Evaluation Of Neuromuscular Disorders Research Articles

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review.

The diagnosis of inherited neuromuscular disorders is challenging due to their genetic and phenotypic variability. Traditionally, neurophysiology and histopathology were primarily used in the initial diagnostic approach to these conditions. Sanger sequencing for molecular diagnosis was less frequently utilized as its application was a time-consuming and cost-intensive process. The advent and accessibility of next-generation sequencing (NGS) has revolutionized the evaluation process of genetically heterogenous neuromuscular disorders. Current NGS diagnostic testing approaches include gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS). Gene panels are often the most widely used, being more accessible due to availability and affordability. In this mini-review, we describe the benefits and risks of clinical genetic testing. We also discuss the utility, benefits, challenges, and limitations of using gene panels in the evaluation of neuromuscular disorders.

Basic requirements to establish a neuromuscular laboratory.

Histopathological analysis of muscle biopsy is a prerequisite in the evaluation of neuromuscular disorders, particularly inflammatory myopathies, metabolic myopathies, congenital myopathies, muscular dystrophies and differentiating myopathies and neurogenic disorders with overlapping clinically features. It not only provides useful information that helps in the diagnosis but also treatment and management. Fundamental skills and basic knowledge regarding handling, processing and analyzing a muscle biopsy are required in any specialized or a general pathology lab supporting neuromuscular clinical services. Care during transport of the muscle biopsy, sample receipt in the laboratory and grossing is very important. Standard operating procedure should be followed for the preanalytical steps (freezing and cryomicrotomy), routine and special staining (enzyme and non enzymatic) and immunohistochemistry. A well organized neuromuscular laboratory with good quality management system is necessary for the practice of myopathology. This article gives an overview of establishing such a laboratory.

Impact of evolution of molecular technologies on evaluation of Neuromuscular Disorders in India at a Centre in Mumbai.

Abstract:
 Advances in molecular methods has made genetic testing as an imperative parameter, to be used in research studies and clinical practice. The present article includes the evolution of Molecular Diagnostic techniques over a period of two decades leading to the corresponding expansion in identification & classification of various Neuromuscular disorders in the population of mainly Western India.
 Initially conventional testing was done by mPCR, RFLP-PCR for single gene disorders like DMD/BMD & SMA respectively; followed by MLPA technique, for deletion duplication analysis. Under a research study, immuno-specific Western Blot was used for protein analysis as an initial screening tool for LGMD2B. Sangers sequencing was done for single gene (for a few LGMD2B cases) & known familial variants of LGMD2B & LGMD2A and GNE myopathy. Availability of Next generation sequencing technique involving massive parallel sequencing of multiple genes, improved the possibility of identifying the disease causing/ pathogenic mutations in phenotypically overlapping NMDs like LGMDs and Hereditary Neuropathies.
 Since last 12 years, over 2,600 patients from mainly western India have been analysed for various neuromuscular disorders. Carrier status of relatives of the probands was also determined in many of the cases. These molecular technologies have enabled to attained definitive diagnosis of different neuromuscular disorders in India. The diagnostic and predictive data generated helps in better management of the disease. It also has immense relevance in carrier and prenatal testing for the families at risk, thereby limiting the occurrence of the diseases in the population.

Portable microcontroller‐based electrostimulation system for nerve conduction studies

Despite nerve conduction study (NCS) being an established procedure in the evaluation of neuromuscular disorders, its utility has been restrained by commercially available products or approaches presented in the literature that are either costly, physically large, dependent on specialised medical personnel to operate or targeted to specific conditions, evaluating only one or two nerves. Therefore, the objective of this work was to develop a point-of-care device for NCS that can be used to evaluate several nerves, yet is still portable, low-cost and easy to operate. The developed device is composed of three modules: (i) controller module and graphical user interface, responsible for system synchronisation and configuration, data management, graphical visualisation of the evoked action potential and stimulus voltage feedback (maximum error of 3.92%); (ii) stimulation module, which operates in a constant voltage mode and delivers a monophasic stimulus pulse with amplitudes between 0.84 and 230 V, with a discrete increment of 2.32 ± 0.64 V (mean ± SD) and duration of 100 or 200 µs; and (iii) data acquisition module, based on the ADS1298 front-end that records the evoked action potentials after the stimulus, with a sample rate of 16 or 32 kHz, 24-bit resolution and selectable voltage gain of 1 up to 12. Results demonstrated that the system could reliably deliver stimulation pulses through different loads (100 Ω, 1 kΩ and 10 kΩ) and accurately record data through frequencies of 10 Hz up to 10 kHz. Additionally, NCS of the ulnar motor nerve in a sample of healthy individuals showed that the device could effectively activate a peripheral nerve and record compound action potentials within normal limits established by the literature.

Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders.

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

The role of magnetic resonance imaging techniques in evaluation and management of the idiopathic inflammatory myopathies.

Magnetic resonance imaging (MRI) is an important tool in the evaluation of neuromuscular disorders. MRI accurately demonstrates muscle oedema, atrophy, subcutaneous pathology and fatty infiltration and also highlights the distribution of muscle involvement. This review examines the role of MRI in evaluation of the idiopathic inflammatory myopathies (IIMs), a heterogeneous group of autoimmune conditions characterised by muscle inflammation and a variety of extra-muscular manifestations. MRI has a clear role in aiding diagnosis of these conditions, guiding muscle biopsy, differentiating subtypes of IIM using a pattern-based approach, and monitoring disease activity in a longitudinal fashion. Whole body MRI is an emerging technique that offers several advantages over regional MRI, but is not currently widely available. We will also consider newer MRI techniques which provide detailed information regarding the metabolism, function and structure of muscle, although their use is restricted to research purposes at present.

Magnetic resonance imaging and spectroscopy in the evaluation of neuromuscular disorders and fatigue

Magnetic resonance imaging represents a validated diagnostic tool in the investigation of neuromuscular disorders. Magnetic resonance imaging can detect key skeletal muscle abnormalities such as size, shape and signal intensity changes reflecting fatty infiltration, muscle atrophy or muscle edema. In vivo phosphorus magnetic resonance spectroscopy is able to provide objective measurements of muscle energy metabolism and cytosolic pH at rest, during exercise, and during recovery from exercise. Its primary role is the investigating of metabolic myopathies, and it has been used to detect the underlying biochemical mechanisms responsible for the development of fatigue. In this mini-review, we report the main contribution provided by conventional and advanced magnetic resonance imaging and phosphorus magnetic resonance spectroscopy in the exploration of fatigue in normal muscle and in neuromuscular disorders.

Differences in EMG spike shape between individuals with and without non-specific arm pain

The purpose of this study was to determine whether spike shape analysis of surface electromyographic (SEMG) activity is a useful tool to study muscle disorders. This study investigated SEMG spike shape parameters at low levels of contraction and changes in SEMG spike shape across different levels of isometric wrist extension contractions in individuals with non-specific arm pain (NSAP), asymptomatic subjects deemed at-risk for repetitive strain injury, and asymptomatic control subjects. Twenty-two asymptomatic control subjects, 8 at-risk subjects, and 16 subjects with NSAP participated. Bipolar SEMG data were recorded from the ECRB muscle during isometric wrist extension contractions at 10, 20, 30, 40, 50, 60, and 70% of maximum voluntary contraction (MVC) force performed in a randomized order. Five criterion measures: mean spike amplitude (MSA), mean spike duration (MSD), mean spike slope (MSS), mean spike frequency (MSF), and mean number of peaks per spike (MNPPS) were computed from each SEMG signal. A one-way analysis of covariance (ANCOVA) of the spike shape parameters computed from the 10% MVC data, with group as a main effect and age as a covariate, revealed a significant group by age interaction for MSA, and significant group main effects for MSS and MNPPS, where the NSAP group had lower MSS and lower MNPPS than the control subjects. An ANCOVA including group as a main effect and contraction level and age as covariates revealed that all three groups showed predictable changes in the spike shape analysis criterion measures over increasing contraction force levels, where motor unit recruitment and rate coding appear to be the primary mechanisms for increasing force output of the muscle. Significant interactions between group and contraction level were observed for MSD, MSA, MSS, and MNPPS. The NSAP group presented with differences in how the spike shape measures change with increasing contraction level that may be indicative of myogenic changes, a result that is consistent with previous quantitative EMG findings. This work provides evidence that NSAP involves myogenic changes in the ECRB muscle and that spike shape analysis may be a valuable non-invasive tool in the evaluation of neuromuscular disorders.

Muscle and nerve biopsy in the evaluation of neuromuscular disorders: The surgeon's perspective

Background/Purpose: A muscle biopsy frequently is requested by the neurologist evaluating a child with neuromuscular symptoms. However, there are no reports discussing the preoperative evaluation for, and diagnostic yield of, this procedure. The authors reviewed our experience over a 10-year period to obtain these data. Methods: The records of 153 patients who underwent muscle biopsy were reviewed with particular attention to the cardiology evaluation, the pathology report, and any resultant change in diagnosis and treatment of the child. Results: All 153 specimens contained adequate tissue for complete histological analysis. Preoperative cardiology consults were obtained in 82% of the children, with abnormalities found in 9%. Severe cardiac dysfunction was found in three chidren, all of whom had a previously diagnosed cardiomyopathy or dysrhythmia. No pathological abnormality was found in 41% of the muscle biopsy specimens, and nonspecific pathological findings were described in 23%. A specific diagnosis was made in 36%. Only 19% of the children had their treatment changed by the results of the muscle biopsy. Conclusions: Muscle biopsies can be performed safely without routine preoperative cardiac evaluation. A specific diagnosis, however, may be made in less than half of the patients with a change in therapy available for even fewer.

Thermography and the Evaluation of Neuromuscular Disorders

Thermography and the Evaluation of Neuromuscular Disorders

Ultrastructural Fiber Typing in Normal and Diseased Human Muscle

Histochemical analysis of muscle biopsies is well established as being essential for the definitive evaluation of neuromuscular disorders. The usefulness of electron microscopy as both a diagnostic and research tool in the study of diseased skeletal muscle has also been demonstrated. Reliable cross-correlation between histochemical and electron microscopic findings would appear to be useful. Based on the variations of the histochemical reaction for myofibrillar ATPase, there appear to be three constant categories in normal human skeletal muscle (types I, IIA and IIB). An attempt has therefore been made to define the ultrastructural correlates of each of these three major fiber types based on the measurements of Z-line and M-line widths. We have recently had the opportunity to study biopsied muscle from patients with 3 muscle disease states in which there was a relative deficiency of at least one of the 3 fiber types.