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.

Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy.

INTRODUCTION: Pain mechanisms in fibromyalgia syndrome (FMS) are not clearly understood. Growing evidence appears to suggest a role for small fiber polyneuropathy (SFPN) in some FMS patients, as measured by epidermal nerve fiber density (ENFD). We aimed to better characterize and distinguish the subset of patients with both fibromyalgia and small fiber, early or mild sensory polyneuropathy (FM-SFSPN). METHODS: 155 FMS patients with neuropathic symptoms completed a Short Form McGill Questionnaire and visual analog scale in addition to having skin biopsies, nerve conduction studies (NCS), and serologic testing. RESULTS: Sural and medial plantar (MP) response amplitudes correlated with ENFD, with markers of metabolic syndrome being more prevalent in this subset of patients. Pain intensity and quality did not distinguish patients. DISCUSSION: The FM-SFSPN subset of patients may be identified through sural and MP sensory NCS and/or skin biopsy but cannot be identified by pain features and intensity. Muscle Nerve 58: 625-630, 2018.

The management and treatment of children with Fabry disease: A United States-based perspective.

Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013-2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, which would warrant treatment initiation. A comprehensive care plan should be implemented by the treating physicians to guide the management of children with Fabry disease.

Neuromuscular junction disorders mimicking myopathy.

INTRODUCTION: Small-amplitude, short-duration motor unit action potentials are non-specific findings seen in myopathies and neuromuscular junction (NMJ) disorders. NMJ studies (repetitive nerve stimulation and single-fiber electromyography) can determine if such findings are related to NMJ abnormalities but are not considered routinely in atypical cases. METHODS: Medical records of 338 patients with confirmed NMJ disorders were reviewed to identify cases with a clinical or electrodiagnostic impression of myopathy during initial evaluation. A history of muscle biopsy with findings that did not support a myopathic process was required for inclusion. RESULTS: Four patients met the inclusion criteria. NMJ studies were abnormal in all cases. One patient had elevated acetylcholine receptor antibodies. Three patients were antibody negative: 2 demonstrated immunotherapy responsiveness, and 1 had a Rapsyn mutation. CONCLUSIONS: NMJ disorders may mimic myopathies, and NMJ studies should be performed to clarify so-called "myopathic" electromyographic findings to avoid unnecessary testing and delayed diagnosis.

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.

Comparison of conventional and decomposition-enhanced spike triggered averaging techniques.

OBJECTIVE: Spike triggered averaging (STA) is a technique to extract an estimate of a recurring motor unit potential from a complex electromyographic (EMG) signal. In conventional STA (C-STA), potentials related to the discharges of single intramuscular motor units are isolated and used to trigger an averager to obtain an individual surface-detected motor unit potential (S-MUP) from an EMG signal. In decomposition-enhanced STA (DE-STA), EMG signal decomposition algorithms determine discharges of a number of different motor units (4 to 10) that can be used to trigger an averager to obtain their corresponding S-MUPs. We tested the accuracy of extracting and averaging S-MUPs using DE-STA compared to C-STA for the same EMG signals. METHODS: We compared the intramuscular potentials used for triggering and the resultant averaged S-MUPs that were common in both techniques. RESULTS: We found no statistically significant differences in the metrics used to describe the triggering potentials and S-MUPs. CONCLUSIONS: We conclude that DE-STA is an accurate and efficient method to obtain a large number of intramuscular motor unit potentials and their corresponding S-MUP in proximal and distal muscles.

Multifocal motor neuropathy: a review of pathogenesis, diagnosis, and treatment.

Multifocal motor neuropathy (MMN) is an uncommon, purely motor neuropathy associated with asymmetric deficits with predilection for upper limb involvement. Even in the early descriptions of MMN, the associations of anti-GM1 antibodies and robust response to immunomodulatory treatment were recognized. These features highlight the likelihood of an underlying autoimmune etiology of MMN. The clinical presentation of MMN can closely mimic several neurological conditions including those with more malignant prognoses such as motor neuron disease. Therefore early and rapid recognition of MMN is critical. Serological evidence of anti GM-1 antibodies and electrodiagnostic findings of conduction block are helpful diagnostic clues for MMN. Importantly, these diagnostic features are not universally present, and patients lacking these characteristic findings can demonstrate similar robust response to immunodulatory treatment. In the current review, recent research in the areas of diagnosis, pathogenesis, and treatment of MMN and needs for the future are discussed. The characteristic findings of MMN and treatment implications are reviewed and contrasted with other mimicking disorders.

Bent spine syndrome as an early manifestation of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is highly variable systemic disorder with prominent myopathic involvement in distal limb, facial, and jaw muscles. Bent spine syndrome presents a diagnostic challenge, and usually, DM1 is not included in the differential. We report 2 cases of DM1 with bent spine syndrome. To further investigate this phenomenon, we compared weakness patterns in a cohort of DM1 with cohorts of amyotrophic lateral sclerosis and inclusion body myositis and found that neck extension weakness is most pronounced in DM1. Our findings emphasize the heterogeneity of DM1 and underscore the importance of considering DM1 as a cause of bent spine syndrome.

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.

Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations.

Charcot-Marie-Tooth Type 2A is a dominantly inherited peripheral neuropathy characterized by axonal degeneration of sensory and motor nerves. The disease is caused by mutations in the mitochondrial fusion gene MFN2. Mfn2 is an integral outer mitochondrial membrane protein composed of a large GTPase domain and two heptad repeat (HR) domains that face the cytoplasm. Mitochondrial membrane fusion and division are balanced processes that are necessary to maintain tubular mitochondrial morphology, respiratory function, and uniform distribution of the organelle throughout the cell. We have utilized primary fibroblasts from CMT2A patients to survey mitochondrial phenotypes associated with heterozygous MFN2 alleles expressed at physiological levels. Our results indicate that, in fibroblasts, mitofusin expression, mitochondrial morphology, ultrastructure, mtDNA content, and respiratory capacity are not affected by the presence of mutant Mfn2 protein. Consistent with a lack of mitochondrial dysfunction, we also show that mitochondrial fusion occurs efficiently in CMT2A patient-derived fibroblasts. Our observations are in agreement with the neuronal specificity of the disease and are consistent with a recent finding that mitochondrial fusion can be maintained in cells that express mutant Mfn2 protein due to complementation by a second mitofusin, Mfn1. We discuss our results and those of others in terms of a comprehensive model for the mechanism(s) by which mutations in MFN2 may lead to CMT2A disease.

Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene.

BACKGROUND: Axonal neuropathy linked to the CMT2A locus was originally associated with a mutation in the KIF1B gene. However, mutations in this gene have not been described associated with any other CMT2A families. Recently, mutations in the MFN2 gene, encoding the mitochondrial GTPase mitofusin 2 (Mfn2), have been identified as causative of CMT2A in seven families. The authors report three additional CMT2A families associated with novel mutations in highly conserved regions of the Mfn2 GTPase domain. METHODS: The authors performed a standardized neuromuscular and nerve conduction examination, genotyped known CMT loci, and analyzed the MFN2 gene by direct sequencing in three pedigrees and 10 additional probands affected by axonal CMT. RESULTS: Sequencing of the MFN2 gene revealed a novel mutation in each family (c.818T>G, c.638T>C, and c.314C>T). The largest family demonstrated an age-independent variable expression such that approximately one quarter of individuals with the mutation presented with features mild enough as to remain occult even with electrophysiologic evaluation. CONCLUSION: These results confirm that the majority of cases of CMT linked to the CMT2A locus are due to MFN2 mutations. The phenotype is largely indistinguishable from KIF1B-related CMT and from CMT2E and CMT2F. At least in some families, as many as 25% of individuals with MFN2 mutations may be asymptomatic and have a normal electrophysiologic examination, although a detailed neuromuscular examination may suggest the trait. Given the frequency of MFN2 mutations among CMT2 probands (3/13, or 23%), genetic testing of CMT2 patients should begin with a screen of the MFN2 gene.

Counting motor units in chronic motor neuropathies.

The degree of motor unit loss can not be accurately quantified in chronic motor neuropathies with routine electrodiagnostic testing or with pathologic examination. We used motor unit number estimation (MUNE), which is a unique electrophysiologic method that can estimate the number of surviving motor units innervating a muscle, to study axonal loss in spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) neuropathies. MUNE is based on the ratio of the maximal compound muscle action potential (CMAP) to the average surface-recorded motor unit potential (S-MUP). The hypothenar muscle group was studied in infant and older subjects with SMA, and the hypothenar and biceps-brachialis muscle groups were studied in adult CMT1A and CMT2 subjects. The multiple point stimulation MUNE technique was used in SMA subjects and the spike triggered averaging MUNE technique was used in CMT subjects. In SMA, motor unit loss was profound in types 1 and 2 subjects and more moderate in type 3 subjects. In CMT, motor unit loss was prominent in distal muscles in both CMT1A and 2 subjects, and present in proximal muscles in CMT2 subjects. MUNE is efficient in assessing the degree of motor unit loss in chronic motor neuropathies. SMA is considered to be a proximal muscle disorder, but loss was marked in distal muscles in all SMA types. In CMT1A, the demyelinating form, motor unit loss was marked in distal muscles, consistent with the idea that axonal loss and not slow conduction velocity is the important pathologic condition. The pattern of proximal motor unit loss differed between CMT1A and 2, suggesting differences in underlying axonal pathology.

Assessment of axonal loss in Charcot-Marie-Tooth neuropathies.

Sensory loss and weakness in Charcot-Marie-Tooth (CMT) neuropathy is due to axonal loss. However, the pattern and degree of axonal loss cannot be accurately determined from routine electrodiagnostic or strength testing due to collateral reinnervation. We sought to quantify axonal loss in two upper extremity muscles in CMT1A and CMT2 subjects using the electrophysiologic endpoint measure of motor unit number estimation (MUNE). Hypothenar and biceps-brachialis muscle groups were studied in 9 CMT1A, 9 CMT2, and 10 control subjects. The spike-triggered averaging (STA) technique was used to collect surface motor unit potentials for MUNE calculations, and a needle electrode was used to collect corresponding intramuscular data. Maximal voluntary hypothenar and handgrip strength was measured quantitatively, while biceps-brachialis strength was measured qualitatively. Compared to normal subjects, CMT1A and CMT2 subjects had significantly lower MUNE values in hypothenar muscles. Biceps-brachialis MUNE values were reduced in CMT2 but not in CMT1A subjects. In support of proximal axonal loss in CMT2 subjects, surface motor unit and intramuscular potential amplitudes were higher in biceps-brachialis muscles compared to controls. Correlations between quantitative strength and MUNE were significant for hypothenar but not for grip muscle groups. Axonal loss is demonstrated in distal muscles in CMT1A and CMT2 supporting a length-dependent axonopathy. Despite clinical findings of normal or near-normal strength and small reductions in compound muscle action potential (CMAP) amplitude, MUNE values were significantly lower in CMT2 subjects in proximal muscles, consistent with more diffuse denervation. These data indicate that subclinical axonal loss is present that cannot be appreciated using clinical examination or routine electrodiagnostic techniques.