New Keys to Early Diagnosis: Muscle Echogenicity,Nerve Ultrasound Patterns,Electrodiagnostic, and Clinical Parameters in 150 Patients with Hereditary Polyneuropathies

Hereditary neuropathies are of variable genotype and phenotype. With upcoming therapies, there is urgent need for early disease recognition and outcome measures. High-resolution nerve and muscle ultrasound is a dynamic, non-invasive, well-established tool in the field of inflammatory and traumatic neuropathies. In this study, we defined nerve and muscle ultrasound parameters as recognition and progression markers in 150 patients with genetically confirmed hereditary neuropathies, including Charcot-Marie-Tooth (CMT) disease (CMT1A, n = 55; other CMT1/4, n = 28; axonal CMT, n = 15; CMTX, n = 15), hereditary neuropathy with liability to pressure palsies (HNPP, n = 16), hereditary transthyretin-amyloidosis (ATTRv, n = 14), and Fabry’s disease (n = 7). The CMT1A, followed by the CMT1/4 group, had the most homogeneous enlargement of the nerve cross-sectional areas (CSA) in the ultrasound pattern sum (UPSS) and homogeneity score. Entrapment scores were highest in HNPP, ATTRv amyloidosis, and Fabry’s disease patients. In demyelinating neuropathies, the CSA correlated inversely with nerve conduction studies. The muscle echo intensity was significantly highest in the clinically most affected muscles, which was independent from the underlying disease cause and correlated with muscle strength and disease duration. Further correlations were seen with combined clinical (CMTES-2) and electrophysiological (CMTNS-2) scores of disease severity. We conclude that nerve ultrasound is a helpful tool to distinguish different types of hereditary neuropathies by pattern recognition, whereas muscle ultrasound is an objective parameter for disease severity. The implementation of neuromuscular ultrasound might enrich diagnostic procedures both in clinical routines and research.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01141-3.     

A mutation in the heptad repeat 2 domain of MFN2 in a large CMT2A family

Dominant mutations in MFN2 cause a range of phenotypes, including severe, early‐onset axonal neuropathy, “classical CMT2,” and late‐onset axonal neuropathies. We report a large family with an axonal polyneuropathy, with clinical onset in the 20s, followed by slow progression.     

Increased mitochondrial fusion in a autosomal recessive CMT2A family with mitochondrial GTPase mitofusin 2 mutations

Charcot‐Marie‐Tooth type 2A disease (CMT2A) is an inherited peripheral neuropathy mainly caused by mutations in the MFN2 gene coding for the mitochondrial fusion protein mitofusin 2. Although the disease is mainly inherited in a dominant fashion, few cases of early‐onset autosomal recessive CMT2A (AR‐CMT2A) have been reported in recent years. In this study, we characterized the structure of the mitochondrial network in cultured primary fibroblasts obtained from AR‐CMT2A family members. The patient‐derived cells showed an increase of the mitochondrial fusion with large connected networks and an increase of the mitochondrial volume. Interestingly, fibroblasts derived from the two asymptomatic parents showed similar changes to a lesser extent. These results support the hypothesis that AR‐CMT2A‐related MFN2 mutations acts through a semi‐dominant negative mechanism and suggest that other biological parameters might show mild alterations in asymptomatic heterozygote AR‐CMT2A patients. Such alterations could be useful biomarkers helping to distinguish MFN2 mutations from variants, a growing challenge with the advent of next generation sequencing into routine clinical practice.     

Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A)

Charcot-Marie-Tooth disease (CMT) has been classified into two types: demyelinating forms (CMT1) and axonal forms (CMT2). Mutations in the CMT2A locus have been linked to the KIF1B and the mitofusin 2 ( MFN2 ) genes. Here, we report a German patient with CMT2 with an underlying spontaneous mutation (c.281G→A) in the MFN2 gene. Clinically, the patient presented with early-onset CMT that was not associated with additional central nervous system pathology. The disease course was rapidly progressive in the first years and slowed afterwards. We also suggest that single patients with early-onset axonal polyneuropathies should be screened for MFN2 mutations.     

Ethambutol toxicity exacerbating the phenotype of CMT2A2

Introduction: CMT2A2 is associated with mutations in the mitofusin 2 gene, which encodes a protein involved in mitochondrial fusion. Ethambutol is an antimycobacterial agent associated with toxic optic neuropathies. Ethambutol‐induced optic neuropathy occurs in patients with mutations in a related fusion gene, OPA1, which is responsible for autosomal dominant optic atrophy. Methods: We describe a patient with CMT2A2 (MFN2 mutation: T669G, F223L) who developed accelerated weakness, vocal cord paralysis, and optic atrophy after receiving ethambutol. Results: Deterioration began within months of initiating ethambutol therapy. After discontinuation of ethambutol, neurologic deterioration stabilized with subsequent improvement in visual fields. Conclusions: CMT2A2 is part of a group of genetic disorders which share an association with the process of mitochondrial fusion. This case shows that patients with CMT2A2, and possibly other mitochondrial fusion defects, may be uniquely susceptible to ethambutol‐induced neurotoxicity. This has implications regarding the underlying pathophysiology of mitochondrial fusion defects. Muscle Nerve, 2013     

Genetic epidemiology,demographic, and clinical characteristics of Charcot‐Marie‐tooth disease in the island of Gran Canaria (Spain)

Charcot‐Marie‐Tooth (CMT) disease is the most common hereditary neuromuscular disorder. This study involves the entire known CMT patient registry in Gran Canaria, represented by 256 patients belonging to 79 unrelated families, who were clinically and genetically characterized, along with physical and neurophysiological evaluation on 181 and 165 patients, respectively. Complete genotyping showed an estimated prevalence of CMT disease of 30.08/100 000 (95% confidence interval [CI] = 26.5;33.9), corresponding mainly (78.5%) to CMT1A (23.6/100 000) and hereditary neuropathy with liability to pressure palsies [HNPP] 17.5%; 5.29/100 000). Most patients (198) with CMT1A carried the 17p11.2 duplication including the PMP22 gene, 45 patients with HNPP were all affected by deletion of the 17p11.2 locus, and 10 patients presented with axonal phenotypes: CMT2A (MFN2), CMT2N (AARS), and CMT1X (GJB1). Despite showing a classical CMT1A phenotype, we found a much earlier age of onset in our CMT1A patients, along with increased frequency of appearance of postural hand tremor. Bilateral tongue atrophy was an additional phenotype observed. Being this CMT1A group, one of the largest cohorts known to date, this study provided a unique opportunity to further define the clinical phenotype of CMT1A patients carrying the 17p11.2 duplication in a homogeneous ethnic group.     

MFN2‐related genetic and clinical features in a cohort of Chinese CMT2 patients

Charcot‐Marie‐Tooth disease 2A (CMT2A), caused by mutations in the mitofusin 2 gene (MFN2), is the most common CMT2 subtype. The aim of our study is to assess the frequency and summarize the genetic and clinical characteristics of Chinese CMT2A patients. A total of 17 coding exons of MFN2 were detected by direct sequencing in 82 unrelated Chinese families diagnosed as CMT2. Clinical evaluations were analyzed among CMT2A patients. We identified 14 missense variants in 9 sporadic and 6 familial cases, including four novel mutations (T129A, S249F, Q367P, and Q674L), 4 known mutations (R94W, R94Q, T105M, C132Y, M376V and Q751X), and 4 rare missense variants (K120E, C217F, K307E and T356S). A total of 23 patients had early‐onset phenotype. Two patients had a CMTNS score of 0 to 10; 16 had a score of 11 to 20; and 7 had a score greater than 20. Five patients were confirmed a de novo origin. Six of 14 variants were located or closed to the GTPase domain. We report four novel mutations and four rare missense variants. MFN2 mutations account for 18% of CMT2 families in mainland China. The common characteristics of Chinese pedigree are early disease onset and moderate phenotypes.     

Diabetes mellitus exacerbates motor and sensory impairment in CMT1A

Abstract Charcot‐Marie‐Tooth disease type 1A (CMT1A) is caused by a duplication of PMP22 on chromosome 17 and is the most commonly inherited demyelinating neuropathy. Diabetes frequently causes predominantly sensory neuropathy. Whether diabetes exacerbates CMT1A is unknown. We identified 10 patients with CMT1A and diabetes and compared their impairment with 48 age‐matched control patients with CMT1A alone. Comparisons were made with the Charcot‐Marie‐Tooth disease (CMT) neuropathy score (CMTNS) and by electrophysiology. The CMTNS was significantly higher in patients with diabetes (20.25 ± 2.35) compared with controls (15.19 ± 0.69; p = 0.01). Values were particularly higher for motor signs and symptoms. Seven of the 10 diabetic patients had CMTNS >20 (severe CMT), while only 7 of the 48 age‐matched controls had scores >20. There was a trend for CMT1A patients with diabetes to have low compound muscle action potentials and sensory nerve action potentials, although nerve conduction velocities were not slower in diabetic patients compared with controls. Diabetes was associated with more severe motor and sensory impairment in patients with CMT1A.     

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.     

Late‐onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2‐related diseases

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot–Marie‐Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53‐year‐old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2‐related diseases. Sequencing of MFN2 should be considered in all patients presenting with late‐onset HSAN.     

Axonal excitability in X-linked dominant Charcot Marie Tooth disease

ObjectiveWe investigated peripheral nerve function in X-linked Charcot–Marie–Tooth disease type 1 (CMTX1), and considered the functional consequences of mutant connexin-32.MethodsTwelve subjects (9 female, 3 male) were assessed clinically, by nerve conduction and excitability studies. A model of myelinated axon was used to clarify the contributing changes.ResultsAll subjects had abnormal nerve conduction. Excitability studies on median nerve axons showed greater threshold changes to hyperpolarising currents, with “fanning out” in threshold electrotonus, and modest changes in the recovery cycle. Modelling suggested shortening of internodal length, increase in nodal fast potassium currents, shift of the voltage activation hyperpolarisation-activated cyclic-nucleotide-gated channels, and axonal hyperpolarisation. Plotting threshold versus extent of hyperpolarising threshold change in threshold electrotonus distinguished the CMTX1 patients from other chronic demyelinating neuropathies reported in the literature except hereditary neuropathy with pressure palsies (HNPP).ConclusionsSome measures of axonal excitability are similar in CMTX1 and HNPP (though not the recovery cycle), but they differ from those in other chronic demyelinating neuropathies. The findings in CMTX1 are consistent with known pathology, but are not correlated to neuropathy severity.SignificanceThe findings in CMTX1 could be largely the result of morphological alterations, rather than plasticity in channel expression or distribution.     

Early onset Charcot‐Marie‐Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2‐related neuropathy

Charcot‐Marie‐Tooth (CMT) syndromes are a group of clinically heterogeneous disorders of the peripheral nervous system. Mutations of mitofusin 2 (MFN2) have been recognized to be associated with CMT type 2A (CMT2A). CMT2A is primarily an axonal disorder resulting in motor and sensory neuropathy. We report a male child with psychomotor delay, dysmorphic features, and weakness of lower limbs associated with electrophysiological features of severe, sensory‐motor, axonal neuropathy. The patient was diagnosed with early onset CMT2A and severe psychomotor retardation associated with c.310C>T mutation (p.R104W) in MFN2 gene. CMT2A should be considered in patients with both axonal sensory‐motor neuropathy and developmental delay.     

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.     

Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot-Marie-Tooth disease (CMT). The aim of this study was to describe a de novo MFN2 p.R104W mutation and characterize the associated phenotype. We screened the entire coding region of MFN2 gene and characterized its clinical phenotype, nerve conduction studies and sural nerve biopsy. Neuropsychological tests and brain MRI were also performed. A de novo mutation was found in exon 4 (c.310C > T; p.R104W). In addition to a severe and early onset axonal neuropathy, the patient presented learning problems, obesity, glucose intolerance, leukoencephalopathy, brain atrophy and evidence of myelin involvement and mitochondrial structural changes on sural nerve biopsy. These results suggest that MFN2 p.R104W mutation is as a hot-spot for MFN2 gene associated to a large and complex range of phenotypes.     

Autosomal recessive Charcot‐Marie‐Tooth disease: from genes to phenotypes

The prevalence of Charcot‐Marie‐Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR‐CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino‐varus, claw‐like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR‐CMT.     

Charcot-Marie-Tooth disease: Histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and Connexin32 mutations (CMTX1)

The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5–10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6 ± 5.5 m/s) than in CMT1A patients (18.2 ± 6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 217–225, 1998     

Clinical and electrophysiologic features of HNPP patients with 17p11.2 deletion

OBJECTIVES: Although the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is important for correct prognostic evaluation and genetic counseling, the diagnosis is frequently missed or delayed. Our main aim on undertaking this study was to characterize the electrodiagnostic features of HNPP. MATERIAL AND METHODS: Clinical, electrophysiologic and molecular studies were performed on Korean HNPP patients with 17p11.2 deletion. The results of electrophysiologic studies were compared with those of Charcot-Marie-Tooth disease type 1 A (CMT1A) patients carrying 17p11.2 duplication. RESULTS: Eight HNPP (50 motor, 39 sensory nerves) and six CMT1A (28 motor, 16 sensory nerves) patients were included. Sensory nerve conduction was slow in 97% of HNPP nerves. Motor nerve conduction at common entrapment sites was also abnormally slow in 87.5%, whereas at non-entrapment sites conduction slowing was infrequent. Distal motor latency (DML) was prolonged in 80% of HNPP nerves, and terminal latency index (TLI) was significantly lower in HNPP than in normal controls and in CMT1A patients (P < 0.01). In contrast to CMT1A, where severity of nerve conduction slowing was not different among nerve groups, HNPP sensory nerve conduction was more slowed in the median and ulnar nerves than in the sural nerve (P < 0.01), and DML was more prolonged in the median nerve than in the other motor nerves (P < 0.01). TLIs were significantly lower in HNPP than in the normal control and CMT1A patients for the median and ulnar nerves (P < 0.01), and were also significantly reduced for the peroneal nerve (P < 0.05) compared with those of the normal controls. CONCLUSION: HNPP is characterized electrophysiologically by a generalized neuropathy, superimposed by focal entrapment neuropathies. The slowing of sensory conduction in nearly all nerves and the distal accentuation of motor conduction abnormalities are the main features of background polyneuropathy in HNPP. The distribution and severity of the background electrophysiologic abnormalities are closely related to the topography of common entrapment or compression sites, which suggests the possible pathogenetic role of subclinical pressure injury at these sites in the development of the distinct background polyneuropathy in HNPP.     

A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light, and kinesin) have been associated with the CMT2 phenotype. We identified a novel neurofilament-light missense mutation (C64T) that causes the disease in a large Slovenian CMT2 family. This novel mutation shows complete co-segregation with the dominantly inherited CMT2 phenotype in our family. Electronic Publication     

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     

Dispersion of compound muscle action potential in hereditary neuropathies and chronic inflammatory demyelinating polyneuropathy

Distal compound muscle action potential (DCMAP) dispersion, defined as a DCMAP duration > or = 9 ms, and proximal-distal (P-D) CMAP dispersion are considered useful in the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Distal and P-D CMAP dispersion have not been fully studied in hereditary neuropathies, and it is not known whether these measures distinguish hereditary from acquired demyelination. We compared DCMAP duration and P-D CMAP dispersion in 91 genetically characterized hereditary neuropathies and 33 subjects with CIDP. DCMAP dispersion was more frequent in nerves affected by CIDP (41.5%) than in Charcot-Marie-Tooth disease (CMT)1A (24.4%), CMT1B (7.4%), hereditary neuropathy with liability to pressure palsies (HNPP) (10.5%), or CMTX (9.8%). P-D CMAP dispersion was more frequent in CIDP (27.7% of nerves) than in hereditary neuropathies (16.3%) when applying American Academy of Neurology (AAN) criteria; however, its frequency was similar in CIDP and the hereditary neuropathies using the more restrictive criteria of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). Although dispersion is more common in CIDP than in the hereditary neuropathies, DCMAP and P-D dispersion occur in at least one motor nerve in a significant proportion of hereditary neuropathies, and cannot be used in isolation to distinguish acquired from hereditary demyelination.