17p11.2– 12, which includes the gene for the peripheral myelin protein 22 kDa (PMP22), is duplicated in more than 95% of patients with CMT type 1A (CMT1A; gene dosage 3) and is deleted in about 90% of subjects suffering from HNPP (gene dosage 1). This duplication/deletion can be detected reliably by interphase-two-color fluorescence in situ hybridization (FISH). We report here a technique for extraction of nuclei from paraffin-embedded and cryofixed sural nerve biopsies for precise molecular diagnosis, employing interphase-two-color FISH in clinically diagnosed CMT1 or HNPP patients. Following this technique we were able to identify six CMT1A duplications in 13 clinically diagnosed CMT1 cases and five HNPP deletions in 6 clinically diagnosed HNPP cases; 8 control persons were included in this study. This is the first report on the use of FISH in the detection of 17p11.2–12 duplication and deletion in archival biopsy material. Received: 10 January 1997 / Revised, accepted: 3 March 1997     

Charcot–Marie–Tooth disease: genetic subtypes in the Sardinian population

Charcot–Marie–Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.     

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.     

Clinical and genetic spectra of Charcot‐Marie‐Tooth disease in Chinese Han patients

Charcot‐Marie‐Tooth disease (CMT) is a common hereditary motor and sensory neuropathy. Epidemiological data for Chinese CMT patients are few. This study aimed to analyze the electrophysiological and genetic characteristics of Chinese Han patients. A total of 106 unrelated patients with the clinical diagnosis of CMT were included. Clinical examination, nerve conduction studies (NCS), next‐generation sequencing (NGS), and bioinformatic analyses were performed. Genetic testing was performed for 82 patients; 27 (33%) patients carried known CMT‐associated gene mutations. PMP22 duplication was detected in 10 (12%) patients and GJB1 mutations in 9 (11%) patients. The mutation rate was higher in patients with a positive family history than in the sporadic cases (50% vs. 27%, p < 0.05). Six novel CMT‐associated gene mutations including BSCL2 (c.461C>T), LITAF (c.32C>G), MFN2 (c.497C>T), GARS (c.794C>T), NEFL (c.280C>T), and MPZ (c.440T>C) were discovered. All except the LITAF (c.32C>G) mutation were identified as “disease causing” via bioinformatic analyses. In this Chinese Han population, the frequency of PMP22 gene duplication in those with CMT1 was slightly (50% vs. 70%–80%) less than in Western/Caucasian populations. The novel CMT‐associated gene mutations broaden the mutation diversity of CMT1. NGS should be considered for genetic analyses in CMT patients.     

腓骨肌萎缩症电生理、病理和基因定位研究

目的研究腓骨肌萎缩症(CMT)临床特征、基因测定、病理及神经电生理检查在其诊断和分型中的价值。方法收集50例CMT患者临床资料,对其进行肌电图检查及腓肠神经活检,并采用PCR技术直接测序进行基因突变分析。结果 40例CMT患者双下肢运动及感觉传导速度减慢(双胫、腓总神经为15~28 m/s,腓肠神经为12~30 m/s),10例双下肢未引出反应电位;50例正中神经运动及感觉传导速度亦减慢分别为19~48 m/s和20~52 m/s。CMT患者神经传导速度减慢的程度和临床表现的严重程度并不平行。腓肠神经活检符合慢性脱髓鞘部分伴轴索改变性周围神经病。PMP22、Cx32、MPZ、MFN2、GDAP1致病基因的突变分析发现14例患者存在PMP22基因的大片段重复突变(28%),13例患者存在Cx32基因的点突变(26%),4例患者存在MPZ基因的点突变(8%),3例患者存在MFN2基因的点突变(6%),未发现GDAP1基因的突变,16例患者未检测出上述基因突变。结论电生理、病理、基因测定在CMT的诊断及分型中有重要价值。     

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.     

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     

Genetic epidemiology of Charcot–Marie–Tooth in the general population

Background and purpose:  The frequency of different Charcot–Marie–Tooth (CMT) genotypes has been estimated in clinic populations, but prevalence data from the general population are lacking. Methods:  Our population‐based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist and classified clinically, neurophysiologically and genetically. Results:  Two hundred and forty‐five persons from 116 families had CMT. This corresponds to 1 per 1214 persons (95% CI 1062–1366) have CMT in the general population. CMT1 (motor conduction velocity (MCV) <38 m/s), CMT2 (MCV >38 m/s) and CMT intermediate (MCV 25–45 m/s) were found in 48.2%, 49.4% and 2.4% of the families. A total of 27.2% of the families and 28.6% of the affected had a mutation in the investigated CMT genes. The prevalence of the peripheral myelin protein 22 (PMP22) duplication and point mutation in the connexin32 (Cx32), myelin protein zero (MPZ) and mitofusin2 (MFN2) genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations in the early growth response 2 (EGR2), PMP22 or small integral membrane protein of lysosome/late endosome (SIMPLE) genes. Conclusions:  CMT is the most common inherited neuropathy. At present, 43 CMT genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is probable that at least 30–50 CMT genes are yet to be identified.     

A novel homozygous variant extending the peripheral myelin protein 22 by 9 amino acids causes early‐onset Charcot‐Marie‐Tooth disease with predominant severe sensory ataxia

Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. A gene copy variation results in CMT1A (duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutations comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallelic mutations of PMP22 are very rare. We describe a 9‐year‐old girl who presented before the age of 1 year with severe locomotor delay. She now requires support for standing and walking in view of her severe sensory ataxia. Strikingly, her muscle power and bulk are close to normal in all segments. Nerve conduction studies showed sensory‐motor velocities below 5 m/s. Genetic analysis revealed a homozygous sequence change in the PMP22 gene causing the loss of termination codon (c.483A > G; p.[*161Trpext*10]), extending the protein by 9 amino acids. Both heterozygous parents have neurophysiological abnormalities consistent with HNPP, consistent with this being a loss‐of‐function mutation. PMP22‐deficient human models are rare but important to decipher the physiological function of the PMP22 protein in vivo. The predominance of large fiber sensory involvement in this and other rare similar cases suggests a pivotal role played by PMP22 in the embryogenesis of dorsal root ganglia in humans.     

LONG-TERM EFFECT OF INTRAVENOUS IMMUNOGLOBLIN THERAPY (IVIg) IN MULTIFOCAL MOTOR NEUROPATHY (MMN)

Peripheral myelin protein 22 (PMP22) plays a dual role in regulating cells growth and peripheral myelin compaction. Charcot‐Marie‐Tooth 1A neuropathy (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP) are respectively due to a duplication and a deletion of the PMP22 gene, leading to over and underexpression of the protein. It is unknown how the altered PMP22 dosage impairs peripheral myelination. By means of transmission electron microscopy (TEM) morphometry we found that myelin periodicity is significantly increased in CMT1A patients (9.79 ± 0.9 nm) and compared to normal sural nerves (9.1 ± 0.7 nm). Conversely, myelin periodicity was slightly reduced in HNPP patients (8.9 ± 0.7 nm). Interestingly, the difference between CMT1A and HNPP patients was highly significant. Moreover, we found an increased myelin periodicity in sciatic nerves of a transgenic rat model of CMT1A (8.9 ± 0.08) and in organotypic dorsal root ganglia cultures (10.1 ± 0.1 nm) established from this rat line, compared to control animals (8.6 ± 0.1) and cultures (9.6 ± 0.1 nm). Since TEM studies suffer considerably from radiation damage, we also used small‐angle X‐ray scattering (SAXS) with a synchrotron radiation microbeam (5 m diameter) for in‐situ experiments on single sural nerves of CMT 1A and HNPP patients and of normal controls. For comparison with the TEM‐data, the periodicities were divided by two. Myelin periodicities ranged from 8.4 to 8.9 nm (mean: 8.7 ± 0.3) in CMT 1A nerves, from 8.0 to 8.4 nm (mean: 8.1 ± 0.3) in normal controls, and from 6.9 to 7.2 nm (mean 7.1 ± 0.3) in HNPP. In conclusion, altered PMP22 levels induce significant changes in myelin lamellae spacing, which may be recorded by appropriate morphometric techniques, and in particular by microbeam SAXS. Differences in term of myelin periodicity between TEM morphometry and x‐ray microbeam analysis may be due to the higher resolution and accuracy of the latter technique to measure periodic structures. Having an altered myelin period could lead to demyelination and subsequent remyelination. Therefore, the pathomechanism of both CMT1A and HNPP may be also related to a dysfunction of PMP22 as a structural protein of peripheral myelin.