Neuromuscular Symptoms Research Articles

Challenges Linked to Post-Polio-Paralysis in Khyber Pakhtunkhwa Region

Background: Poliomyelitis is a highly infectious viral disease often causing permanent paralysis. Post-Polio Paralysis (PPP) involves the delayed onset of new or worsening neuromuscular symptoms years after the initial attack. Polio survivors face numerous physical disabilities and significant social, financial, and human rights barriers. Aims: To identify the challenges faced by individuals with PPP in the Khyber Pakhtunkhwa region. Methods: The study employed a cross-sectional survey design with a sample size of n=200, selected through non-probability convenience sampling. Data were collected using the Post-Polio Clinic Questionnaire and analyzed with SPSS 22. Results: The gender distribution was 21.50% female and 78.50% male. New health and physical problems (neurological, arthritis, and physiological) were observed in 64.5% (n=129) of participants. Aggravated previous complications, such as pain, fatigue, and muscular atrophy, were reported by 91.5% (n=183). Difficulty performing heavy tasks was noted by 49.5% (n=99). Using public transport was a challenge for 46.5% (n=93), and driving a car was deemed impossible by 70% (n=140). Using an Indian commode as a toilet was a complication for 58% (n=116) of participants. Conclusion: The study reveals significant health and daily life challenges for polio survivors in Khyber Pakhtunkhwa, including a high prevalence of new and worsening neuromuscular symptoms, aggravated complications like pain and fatigue, and difficulties with heavy tasks, public transport, driving, and using certain toilets. These findings underscore the urgent need for targeted interventions to improve the quality of life for polio survivors by addressing their physical health and social and financial barriers.

Characterization of SMA type II skeletal muscle from treated patients shows OXPHOS deficiency and denervation.

Spinal muscular atrophy (SMA) is a recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (survival of motor neuron 1). SMA is characterized by neuromuscular symptoms and muscle weakness. Several years ago, SMA treatment underwent a radical transformation, with the approval of 3 different SMN-dependent disease-modifying therapies. This includes 2 SMN2 splicing therapies - risdiplam and nusinersen. One main challenge for type II SMA patients treated with these drugs is ongoing muscle fatigue, limited mobility, and other skeletal problems. To date, few molecular studies have been conducted on SMA patient-derived tissues after treatment, limiting our understanding of what targets remain unchanged after the spinal cord-targeted therapies are applied. Therefore, we collected paravertebral muscle from 8 type II patients undergoing spinal surgery for scoliosis and 7 controls. We used RNA-seq to characterize their transcriptional profiles and correlate these molecular changes with muscle histology. Despite the limited cohort size and heterogeneity, we observed a consistent loss of oxidative phosphorylation (OXPHOS) machinery of the mitochondria, a decrease in mitochondrial DNA copy number, and a correlation between signals of cellular stress, denervation, and increased fibrosis. This work provides new putative targets for combination therapies for type II SMA.

Unveiling the menstrual mind: Exploring proprioceptive proficiency, reaction responsiveness, and motor mastery in premenstrual syndrome versus Non-PMS cohorts: A two-arm parallel non-blinded cross-sectional study

IntroductionPremenstrual syndrome (PMS) is characterized by cyclical physical and mood disturbances during the luteal phase. Symptoms gradually intensify during this phase and typically subside a few days after menstruation begins. PMS encompasses neuromuscular and psychological symptoms that can significantly affect the quality of life of affected females. This study aims to compare proprioception, reaction time, and coordination between females with PMS and those with non-PMS. Material and methodsA cross-sectional study, conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, recruited 998 females with PMS and without PMS, aged 18–40 years based on premenstrual dysphoric disorder criteria. Participants underwent assessments of proprioception and reaction time using the Sensbalance Miniboard. Coordination was assessed using Lower Extremity Motor Coordination Test. Data analysis utilized the Kolmogorov-Smirnov test to determine the normality of the data while Mann Whitney-U test was used to compare the between group differences of the variables. ResultsSignificant differences were observed with p-value <0.05 for all the variables, proprioception (front, back, right and left), reaction time (front, back, right and left), coordination (right and left) between the PMS and non-PMS groups. ConclusionsFemales with PMS were associated with great variation in proprioception, reaction time and coordination when compared with females without PMS.

Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.

Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population. This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants. A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership. The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity. This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.

Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency

Triosephosphate isomerase deficiency (TPI Df) is a rare multisystem disorder with severe neuromuscular symptoms which arises exclusively from mutations within the TPI1 gene. Studies of TPI Df have been limited due to the absence of mammalian disease models and difficulties obtaining patient samples. Recently, we developed a novel murine model of TPI Df which models the most common disease-causing mutation in humans, TPI1E105D. Using our model in the present study, the underlying pathogenesis of neuromuscular symptoms has been elucidated. This is the first report detailing studies of neuromuscular pathology within a murine model of TPI Df. We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size. TPI Df mice also exhibited signs of cardiac pathology and displayed a deficit in vascular smooth muscle functionality. Together, these findings provide insight into pathogenesis of the neuromuscular symptoms in TPI Df and can guide the future development of therapeutics.

Mitochondrial DNA disorders in neuromuscular diseases in diverse populations.

Neuromuscular features are common in mitochondrial DNA (mtDNA) disorders. The genetic architecture of mtDNA disorders in diverse populations is poorly understood. We analysed mtDNA variants from whole-exome sequencing data in neuromuscular patients from South Africa, Brazil, India, Turkey and Zambia. In 998 individuals, there were two definite diagnoses, two possible diagnoses and eight secondary findings. Surprisingly, common pathogenic mtDNA variants found in people of European ancestry were very rare. Whole-exome or -genome sequencing from undiagnosed patients with neuromuscular symptoms should be re-analysed for mtDNA variants, but the landscape of pathogenic mtDNA variants differs around the world.

Skeletal muscle vulnerability in a child with Pitt-Hopkins syndrome

BackgroundTCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle.MethodTo address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling.ResultsWe report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression.ConclusionOur combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.

Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood–brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.

Myotonic dystrophy type 1 in South Korea: a comprehensive analysis of cancer and comorbidity risks.

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder characterized by myotonia and progressive muscle weakness. Beyond the primary symptoms, there is growing concern regarding a higher incidence of certain comorbidities in DM1 patients, including cancer, diabetes, thyroid dysfunction, and cataracts. This study was designed to examine the occurrence of these conditions among patients diagnosed with DM1 in South Korea, using data from the National Health Insurance Service database. The study undertook a comprehensive review of 3,842 patients diagnosed with DM1 between 2012 and 2018. We assessed the incidence of cancer and the prevalence of diabetes, thyroid dysfunction, and cataracts among these patients, comparing their rates to those in the general population. In the study cohort, 463 out of 3,842 DM1 patients (12.04%) were diagnosed with cancer, indicating a substantial elevation in cancer risk with an overall standard incidence ratio of 1.9 (95% CI = 1.6-2.3, p < 0.01) when compared to the expected rates in the general population. Moreover, the prevalence of diabetes (15.2%) and thyroid dysfunction (17.6%) was noteworthy in the DM1 population. The mean age at which DM1 patients underwent cataract surgery was 55.07years, noticeably younger than the mean age of 69.25years for cataract surgery in the general population. DM1 patients have a noteworthy occurrence of several comorbidities such as cancer, diabetes, thyroid dysfunction, and earlier cataract surgery. This highlights the importance of a comprehensive and integrative approach to the management and treatment of DM1, going beyond addressing only the primary neuromuscular symptoms. More research is required to understand the underlying mechanisms contributing to these comorbidities in DM1 patients, which may inform preventative measures and guide improvements in patient care.

Distinguish different sensorimotor performance of the hand between the individuals with diabetes mellitus and chronic kidney disease through deep learning models.

Diabetes mellitus and chronic kidney disease represent escalating global epidemics with comorbidities akin to neuropathies, resulting in various neuromuscular symptoms that impede daily performance. Interestingly, previous studies indicated differing sensorimotor functions within these conditions. If assessing sensorimotor features can effectively distinguish between diabetes mellitus and chronic kidney disease, it could serve as a valuable and non-invasive indicator for early detection, swift screening, and ongoing monitoring, aiding in the differentiation between these diseases. This study classified diverse diagnoses based on motor performance using a novel pinch-holding-up-activity test and machine learning models based on deep learning. Dataset from 271 participants, encompassing 3263 hand samples across three cohorts (healthy adults, diabetes mellitus, and chronic kidney disease), formed the basis of analysis. Leveraging convolutional neural networks, three deep learning models were employed to classify healthy adults, diabetes mellitus, and chronic kidney disease based on pinch-holding-up-activity data. Notably, the testing set displayed accuracies of 95.3% and 89.8% for the intra- and inter-participant comparisons, respectively. The weighted F1 scores for these conditions reached 0.897 and 0.953, respectively. The study findings underscore the adeptness of the dilation convolutional neural networks model in distinguishing sensorimotor performance among individuals with diabetes mellitus, chronic kidney disease, and healthy adults. These outcomes suggest discernible differences in sensorimotor performance across the diabetes mellitus, chronic kidney disease, and healthy cohorts, pointing towards the potential of rapid screening based on these parameters as an innovative clinical approach.

Macrophage migration inhibitory factor favors Neospora caninum infection in mice

Neospora caninum is a protozoan parasite with worldwide incidence, acting as a major cause of reproductive failures in ruminants and neuromuscular symptoms in dogs. Macrophage Migration Inhibitory Factor (MIF) is produced by several cell types and exhibits a central role in immune responses against intracellular pathogens. The present study aimed to comprehend the role of MIF in the relationship between N. caninum and its host. We used in vivo, in vitro and ex vivo experiments in a model of infection based on genetically deficient mice to analyze the infection kinetics and inflammatory markers. MIF production was measured in response to N. caninum during the acute and chronic phases of the infection. While Mif−/− mice survived lethal doses of NcLiv tachyzoites, sublethal infections in these mice showed that parasite burden was controlled in target tissues, alongside with reduced inflammatory infiltrates detected in lung and brain sections. TNF was increased at the initial site of the infection in genetically deficient mice and the MIF-dependent reduction was confirmed in vitro with macrophages and ex vivo with primed spleen cells. In sum, MIF negatively regulated host immunity against N. caninum, favoring disease progression.

A New Case of Abetalipoproteinemia Caused by Novel Compound Heterozygote Mutations in the MTTP Gene without Fat or Vitamin Malabsorption.

Abetalipoproteinemia (ABL) is a rare disease characterized by extremely low apolipoprotein B (apoB)-containing lipoprotein levels, dietary fat, and fat-soluble vitamin malabsorption, leading to gastrointestinal, neuromuscular, and ophthalmological symptoms. We herein report a case of ABL with novel compound heterozygous mutations in the microsomal triglyceride transfer protein gene (c.1686_1687del [p.Ser563TyrfsTer10] and c.1862T>C [p.Ile621Thr]), identified via panel sequencing. Although the patient had extremely reduced low-density lipoprotein cholesterol levels and a fatty liver, he did not exhibit other typical complications. Furthermore, unlike typical ABL, this patient had a preserved apoB-48 secretion and increased concentrations of high-density lipoprotein cholesterol, which may account for the normal serum fat-soluble vitamin levels.

Idiopathic Hypoparathyroidism Presenting with Erythrodermic Psoriasis and Fahr’s Syndrome: A Case Report

Idiopathic hypoparathyroidism may remain asymptomatic or present with hypocalcaemic neuromuscular manifestations. Dermatological manifestations like exfoliative dermatitis, pustular psoriasis and symmetrical brain calcification known as Fahr’s syndrome are uncommon in clinical practice. Even in absence of neuromuscular symptoms, hypocalcaemia associated with exfoliative skin lesions and symmetrical brain calcification should prompt investigation for hypoparathyroidism. A 40-year-old male presented with diffuse erythematous pruritic plaques and fever of 10 days duration. Auspitz sign was positive on examination. Investigations showed leucocytosis with neutrophilic predominance. He was admitted with a diagnosis of erythrodermic psoriasis with secondary infection. On the second day of admission he developed an episode of generalised tonic clonic seizure for the first time. Investigations into the cause of seizure revealed low serum calcium while computerised tomography of head revealed symmetrical calcification of bilateral basal ganglia. Further, he was found to have a low level of intact Parathyroid Hormone (PTH) level and hyperphosphataemia. Based on clinical, biochemical and radiological findings, a diagnosis of idiopathic hypoparathyroidism, psoriasis and Fahr’s syndrome was made. Serum calcium was corrected with infusions of calcium gluconate followed by oral calcium carbonate. The patient was kept under observation for seizure recurrence. Calcium and vitamin D supplements and hydrochlorothiazide were started and psoriasis treatment was continued. His skin lesions resolved over the next two weeks, serum calcium levels returned to normal level and no seizure episodes were reported over three months of follow-up.

Human motor neurons derived from induced pluripotent stem cells are susceptible to SARS-CoV-2 infection.

COVID-19 typically causes Q7 respiratory disorders, but a high proportion of patients also reports neurological and neuromuscular symptoms during and after SARSCoV-2 infection. Despite a number of studies documenting SARS-CoV-2 infection of various neuronal cell populations, the impact of SARS-CoV-2 exposure on motor neuronal cells specifically has not been investigated so far. Thus, by using human iPSC-derived motor neurons (iPSC-MNs) we assessed: (i) the expression of SARS-CoV-2 main receptors; (ii) iPSC-MN infectability by SARS-CoV-2; and (iii) the effect of SARS-CoV-2 exposure on iPSC-MN transcriptome. Gene expression profiling and immunofluorescence (IF) analysis of the main host cell receptors recognized by SARS-CoV-2 revealed that all of them are expressed in iPSC-MNs, with CD147 and NRP1 being the most represented ones. By analyzing SARS-CoV-2 N1 and N2 gene expression over time, we observed that human iPSC-MNs were productively infected by SARS-CoV-2 in the absence of cytopathic effect. Supernatants collected from SARS-CoV-2-infected iPSC-MNs were able to re-infect VeroE6 cells. Image analyses of SARS-CoV-2 nucleocapsid proteins by IF confirmed iPSC-MN infectability. Furthermore, SARS-CoV-2 infection in iPSCMNs significantly altered the expression of genes (IL-6, ANG, S1PR1, BCL2, BAX, Casp8, HLA-A, ERAP1, CD147, MX1) associated with cell survival and metabolism, as well as antiviral and inflammatory response. These results suggest for the very first time that SARS-CoV-2 can productively infect human iPSC-derived MNs probably by binding CD147 and NRP1 receptors. Such information will be important to unveil the biological bases of neuromuscular disorders characterizing SARS-CoV-2 infection and the so called long-COVID symptoms.

A Case Series of 11 Patients With Subacute Serotonin Syndrome

Serotonin syndrome is an acute, life-threatening illness characterized by mental status changes, neuromuscular symptoms, and autonomic instability. Some patients taking serotonergic antidepressants have been noted to have unexplained mental status changes and/or neuromuscular changes without autonomic instability raising the possibility of a more chronic or attenuated form of serotonin syndrome. Assessment of antidepressant blood levels to support the diagnosis of a subacute serotonin syndrome. At a tertiary psychiatric outpatient clinic, patients with unexplained mental status and/or neuromuscular changes without autonomic instability had antidepressant blood levels assessed. Eleven patients were identified with signs and symptoms partially consistent with serotonin syndrome. Nine patients had cognitive changes, while four patients had motor changes, and three patients had psychosis. All patients had elevated blood levels of a single serotonergic antidepressant. Limited follow-up suggests that symptoms improve with reduction of antidepressant medication. These cases suggest that a more chronic, attenuated form of serotonin syndrome exists. Diagnostic criteria are proposed for a distinct clinical entity: subacute serotonin syndrome (SSS). Further research is required to validate these criteria. Clinicians should consider drawing antidepressant levels for patients with symptoms and signs suggestive of SSS-especially those at increased vulnerability for excessive serotonergic agonism. Given the high prevalence of antidepressant medication use, the awareness of SSS could lead to improved patient outcomes and public health.

Utility of split hand index with different motor unit number estimation techniques in ALS

ObjectiveUtility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SICMAP amp). A motor unit number index (MUNIX) based SI method (SIMUNIX) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SIMScanFit-MUNE) methods, in ALS. MethodsSixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi. ResultsSICMAP amp, SIMUNIX and SIMScanFit-MUNE were significantly reduced in ALS, with SICMAP amp (area under curve (AUC) = 0.801) and SIMScanFit-MUNE (AUC = 0.805) exhibiting greater diagnostic utility than SIMUNIX (AUC = 0.713). SICMAP amp and SIMScanFit-MUNE exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles. ConclusionsSI differentiated ALS from mimic disorders, with SICMAP amp and SIMScanFit-MUNE exhibiting greater utility. SignificanceThe split hand index represents could serve as a potential diagnostic biomarker in ALS.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro

PurposeHypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro.MethodsC2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated.ResultsThe combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells.ConclusionsOur results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

FRI197 Patient Suffering From Resistant HTN For 15 Years With Negative CT Diagnosed With Hyperaldosteronism Due To Adrenal Cortical Adenoma

Abstract Disclosure: J. Seidenberg: None. M.J. Ansari: None. Background: Resistant HTN, blood pressure remaining above goal despite concurrent use of three antihypertensives of different classes at maximum doses is a common presentation in both endocrinology and primary care settings. Patients can often be prescribed multiple max-dosed antihypertensives with varying results and adverse effects and still spend years with uncontrolled HTN leading to long term health concerns. Hyperaldosteronism is diagnosed for resistant HTN in 4% of primary care patients and 10% endocrinology-referred patients. Adrenal adenomas account for 40% of all cases characterized by high aldosterone/renin activity ratio, hypokalemia, mild hypernatremia and hypomagnesemia commonly diagnosed with a mass found in the adrenals on CT. Clinical Case: Patient is a 39 year old Female who presented to the endocrinology office due to elevated urine metanephrine levels, BP 159/100. Patient had resistant HTN since her early 20s treated currently with labetalol and nifedipine, and hypokalemia treated with potassium supplements. Lab results revealed potassium 3.4 mmol/L (3.6 -5.2 mmol/L), normetanephrines 787 mcg/g (0-145 mcg/g) , aldosterone 11 ng/dL (2-9 ng/dL) , renin 0.2 ng/mL/h (0.7- 3.3 ng/mg/hr), aldosterone/renin activity ratio 55 (&amp;lt;25) . Renal US showed no renal artery stenosis. The patient was suspected of having hyperaldosteronism using cutoff ratios aldosterone renin ratio &amp;gt;30, and 15 years of potassium levels between 3.0 and 3.5. CT of the adrenals revealed no masses. Patient underwent IR guided venous sampling which indicated R adrenal gland producing 45x more aldosterone than the L adrenal gland. Patient underwent R sided adrenalectomy for definitive management of primary hyperaldosteronism. Pathology showed cortical adenoma. Patient was continued on chlorthalidone, losartan and nifedipine, and within 3 months her BP averaged 120/70 mmHg, with potassium within normal limits, Aldosterone 13 ng/dL, renin 1.25 ng/mL. Conclusion: Concurrent hyperaldosteronism with essential HTN is an uncommon but potential cause of resistant HTN. Patients with resistant HTN, prescribed multiple max-dosage antihypertensive medications while also having negative renal artery US result should undergo aldosterone and renin lab work. CT scans can have low sensitivity for adrenal adenoma. Concerning lab work should be followed up by IR-guided venous sampling for evaluation of an adrenal cortical adenoma, which can be treated surgically. Underlying essential HTN will still require treatment, but at significantly decreased medication dosages. Patients with resistant HTN should be evaluated for hyperaldosteronism early in their disease course regardless of a negative CT to prevent sequelae of untreated hyperaldosteronism including cardiac hypertrophy, arrhythmias, nephrogenic diabetes insipidus and neuromuscular symptoms. Presentation: Friday, June 16, 2023

Infantile onset encephalomyopathy, retinopathy, optic atrophy, and mitochondrial DNA depletion associated with a novel pathogenic DHX16 variant.

We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH-box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient-derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease.

Phosphaturic Mesenchymal Tumors with or without Phosphate Metabolism Derangements.

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms, which can give rise to a multifaceted syndrome, otherwise called tumor-induced osteomalacia (TIO). Localizing these tumors is crucial to obtain a cure for the phosphate metabolism derangement, which is often the main cause leading the patient to seek medical help, because of invalidating physical and neuromuscular symptoms. A proportion of these tumors is completely silent and may grow unnoticed, unless they become large enough to produce pain or discomfort. FGF-23 can be produced by several benign or malignant PMTs. The phosphate metabolism, radiology and histology of these rare tumors must be collectively assessed by a multidisciplinary team aimed at curing the disease locally and improving patients' quality of life. This narrative review, authored by multiple specialists of a tertiary care hospital center, will describe endocrine, radiological and histological features of these tumors, as well as present surgical and interventional strategies to manage PMTs.