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Background/Aims: Peripheral neuropathies perturbate the sensorimotor system, causing difficulties in walking‐related motor tasks and, eventually, falls. Falls result in functional dependency and reliance on healthcare, especially in older persons. We investigated if peripheral neuropathy is a genuine risk factor for falls in the elderly and if quantification of postural control via posturography is helpful in identifying subjects at risk of falls. Methods: Seventeen older persons with a clinical polyneuropathic syndrome of the lower limbs and converging electrophysiology were compared with 14 older persons without polyneuropathy. All participants were characterized via quantitative motor and sensory testing, neuropsychological assessment, and self‐questionnaires. Video‐nystagmography and caloric test excluded vestibulocochlear dysfunction. For further analysis, all subjects were stratified into fallers and non‐fallers. Overall, 28 patients underwent computerized dynamic posturography for individual fall risk assessment. Regression analyses were performed to identify risk factors and predictive posturography parameters. Results: Neuropathy is an independent risk factor for falls in the elderly, while no differences were observed for age, gender, weight, frailty, DemTect test, timed "Up & Go" test, and dizziness‐related handicap score. In computerized dynamic posturography, fallers stepped more often to regain postural control in challenging conditions, while the Rhythmic Weight Shift test showed a lack of anterior‐posterior bidirectional voluntary control. Interpretation: Our study confirms peripheral neuropathy as a risk factor for older persons' falls. Fallers frequently used stepping to regain postural control. The voluntary control of this coping movement was impaired. Further investigations into these parameters' value in predicting the risk of falls in the elderly are warranted. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Myotonia is a key symptom of myotonic dystrophies (DM), and its quantification is challenging. This exploratory study evaluated the utility of tissue Doppler ultrasound (TDU) to assess myotonia in DM. Methods: Twelve DM patients (seven type‐1 DM [DM1] and five type‐2 DM [DM2]) and 20 age‐matched healthy subjects were included in this cross‐sectional study. After measuring cross‐sectional areas of the flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) muscles in a resting state, muscle contraction/relaxation time, time to peak tissue velocity, peak tissue velocity and velocity gradients of these muscles were measured via TDU while performing forced fist unclenching after fist closure. Additionally, grip strength, Medical Research Council Sum score and patient‐reported myotonia severity scores were assessed. Results: DM1 and DM2 patients had a lower grip strength than healthy subjects (p =.0001/p =.002). Patient‐reported myotonia did not differ between DM1 and DM2 patients. DM1 patients revealed FDS and EDC atrophy compared to DM2 patients and healthy subjects (p =.003/p =.004). TDU revealed prolonged muscle contraction and relaxation times in both DM subtypes, with prolonged time to reach FDS peak relaxation velocity and altered peak FDS relaxation velocity only in DM1 patients (p =.03/p =.003). Peak FDS relaxation velocity correlated inversely with C(C)TG repeat numbers in DM patients. Sensitivity of TDU parameters to detect myotonic dystrophy varied between 50% and 75%, with a specificity of 95%. Discussion: Our exploratory study suggests that TDU could serve as a novel tool to quantify myotonia in DM patients, but larger follow‐up studies are warranted to validate its diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Background: Recently, a disease modifying therapy has become available for transthyretin amyloid cardiomyopathy (ATTR-CM). A validated monitoring concept of treatment is lacking, but a current expert consensus recommends three clinical domains (clinical, biomarker and ECG/imaging) assessed by several measurable features to define disease progression. Methods: We retrospectively analyzed data of wild-type ATTR-CM patients initiating tafamidis therapy assessed within our local routine protocol at baseline and 6-months follow-up with respect to the frequency of values beyond the proposed thresholds defining disease progression. Additionally, associations of cardiac magnetic resonance (CMR) tomography with clinical domains were examined within a subgroup. Results: Sixty-two ATTR-CM patients were included (88.7% male, mean age 79 years). In total, 16.1% of patients had progress in the clinical and functional domain, 33.9% in the biomarker domain and 43.5% in the imaging/electrocardiography (ECG) domain, with the latter driven by deterioration of the diastolic dysfunction grade and global longitudinal strain. In total, 35.5% of patients showed progress in none, 35.5% in one, 29.0% in two and no patient in three domains, the latter indicating overall disease progression. A subgroup analysis of twenty-two patients with available baseline and follow-up CMR data revealed an increase in CMR-based extracellular volume by more than 5% in 18.2% of patients, with no significant correlation with progress in one of the clinical domains. Conclusions: We provide first frequency estimates of the markers of disease progression according to a recent expert consensus statement, which might help refine the multiparametric monitoring concept in patients with ATTR-CM. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Nonsystemic vasculitic neuropathy (NSVN) is characterized by a predominant lower limb involvement in many patients. Motor unit changes in upper extremity muscles have not been investigated in this subgroup but may be of interest for improving our understanding of the multifocal nature of the disease and counseling of patients about potential future symptoms. In this study we aimed to better understand subclinical motor involvement in the upper extremity muscles of patients with lower limb–predominant NSVN using the new motor unit number estimation (MUNE) method MScanFit. Methods: In this single‐center, cross‐sectional study, 14 patients with biopsy‐proven NSVN, with no clinical signs of upper extremity motor involvement, were investigated and compared with 14 age‐matched healthy controls. All participants were assessed clinically and by the MUNE method MScanFit to the abductor pollicis brevis muscle. Results: The number of motor units and peak CMAP amplitudes were significantly reduced in patients with NSVN (P =.003 and P =.004, respectively). Absolute median motor unit amplitudes and CMAP discontinuities were not significantly different (P =.246 and P =.1, respectively). CMAP discontinuities were not significantly correlated with motor unit loss (P =.15, rho = 0.4). The number of motor units did not correlate with clinical scores (P =.77, rho = 0.082). Discussion: Both MUNE and CMAP amplitudes showed motor involvement in upper extremity muscles in lower limb–predominant NSVN. Overall, there was no evidence of significant reinnervation. Investigations of the abductor pollicis brevis muscle did not show a correlation with overall functional disability of the patients. [ABSTRACT FROM AUTHOR]

Although—considering the risk–benefit ratio—botulinum neurotoxin A (BoNT/A) is unequivocally recommended to treat severe neurological diseases such as dystonia, this has not yet been determined for its endoscopic intragastric injection aimed at weight reduction in obesity. However, severe adverse effects of intragastric BoNT/A had not yet been reported, prompting some European countries to endorse its (off‐label) use and treat patients transnationally. We here present three cases of botulism after intragastric BoNT/A injections for obesity treatment in a Turkish hospital. Patients presented with cranial nerve affection, bulbar symptoms, and descending paresis, and benefited from treatment with BoNT antitoxin and pyridostigmine. We assume that iatrogenic botulism was induced by overdosing in combination with toxin spread via the highly vascularized gastric tissue. Of note, within a few weeks, more than 80 cases of iatrogenic botulism were reported across Europe after identical intragastric BoNT/A injections. These cases demonstrate the risks of BoNT/A injections if they are not applied within the limits of evidence‐based medicine. There is a need for international guidelines to define the indication and a safe dosing scheme, especially in the context of medical tourism. [ABSTRACT FROM AUTHOR]

Background and purpose: This study assessed the prevalence of anti‐SARS‐CoV‐2 antibodies in therapeutic immunoglobulin and their impact on serological response to COVID‐19 mRNA vaccine in patients with intravenous immunoglobulin (IVIg)‐treated chronic immune neuropathies. Methods: Forty‐six samples of different brands or lots of IVIg or subcutaneous IgG were analyzed for anti‐SARS‐CoV‐2 IgG using enzyme‐linked immunosorbent assay and chemiluminescent microparticle immunoassay. Blood sera from 16 patients with immune neuropathies were prospectively analyzed for anti‐SARS‐CoV‐2 IgA, IgG, and IgM before and 1 week after IVIg infusion subsequent to consecutive COVID‐19 mRNA vaccine doses and after 12 weeks. These were compared to 42 healthy subjects. Results: Twenty‐four (52%) therapeutic immunoglobulin samples contained anti‐SARS‐CoV‐2 IgG. All patients with immune neuropathies (mean age = 65 ± 16 years, 25% female) were positive for anti‐SARS‐CoV‐2 IgG after COVID‐19 vaccination. Anti‐SARS‐CoV‐2 IgA titers significantly decreased 12–14 weeks after vaccination (p = 0.02), whereas IgG titers remained stable (p = 0.2). IVIg did not significantly reduce intraindividual anti‐SARS‐CoV‐2 IgA/IgG serum titers in immune neuropathies (p = 0.69). IVIg‐derived anti‐SARS‐CoV‐2 IgG did not alter serum anti‐SARS‐CoV‐2 IgG decrease after IVIg administration (p = 0.67). Conclusions: Our study indicates that IVIg does not impair the antibody response to COVID‐19 mRNA vaccine in a short‐term observation, when administered a minimum of 2 weeks after each vaccine dose. The infusion of current IVIg preparations that contain anti‐SARS‐CoV‐2 IgG does not significantly alter serum anti‐SARS‐CoV‐2 IgG titers. [ABSTRACT FROM AUTHOR]

Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia. Gene therapy, in particular adeno-associated virus (AAV)-based, is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies, such as tauopathies. Employing AAV-based gene therapy to treat, in particular, genetic tauopathies has many potential therapeutic benefits, but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies. In this Viewpoint, we briefly introduce some potentially treatable tauopathies, classify them according to their etiology, and discuss the potential advantages and possible problems of AAV-based gene therapy. Finally, we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies. [ABSTRACT FROM AUTHOR]

A man in his 20s gave a 9- year history of recurrent muscle pain and weakness, occurring mostly after exercise, and lasting for up to 2 days. There had been one episode of severe rhabdomyolysis after cold exposure. He also had longstanding hypokalaemia, which was key to his correct diagnosis but was not followed. This case highlights the importance of an appropriately methodical investigation of weak hypokalaemic patients, and the relevance of hypokalaemia as a cause of neuromuscular symptoms not related to muscular channelopathies. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to assess the organization and short‐term changes of motor units in adult patients with spinal muscular atrophy (SMA) treated with nusinersen. Methods: In this single‐centre cross‐sectional and longitudinal study 15 adult patients with SMA type 3 were assessed and compared to 15 age‐matched healthy controls and nine patients with amyotrophic lateral sclerosis. Moreover, 10 patients with SMA were followed up after 4–8 months. All patients were investigated clinically and by the motor unit number estimation method MScanFit of the abductor pollicis brevis muscle. Results: The number of motor units (p < 0.001) was significantly lower in patients with SMA compared to healthy controls at study entry. Mean unit amplitude, median amplitude and largest unit (p < 0.001) were significantly increased in patients with SMA. Patients with amyotrophic lateral sclerosis showed a significant reduction of compound muscle action potential (p = 0.005) and number of motor units (p = 0.03) compared to patients with SMA, accompanied by a larger median amplitude (p = 0.03). A prospective analysis identified patients with the ability to walk to improve the number of motor units (p = 0.046) accompanied by a decreased median amplitude (p = 0.03). Electrophysiological measures showed a moderate to strong correlation with clinical scores. Conclusion: Patients with SMA show loss of motor units in distal muscles. MScanFit variables indicate that compound muscle action potential amplitudes are maintained by collateral sprouting. Prospective analyses suggest that milder affected adult patients with SMA preferentially benefit from nusinersen treatment through recovery of smaller motor units. Correlations with clinical scores underline the potential of MScanFit as a surrogate marker. [ABSTRACT FROM AUTHOR]

Keywords: VPS13D; phenotype-genotype correlation EN VPS13D phenotype-genotype correlation 803 806 4 07/21/21 20210701 NES 210701 Here, we report two siblings with compound heterozygous variants in I VPS13D i but a considerable divergent phenotype highlighting the difficulties of phenotype-genotype correlation in this rare disease. In contrast, non-essential splice site/LOF mutations or other mutation type combinations might be associated with a broader and more severe spectrum of phenotypes.2 Given our siblings' identical compound heterozygous I VPS13D i variants and their unlike phenotypes, a specific phenotype-genotype correlation seems questionable. This makes it even more important to be aware of this gene, especially in patients presenting with childhood-onset ataxia-plus syndrome or suspected hereditary spastic paraplegia with or without mental disability. [Extracted from the article]

Hereditary lower motor neuron diseases (LMND) other than 5q‐spinal muscular atrophy (5q‐SMA) can be classified according to affected muscle groups. Proximal and distal forms of non‐5q‐SMA represent a clinically and genetically heterogeneous spectrum characterized by significant overlaps with axonal forms of Charcot–Marie–Tooth (CMT) disease. A consensus for the best approach to molecular diagnosis needs to be reached, especially in light of continuous novel gene discovery and falling costs of next‐generation sequencing (NGS). We performed exome sequencing (ES) in 41 families presenting with non‐5q‐SMA or axonal CMT, 25 of which had undergone a previous negative neuromuscular disease (NMD) gene panel analysis. The total diagnostic yield of ES was 41%. Diagnostic success in the cohort with a previous NMD‐panel analysis was significantly extended by ES, primarily due to novel gene associated‐phenotypes and uncharacteristic phenotypic presentations. We recommend early ES for individuals with hereditary LMND presenting uncharacteristic or significantly overlapping features. As mitochondrial dysfunction was the underlying pathomechanism in 47% of the solved individuals, we highlight the sensitivity of the anterior horn cell and peripheral nerve to mitochondrial imbalance as well as the necessity to screen for mitochondrial disorders in individuals presenting predominant lower motor neuron symptoms. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord, and comprises a broad clinical spectrum. With the advent of new therapies (e.g., Nusinersen) for patients of all ages and disease stages, sensitive clinical measures are needed to detect slight changes in muscle force even in immobilized, severely affected patients often unable to move limbs. As for these patients, well-established outcome scales set out to evaluate motor function do not work properly, we propose measurement of maximum bite force which is able to detect subtle changes of bulbar function. Requirements for this approach are mentioned, challenges are discussed, and first insights from a pilot study are presented. Finally, a study design is proposed to evaluate the measurement of maximum bite force during the follow up of SMA patients with and without a disease modifying therapy. [ABSTRACT FROM AUTHOR]

We aimed to systematically investigate the neuromuscular involvement of individuals with PRUNE mutations who may have a major spinal motor neuron involvement as part of the PRUNE-associated neurodegenerative phenotype. The complex neurological phenotypes associated with Prune mutations include microcephaly with brain abnormalities, spasticity, seizures, severe developmental delay and developmental regression. We used whole exome sequencing to identify the mutation and electrophysiological and muscle biopsy studies to evaluate the signs of spinal motor neuron involvement. The affected individuals carry homozygous PRUNE mutation (NM&lowbar;021222.1, c.316G>A, p.D106N), showing the signs of spinal motor neuron involvement supported by electrophysiological and muscle biopsy findings and also persistent high creatine kinase levels. We confirm that individuals with PRUNE mutations may have a major spinal motor neuron involvement as part of the PRUNE-associated neurodegenerative phenotype. The PRUNE gene should be considered in all the individuals with non-5q spinal muscular atrophy. High creatine kinase values may be a part of PRUNE disease spectrum. [ABSTRACT FROM AUTHOR]

Abstract: Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non‐5q‐SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large‐scale studies are not available. We tested the clinical utility of targeted sequencing in non‐5q‐SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent‐AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent‐SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate. [ABSTRACT FROM AUTHOR]

Background: Small fiber neuropathy (SFN) is a challenging subtype of peripheral neuropathies. Once the diagnosis has been established, there is an uncertainty how SFN may progress, whether larger fibers will become involved over time, whether quality of life may be compromised, or whether repeated diagnostic workup in patients with unknown underlying cause may increase the yield of treatable causes of SFN. Methods: We evaluated 16 patients with documented long-time course of idiopathic SFN. Results: Clinical and electrophysiological course remained stable in 75% of the patients, while 25% SFN-patients developed large fiber neuropathies. Conclusions: Our data suggest that SFN represents a benign disease course in the majority of patients without severely limiting the quality of life. [ABSTRACT FROM AUTHOR]