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     

Nerve ultrasound in miller fisher variant of Guillain–Barré syndrome

Introduction: Focal enlargement of the peripheral and spinal nerves, visualized using high‐resolution ultrasound (HRUS), has been reported in early Guillain–Barré syndrome, but not in the Miller Fisher variant. We report the use of HRUS in 2 patients who presented with acute ataxic neuropathy, areflexia, and ophthalmoparesis. Methods: Ultrasound and/or nerve conduction studies (NCS) of peripheral nerves, the vagus, and spinal nerves C5/6 were performed at onset and 2 weeks after immunoglobulin therapy. Results: Both patients fulfilled criteria for diagnosis of Miller Fisher syndrome (MFS). Laboratory findings revealed elevated ganglioside Q1b antibodies in both and an albuminolocytologic dissociation in 1 patient. In addition, 1 patient had NCS evidence for demyelinating neuropathy. However, ultrasound showed focal enlargement in the vagus, the spinal nerves, and/or in the peripheral nerves in both patients. After therapy, nerve enlargement decreased in parallel with clinical improvement. Conclusion: Spinal and/or peripheral nerve enlargement supports the diagnosis of MFS in early phases of the disease. Muscle Nerve 52 : 1106–1110, 2015     

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     

Ultrasonography of the peripheral nervous system in the early stage of Guillain‐Barré syndrome

Ultrasonography can be used to visualize peripheral nerve abnormalities in immune‐mediated neuropathies. The objective of this study was to prove the role of ultrasonography (US) in acute phase of Guillain‐Barré syndrome (GBS). Systematic ultrasonic measurements of several peripheral nerves including the vagal nerve as well as the sixth cervical nerve root were performed in 18 patients with GBS at days 1–3 after symptom onset and compared to 21 healthy controls. Nerve conduction studies (NCS) of corresponding nerves were undertaken. Consequently, significant differences between the groups were found in compound muscle action potential amplitudes, F‐wave latency, and persistency. Ultrasonic cross‐sectional areas (CSAs) showed significant enlargement in all nerves except of the ulnar nerve (upper arm) and the sural nerve compared to healthy controls, most prominent in proximal and middle median nerve (p < 0.01). The vagal nerve also showed enlargement compared to controls (p < 0.05), which was most pronounced in patients with autonomic dysfunction compared to patients without (p < 0.05). C6 root diameter showed a significant correlation to the amount of cerebrospinal fluid (CSF)‐protein (Pearson correlation, p < 0.05). US shows nerve enlargement in several peripheral nerves including vagal nerve and C6 root in acute phase of GBS and could be an additional diagnostic tool for example, in GBS of atypical onset and autonomic dysfunction.     

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     

Normal nerve striations are altered in the trembler‐J mouse,a model of charcot–marie–tooth disease

Introduction: This study was initiated because it was noted that the peripheral nerves of Trembler‐J mice (a model of human Charcot–Marie–Tooth disease) appear to lack normal striations. Methods: We performed confocal microscopy of whole sciatic nerves and tested the effect of axial stress on impulse conduction. Results: We found that the axons of mutant mice were longer than those of the wild‐type (1.55 mm of axon/mm length of nerve vs. 1.28 mm/mm respectively). This axonal elongation altered the helical nerve striations (bands of Fontana). As nerves were stretched axially, the conduction distance became correspondingly shorter. The effect on latency was significantly greater in the more coiled nerves of Trembler‐J mice (P = 0.038). Conclusions: The finding that mice with a mutated peripheral myelin protein 22 (PMP22) possess excessively long axons may be related to the excess Schwann cell numbers found in this disorder. Muscle Nerve 51 : 246–252, 2015     

A charcot-marie-tooth type 1B kindred associated with hemifacial spasm and trigeminal neuralgia

Introduction: Charcot-Marie-Tooth (CMT) phenotypes can be distinguished by electrophysiology and genetic analysis but few can be identified by their clinical characteristics. Distinctive phenotypes are useful in identifying affected individuals and providing additional clues about the mechanism of the neuropathy. Cranial neuropathies are uncommon features of CMT, and few reports of familial hemifacial spasm (HFS) and trigeminal neuralgia (TN) have been published. Methods: Sixty-three members of a large CMT 1B kindred were assessed for signs of peripheral neuropathy and cranial neuropathies then tested for the G163R mutation in the myelin protein zero (MPZ) gene. Results: Of 27 individuals with the G163R mutation in MPZ, 10 had HFS or TN. Co-existing HFS and TN were found in 3 of these and 4 had bilateral HFS or TN. Conclusions: This kindred exhibits a distinct CMT phenotype characterized by the development of HFS or TN decades after clinical signs of hereditary neuropathy are manifest. Muscle Nerve, 2019     

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.     

Ultra–high‐frequency ultrasound imaging of sural nerve: A comparative study with nerve biopsy in progressive neuropathies

Introduction: Nerve ultrasound has been used increasingly in clinical practice as a complementary test for diagnostic assessment of neuropathies, but nerve biopsy remains invaluable in certain cases. The aim of this study was to compare ultra–high‐frequency ultrasound (UHF‐US) to histologic findings in progressive polyneuropathies. Methods: Ten patients with severe, progressive neuropathies underwent ultrasound evaluation of the sural nerve before nerve biopsy. Ultrasound data were compared with histologic results in a retrospective manner. Results: Sural nerves were easily identified on UHF‐US. Nerve hyperechogenicity correlated with inflammatory infiltrates on biopsy. Nerve fascicles could be identified and measured on ultrasound in the majority of patients. Discussion: Hyperechogenicity on UHF‐US may be a marker of nerve inflammation in neuropathies. Furthermore, the UHF‐US probe allows for evaluation of sensory nerves in spite of their small size, providing valuable information on their size and on their internal structure.     

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.     

Coexistence of two chronic neuropathies in a young child: Charcot–marie–tooth disease type 1A and chronic inflammatory demyelinating polyneuropathy

We report an 18‐month‐old Charcot–Marie–Tooth type 1A (CMT1A) patient who developed a rapid‐onset neuropathy, with proximal and distal weakness, and non‐uniform nerve conduction studies. The neuropathy responded well to immunomodulation, confirming the coexistence of an inherited and an inflammatory neuropathy. Unexpected clinical and/or electrophysiological manifestations in CMT1A patients should alert clinicians to concomitant inflammatory neuropathy. In addition, this association raises reflections about disease mechanism in CMT1A. Muscle Nerve, 2010     

Peripheral nerve size in normals and patients with polyneuropathy: An ultrasound study

Ultrasound has been used for visualizing peripheral nerve pathology. Our goal was to use ultrasound to quantitate the sizes of upper extremity nerves along their length in control subjects and patients with neuropathy. We measured median and ulnar nerve cross‐sectional areas (NCSA) in the arms of 190 subjects, including 100 with neuropathies and 90 controls. We found that NCSAs in healthy child and adult controls were greater with increasing height, at proximal sites, and at sites of entrapment. Nerves were enlarged in all Charcot–Marie–Tooth 1A (CMT‐1A) (11 of 11; 100%), most chronic inflammatory demyelinating polyneuropathy (CIDP) (31 of 36; 86%), half of Guillain–Barré syndrome (GBS) (8 of 17; 47%), but few axonal neuropathy (7 of 36, 19%) subjects. In GBS, nerve enlargement occurred early and with minimal electrodiagnostic abnormalities in some patients. We conclude that NCSA measured by ultrasound is a quantifiable marker of nerve features that should be corrected for patient characteristics and nerve site. NCSA is generally larger in demyelinating than it is in axonal polyneuropathies. Muscle Nerve, 2009     

Peripheral Neuropathy: Assessment of Proximal Nerve Integrity By Diffusion Tensor Imaging

Introduction: We investigated the utility of diffusion tensor imaging (DTI) for detecting neuropathic changes in proximal nerve segments in patients with peripheral neuropathy. Methods: Twenty‐one individuals with (n = 11) and without (n = 10) peripheral neuropathy underwent DTI of a defined sciatic nerve segment. Patients and controls were evaluated by clinical examination and nerve conduction studies at baseline and 6 months after the initial DTI scan. Results: The mean fractional anisotropy (FA) value was significantly lower in sciatic nerves from patients with peripheral neuropathy as compared with controls. Sciatic nerve FA values correlated with clinical disability scores and electrophysiological parameters of axonal damage at baseline and 6 months after MRI scan. Conclusions: DTI‐derived FA values are a sensitive measure to discriminate healthy from functionally impaired human sciatic nerve segments. DTI of proximal nerve segments may be useful for estimating the proximal axonal degeneration burden in patients with peripheral neuropathies. Muscle Nerve 48 : 889–896, 2013     

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     

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.     

Report of a novel mutation in the PMP22 gene causing an axonal neuropathy

Introduction: Point mutations in the peripheral myelin protein 22 (PMP22) gene rarely cause the hereditary neuropathies Charcot–Marie–Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), both of which show a demyelinating phenotype. Methods: In this study we characterized a family with an axonal neuropathy. Results: Three family members carried a heterozygous point mutation of the PMP22 gene, resulting in amino acid substitution R159C. Screening of 185 healthy controls did not reveal the R159C allele in any case. Discussion: The novel R159C mutation represents a very rare case of a dominant PMP22 mutation causing an axonal neuropathy. Muscle Nerve, 2011     

Pain and small fiber function in charcot–marie–tooth disease type 1A

Introduction: Charcot–Marie–Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively. Methods: We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds. Results: Forty‐three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively. Conclusions: Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers. Muscle Nerve 50 : 366–371, 2014     

Charcot–marie–tooth disease with intermediate conduction velocities caused by a novel mutation in the MPZ gene

Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited sensory and motor neuropathies. Mutations in the gene that encodes for myelin protein zero (MPZ) can produce different phenotypes: CMT1 (with low conduction velocities), CMT2 (less frequent and with unaffected conduction velocities), and CMTID (with intermediate conduction velocities). We report a study of seven patients from a four‐generation family. All the affected members of the family had a typical CMT phenotype, but three of them had calf hypertrophy. The nerve conduction velocities (NCV) in all of them were between 35 and 43 m/s. Molecular study revealed the novel mutation Lys214Met in the MPZ gene. Molecular study of the MPZ gene would be useful in cases of CMT in families with intermediate NCV, especially if no mutations in the GJB‐1 gene are found or there is male‐to‐male transmission. Muscle Nerve, 2010     

Electromyographic tendon reflex recording: An accurate and comfortable method for diagnosis of charcot‐marie‐tooth disease type 1a

Introduction: We analyzed the utility of tendon reflex (T‐reflex) testing in Charcot‐Marie‐Tooth disease type 1A (CMT1A). Methods: A total of 82 subjects from 27 unrelated CMT1A pedigrees were evaluated prospectively. The series also comprised 28 adult healthy controls. Electrophysiology included evaluation of biceps T‐reflex and soleus T‐reflex. Results: Seventy‐one individuals (62 adults and 9 children) had clinical and electrophysiological features of CMT1A. The remaining 11 (8 adults and 3 children) were unaffected. On electrophysiological testing, the biceps T‐reflex was elicited in 58 of 62 (93%) adult CMT1A patients and in all 9 affected children. Latencies of the biceps T‐reflex were always markedly prolonged, and a cut‐off limit of 16.25 ms clearly separated adult patients and controls or unaffected kin adult individuals. In affected children, the soleus T‐reflex latency was also prolonged when compared with age and height normative data. Conclusion: T‐reflex testing is an accurate diagnostic technique for CMT1A patients. Muscle Nerve 52 : 39–44, 2015     

Major histocompatibility complex class II expression and macrophage responses in genetically proven Charcot–Marie–Tooth type 1 and hereditary neuropathy with liability to pressure palsies

This study examined major histocompatibility complex (MHC) class II expression and macrophage infiltration in sural nerve biopsies from patients with genetically proven Charcot–Marie–Tooth (CMT) 1A and 1B and hereditary neuropathy with liability to pressure palsies (HNPP) by immunocytochemistry. In both young and older patients with duplication of the PMP22 gene, MHC class II expression was consistently up-regulated and not closely related to the extent of macrophage infiltration. On the other hand, MHC class II expression was more variable in CMT1A and CMT1B caused by point mutations and in HNPP. The extent of nerve pathology as assessed by teased fiber preparations or electron microscopy was not predictive for the degree of MHC class II expression in CMT1/HNPP. We conclude that MHC class II up-regulation is a common feature in hereditary neuropathies. As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1419–1427, 1998