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Neuropathology and Applied Neurobiology Jun 2024Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult...
AIMS
Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency.
METHODS
We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy.
RESULTS
The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen.
CONCLUSIONS
The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.
Topics: Humans; Muscle, Skeletal; Middle Aged; Glucans; Proteomics; Glycogen Storage Disease; Male; Muscular Diseases; Glucosyltransferases; Glycoproteins; Nervous System Diseases
PubMed: 38923610
DOI: 10.1111/nan.12995 -
Molecular Genetics & Genomic Medicine Jun 2024To further comprehend the phenotype of multiple mitochondrial dysfunction syndrome type 3 (MMDS3:OMIM#615330) caused by IBA57 mutation. We present a case involving a...
OBJECTIVE
To further comprehend the phenotype of multiple mitochondrial dysfunction syndrome type 3 (MMDS3:OMIM#615330) caused by IBA57 mutation. We present a case involving a patient who experienced acute neurological regression, and the literature was reviewed.
METHODS
Clinical data and laboratory test results were collected; early language and development progress were tested; and genetic testing was performed. Bioinformatics analysis was performed using Mutation Taster and PolyPhen-2, and the literature in databases such as PubMed and CNKI was searched using MMDS3 and IBA57 as keywords.
RESULTS
The child, aged 1 year and 2 months, had motor decline, unable to sit alone, limited right arm movement, hypotonia, hyperreflexia of both knees, and Babinski sign positivity on the right side, accompanied by nystagmus. Blood lactate levels were elevated at 2.50 mmol/L. Brain MR indicated slight swelling in the bilateral frontoparietal and occipital white matter areas and the corpus callosum, with extensive abnormal signals on T1 and T2 images, along with the semioval center and occipital lobes bilaterally. The multiple abnormal signals in the brain suggested metabolic leukoencephalopathy. Whole-exome sequencing analysis revealed that the child had two heterozygous mutations in the IBA57 gene, c.286T>C (p.Y96H) (likely pathogenic, LP) and c.992T>A (p.L331Q) (variant of uncertain significance, VUS). As of March 2023, a literature search showed that 56 cases of MMDS3 caused by IBA57 mutation had been reported worldwide, with 35 cases reported in China. Among the 35 IBA57 mutations listed in the HGMD database, there were 28 missense or nonsense mutations, 2 splicing mutations, 2 small deletions, and 3 small insertions.
CONCLUSION
MMDS3 predominantly manifests in infancy, with primary symptoms including feeding difficulties, neurological functional regression, muscle weakness, with severe cases potentially leading to mortality. Diagnosis is supported by elevated lactate levels, multisystem impairment (including auditory and visual systems), and distinctive MRI findings. Whole-exome sequencing is crucial for diagnosis. Currently, cocktail therapy offers symptomatic relief.
Topics: Humans; Infant; Male; Phenotype; Mutation; Female; Microfilament Proteins; Carrier Proteins; Mitochondrial Diseases
PubMed: 38923322
DOI: 10.1002/mgg3.2485 -
Neuropathology : Official Journal of... Jun 2024Glycogen storage diseases (GSDs) are a group of metabolic disorders affecting glycogen metabolism, with polyglucosan body myopathy type 1 (PGBM1) being a rare variant...
Glycogen storage diseases (GSDs) are a group of metabolic disorders affecting glycogen metabolism, with polyglucosan body myopathy type 1 (PGBM1) being a rare variant linked to RBCK1 gene mutations. Understanding the clinical diversity of PGBM1 aids in better characterization of the disease. Two unrelated Iranian families with individuals exhibiting progressive muscle weakness underwent clinical evaluations, genetic analysis using whole exome sequencing (WES), and histopathological examinations of muscle biopsies. In one case, a novel homozygous RBCK1 variant was identified, presenting with isolated myopathy without cardiac or immune involvement. Conversely, the second case harbored a known homozygous RBCK1 variant, displaying a broader phenotype encompassing myopathy, cardiomyopathy, inflammation, and immunodeficiency. Histopathological analyses confirmed characteristic skeletal muscle abnormalities consistent with PGBM1. Our study contributes to the expanding understanding of RBCK1-related diseases, illustrating the spectrum of phenotypic variability associated with distinct RBCK1 variants. These findings underscore the importance of genotype-phenotype correlations in elucidating disease mechanisms and guiding clinical management. Furthermore, the utility of next-generation sequencing techniques in diagnosing complex neurogenetic disorders is emphasized, facilitating precise diagnosis and enabling tailored genetic counseling for affected individuals and their families.
PubMed: 38922716
DOI: 10.1111/neup.12993 -
JMIR Biomedical Engineering Jun 2024The hand is crucial for carrying out activities of daily living as well as social interaction. Functional use of the upper limb is affected in up to 55% to 75% of stroke...
BACKGROUND
The hand is crucial for carrying out activities of daily living as well as social interaction. Functional use of the upper limb is affected in up to 55% to 75% of stroke survivors 3 to 6 months after stroke. Rehabilitation can help restore function, and several rehabilitation devices have been designed to improve hand function. However, access to these devices is compromised in people with more severe loss of function.
OBJECTIVE
In this study, we aimed to observe stroke survivors with poor hand function interacting with a range of commonly used hand rehabilitation devices.
METHODS
Participants were engaged in an 8-week rehabilitation intervention at a technology-enriched rehabilitation gym. The participants spent 50-60 minutes of the 2-hour session in the upper limb section at least twice a week. Each participant communicated their rehabilitation goals, and an Action Research Arm Test (ARAT) was used to measure and categorize hand function as poor (scores of 0-9), moderate (scores of 10-56), or good (score of 57). Participants were observed during their interactions with 3 hand-based rehabilitation devices that focused on hand rehabilitation: the GripAble, NeuroBall, and Semi-Circular Peg Board. Observations of device interactions were recorded for each session.
RESULTS
A total of 29 participants were included in this study, of whom 10 (34%) had poor hand function, 17 (59%) had moderate hand function, and 2 (7%) had good hand function. There were no differences in the age and years after stroke among participants with poor hand function and those with moderate (P=.06 and P=.09, respectively) and good (P=.37 and P=.99, respectively) hand function. Regarding the ability of the 10 participants with poor hand function to interact with the 3 hand-based rehabilitation devices, 2 (20%) participants with an ARAT score greater than 0 were able to interact with the devices, whereas the other 8 (80%) who had an ARAT score of 0 could not. Their inability to interact with these devices was clinically examined, and the reason was determined to be a result of either the presence of (1) muscle tone or stiffness or (2) muscle weakness.
CONCLUSIONS
Not all stroke survivors with impairments in their hands can make use of currently available rehabilitation technologies. Those with an ARAT score of 0 cannot actively interact with hand rehabilitation devices, as they cannot carry out the hand movement necessary for such interaction. The design of devices for hand rehabilitation should consider the accessibility needs of those with poor hand function.
PubMed: 38922668
DOI: 10.2196/54159 -
Toxins May 2024This retrospective, observational study describes the clinical findings, case management trends, and outcomes of 83 dogs and nine cats exposed to eastern coral snakes in...
Retrospective Evaluation of Clinical and Clinicopathologic Findings, Case Management, and Outcome for Dogs and Cats Exposed to (Eastern Coral Snake): 92 Cases (2021-2022).
This retrospective, observational study describes the clinical findings, case management trends, and outcomes of 83 dogs and nine cats exposed to eastern coral snakes in a university teaching hospital setting. The medical records of dogs and cats that received antivenom following coral snake exposure were reviewed. Data collected included signalment, time to antivenom administration, physical and laboratory characteristics at presentation, clinical course during hospitalization, length of hospitalization, and survival to discharge. The mean time from presentation to coral snake antivenom administration was 2.26 ± 1.46 h. Excluding cases where the owner declined in-hospital care, the mean hospitalization time for dogs and cats was 50.8 h and 34 h, respectively. The mean number of antivenom vials was 1.29 (1-4). Gastrointestinal signs (vomiting and ptyalism) occurred in 42.2% (35/83) of dogs and 33.3% (3/9) of cats. Peripheral neurologic system deficits (ataxia, paresis to plegia, absent reflexes, and hypoventilation) were noted in 19.6% (18/92) of dogs and cats. Hemolysis was also common in 37.9% (25/66) of dogs but was not observed in cats. Mechanical ventilation (MV) was indicated in 12% (10/83) of dogs but no cats. Acute kidney injury (AKI), while rare, was a common cause of euthanasia at 20% (2/5) and was the most common complication during MV at 44.4% (4/9). Pigmenturia/hemolysis occurred in 88.9% (8/9) of MV cases and in all cases with AKI. Despite delays in antivenom administration by several hours, dogs and cats with coral snake exposure have low mortality rates (6% of dogs (5/83) and 0% of cats). Gastrointestinal signs were common but were not predictive of progression to neurological signs. Thus, differentiating between coral snake exposure and envenomation before the onset of neurological signs remains challenging.
Topics: Animals; Dogs; Antivenins; Retrospective Studies; Cats; Coral Snakes; Snake Bites; Cat Diseases; Elapid Venoms; Male; Female; Dog Diseases; Treatment Outcome; Venomous Snakes
PubMed: 38922141
DOI: 10.3390/toxins16060246 -
Neurology International Jun 2024Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy...
Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is to describe the efficacy and safety of nusinersen in treating spinal muscular atrophy in 20 pediatric and 18 adult patients across six treatment centers in Kuwait. Functional motor assessments (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module) were used to assess changes in motor function following nusinersen treatment. The safety assessment involved clinical monitoring of adverse events. The results demonstrate clinically meaningful or considerable improvement in motor performance for nearly all patients, lasting over 4 years in some cases. A total of 70% of patients in the pediatric cohort and 72% of patients in the adult cohort achieved a clinically meaningful improvement in motor function following nusinersen treatment. Additionally, nusinersen was well-tolerated in both cohorts. These findings add to the growing body of evidence relating to the clinical efficacy and safety of nusinersen.
PubMed: 38921951
DOI: 10.3390/neurolint16030047 -
Tomography (Ann Arbor, Mich.) Jun 2024The aim of the present study was to determine the gender respiratory differences of bilateral diaphragm thickness, respiratory pressures, and pulmonary function in...
The aim of the present study was to determine the gender respiratory differences of bilateral diaphragm thickness, respiratory pressures, and pulmonary function in patients with low back pain (LBP). A sample of 90 participants with nonspecific LBP was recruited and matched paired by sex (45 women and 45 men). Respiratory outcomes included bilateral diaphragm thickness by ultrasonography, respiratory muscle strength by maximum inspiratory (MIP) and expiratory (MEP) pressures, and pulmonary function by forced expiratory volume during 1 s (FEV), forced vital capacity (FVC) and FEV/FVC spirometry parameters. The comparison of respiratory outcomes presented significant differences ( < 0.001), with a large effect size ( = 1.26-1.58) showing means differences (95% CI) for MIP of -32.26 (-42.99, -21.53) cm HO, MEP of -50.66 (-64.08, -37.25) cm HO, FEV of -0.92 (-1.18, -0.65) L, and FVC of -1.00 (-1.32, -0.69) L, with lower values for females versus males. Gender-based respiratory differences were presented for maximum respiratory pressures and pulmonary function in patients with nonspecific LBP. Women presented greater inspiratory and expiratory muscle weakness as well as worse lung function, although these differences were not linked to diaphragm thickness during normal breathing.
Topics: Humans; Male; Female; Diaphragm; Low Back Pain; Ultrasonography; Adult; Middle Aged; Sex Factors; Respiratory Function Tests; Lung; Spirometry; Muscle Strength; Vital Capacity; Forced Expiratory Volume
PubMed: 38921944
DOI: 10.3390/tomography10060067 -
Development of a clinical diagnostic model for Bell's palsy in patients with facial muscle weakness.Biomolecules & Biomedicine Jun 2024Early diagnosis of Bell's palsy is crucial for effective patient management in primary care settings. This study aimed to develop a simplified diagnostic tool to enhance...
Early diagnosis of Bell's palsy is crucial for effective patient management in primary care settings. This study aimed to develop a simplified diagnostic tool to enhance the accuracy of identifying Bell's palsy among patients with facial muscle weakness. Data from 240 patients were analyzed using seven potential clinical evaluation indicators. Two diagnostic benchmarks were established: one based on clinical assessment and the other incorporating magnetic resonance imaging (MRI) findings. A multivariate logistic regression model was developed based on these benchmarks, resulting in the construction of a predictive tool evaluated through latent class models. Both models retained four key clinical indicators: absence of forehead wrinkles, accumulation of food and saliva inside the mouth on the affected side, presence of vesicular rash in the ear or pharynx, and lack of pain or symptoms associated with tick exposure, rash, or joint pain. The first model demonstrated excellent discriminative ability (area under the curve [AUC] = 0.96, 95% confidence interval [CI] 0.94 - 0.99) and calibration (P < 0.001), while the second model also showed good performance (AUC = 0.88, 95% CI 0.83 - 0.92) and calibration (P = 0.005). Bootstrap validation indicated no significant overfitting. The latent class defined by the first model significantly aligned with the clinical diagnosis group, while the second model showed lower consistency.
PubMed: 38920750
DOI: 10.17305/bb.2024.10677 -
Cureus May 2024Idiopathic inflammatory myopathy (IIM) represents a rare group of autoimmune conditions resulting in muscle weakness and includes polymyositis, dermatomyositis,...
Idiopathic inflammatory myopathy (IIM) represents a rare group of autoimmune conditions resulting in muscle weakness and includes polymyositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), overlap myositis, and inclusion body myositis. Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody IMNM represents a rare but increasingly recognized subtype of IIM. Here we report a case of a 65-year-old woman on rosuvastatin who presented with two months of progressive proximal muscle weakness, significant truncal weakness, and elevated creatine kinase concerning for rhabdomyolysis and inflammatory myopathy. The patient was eventually diagnosed on day 8 of her hospital stay with anti-HMGCR antibody IMNM after delayed testing for this specific myopathy. Increased awareness of this IIM subtype, as well as its risk factors and presenting features, might improve rapidity of testing and shorten hospital stays if the diagnosis is considered in the emergency department or early in the hospital course.
PubMed: 38919212
DOI: 10.7759/cureus.61094 -
Otology & Neurotology : Official... Jun 2024The purpose of this study was to evaluate the value of asymmetry values, gain, and pathological saccades of the video head impulse test (vHIT) in sudden sensorineural...
OBJECTIVE
The purpose of this study was to evaluate the value of asymmetry values, gain, and pathological saccades of the video head impulse test (vHIT) in sudden sensorineural hearing loss (SSNHL).
STUDY DESIGN
Retrospective study.
SETTING
Tertiary referral center.
PATIENTS
A total of 226 individuals diagnosed with unilateral definite SSNHL were hospitalized. The assessment included a comprehensive evaluation of medical history, pure-tone test, acoustic impedance, positional test, video nystagmography (VNG), vHIT, vestibular evoked myogenic potentials (VEMPs) and magnetic resonance.
INTERVENTIONS
vHIT, VNG, cVEMP, oVEMP. Statistical analysis was performed with SPSS version 22.0 for Windows.
MAIN OUTCOME MEASURES
The asymmetry values, gain, and pathological saccades of the vHIT.
RESULTS
The abnormal gain of vHIT in anterior, horizontal, and posterior canal in SSNHL patients with vertigo were revealed in 20 of 112 (17.9%), 24 of 112 (21.4%), and 60 of 112 (53.6%), respectively. The vHIT pathological saccades (overt + covert) of anterior, horizontal, and posterior canal in SSNHL patients with vertigo were observed in 5 of 112 (4.6%), 52 of 112 (46.4%), and 58 of 112 (51.8%), respectively. Multivariate analysis indicated that the prognosis of patients with vertigo was correlated with vHIT gain of posterior canal, pathological saccade in horizontal canal, asymmetric ratio of horizontal canal gain, asymmetric ratio of posterior canal gain, Canal paresis (%) on caloric test and spontaneous nystagmus.
CONCLUSION
In the vHIT of patients with SSNHL with vertigo, the posterior canal is most easily affected. Reduced gain of posterior canal, pathological saccade of horizontal canal, and larger asymmetric gain of posterior canal and horizontal canal may be negative prognostic factors.
PubMed: 38918071
DOI: 10.1097/MAO.0000000000004247