Generalized Muscle Weakness Research Articles

Ранняя манифестация младенческой формы болезни Помпе (случай из практики)

Despite the fact that more than 70% of hereditary diseases can be considered rare, their prevalence in the population is 2%. Pompe disease (glycogen storage disease type II, glycogenosis type II) is a rare genetic disease that is accompanied with a damage to muscle cells and nerve fibers due to the accumulation of glycogen in them. The latter is due to a deficiency of the acid alpha-glucosidase enzyme. The relevance of Pompe disease is due to her rarity and the set of nonspecific symptoms, as well as the fact that it can manifest at any age. Depending on the onset, early infantile and late adult forms are distinguished. The early infantile form of Pompe disease manifests itself from the first months of life, the clinic includes generalized muscle weakness, frequent respiratory infections, macroglossia, hepato- and cardiomegaly. The article describes a case of infantile Pompe disease in a child of the first year of life, which shows that without the results of specific tests, including genetic ones, the diagnosis will not be verified, and the way to a reasonable assignment of such tests often turns out to be long. A pediatrician, as well as subspecialist physicians, should be wary of infants with unusual combinations of symptoms, multiple organ lesions, since it is extremely important to transfer such a child for a consultation with a geneticist in a timely manner. Such actions will help not only save lives, but also preserve the quality of life of these patients. Due to the complexity of diagnosis, today it is promising to include Pompe disease in the list of diseases for newborn screening. In this case, the treatment will be preventive and will not allow the symptoms of the disease to develop. Preventive therapy will allow not only reduce the risk of fatal outcome in Pompe disease, but also significantly decrease the percentage of disability.

Clinical and Genetic Aspects of Juvenile Onset Pompe Disease.

Little is known about clinical symptomatology and genetics of juvenile onset Pompe disease (JOPD). The aims of this study were to analyze how these children are diagnosed, what clinical problems they have, and how phenotype is related to genotype. To accomplish this, we analyzed retrospectively data of 34 patients diagnosed after their first and before completion of their 18th birthday. Median age at diagnosis was 3.9 (range 1.1-17) years. Eight patients (23.5%) developed initial symptoms in the first year, 12 (35%) between 1 and 7 years, and 6 (18%) thereafter. Eight (23.5%) had no clinical symptoms at the time of diagnosis. Indications for diagnostics were a positive family history in three (9%), hyperCKemia in eight (23.5%), motor developmental delay in three (9%), and muscle weakness and/or pain in 17 (50%). Rare clinical signs were failure to thrive, recurrent diarrhea, and suspected hepatopathy with glycogen storage. Thirty-two different mutations were identified. Twenty-seven patients (79.5%) carried the milder c.32-13T > G mutation, known to be associated with a broad range of phenotypes. Three out of eight patients manifesting within the first year of life showed generalized muscle weakness, hypertrophic cardiomyopathy, and had to be ventilated during the course of disease, thereby demonstrating clinical overlap with infantile onset Pompe disease.These findings demonstrate that the phenotype of JOPD is broad and that the differential is not only restricted to neuromuscular disorders. Genotypic analysis was useful to delineate subjects with early onset JOPD from those with IOPD, but overall genotype-phenotype correlation was poor.

Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.

Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 variants, one shared variant (c.286T>C) has been previously reported, the remaining two (c.189delC and c.580A>G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.

Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection

Short-term and long-term persistent postacute sequelae of COVID-19 (PASC) have not been systematically evaluated. The incidence and evolution of PASC are dependent on time from infection, organ systems and tissue affected, vaccination status, variant of the virus, and geographic region. To estimate organ system-specific frequency and evolution of PASC. PubMed (MEDLINE), Scopus, the World Health Organization Global Literature on Coronavirus Disease, and CoronaCentral databases were searched from December 2019 through March 2021. A total of 2100 studies were identified from databases and through cited references. Studies providing data on PASC in children and adults were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for abstracting data were followed and performed independently by 2 reviewers. Quality was assessed using the Newcastle-Ottawa Scale for cohort studies. The main outcome was frequency of PASC diagnosed by (1) laboratory investigation, (2) radiologic pathology, and (3) clinical signs and symptoms. PASC were classified by organ system, ie, neurologic; cardiovascular; respiratory; digestive; dermatologic; and ear, nose, and throat as well as mental health, constitutional symptoms, and functional mobility. From a total of 2100 studies identified, 57 studies with 250 351 survivors of COVID-19 met inclusion criteria. The mean (SD) age of survivors was 54.4 (8.9) years, 140 196 (56%) were male, and 197 777 (79%) were hospitalized during acute COVID-19. High-income countries contributed 45 studies (79%). The median (IQR) proportion of COVID-19 survivors experiencing at least 1 PASC was 54.0% (45.0%-69.0%; 13 studies) at 1 month (short-term), 55.0% (34.8%-65.5%; 38 studies) at 2 to 5 months (intermediate-term), and 54.0% (31.0%-67.0%; 9 studies) at 6 or more months (long-term). Most prevalent pulmonary sequelae, neurologic disorders, mental health disorders, functional mobility impairments, and general and constitutional symptoms were chest imaging abnormality (median [IQR], 62.2% [45.8%-76.5%]), difficulty concentrating (median [IQR], 23.8% [20.4%-25.9%]), generalized anxiety disorder (median [IQR], 29.6% [14.0%-44.0%]), general functional impairments (median [IQR], 44.0% [23.4%-62.6%]), and fatigue or muscle weakness (median [IQR], 37.5% [25.4%-54.5%]), respectively. Other frequently reported symptoms included cardiac, dermatologic, digestive, and ear, nose, and throat disorders. In this systematic review, more than half of COVID-19 survivors experienced PASC 6 months after recovery. The most common PASC involved functional mobility impairments, pulmonary abnormalities, and mental health disorders. These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low- and middle-income countries.

Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor.

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.

Repetitive nerve stimulation test in patients with myasthenia gravis

Myasthenia gravis (MG) is a rare and an autoimmune disease mainly caused by antibodies against the acetylcholine receptor on the postsynaptic membrane at the neuromuscular junction. Localized or generalized muscle weakness is the predominant symptoms. Repetitive nerve stimulation (RNS) confirms diminished neuromuscular transmission. We aimed to study the RNS test in myasthenic patients in Mongolia.

Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy.

Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease’s severity.This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies.We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression.This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.

Abnormal Lower Extremity Movements in a Term Infant.

Abnormal Lower Extremity Movements in a Term Infant.

NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis.

Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.

Thymectomy for non-thymomatous myasthenia gravis: Short and long term outcomes, a single-center 10 years' experience

BackgroundMyasthenia gravis (MG) is an auto-immune disorder characterized by the production of abnormal antibodies to the acetylcholine receptors at the neuromuscular junction. Radical thymectomy in many forms of MG may lead to clinical improvement in 70–80% of cases. Our objectives were to demonstrate our short and long-term results of radical trans-sternal thymectomy. Patients and methodsRetrospective analysis of prospectively collected data from 48 consecutive patients with non-thymomatous MG, managed over 10 years. All patients with thymomatous MG were excluded. The myasthenia gravis activities of daily living (MG-ADL) scoring performed for all patients and the stage of disease determined by the Myasthenia Gravis Foundation of America (MGFA) classification. The primary endpoint of this study was to evaluate early first 30 days postoperative outcomes and the secondary endpoint was to determine complete stable remission, time of pharmacological remission, and decreasing MG-ADL scoring over 5 years follow-up. ResultsTotally, 48 patients included: 41 females (85.4%) and 7 males (14.5%). Generalized muscle weakness, shortness of breath, and easy fatigability were the most common presenting features. During 5 years follow up, 38 patients (79.1%) had decreased their medication dose. Time of pharmacological remission started (6–60) months. Complete stable remission (CSR) achieved in 44 patients (91.6%) over 60 months. Post-operative MG-ADL levels ranged between (12–24) scores, at the end of the follow-up period decrease to less than 10 scores. ConclusionRadical trans-sternal thymectomy for non-thymomatous MG is an effective and well-tolerated procedure that is associated with significant clinical improvement in the majority of patients.

Whole exome sequencing revealed a mutation in COL6A1 associated with ullrich congenital muscular dystrophy

Collagen type VI-related disorders consist of Ullrich congenital muscular dystrophies (UCMD) and Bethlem myopathy, in which these entities are at two opposite extremes of the phenotype continuum. Clinical characteristics include proximal joint contracture, distal joint hyperlaxity, generalized muscle weakness, normal cognitive function, and pulmonary insufficiency. Affected individuals have trouble standing up and walking independently. Mutations in 3 genes (COL6A1, COL6A2, and COL6A3) are associated with decreasing collagen-VI production and disrupting the microfibrillar network between skeletal muscles. In the present study, using whole-exome sequencing (WES), a pathogenic variant in the COL6A1 gene (NM_001848, c.868G>C, p.G290R) was detected in a Vietnamese family with UCMD patients. Segregation analysis by Sanger sequencing confirmed that this mutation was inherited in an autosomal dominant pattern. This study expands the breadth of congenital muscular dystrophies research landcape and underscores the efficiency of WES in investigating the etiology of this group of heterogeneous diseases. Insight about the underlying genetic causes could contribute to develop a well-timed treatment regimen and help patients make an informed decision about reproductive health.

The Right to Choose

The Right to Choose

Liver enzyme elevation and eosinophilia with atorvastatin: a case of probable DRESS without cutaneous symptoms

BackgroundDrug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening hypersensitivity reaction to medication. While a relatively rare phenomenon, early identification and discontinuation of the offending agent is pivotal to patient management. To our knowledge this is the first reported case of probable atorvastatin induced DRESS syndrome without rash.Case presentationAn adult female presented with 4 days of persistent fevers, abdominal and flank pain, malaise, and generalized muscle weakness without any cutaneous reaction following 20 days of therapy with atorvastatin. She was febrile (38.5 °C), at presentation with a heart rate of 72, and blood pressure of 93/51 mmHg. Her laboratory investigations at their peak demonstrated an Alkaline Phosphatase (ALP) of 792 U/L, Alanine aminotransferase (ALT) of 265 U/L, gamma glutamyl transferase (GGT) of 236 U/L, total bilirubin at 21 mg/dL, eosinophils 3100 cells/µL, leukocytes 20.2 K/µL, hemoglobin of 12.5 gm/dL. During her admission she had normal creatinine and troponin. Her serology for Hepatitis A, B and C were negative. Cytomegalovirus, Epstein-Barr viral serologies were negative. Antinuclear Antibody (ANA), rheumatoid factor, anti-neutrophil cytoplasmic antibody (ANCA), mitochondrial antibody, and smooth muscle antibody were negative. The patient was initially diagnosed as having pyelonephritis due to nonspecific bilateral flank pain but given ongoing fevers and lack of clinical and laboratory improvement with antibiotics, a diagnosis of atorvastatin induced DRESS syndrome was considered probable, and atorvastatin was discontinued. The patients’ clinical status improved gradually without any further therapy and her liver enzymes and eosinophils normalized over the course of a month.ConclusionIn patients who present with systemic organ involvement and eosinophilia, even without cutaneous manifestations, clinicians should apply the RegiSCAR criteria for DRESS syndrome. This can then help guide treatment with discontinuation of offending agent, or treatment with systemic corticosteroids.

A Phase II Clinical Trial of the Pan PI3K Inhibitor, Buparlisib, for the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia: Canadian Cancer Trials Group IND.216

Introduction: Inhibition of the phospho-inositol 3 kinase (PI3K) delta isoform is effective in the treatment of relapsed and refractory chronic lymphocytic leukemia (CLL) (Pongas G, et al. Semin Oncol 2016; 43: 647). The efficacy of this class of drugs is limited by the potency of the inhibitor and its toxicity profile. Buparlisib is an orally available pan-Class I PI3K inhibitor which has greater potency than idelalisib in vitro . Low P70S6k and raptor levels, both of which are downstream regulators of the PI3K/mTOR pathway, correlate with sensitivity to PI3K inhibitor activity in CLL lymphocytes in vitro (Amrein L, et al. Int J Cancer 2013; 133: 247-52). The recommended phase II dose of buparlisib is 100 mg daily po and the main toxicities in Phase I were hyperglycemia, hypertension and mood disturbance (Bendell JC, et al. J Clin Oncol. 2012;30:282-90). We conducted a single arm phase II trial of buparlisib in patients with relapsed and refractory CLL (NCT02340780) and attempted to correlate response with P70S6k and raptor levels.Methods: Patients with CLL requiring re-treatment after at least one prior line of therapy were eligible. Buparlisib 100 mg daily was administered continuously on 28-day cycles with dose reductions to 80 mg and 60 mg in the event of toxicity. Mood questionaires (PHQ-9 and GAD-7) were administered at study entry and with each treatment cycle. The primary endpoint was overall response rate, defined according to the Revised International Workship on CLL (Hallek 2008) incorporating updated recommendations for novel targeted agents (Cheson 2012). Additional endpoints included safety, duration of response and progression free survival. Levels of P70S6k and raptor were measured in isolated CLL cells prior to therapy with buparlisib and compared with mean values as per Amrein et al. Int J Cancer 2013;133: 247-52).Results: Between April 2015 and January 2017, fourteen patients were enrolled; Rai stage high (n=7), intermediate (n=6) and low (n=1). Of these, 13 were eligible for toxicity (1 ineligible due to inadequate washout period) and 11 for response assessment (2 did not complete 1 cycle of therapy). The median age was 74 years (61-87), male:female 8:5, ECOG 0-1 and median number of prior therapies 1 (range 1-3). No patients received prior therapy with idelalisib or other PI3K inhibitor; 3 received prior ibrutinib, including the ineligible patient. Six of 13 patients had a partial response (46.2%, 95%, CI: 19.2,74.9%), with a median duration of response of 14.4 months. Five patients with a best response of stable disease all experienced tumor shrinkage (figure). There were no complete responses. Patients received a median of 5 cycles of therapy (range 1 to 20), the dose intensity was 485.6 mg per week and 27.3% received > 90% of planned doses. Ten patients have stopped protocol therapy, 1 for progressive disease and 9 for therapy-related adverse events: hyperglycemia (n=4), mood disorder (n=3), fatigue and generalized muscle weakness (n=1), elevated AST (n=1), hypertension (n=1) and thrombocytopenia (n=1). Mood disorders improved after stopping therapy in all 3 patients. The most common related adverse events (>15%) were diarrhea, nausea, fatigue, anorexia and dysguesia; all were <grade 3 except for fatigue. Hyperglycemia was seen in 9/13 patients. There were no related serious adverse events. Among the 8 patients tested, no correlation was observed between biomarker level and response or progression free survival.Conclusion: The response rates of single-agent idelalisib (Brown JR, et al. JCO ASCO Annual Meeting Abstracts. 2013;31 abstract 7003) and buparlisib are comparable with a different toxicity profile, making buparlisib another potential therapeutic option in CLL. Better mitigation of toxicity is required to make this an acceptable therapy for patients and rational drug combinations are needed to improve the efficacy of this agent. We could not confirm the importance of P70S6K or raptor in this small clinical trial. Validating these biomarkers in a larger cohort may help to predict which CLL patients are most likely to benefit from therapy with a PI3K inhibitor. [Display omitted] DisclosuresAssouline:Bristol Myer Squibb: Speakers Bureau; Novartis Canada Inc.: Honoraria; Pfizer: Speakers Bureau; Paladin: Speakers Bureau; Janssen: Honoraria. Banerji:Roche: Research Funding; Lundbeck: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Caplan:Janssen: Honoraria. Owen:Roche: Consultancy, Honoraria, Research Funding; Lundbeck: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria; Celgene: Honoraria; AstraZeneca: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding. Robinson:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Abbvie: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Peters:Abbvie: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Hay:Roche: Research Funding; Abbvie: Research Funding; Kite: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding.

Mutational Profile and Analysis of Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Luspatercept: Phase 2 PACE-MDS Study

Background: Management of anemia is a common therapeutic challenge in patients (pts) with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept acts as a ligand trap for GDF11 and other TGF-β family ligands to suppress Smad2/3 signaling, promote late-stage erythroid differentiation, and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014; Attie K, Am J Hematol, 2014). Luspatercept has demonstrated clinical activity in ring-sideroblast positive (RS+,≥15% in bone marrow) MDS pts and comparable responses in non-RS+ pts with EPO<500 U/L. While RS+ pts have distinct clinical and molecular features including SF3B1 splicing mutations, non-RS+ pts have a more heterogeneous population of mutations.Aims: This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in pts with lower-risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI,≥8 weeks), and duration of HI-E. New analyses focus on clinical, molecular, and bone marrow morphological features of disease and factors associated with luspatercept response.Methods: Inclusion criteria: MDS IPSS low or int-1, age ≥18 yr, Hgb<10 g/dL (if <4U RBC/8 wks), no prior HMA, no current lenalidomide or erythropoiesis-stimulating agent (ESA). The dose-escalation phase of the study is completed. An expansion cohort was added to this phase 2 study to evaluate response in pts not qualified for the phase 3 MEDALIST trial (for regularly transfused RS+ pts refractory to ESA or EPO>200 U/L). These include pts with low transfusion burden (<4U RBC/8 weeks) and either 1) RS+ with baseline EPO ≤200 U/L or 2) non-RS+ and any EPO level. Non-RS+ pts allowed up to 6U RBC/8 wks. Pts treated every 3 weeks subcutaneously for up to 5 doses (titration up to 1.75 mg/kg) in the base study (NCT01749514) and are then eligible for long-term treatment up to 5 additional years (NCT02268383).Results: Data (as of 13Apr2017) were available for 88 pts treated at therapeutic dose levels (≥0.75 mg/kg) in both the base and ext studies. 88 pts were evaluable for IWG HI-E and 60 pts were evaluable for RBC-TI (baseline transfusions of ≥2 units/8 wks). 75 pts were evaluable for mutational data analysis.Baseline characteristics are shown in Table 1. In pts with mutational data, the most common mutations were SF3B1 (57%), TET2 (39%), DNMT3A (21%), ASXL1 (17%), and SRSF2 (11%). Response by subgroup is shown in Table 2.Responses were observed in both RS+ and non-RS+ pts of various mutational backgrounds. Many pts possessed mutations in multiple genes; pts carrying SF3B1 mutations tended to have increased response rates compared to SF3B1 WT pts. Other commonly observed (>10%) mutations (TET2, DNMT2A, ASXL1, and SRSF2) demonstrated similar responses in pts when either mutated or not. Longer-term data on all pts plus additional exploratory analyses of molecular, cellular, and morphologic parameters and their relationship to response will be presented at the meeting.Luspatercept has been well tolerated, with seven possibly related grade 3 non-serious adverse events (AE): ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, platelet count increase, and pleural effusion and four possibly related SAEs as of 15June2017: ataxia, general physical health deterioration, muscle weakness, and myalgia. Related AEs in >2 pts were headache, fatigue, hypertension, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and peripheral edema.Conclusions: Lower-risk MDS pts treated long-term with luspatercept demonstrated robust and sustained increases in Hgb and decreases in transfusion burden and a high rate of RBC-TI. Encouraging responses were seen across EPO levels up to 500 U/L in both RS+ and non-RS+ patients. The presence of an SF3B1 mutation was associated with a higher response in this initial cohort of pts and responses were also observed in SF3B1 WT pts with mutations typically associated with poor prognosis (e.g., ASXL1). The data support continued study of luspatercept in MDS pts, including aPhase 3 study in regularly-transfused RS+ pts with lower-risk MDS according to IPSS-R (MEDALIST study; NCT02631070; fully enrolled) and a future Phase 3 study planned in first-line lower-risk MDS pts. [Display omitted] DisclosuresPlatzbecker:Acceleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kiewe:Acceleron: Consultancy, Honoraria, Research Funding. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Radsak:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Gilead: Other: Travel support; Acceleron: Research Funding. Wilson:Acceleron: Employment, Equity Ownership. Zhang:Acceleron: Employment, Equity Ownership. Rovaldi:Acceleron: Employment, Equity Ownership. Laadem:Celgene: Employment, Equity Ownership. Sherman:Acceleron: Employment, Equity Ownership. Attie:Acceleron: Employment, Equity Ownership. Reynolds:Acceleron: Employment, Equity Ownership. Linde:Acceleron: Employment, Equity Ownership. Giagounidis:Celgene: Consultancy; Acceleron: Consultancy.

Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy.

The debilitating neuromuscular disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which harm 1 in 5000 newborn males and 1 in 11,000 newborns, respectively, are marked by progressive muscle wasting among other complications. While DMD causes generalized muscle weakness due to the absence of the dystrophin protein, SMA patients generally face motor neuron degeneration because of the lack of the survival motor neuron (SMN) protein. Many of the most promising therapies for both conditions restore the absent proteins dystrophin and SMN. Antisense oligonucleotide-mediated exon skipping and inclusion therapies are advancing clinically with the approved DMD therapies casimersen, eteplirsen, golodirsen, and viltolarsen, and the SMA therapy nusinersen. Existing antisense therapies focus on skeletal muscle for DMD and motor neurons for SMA, respectively. Through innovative techniques, such as peptide conjugation and multi-exon skipping, these therapies could be optimized for efficacy and applicability. By contrast, gene replacement therapy is administered only once to patients during treatment. Currently, only onasemnogene abeparvovec for SMA has been approved. Safety shortcomings remain a major challenge for gene therapy. Nevertheless, gene therapy for DMD has strong potential to restore dystrophin expression in patients. In light of promising functional improvements, antisense and gene therapies stand poised to elevate the lives of patients with DMD and SMA.

Phase 1b study of H3B-6545 in combination with palbociclib in women with metastatic estrogen receptor–positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

e13025 Background: H3B-6545, a highly Selective ERα Covalent Antagonist (SERCA), inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. At the dose of 450 mg daily, H3B-6545 has a manageable safety profile and demonstrated preliminary single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (Hamilton et al, San Antonio Breast Cancer Symposium, 2020). Methods: The study evaluates the safety, pharmacokinetics (PK), and efficacy of H3B-6545 in combination with palbociclib in patients with ER+, HER2- metastatic breast cancer (MBC). The escalation phase enrolls patients with 2 or more prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor were allowed. Results: As of January 31, 2021, 10 patients were enrolled; 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 3 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). One patient in Cohort 1 was not evaluable for dose limiting toxicity (DLT) assessment and no DLT was observed in the 6 evaluable patients. One patient discontinued study treatment because of progression and no patients discontinued study treatment due to adverse events (AE). Grade 3 or 4 neutropenia and thrombocytopenia were observed in 4 patients and 1 patient, respectively. One patient had grade 3 hypercalcemia, generalized muscle weakness, hypophosphatemia, fall, and anemia and one patient had grade 3 lipase increase. Four patients had grade 1 bradycardia or sinus bradycardia (asymptomatic) 1 patient had grade 2 sinus bradycardia (symptomatic, no intervention required). Preliminary PK analysis suggested no clinically relevant drug-drug interactions between H3B-6545 and palbociclib, to be confirmed with data from additional cohorts. Recruitment is currently ongoing in Cohort 2. Updated results will be presented. Conclusions: H3B-6545, in combination with palbociclib, was well-tolerated. Clinical trial information: NCT04288089.

A Challenging Diagnosis of Primary Hyperparathyroidism in an Adolescent Female

Background: Hypercalcemia secondary to primary hyperparathyroidism (PHPT) is less common in children than adults. Single parathyroid adenoma is commonly the cause of primary hyperparathyroidism in children. Clinical Case: We present a 15-year-old female with one-week history of abdominal pain despite taking over the counter antacids. Her initial work up by her primary care provider revealed serum calcium of 11.8 mg/dL (9.0–11.5) and creatinine of 0.8 mg/dL (0.4–1.2). A week later, she presented to the emergency department with same complaint. In ED, she was found to have hypercalcemia (12.8 mg/dl) with elevated parathyroid hormone (PTH) at 78.5 pg/mL (15–65). Her random urine calcium creatinine ratio was high at 2.1. Her 25OHD was 25 ng/mL (30–100). She had negative urine pregnancy test but had trace ketones, leukocyte esterase, blood and bacteria. CBC and CMP were otherwise unremarkable. She continued to complain abdominal pain with nausea, decrease appetite, fatigue, and general muscle weakness. There was no known family history of calcium or metabolic bone disorders. Her vital signs and physical exam were normal. Subsequent labs showed mild improvement of calcium between (11–12.3 mg/dL), PTH between 54.5 and 77 pg/mL, normal thyroid function. Ionized calcium was mildly elevated 6.0 mg/dL (4.5–5.3) but her repeat 25OHD was low at18 ng/mL. Serum phosphorus levels were relatively normal with lowest level of 2.5 mg/dL (2.7–4.5). Gliadin Deamidated IgA was detectable 15 U/mL (< 15.0 U/). Ultrasound of abdomen was significant for nonspecific mild hepatomegaly; kidneys were normal in size and appearance. Ultrasound of thyroid was significant for probably intrathyroid parathyroid, measuring 6 x 8 x 8 mm. Tc-Sestamibi scan did not confirm a parathyroid adenoma. Genetic testing for MEN-1 was negative. FHH- related genes (i.e. CASR) was positive for p.R990G variant resulting in a mild gain of function of the calcium-sensing receptor. Although previous Tc-Sestamibi scan was unremarkable, an over read of it raised a concern for questionable uptake in the left superior lobe. SPEC-CT demonstrated possible abnormal parathyroid tissue in the upper pole of the left thyroid. FNA of the left thyroid nodule confirmed likely intrathyroidal parathyroid adenoma. Subsequent follow up and treatment, including parathyroidectomy, was done by another institution. She underwent a left parathyroidectomy with normalization of serum calcium and PTH levels post operatively (10.1 mg/dl and 8 pg/mL, respectively) and has complete resolution of her previous abdominal and gastrointestinal symptoms. Conclusion: PHPT is uncommon in children and adolescents and is typically associated with a single parathyroid adenoma. High index of suspicion is key for early diagnosis of PHPT despite a negative Tc-Sestamibi initially.

A rare concurrence of giant cell tumor and Myasthenia gravis

Giant Cell tumors are rare, locally aggressive tumors, seen most commonly in long bones. These benign bone tumors are usually associated with disturbance of the bony architecture whereas, myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction and manifests as a generalized muscle weakness that might involve the respiratory muscles and can lead to development of other autoimmune conditions and myasthenic crisis. Here we are reporting a rare concurrence of Giant cell tumor and myasthenia gravis in a 50 year old patient in which we used sandwich technique of reconstruction, without any perioperative complications, that resulted in good functional outcome.

Myasthenia Gravis Misdiagnosed as Post-Thyroidectomy Recurrent Laryngeal Nerve Palsy: A Case Report

About 85% of patients with myasthenia gravis present with ptosis and generalised muscle weakness, but 15% may present with pure bulbar symptoms which can be misdiagnosed. We describe a 60-year old female patient with multinodular goitre who had symptom of dysphagia and was subjected to total thyroidectomy. Post-operatively she developed respiratory distress and had difficulty in phonation. Bilateral vocal cord palsy was identified and emergency tracheostomy was done. Review of the patient revealed a mass in the anterior mediastinum and the patient showed improvement with pyridostigmine. Thymoma was confirmed in the computed tomography scan. This case highlights the unanticipated problems faced due to an undiagnosed myasthenia gravis and the importance of having a high index of suspicion of myasthenia gravis in patients with subtle bulbar symptoms.