Genetic test for Mendelian fatigue and muscle weakness syndromes.
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ABSTRACT:
SUBMITTER: Kiani AK
PROVIDER: S-EPMC8023128 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Chronic fatigue (CFg) is a prevalent symptom in Gaucher disease (GD) at diagnosis (79%) and remains in a quarter of patients after years of therapy. Bone abnormalities are present in over 70% and peripheral neuropathy in about 11% of the patients, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors such as muscle-tendinous weakness could have influence in the development of CFg. METHODS:We have evaluated the fiber structure and elasticity of muscle-tendinous unit by strain-elastography (S-ELA) and analyzed their influence in the CFg. S-ELA study was performed in Achilles tendon in 25 type 1 and two type 3 GD patients, all of them with fatigue and were on enzymatic replacement therapy for mean 13 years; simultaneously, bone marrow burden by MRI and calcaneus ultrasound densitometry were evaluated. Blood cell counts, plasma biomarkers, GBA1 genotyping, and SF36 quality of life scale (QoL) were also performed. STATISTICAL ANALYSIS:descriptive and comparative test. RESULTS:All patients showed a normal Achilles tendinous structure. Abnormal stiff grade 2-3 was found in 17/27 (62.9%); in 11/27 (40.7%) of patients, the alteration was bilateral. There were no correlations between the S-ELA results to other variables; nevertheless, a significant correlation between the degree of tendon hardness and the low score on the QoL scales (p = 0.0035) was found. The S-ELA is a sensitive painless, fast, and low cost method to detect muscle-tendinous subclinical dysfunction that could contribute to CFg in GD. The identification of subclinical tendon alteration would be a sign of alarm, focused on the risk of development of bone complications. CONCLUSION:Intratendinous alteration in strain-elastography is an independent variable in GD patients with persistent fatigue.
| S-EPMC6873505 | biostudies-literature
Project description:Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.
| S-EPMC8461820 | biostudies-literature
Project description:Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.
| S-EPMC9290089 | biostudies-literature
Project description:Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.
| S-EPMC9223019 | biostudies-literature
Project description:IntroductionLong-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits.MethodsMuscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control.ResultsMVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT.DiscussionElectrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.
| S-EPMC10702731 | biostudies-literature
Project description:Background/aimsWith improvements in the survival of liver transplantation (LT) recipients, the focus is shifting to patient quality of life (QOL), and employment is an important factor in aiding the social reintegration of LT patients. This study aims to evaluate the current employment status of liver graft recipients and various factors that may hinder reemployment.MethodsFifty patients above age 18 who underwent either living or deceased donor LT at a single center from March 2009 to July 2016 were interviewed during their visit to the outpatient clinic. The internally developed questionnaire consisted of 10 items. The Karnofsky Performance Scale and EQ-5D were used to evaluate patient function and QOL.ResultsA total of 25 (50%) patients returned to work after transplantation (the working group), and 21 (84%) patients in the working group returned to work within the first year after transplantation. In the non-working group (n=25), 17 (68%) answered that their health was the reason for unemployment. Fatigue and weakness were the most frequent symptoms.ConclusionThe data shows that as many as 50% of total patients returned to work after receiving LT. Fatigue and weakness were the most common complaints of the unemployed group, and resolving the causes of these symptoms may help to increase the employment rate.
| S-EPMC6313025 | biostudies-literature
Project description:OBJECTIVE:To describe the phenomenon of acute illness-associated weakness (AIAW) in patients with dystroglycanopathy (DG), determine the frequency of this phenomenon in DGs, and compare it to the frequency in Duchenne-Becker muscular dystrophy (DBMD). METHODS:Patients enrolled in a DG natural history study provided medical history, including major illnesses or hospitalizations, at enrollment and annually. We noted a recurring syndrome of profound transient weakness in the setting of febrile illness. To determine the frequency of this phenomenon in the DG cohort and compare it to a cohort with another membrane-related muscular dystrophy, DBMD, we surveyed patients (e-survey tool), collecting demographics and information about episodes of sudden progression of weakness and events surrounding the episodes. RESULTS:Surveys were completed by 52 (56.6%) patients with DG and 51 (27.3%) patients with DBMD. AIAW was reported in 12 (23%) patients with DG and 2 (4%) patients with DBMD (odds ratio 7.35; 95% confidence interval 1.55, 34.77; p = 0.005). Altogether (history or survey), 21 patients with DG, with mutations in FKRP, FKTN, POMT1, POMT2, or POMGNT1, reported AIAW. These events typically occurred in children <7 years old, and the preceding illness usually included respiratory symptoms. In 10 (47.6%) patients with DG, AIAW preceded the diagnosis of muscular dystrophy. CONCLUSIONS:People with DG, across genotypes, can experience acute, transient weakness associated with a febrile illness, a phenomenon that rarely occurs in DBMD. The physiologic basis of this phenomenon is unknown. CLINICALTRIALSGOV IDENTIFIER:NCT00313677.
| S-EPMC5719925 | biostudies-literature
Project description:BackgroundQuadriceps muscle weakness and reduced exercise tolerance are prevalent and associated with a worse prognosis in patients with cystic fibrosis (CF). The one-minute sit-to-stand test (1STST) has been proposed to evaluate functional exercise capacity and quadriceps strength.Research questionThe aim of the study was to verify the relationship between the 1STST and the maximal isometric voluntary contraction of the quadriceps (MVCQ) evaluated by the dynamometer in stable patients with CF and to evaluate the impact of intravenous (IV) antibiotherapy.MethodsDynamometer and 1STST were performed in stable patients with CF at a routine visit, the admission and the discharge of an IV antibiotherapy. Patients wore an activity monitor during 72 h during IV treatment.Results and significance51 stable patients with CF at a routine visit and 30 treated with IV antibiotherapy were recruited. In stable patients, the 1STST was reduced to a mean of 2101 nxkg (657-SD), representing a median of 79% (7; 142-min; max)) of the predicted values (%PV) as well as the MVCQ to 78.64 N-m (23.21; 170.34), representing 57%PV (26). The 1STST was correlated to MVCQ (r = 0.536; p < 0.0001) and lung function (r = 0.508; p = 0.0001). Over the IV antibiotherapy course, the 1STST improves significantly like lung function and body mass index while a positive trend for MVCQ was observed. The gain of 1STST was correlated to the change in MVCQ (r = 0.441; p = 0.02) and was significantly higher in hospitalized patients versus home therapy. The 1STST is a good alternative to the dynamometer to evaluate and assess muscular weakness for the routine visit and IV antibiotherapy.
| S-EPMC9508743 | biostudies-literature
Project description: Not available
| S-EPMC10467031 | biostudies-literature
Project description:Congenital facial weakness is present in a heterogeneous group of conditions. Among them is Moebius syndrome, which has been defined as a disorder with congenital, non-progressive facial weakness and limited abduction of one or both eyes. It is typically attributed to agenesis of the abducens and facial cranial nerves. This paper details ocular motor findings of 40 subjects (23 months to 64 years; 24 females, 16 males) with congenital facial weakness: 38 presented at a Moebius Syndrome Conference and two were clinic patients. A new classification scheme of patterns based on ocular motor phenotype is presented. Of 40 subjects, 37 had bilateral and three had unilateral facial weakness. The most common ocular motor pattern (Pattern 1, n=17, 43%) was bilateral horizontal gaze palsy with intact vertical range. Pattern 2 (n=10, 26%) was bilateral horizontal gaze palsy with variable vertical limitations. Pattern 3, which was rare, was isolated abduction deficits (n=2, 5%). Others had full motility range and did not meet minimal criteria for the diagnosis of Moebius syndrome (Pattern 4, n=10, 26%). One subject was too severely affected to characterize. Abnormal vertical smooth pursuit was present in 17 (57%) of 30 subjects: nine with Pattern 1, five with Pattern 2, and three with Pattern 4. Abnormal vertical saccades were present in 10 (34%) of 29 subjects. Vertical saccades appeared slow in nine: six with Pattern 1 and three with Pattern 2. Vertical saccades were absent in one subject with Pattern 2. Abnormal vertical optokinetic nystagmus was present in 19 (68%) of 28 subjects: 10 with Pattern 1, six with Pattern 2, one with Pattern 3, and two with Pattern 4. Reduced convergence was present in 19 (66%) of 29 subjects: nine with Pattern 1, six with Pattern 2, one with Pattern 3, and three with Pattern 4. The most common pattern of ocular motor deficit in Moebius syndrome is bilateral horizontal gaze palsy from pontine abducens nuclear defects, rather than abducens nerve involvement. Defects in the range or dynamic properties of vertical movements in subjects with congenital facial weakness may suggest involvement of ocular motor structures in the midbrain, including oculomotor nerves or nuclei, vertical supranuclear saccadic centres, and convergence neurons. Such deficits were found even in subjects with full vertical motility range. Classification of patterns of ocular motor deficits in congenital facial weakness may assist with further delineation of anatomic localization and identification of genetic deficits underlying these disorders.
| S-EPMC3959556 | biostudies-literature