The shifting landscape of genetic testing for Charcot–Marie–Tooth disease

Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the “giant” axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot–Marie–Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as “giant axonal neurodegeneration.” Muscle Nerve 50 : 467–476, 2014     

Genetic testing practices for Charcot–Marie–Tooth type 1A disease

Introduction: Charcot–Marie–Tooth disease type 1A (CMT1A) is caused by a PMP22 gene duplication. CMT1A has a robust electrical phenotype that can be used to direct genetic testing. We compared specialty CMT center CMT1A diagnosis rates to those of outside physicians. Methods: Charts were reviewed for 102 patients with CMT1A seen at a specialty CMT clinic between 2001 and 2009. Nerve conduction studies, family history, date of genetic testing, and type of genetic testing (single gene vs. panel) were collected. Results: Although the specialty clinic ordered more PMP22 duplication testing alone beginning at an earlier year, thereby reducing costs, both the specialty clinic and outside physicians began the decade doing panel testing and ended the decade looking at only PMP22. Conclusions: Specialty centers adapt earlier to changes in testing practice than non‐specialty centers. As the landscape of genetic testing changes, the algorithms for testing will also likely change. Muscle Nerve 49:478–482, 2014     

Disease mechanisms and potential therapeutic strategies in Charcot–Marie–Tooth disease

Until 10 years ago, the genetic basis of Charcot–Marie–Tooth (CMT) disease was largely unknown. With the finding of an intrachromosomal duplication on chromosome 17 in 1991, associated with the most commonly found subtype CMT1A, and the discovery of a point mutation in the peripheral myelin protein-22 (pmp22) gene in the Trembler mouse in 1992, the groundwork was laid down for a novel chapter in the elucidation of the molecular basis of this large group of peripheral neuropathies. In the meantime, several different genes have been found to be associated with different forms of demyelinating and axonal forms of CMT. In this review, we will summarize what is known today about the genetics of this group of disease which constitute the most common known monogenetic disorder affecting the nervous system in man, the animal models that have been generated, and what we have learned about the underlying disease mechanisms. Furthermore, we will review how this gain of knowledge about CMT may open new avenues to the development of novel treatment strategies.     

Hip flexor fatigue limits walking in Charcot–Marie–Tooth disease

Charcot–Marie–Tooth (CMT) disease results in distal lower limb weakness that affects walking. In this study we assess the role of the hip flexors in compensating for distal weakness while walking and the effects of prolonged walking on these putative compensatory strategies. Eighteen subjects with CMT disease were compared with 14 matched controls while they walked on a treadmill to a predetermined point of perceived effort. A significant reduction was observed in peak hip flexor velocity during walking and hip flexor maximal voluntary contraction. In a second session following selective fatigue of the hip flexors, hip flexor velocity decreased immediately on walking, and walking duration was greatly reduced. This study suggests that hip flexors compensate for distal weakness and that fatigue in the hip flexors can limit walking duration. Treatments directed toward improving proximal muscle strength may therefore help to delay onset of hip flexor fatigue and thus prolong walking duration. Muscle Nerve, 2009     

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.     

Screening of dominantly inherited Charcot–Marie–Tooth neuropathies

Sixty-three families with dominantly inherited Charcot–Marie–Tooth (CMT) neuropathies including 730 subjects (total) from which 356 affected were studied clinically, electrophysiologically (MNCVs and EMGs), by genetic linkage, and screened for DNA duplication. Thirtyeight families (60.3%) were type 1A (demyelinating CMT mapped on chromosome 17). DNA duplication was present in 36 families (94.8% of CMT1A families). One CMT1A family (2.6%) showed no duplication but suggested genetic linkage with markers of chromosome 17. One CMT1A family (2.6%) revealed nonduplication in some affected members and duplication in other affected members. The disease in that family segregated with the same chromosome 17 markers regardless of duplication status. The other CMT families with dominant inheritance but without duplication included one family with CMT1B (demyelinating CMT mapped on chromosome 1) (1.6%), 14 families with CMT2 axonal neuropathy (22.2%), and 10 families with X-linked dominant CMT (15.9%). © 1993 John Wiley & Sons, Inc.     

Ultrastructural protein zero expression in Charcot–Marie–Tooth type 1B Disease

Charcot–Marie–Tooth type 1B (CMT 1B) disease, an inherited demyelinating peripheral neuropathy, results from different point mutations located in the P0 gene on chromosome 1 q21–23. We have quantified, at the ultrastructural level, the immunocytochemical expression of the P0 protein in two unrelated CMT 1B patients with mutations (Ser 78 to Leu and Asn 122 to Ser) located in two different exons in the extracellular domain of the protein. A twofold decrease in P0 expression was observed in compact myelin in each case, compared with age‐matched controls. The severity of the phenotypes showed no direct relationship to the levels of P0 protein expression in these 2 patients. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 99–104, 1999     

Diagnostic nerve ultrasound in Charcot–Marie–Tooth disease type 1B

Ultrasound is emerging as a useful tool for evaluation of neuromuscular conditions, because it can provide high‐resolution anatomic information to complement electrodiagnostic data. There have been few studies in which ultrasound was used to assess the peripheral nerves of individuals with Charcot–Marie–Tooth (CMT) disease and none involving CMT type 1B. In this study we compared nerve cross‐sectional area in individuals from a single large family with CMT 1B with normal, healthy controls. We also assessed for cranial nerve enlargement in those with CMT 1B with cranial neuropathies compared to those with CMT 1B without cranial neuropathies. Individuals with CMT 1B have significantly larger median and vagus nerves than healthy controls, but no difference was seen in cranial nerve size between those with versus those without cranial neuropathies. This is the first study to characterize the ultrasonographic findings in the peripheral nerves of individuals with CMT 1B. Muscle Nerve 40: 98–102, 2009     

Role of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A

Charcot–Marie–Tooth disease (CMT) is the most common form of hereditary peripheral neuropathy. The main axonal form of CMT, CMT2A, preferentially affects peripheral neurons with the longest neurites. CMT2A has been recently linked to mutations in the mitofusin 2 (Mfn2) gene. Mfn2 participates in mitochondrial fusion a process that together with mitochondrial fission, contributes to mitochondrial morphology. Many hypotheses have been postulated to understand how mutations in Mfn2 lead to CMT2A. In this review, we will describe the physiological role of Mfn2, the pathophysiology of CMT2A and current hypotheses about the deleterious role of mutant Mfn2 in neuronal function.     

A Patient with neurofibromatosis type 1 and Charcot–Marie–Tooth disease type 1B

We describe a patient with both neurofibromatosis type 1 and Charcot–Marie–Tooth disease type 1B. Although one might expect an overwhelming tumor burden due to the combination of these two disorders, the two mutations did not appear to interact. Muscle Nerve 41: 555–558, 2010     

Plasma neurofilament heavy chain is not a useful biomarker in Charcot–Marie–Tooth disease

Introduction: The negative results in trials of vitamin C in Charcot–Marie–Tooth disease (CMT) type 1A have highlighted the lack of sensitive outcome measures. Neurofilaments are abundant neuronal cytoskeletal proteins, and their concentration in blood is likely to reflect axonal breakdown. We therefore examined plasma neurofilament heavy‐chain (NfH) concentration as a potential biomarker in CMT. Methods: Blood samples were collected from healthy controls and patients with CMT over a 2‐year period. Disease severity was measured using the CMT Examination Score. An in‐house enzyme‐linked immunoabsorbent assay was used to measure plasma NfH levels. Results: There was no significant difference in plasma NfH concentrations between CMT patients and controls (P = 0.449). There was also no significant difference in plasma NfH levels in the CMT group over 1 year (mean difference = –0.02, SEM = 4.44, P = 0.98). Conclusions: Plasma NfH levels are not altered in patients with CMT and are not a suitable biomarker of disease activity. Muscle Nerve 53 : 972–975, 2016     

Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot–Marie–Tooth disease

The connexins are a family of homologous integral membrane proteins that form channels that provide a low resistance pathway for the transmission of electrical signals and the diffusion of small ions and non-electrolytes between coupled cells. Individuals carrying mutations in the gene encoding connexin 32 (Cx32), a gap junction protein expressed in the paranodal loops and Schmidt–Lantermann incisures of myelinating Schwann cells, develop a peripheral neuropathy — the X-linked form of Charcot–Marie–Tooth disease (CMTX). Over 160 different mutations in Cx32 associated with CMTX have been identified. Some mutations will lead to complete loss of function with no possibility of expression of functional channels. Some mutations in Cx32 lead to the abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus; CMTX may arise due to incorrect trafficking of Cx32 or to interference with trafficking of other proteins. On the other hand, many mutant forms of Cx32 can form functional channels. Some functional mutants have conductance voltage relationships that are disrupted to a degree which would lead to a substantial reduction in the available gap junction mediated communication pathway. Others have essentially normal steady-state g–V relations. In one of these cases (Ser26Leu), the only change introduced by the mutation is a reduction in the pore diameter from 7 Å for the wild-type channel to less than 3 Å for Ser26Leu. This reduction in pore diameter may restrict the passage of important signaling molecules. These findings suggest that in some, if not all cases of CMTX, loss of function of normal Cx32 is sufficient to cause CMTX.     

The devastating combination of Charcot–Marie–Tooth disease and facioscapulohumeral muscular dystrophy

A patient with both Charcot–Marie–Tooth (type 1a) disease and facioscapulohumeral muscular dystrophy inherited these from her father and mother, respectively. Either disease alone does not significantly alter life expectancy, but the unusual combination of these two disease processes was devastating and resulted in severe generalized weakness and early death. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:788–791, 1998.     

Prevalence and orthopedic management of foot and ankle deformities in Charcot–Marie–Tooth disease

Introduction: Foot deformities are frequent complications in Charcot–Marie–Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. Methods: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. Results: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. Discussion: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57 : 255–259, 2018     

Clinical characterization and genetic analysis of Korean patients with X‐linked Charcot‐Marie‐Tooth disease type 1

Mutations in the gap junction protein beta 1 gene (GJB1) cause X‐linked Charcot‐Marie‐Tooth disease type 1 (CMTX1). CMTX1 is representative of the intermediate type of CMT, having both demyelinating and axonal neuropathic features. We analyzed the clinical and genetic characterization of 128 patients with CMTX1 from 63 unrelated families. Genetic analysis revealed a total of 43 mutations including 6 novel mutations. Ten mutations were found from two or more unrelated families. p.V95M was most frequently observed. The frequency of CMTX1 was 9.6% of total Korean CMT family and was 14.8% when calculated within genetically identified cases. Among 67 male and 61 female patients, 22 females were asymptomatic. A high‐arched foot, ataxia, and tremor were observed in 87%, 41%, and 35% of the patients, respectively. In the male patients, functional disability scale, CMT neuropathy score, and compound muscle action potential of the median/ulnar nerves were more severely affected than in the female patients. This study provides a comprehensive summary of the clinical features and spectrum of GJB1 gene mutations in Korean CMTX1 patients.