Group Of Disorders Research Articles

The Detection of Invalid Responses Using the Dissociative Experiences Scale-V (DES-V)

ABSTRACT The Dissociative Experiences Scale (DES) is the most widely used self-report measure of dissociation but lacks a validity scale. Abu-Rus et al. (2020) created the DES-V by embedding atypical and inconsistency items in the DES, ultimately concluding that atypicality demonstrated the greatest ability to differentiate honest respondents from feigners. Among their study limitations, Abu-Rus et al. noted the homogeneous nature of their clinical group (i.e., largely comprising individuals with PTSD) and the potential need to refine the existing atypicality items for a more heterogenous dissociation population. The current study aimed to refine the DES-V by enlisting dissociation experts to improve the believability of the atypical items (while simultaneously ensuring they did not betoken any actual dissociative symptomology) and by supplementing the online sample with a clinical sample that included a broad range of dissociative disorders. Data cleaning comprised eight different techniques, to better ensure the validity of the online sample. Honest and Feigning groups completed the assessments through Amazon’s Mechanical Turk; the clinical dissociative disorder group completed hard copy versions. The atypicality scale discriminated the three groups well, with the Feigning group scoring significantly higher than both of the honest groups (online and clinical). The mean atypicality scores of the two honest groups did not differ significantly. In addition, the scale incremented over the original DES-V in a logistic regression predicting honest and feigning participants. These robust results suggest that the revised DES-V could provide researchers with a valuable tool for validating online samples with greater precision – an increasingly vital need in light of the growing reliance on online samples.

7289 An interesting case of Diabetes Mellitus Type 1 induced Renal Tubal Acidosis Type 1

Abstract Disclosure: R. Ripa: None. A. Itani: None. S.K. Patel: None. Introduction: Renal Tubular Acidosis (RTA) are a group of disorders that involve dysfunctional transporters and channels in the renal system. These disorders can be acquired (idiopathic, medication side effects, and medical disorders) or inherited. The most common type worldwide is type 4 RTA, the main cause is diabetic nephropathy leading to hypoaldosteronism. The association of type 1 RTA with diabetes has rarely been reported in studies. Here, we report the presentation, diagnosis and management of a rare case of type 1 RTA in a patient with a history of diabetes mellitus type 1. Case: A male in his 50s with a 30-year history of uncontrolled type 1 diabetes mellitus on insulin pump and coronary artery disease presented to his cardiologist with worsening chest pain, fatigue, polyuria, weight loss of 15 lbs, and recent insulin pump change. Blood tests revealed serum bicarbonate of 10 mmol/L and he was sent to the hospital. On examination, he was hypotensive and bradycardic with dry mouth and decreased skin turgor. His blood tests were consistent with type 1 RTA, he was treated with intravenous fluids containing bicarbonate plus potassium and transitioned to oral potassium citrate on discharge. He underwent renal biopsy as work up was unrevealing for a cause of type 1 RTA. Biopsy revealed normal glomeruli with negative immunofluorescence and Congo red stain. The biopsy, however, did show mild patchy chronic interstitial fibrosis with lymphocytes and mild tubular atrophy. At one year follow up, he remained on oral potassium citrate with resulting serum bicarbonate of 26 mmol/L and a normal renal function. Discussion: Diabetes mellitus can lead to a variety of renal pathologies, specifically metabolic acidosis that can be either seen as diabetic ketoacidosis or hyporeninemic hypoaldosteronism (Type 4 RTA). In our patient, despite being a diabetic, he did not present with either elevated anion gap, ketonuria or hyperkalemic hyperchloremic acidosis typical of type 4 RTA. He was noted to have hypokalemic hyperchloremic acidosis, with a positive urine anion gap, and an alkaline urine, all characteristic of type 1 RTA. Acquired distal RTA occurs more commonly due to certain medications or autoimmune diseases as in Sjögren’s syndrome. The relationship between distal RTA and Sjögren’s syndrome has already been established, unlike the relationship with type 1 diabetes. There have been few case reports of distal RTA in association with type 1 diabetes mellitus, implying a possible autoimmune pathology. Prior case reports also not only had patients who were insulin dependent, but diabetes was present for more than a decade at least suggesting chronicity of disease is needed. Traditional management consists of alkaline therapy and treatment of the underlying disease, or removal of offending medication. In this case, we hope to highlight distal RTA in a diabetic who doesn’t meet criteria for DKA or type 4 RTA. Presentation: 6/1/2024

6664 A Case of Undistinguished Congenital Adrenal Hyperplasiain a Patient with Hypertensive Emergency and Hypokalemia

Abstract Disclosure: V.L. Del Signore: None. S.T. Kaufman: None. CAH is a group of autosomal recessive disorders resulting in alterations of adrenal steroid biosynthesis. With 95% of CAH cases due to 21-hydroxylase deficiency; other causes are rare. The metabolic, phenotypic, and physiologic derangements are specific to the altered enzymatic pathways, most of which are life threatening. Identifying the enzymatic defect is crucial to treat the patient. We present a case of undifferentiated CAH in an adult resulting in significant systemic illness. A 26-year-old well virilized male presented with chief complaint of shortness of breath, lower extremity swelling, and abdominal distension for 3 weeks. He was found to have acute decompensated heart failure with LVEF 20-25%, NSTEMI, atrial fibrillation, hypertensive emergency with BP of 224/102, and potassium (K+) of 2.7 (3.5-5mmol/L). PMH included hypertension and CAH diagnosed at birth. Patient was unsure of his CAH defect. Pediatric endocrinology prescribed glucocorticoids until age 17 at which point he was told steroids were no longer required. He had been lost to follow up for 9 years. Pediatric records were unattainable. Patient remained hypokalemic and hypertensive despite aggressive K+ repletion and multiple IV antihypertensives. Endocrine work up revealed renin 0.19 (0.25- 5.82ng/mL/hr), aldosterone 4 (< or = 21ng/dL), DHEAs 97 (74-617ug/dL), FSH <0.3 (1.4 - 18.1 m[IU]/mL), LH <0.3 (1.5 - 9.3 m[IU]/mL), total testosterone 306 (250-1,100 ng/dL), SHBG 32 (10-50nmol/L), progesterone 7 (0.2-1.4 ng/mL), ACTH 345 (6-50 pg/mL), AM cortisol 4.4 (5-23 ug/dL), 17 hydroxyprogesterone 311 (32-307 ng/dL), androstenedione 1,926 (50-220 ng/dL), 11-deoxycortisol >10,000 (< or = 119 ng/dL). Cosyntropin stimulation test: 30-minute cortisol 11.1 (>18 ug/dL) and 60-minute cortisol 10.4 (>18 ug/dL). Based on clinical and lab findings a diagnosis of 11-beta hydroxylase deficiency was made. Spironolactone was started to counteract the excessive mineralocorticoid effects of deoxycorticosterone and hydrocortisone to decrease ACTH production. With this treatment, patient’s potassium and blood pressure gradually improved. IV antihypertensives were weaned as he transitioned to oral agents. This case demonstrates the importance of understanding and identifying the underlying pathophysiology of CAH to treat patients appropriately. This patient had a mineralocorticoid excess state, but adequate cortisol precursors to prevent adrenal crisis. He requires glucocorticoid therapy to prevent excessive ACTH from driving their BP and metabolic derangements. With appropriate diagnosis of 11-beta hydroxylase deficiency, patient’s excess risk of morbidity and mortality due to the downstream effects of uncontrolled CAH can be minimized. Presentation: 6/3/2024

7255 Tirzepatide Helps Achieve Glycemic Control and Lower Triglycerides in Seven Patients with Lipodystrophy

Abstract Disclosure: R. Meral: None. E.D. Frontera: None. M. Celik Guler: None. M.C. Foss de Freitas: None. N. Nachawi: None. D.T. Broome: Consulting Fee; Self; Tayco, Inc.. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals. S.I. Taylor: None. E.A. Oral: Advisory Board Member; Self; Amryt, Regeneron Pharmaceuticals. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Fractyl, Ionis Pharmaceuticals Inc., GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Lipodystrophy encompasses a group of rare disorders associated with severe metabolic disease. These disorders are defined by abnormal distribution of fat, with near-total (generalized lipodystrophy, GL) or partial (partial lipodystrophy, PL; i.e. familial partial lipodystrophy, FPLD) absence of adipocyte mass leading to a decreased ability to store triglycerides safely. Excess triglycerides are more likely to be stored in ectopic tissues such as hepatocytes, which leads to the metabolic manifestations of the disease state. Patients with GL have near absent levels of leptin hormone and leptin replacement therapy leads to dramatic improvement, which has mainly been attributed to a reduction in caloric intake. Patients with PL are not as leptin deficient and their response to leptin replacement therapy has been variable. We hypothesized that the clinical use of tirzepatide in patients with lipodystrophy may lead to favorable outcomes through the reduction of caloric intake. We closely observed 7 patients who were prescribed tirzepatide for their diabetes with information presented respectively [Age: 44; 54; 34; 53; 44; 46; 38 years | Sex: F; F; F; F; F; M; F | Subtype: FPLD type 1; FPLD type 2; FPLD type 1; Acquired GL; FPLD type 2; FPLD type 1; FPLD type 3]. At baseline, all patients had poor control of their disease despite aggressive medical therapy (except patient #5). Follow-up durations varied due to the observational nature of the study [follow-up duration (months): 6; 12; 7; 3; 8; 9; 5]. Reductions in A1c, triglycerides, and body mass index (BMI) were observed [A1c (%): 13.4->7.1; 7.1->6.6; 7.6->5.2; 8.7->6.9; 5.4->5.1; 8.9->7.8; 9.7->7.1 | triglycerides (mg/dL): 539->339; 164->109; 367->NA; 151->113; 388->101; 459->319; 4081->259 | BMI (Kg/m2): 25.0->24.5; 30.6->28.3; 37.7->33.9; 22.8->20.9; 27.6->23.4; 40.1->37.9; 24.0->24.9]. Those who were on insulin had decreased daily requirements [total daily insulin requirement (units): 160->25; 82->18; not on insulin; 85->0; not on insulin; 280->200; 124->111]. All patients reported a reduction in their daily food intake. Treatment related complications were limited to known gastrointestinal issues which the patients rated as tolerable. Based on our results, a randomized controlled trial to test the efficacy of tirzepatide in patients with lipodystrophy may be warranted. Presentation: 6/3/2024

9209 Functional Evaluation Of Novel CYP21A2 Variants: Expanding The Genetic Basis Of Non-classic CAH

Abstract Disclosure: A. Matveeva: None. Y. Xu: None. V. Tardy-Guidollet: None. A.V. Pandey: None. Introduction: Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive genetic disorders affecting the production of glucocorticoids, mineralocorticoids, and gonadocorticoids. In approximately 95% of cases, CAH results from a deficiency in CYP21A2. A Non-Classic form of CAH (NC-CAH) arises when CYP21A2 activity decreases to 20-50% of the normal level, occurring at an estimated frequency of 1 in 200 - 1000 individuals. The clinical picture is characterized by the accumulation of androgen precursors, causing hirsutism, acne, metabolic syndrome, menstrual irregularities, infertility in females, and androgenic alopecia, oligospermia in males. Methods: We selected mutations from CYP21A2 sequence data of patients with NC-CAH symptoms admitted to CHU Lyon, France (L49V, A81T, R125G, I161T, L199F, L289H, L289F, V306D, L462P). Additional variants were selected from the SNP databases (dbSNP, gnomAD, ClinVar) based on a high frequency in humans (H393Q, P387L, T201A, S203G S274Y, S494N, R76K, Leu10del). All variants underwent in silico assessment considering evolutionary, structural, and functional aspects (ConSurf, Predict SNP2, CADD, DANN, FATHMM, FunSeq2, GWAVA, PANTHER, SNPs&GO, PhD-SNP, SIFT, SNAP, Meta-SNP, Polyphen2, HDIV, DUET). The CYP21A2 proteins carrying the mutations were overexpressed in HEK 293T cells. We evaluated CYP21A2 enzyme activities by measuring the conversion of 14C-Progesterone into 11-deoxycortisol by thin layer chromatography and autoradiography. Samples were tested in duplicates, using the activity of WT CYP21A2 as a control. Results: Computational analysis revealed that A81T, R125G, I161T, and L289H substitutions significantly impair protein structure, while other variants showed moderate effects. Except for L199F, all patient-derived variants exhibited reduced 21-hydroxylase (CYP21A2) activity associated with NC-CAH phenotypes. Variants from databases did not demonstrate a significant loss of function related to CAH. Conclusion: In this study we investigate the pathogenicity of uncharacterized CYP21A2 variants in relation to non-classic congenital adrenal hyperplasia (NC-CAH), contributing to a better understanding of associated phenotypes. The findings, particularly the identification of novel mutations and the assessment of their impact on CYP21A2 activity, hold promise for improving diagnosis and treatment strategies aimed at mitigating severe outcomes of NC-CAH, such as miscarriages or irreversible alopecia. It also raises awareness among heterozygous carriers, assisting in family planning and medical decisions. Presentation: 6/1/2024

Resolving Phenotypic Variability in Mitochondrial Diseases: Preliminary Findings of a Proteomic Approach

The introduction of new sequencing approaches into clinical practice has radically changed the diagnostic approach to mitochondrial diseases, significantly improving the molecular definition rate in this group of neurogenetic disorders. At the same time, there have been no equal successes in the area of in-depth understanding of disease mechanisms and few innovative therapeutic approaches have been proposed recently. In this regard, the identification of the molecular basis of phenotypic variability in primary mitochondrial disorders represents a key aspect for deciphering disease mechanisms with important therapeutic implications. In this study, we present data from proteomic investigations in two subjects affected by mitochondrial disease characterized by a different clinical severity and associated with the same variant in the TWNK gene, encoding the mitochondrial DNA and RNA helicase with a specific role in the mtDNA replisome. Heterozygous pathogenic variants in this gene are associated with progressive external ophthalmoplegia and ptosis, usually with adult onset. The overall results suggest an imbalance in glucose metabolism and ROS production/regulation, with possible consequences on the phenotypic manifestations of the enrolled subjects. Although the data will need to be validated in a large cohort, proteomic investigations have proven to be a valid approach for a deep understanding of these neurometabolic disorders.

6556 Does Autoimmune Hashimoto’s Hypothyroidism Mask the Diagnosis of Ehlers-Danlos-Syndrome?

Abstract Disclosure: S. Azmat: None. U. Rafat: None. J.L. Gilden: None. Does Autoimmune Hashimoto’s Hypothyroidism Mask the Diagnosis of Ehlers-Danlos Syndrome? Background: Hypothyroidism is well-known to be associated with muscle weakness and fatigue. There are other etiologies for decreased muscle tone such as Ehlers-Danlos syndrome (EDS) which is group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility. Other rheumatological and cardiac conditions associated with this syndrome can pose diagnostic challenges. We present case of 32-year-old female presenting with facial muscle weakness and newly diagnosed Hashimoto’s hypothyroidism. We highlight importance of keeping EDS as another differential in patients with muscle weakness allowing for accurate, prompt diagnosis and treatment to be done in timely manner. Case Description: A 32-year-old female professional musician was referred to Endocrine for mouth muscles weakness and decreasing ability to play her French Horn wind instrument with vocal dystonia and the question of whether these were symptoms of hypothyroidism. She was noted to have mild thyroid enlargement and abnormal thyroid function tests with positive thyroid antibodies. Initial TSH was 7.506 uIU/mL(0.55-4.78), free T4 0.9 ng/dL (0.76-1.46), peroxidase antibody = 96,061U/mL (0-60) and thyroglobulin of 134.9 U/mL (0-60). She also reported low energy, intermittent difficulty swallowing and decreased muscle strength. There was no prior personal and family history of hypo/hyperthyroidism or any other disorders. VS were normal, physical exam showe d no thyromegaly, reflexes revealed objective decrease but normal muscle strength. The skin was noted to be hyperextensible with passive hyperextension of fifth metacarpophalangeal joint beyond 90 degrees, thumb to flexor aspect of forearm and elbows bilaterally with positive Beighton criteria for EDS. She later admitted to intermittent palpitations and easy bruising. Subsequent lab tests were negative ANA, anti-mitochondrial, PCEL and striated muscles antibodies. Additionally she had normal IGA, PTH, AM cortisol- ACTH, vitamin B12 levels with negative 21 hydroxylases antibodies and celiac titers. She was started on levothyroxine 25 mcg and recommended for Cardiology evaluation and genetic testing. Physiotherapy was started. Upon six months follow-up she clinically felt better with improved muscle strength, swallowing and energy level. Repeat lab testing showed improved TSH of 2.67 uIU/mL(0.55-4.78) with free T4 of 1.0 ng/dL (0.76-1.46). Conclusion: This case demonstrates that although muscle weakness can be symptom of hypothyroidism one must evaluate all patients for other possible causes. We highlight importance of keeping EDS as a differential especially in female patients with muscle weakness. Though history and physical exam is crucial allowing for prompt diagnosis and treatment for other conditions. Presentation: 6/1/2024

12279 Molecular Strategy And Genetic Characterization Of A Large Cohort Of Pediatric Patients With Hereditary Hypophosphatemic Rickets: Advantages Of Next Generation Sequencing

Abstract Disclosure: N. Perez Garrido: None. P. Ramirez: None. G.L. Viterbo: None. M. del Pino: None. S. Abbate: None. N.I. Saraco: None. F. Tesan: None. M. Ciaccio: None. V. Fano: None. A. Belgorosky: None. R. Marino: None. Background: Hereditary hypophosphatemic rickets (HHR) is a group of rare disorders characterized by renal phosphate wasting and impairment of vitamin D metabolism. Different genetic defects can cause HHR, although they share similar clinical, radiological and biochemical features. Dominant X-linked HR (XLHR) is the most frequent form (1/ 20,000) caused by inactivating variants in PHEX gene. As affected individuals present with a broad phenotypic spectrum next generation sequencing (NGS) represent a useful tool for molecular diagnosis characterization. Aim: To report a molecular strategy and genetic characterization of a large cohort of pediatric patients with HHR followed in a single tertiary institution. Patients and Methods: We analyzed 77 affected patients from 60 non related families (and 58 parents) sent to our laboratory for molecular genetic testing under suspicion of HHR based on clinical, radiological and laboratory studies.In patients without hypercalciuria, Sanger sequencing of PHEX gene was initially performed. In female cases in which no alteration was detected, MLPA analysis was used to detect copy number variations. A group of patients with no proven variations in PHEX gene and those with hypercalciuria were analyzed using a NGS custom panel including 14 related genes. Results: Of the total 60 non related cases a pathogenic variant was found in 52 (87%). Regarding PHEX gene analysis, a pathogenic variant was found in 48/60 (80%), 27 were sporadic and 21 familial cases. Forty-one different pathogenic variants were found (5 gross deletions, 13 nonsense, 9 frameshift, 5 splice-site and 9 missense) distributed throughout the gene with higher prevalence from exon 15 to 22. 18/41 (44%) of variants were novel. RNA analysis was performed in 2 novel splice variants (c.849G>A-p.Glu283Glu and c.1586+6T>A) in which an abnormal splicing was confirmed.We found a pathogenic variant in 5/9 cases analyzed by NGS. Three of them in SLC34A3 gene (2 homozygous, 1 compound heterozygous), 1 in ENPP1 gene (compound heterozygous) and 1 in PHEX gene non-detected by Sanger sequencing. Discussion: This molecular strategy, along with a careful clinical and biochemical selection of patients, allowed us to perform genetic diagnosis in 87 % of non-related families. This study reports 21 novel pathogenic variants and it shows the greatest genetic characterization in pediatric HHR patients in Argentine population. The results obtained confirmed that PHEX is the most responsible gene for HHR phenotype, as previously described. By NGS, less common forms of rickets could be detected. Among them, the most frequent was HHR with hypercalciuria due to recessive mutations in SLC34A3 gene. NGS studies represent a useful tool, especially in those complex cases, to reach an accurate diagnosis, and they contribute to improve long term follow up of patients and genetic counseling. Presentation: 6/2/2024

8368 Functional Evaluation Of Novel CYP21A2 Variants: Expanding The Genetic Basis Of Non-classic CAH

Abstract Disclosure: A. Matveeva: None. Y. Xu: None. V. Tardy-Guidollet: None. A.V. Pandey: None. Introduction: Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive genetic disorders affecting the production of glucocorticoids, mineralocorticoids, and gonadocorticoids. In approximately 95% of cases, CAH results from a deficiency in CYP21A2. A Non-Classic form of CAH (NC-CAH) arises when CYP21A2 activity decreases to 20-50% of the normal level, occurring at an estimated frequency of 1 in 200 - 1000 individuals. The clinical picture is characterized by the accumulation of androgen precursors, causing hirsutism, acne, metabolic syndrome, menstrual irregularities, infertility in females, and androgenic alopecia, oligospermia in males. Methods: We selected mutations from CYP21A2 sequence data of patients with NC-CAH symptoms admitted to CHU Lyon, France (L49V, A81T, R125G, I161T, L199F, L289H, L289F, V306D, L462P). Additional variants were selected from the SNP databases (dbSNP, gnomAD, ClinVar) based on a high frequency in humans (H393Q, P387L, T201A, S203G S274Y, S494N, R76K, Leu10del). All variants underwent in silico assessment considering evolutionary, structural, and functional aspects (ConSurf, Predict SNP2, CADD, DANN, FATHMM, FunSeq2, GWAVA, PANTHER, SNPs&GO, PhD-SNP, SIFT, SNAP, Meta-SNP, Polyphen2, HDIV, DUET). The CYP21A2 proteins carrying the mutations were overexpressed in HEK 293T cells. We evaluated CYP21A2 enzyme activities by measuring the conversion of 14C-Progesterone into 11-deoxycortisol by thin layer chromatography and autoradiography. Samples were tested in duplicates, using the activity of WT CYP21A2 as a control. Results: Computational analysis revealed that A81T, R125G, I161T, and L289H substitutions significantly impair protein structure, while other variants showed moderate effects. Except for L199F, all patient-derived variants exhibited reduced 21-hydroxylase (CYP21A2) activity associated with NC-CAH phenotypes. Variants from databases did not demonstrate a significant loss of function related to CAH. Conclusion: In this study we investigate the pathogenicity of uncharacterized CYP21A2 variants in relation to non-classic congenital adrenal hyperplasia (NC-CAH), contributing to a better understanding of associated phenotypes. The findings, particularly the identification of novel mutations and the assessment of their impact on CYP21A2 activity, hold promise for improving diagnosis and treatment strategies aimed at mitigating severe outcomes of NC-CAH, such as miscarriages or irreversible alopecia. It also raises awareness among heterozygous carriers, assisting in family planning and medical decisions. Presentation: 6/1/2024

8131 A Rare Case of Autoimmune Polyendocrine Syndrome; a Menopause Despite Replacement Therapy

Abstract Disclosure: M.E. Chacon Cruz: None. M. Sanchez Cordero: None. R.M. Roman Torres: None. G. Guerra Velazquez: None. Polyendocrinopathy is a heterogeneous group of disorders leading to dysfunction of multiple endocrine glands and other tissues. The syndromes can occur in patients from early infancy to old age and new components of a given syndrome can appear throughout life. APS can be classified into APS type 1 and APS2-4. APS-1 is a rare monogenic autosomal recessive autoimmune disorder consisting of the triad of chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. APS2 require presence of Addison disease, autoimmune thyroid disorder and type 1 diabetes. APS 3 requires presence of Thyroid autoimmune disease associated with other autoimmune diseases. APS4 is a combination of organ specific autoimmune disease non included in a previous group. Autoimmune oophoritis is found in approximately 4 percent of females who presented with spontaneous primary ovarian insufficiency and may occur in type I and II syndromes of polyglandular autoimmune failure. This is the case of 44 year old female patient with history of hypertension, hypoparathyroidism diagnose at the age of 9 year old, vitiligo and premature ovarian failure diagnose at the age of 16 year old. Patient reported that started with multiple episodes of watery non bloody diarrhea and arthralgia. Patient went to her Pediatrician and they found hypocalcemia hyperphospathemia. Patient mineral was replaced with medication and then followed by pediatric endocrinologist. Patient continues with normal life, but menstrual periods had not started even at age 16th. Laboratory work up was done and premature ovarian failure was diagnosed after that, patient started with progesterone and estrogen to induce menstrual periods. Menstrual periods began regularly and monthly. Patient continues taking medication regularly, phoslo, calcitriol, progestin and estradiol without problem until this year that despite regular medication, started with signs and symptoms of menopause with irregular menstrual periods, palpitations hot flashes, sweating, anxiety and sleep problems. Patient met criteria for APS4 due to combination of organ specific autoimmune disease such premature ovarian failure, vitiligo and hypoparathryroidism. This case is extremely important since despite the fact that there is no family history of either endocrinological or autoimmune diseases, our patient debuts throughout her life with several autoimmune diseases, such as premature ovarian failure and vitiligo. Patient had Schedule appointment with gynecologist who increased the dose of progestin and estradiol. This case highlights the importance of being vigilant about new components of a syndrome developing at different times though a patient's life. As described, autoimmune diseases commonly are related to other diseases, but without a good clinical history and physical examination could be misdiagnosed affecting the quality of life of those patients. Presentation: 6/2/2024

A Comparative Study between Functional Therapy and Conventional Therapy for Children with Cerebral Palsy

Background: Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non- progressive disturbances that occurred in the developing foetal or infant brain. In the industrialized world, the incidence of cerebral palsy is about two per 1000 live births. The incidence is higher in males than in females. The purpose of this study was to examine the motor abilities of children with cerebral palsy who received functional Physiotherapy and the improvement compared to the motor abilities of children in a reference group whose therapy was based on the principle of normalization of the quality of movement. Methodology: A comparative experimental study consisting of 30 cerebral palsy children assigned into two groups. Experimental (n=15) who underwent functional therapy and control (n=15) who underwent conventional physiotherapy were assessed for their improvement in functional skills. Result: Gross Motor functional measures (GMFM) reflects that Group A (Treated with functional therapy) is more effective than Group B (Treated with conventional therapy). Conclusion: This study concluded that there is a significant difference between the efficacies of functional physical therapy and conventional therapy in the treatment of CP children.

Long-term follow-up of givosiran treatment in patients with acute intermittent porphyria from a phase 1/2, 48-month open-label extension study

BackgroundAcute hepatic porphyria is a group of multisystem disorders of which acute intermittent porphyria is the most common subtype. Givosiran, a subcutaneously administered RNA interference therapeutic targeting liver ALAS mRNA, is approved for treating these disorders. This Phase 1/2 open-label extension study (NCT02949830) evaluated the long-term safety and efficacy of givosiran in adults with acute intermittent porphyria, with follow-up of up to 48 months, which is the longest follow-up of givosiran treatment to date. Participants were adults aged 18–65 years who completed part C of the Phase 1 givosiran study (NCT2452372).MethodsEnrollees received givosiran for up to 48 months. Primary and secondary endpoints included the incidence of adverse events, changes in urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, annualized rate of porphyria attacks, and annualized hemin use. Quality of life was assessed using the EQ-5D-5L instrument as an exploratory endpoint.ResultsSixteen patients (median age: 39.5 years) participated. Common adverse events included abdominal pain, nasopharyngitis, and nausea (50% each), with injection-site erythema (38%) and injection-site pruritus (25%) noted as frequent treatment-related reactions. Givosiran therapy reduced annualized rates of porphyria attacks and hemin use by 97% and 96%, respectively. From months > 33 to 48, all patients were free from attacks requiring significant medical intervention and did not use hemin. There were substantial reductions in median urinary ALA and PBG of 95% and 98%, respectively. Additionally, a clinically meaningful improvement in quality of life was observed.ConclusionsIn the longest follow-up of givosiran-treated patients reported to date, the therapy maintained an acceptable safety profile and demonstrated sustained improvements in clinical outcomes over 4 years in patients with acute intermittent porphyria.

Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy-Related Thrombotic Microangiopathy.

Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.

Kidney Disease in Systemic Amyloidosis: A Review of AL, AA, ALECT2, ATTR.

Systemic amyloidoses are a group of disorders that can be hereditary or acquired and have various renal manifestations and outcomes. Light chain amyloid has been considered the most common renal amyloid and thus been the focus of substantial research and therapeutic interest but with improvement in diagnostic techniques. However, there has been growing interest in rarer forms of renal amyloid, including amyloid serum A protein, leukocyte chemotactic factor 2 amyloid, and transthyretin amyloid. In this review, we provide an update on diagnostics, renal outcomes, and therapeutic landscape in these specific types of amyloid.

B-080 Development and Validation of a GQ1b IgG ELISA as a Diagnostic Aid for Subacute Demyelinating Polyneuropathies

Abstract Background Autoimmunity targeting GQ1b is associated with group of disorders that includes Miller-Fisher Syndrome (MFS), Bickerstaff Brainstem Encephalitis (BBE) and classic Guillain Barre Syndrome (GBS) with ophthalmoplegia. Collectively these are referred to as GQ1B-IgG related syndromes. The prevalence of GQ1b-IgG in this population of patients is high and has been reported to be >80% in well-defined clinical cohorts. Clinical phenotypic presentation is diverse and requires highly accurate antibody testing. The objective of this study was to evaluate a newly developed custom GQ1b-IgG assay, using a semi-quantitative ELISA-based method. Methods A GQ1b-IgG ELISA was developed and validated. Patient sera along with assay controls and a single-point calibrator are diluted and incubated in duplicate wells in a 96-well plate coated with GQ1b antigen. The plate is washed and incubated with anti-human-IgG secondary antibody conjugated with HRP. After a colorimetric reaction, optical densities (OD) are read. The OD of patient samples are compared against the calibrator, generating a cut-off index (COI). Samples ≥1.0 COI are considered positive. During the validation phase, analytical and clinical performance characteristics were evaluated. Studies included assessment of imprecision at multiple concentrations of GQ1b-IgG, accuracy using method comparison, analytical sensitivity and specificity, reference range, common interferences, plate drift, and clinical performance in relevant disease and control cohorts. Results Intra-assay imprecision (coefficient of variation; %CV) ranged from 1.0 - 16% across all concentrations of GQ1b-IgG. Inter-assay imprecision (%CV) ranged from 12.4 - 44.5% but was <20% at or above the assay cut-off. We found perfect qualitative agreement with an independent ELISA reference method (20 positive and 20 negative samples selected based on reference method results [reference interval <1:100]). Limit of detection (LOD) was calculated at a COI of 0.22. To assess analytical specificity, 40 samples with high concentrations of immunoglobulins (hypergammaglobulinemia [N=15], IgG M-protein [N=15] and systemic lupus erythematosus [N=10] were tested and all were negative. A reference interval study was performed on 140 healthy donor serums, all were negative. Interference studies were conducted on 2 positive and 2 negative serum samples, spiked for highly hemolytic (1000 mg/dL), lipemic (2000 mg/dL) and icteric (60 mg/dL) conditions. There was no impact on the assay even with high levels of a given interferent. Plate drift on 2 distinct patient pools tested across the plate (COI range 0.7 - 1.3) had overall plate CV’s ≤10%. ROC analysis was performed on a cohort of 278 patient samples (15 MFS cases and 263 controls [suspected demyelinating neuropathy or disease mimics]). A cut-off value of 1.0 (COI) was selected based on the Youden index. At this cut-off, clinical sensitivity for MFS was 87% while clinical specificity was 99.2%. Conclusions The observed performance of the GQ1b-IgG ELISA was acceptable for clinical laboratory implementation. A COI of ≥ 1.0 was selected for clinical use.

Neuropsychiatric Manifestations of Degenerative Cerebellar Ataxia.

Degenerative cerebellar ataxias (DCA) present a group of complex neurological disorders primarily affecting the cerebellum and its pathways. Classic manifestations include motor symptoms of cerebellar ataxia. However, emerging evidence suggests that the cerebellum also plays a crucial role in various cognitive and emotional processes. The objective was to assess the psychiatric profile of a heterogeneous group of patients with degenerative cerebellar ataxia. Our sample comprised 107 participants diagnosed with cerebellar degenerative ataxia. All patients were clinically evaluated using SARA, INAS, and different neuropsychiatric scales (ACE-R, HAMA, HAMD, AS, and GAF). The majority of patients had autosomal dominant ataxia (38.3%) followed by sporadic ataxia (32.7%) with an average age at the moment of diagnosis of 35.3 ± 16.23 years, while the mean duration of disease at the study beginning was 12.1 ± 9.9 years. Psychiatric disorders were present in 40 patients (37.4%), with dysthymia (14.2%), major depressive disorder (9.4%), and MDD with melancholic features (7.6%). The presence of MDD with melancholic features was statistically significantly correlated with a lower ACE-R total score (r = -0.223; p = 0.022), while dysthymia was statistically significantly associated with a shorter duration of the disease (r = -0.226; p = 0.020) and older age (r = 0.197; p = 0.043). Statistically significant differences were observed between MSA-C patients and those with sporadic ataxia (HDRS p < 0.001, HARS p < 0.001, Apathy Scale p = 0.003, and GAF p = 0.004). Based on our findings, we can conclude that the degree of motor deficit has a significant impact on the development of psychiatric disorders, including depression, anxiety, and apathy. However, it is not the only factor, and the impact also depends on the type of DCA.

Analysis of rare genetic variants in All of Us cohort patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a group of genetic disorders involving more than a dozen genetic loci and characterized by a deficiency in specific antibody isotypes leading to poor immune responses and recurrent infection. CVID affects approximately 1 in 10,000 to 1 in 50,000 people worldwide with substantial heterogeneity in disease severity, including asymptomatic individuals designated as hypogammaglobulinemia of undetermined significance (HGUS). As expected of humoral immunodeficiency, the molecular causes of CVID primarily affect the maturation, activation, or survival of B cells and plasma cells. In this retrospective analysis, we defined a cohort of 21 patients with a primary CVID or HGUS diagnosis in the v7 release of the All of Us Research Program database and performed gene annotation and variant effect prediction. Our analysis identified both known disease-causing variants and rare genetic variants overlapping with other immunodeficiency syndromes.

DNA methylation inhibitors adverse reaction characteristic analysis: a descriptive analysis from WHO-VigiAccess.

DNA methylation inhibitors (azacitidine, decitabine) have revolutionized the treatment dilemma of myelodysplastic syndromes (MDS), a group of malignant hematopoietic disorders. This study evaluates the adverse drug reactions (ADRs) following the use of DNA methylation inhibitors in the World Health Organization (WHO) VigiAccess database and compares the characteristics of ADRs between the two drugs to select the drug with the minimum individualized risk for patients. This study employed a retrospective descriptive analysis method. We compiled ADR reports for two marketed DNA methylation inhibitors for the treatment of MDS from WHO-VigiAccess. Data collected included demographic data such as age groups, gender, and regions of global patients covered by ADR reports, as well as data on the disease systems and symptoms caused by ADRs recorded in the annual reports and reports received by WHO. By calculating the proportion of ADRs reported for each drug, we compared the similarities and differences in ADRs between the two drugs. Overall, 23,763 adverse events (AEs) related to the two DNA methylation inhibitors were reported in VigiAccess. The results showed that the top 10 most common AEs were febrile neutropenia, bone marrow suppression, neutropenia, anemia, pancytopenia, leukopenia, thrombocytopenia, bone marrow failure, agranulocytosis, and hematotoxicity. The top five common types of DNA methylation inhibitor AEs were blood and lymphatic system disorders (11,178 cases, 47.0%), cardiac organ diseases (1,488 cases, 6.3%), various congenital familial genetic diseases (49 cases, 0.2%), ear and labyrinth diseases (100, 4.2%), and endocrine system diseases (57, 2.4%). There is no Strong correlation between DNA methylation inhibitors and ADRs. Current comparative observational studies of these inhibitors show that there are common and specific adverse reactions in the ADR reports received by WHO for these drugs. Clinicians should improve the rational use of these drugs based on the characteristics of ADRs.

A-037 A1c by separation and enzymatic methods: what's the difference?

Abstract Background Accurate values for hemoglobin A1c (HbA1c) are crucial for diagnosing and monitoring diabetes mellitus. Two common methods to measure HbA1c are capillary electrophoresis (CE) and immunoassay (IA). Many methods used to measure HbA1c are prone to interferences from hemoglobin variants and abnormalities affecting the red blood cell’s (RBC) turnover. Consequently, the average estimated glucose levels using the HbA1c value can be unreliable in diabetics with hemoglobinopathies and other RBC lifetime disorders. Separation methods such as CE can capture hemoglobinopathy information, while IA methods may not. We performed this study in a population with relatively high levels of hemoglobin disorders to evaluate the performance of HbA1c testing on the Alinity platform (IA) against the Sebia Capillarys 3 Tera instrument (CE). Methods Samples were identified retrospectively based on a search of the Electronic Medical Record for all patients with an ordered and resulted HbA1c and complete blood count in the Montefiore Medical Center the day prior to sampling. Routine HbA1c testing was performed by an Abbott Immunoassay method on the Abbott Alinity Instrument and CBC results were obtained from a Sysmex XN2100 instrument. Records were compared by patient name, medical record number, and sample collection time to identify all patients with CBC and HbA1c drawn within one hour of each other. Those samples were retrieved from storage (a 4° automated refrigerator) within 48 hours of draw and tested via the Sebia Capillarys 3 Tera instrument using HBA1c kits. Results In this large representative population study (N=2075), there was overall excellent agreement between IA and CE. The correlation coefficient (R2) of the whole dataset was 0.989, with an average bias of 2.7% between the two methods. Additional analysis was performed on those with possible RBC turnover disorder (patients with RBC counts below 4x106/uL or above 6x106/uL, MCVs above 96 fL or below 80 fL, RDW above 17%, or abnormal A2 value: total of 638 samples), those with a hemoglobin variant as detected by the Capillarys 3 instrument (162 samples), or with a measurable hemoglobin F value detected by the Capillarys 3 instrument (37 samples). Samples were sorted into these groups independently and thus there was significant overlap between groups, notably with 23 of 37 samples with elevated HbF also having a hemoglobin variant. In both the RBC disorder and hemoglobinopathies group, similar low bias and high correlations were seen. The elevated F samples showed a clear negative bias (5.6%) for all patients on the IA method as compared with CE. The IA method states that samples with HbF above 5% should not be tested. However, as this is not a separation method, there is no way to test samples for HbF before analysis, and bias was seen for samples below 5%. Conclusions The IA and CE methods showed similar performance across patients regardless of RBC lifetime or hemoglobin disorder status, though presence of HbF is a potential interference and should be considered. Further questions remain for these instruments in terms of correlation with average glucose levels as calculated through CGM instruments.

Ameliorative Review on Exploration of Spices in Aspects of Phytochemical Screening for their Antidiabetic Action

Diabetes is a diverse group of disorder characterized by hyperglycemia due to an deficiency in insulin production. Diabetes mellitus's chronic hyperglycemia is linked to end organ damage, dysfunction, and failure, including blood vessel, kidney, retina, and nervous system. With over 62 million cases of diabetes being identified in India, the disease is rapidly turning into a true epidemic. The majority of synthetic oral hypoglycemic medications available for the disease's treatment are costly, have significant adverse effects, and/or cannot be used while pregnant. As a result, a growing number of people worldwide are turning to traditional herbal remedies to prevent and treat diabetes. Spices having antioxidant, hypoglycemic, and hypolipidemic characteristics may be effective in the therapy of diabetes. As a result, these spices are growing in popularity due to their potential efficacy, little to nonexistent adverse effects, and synergistic effects. Spices are compounds used in food as coloring, flavoring, or preservation. They might be fresh or dried seeds, bark, roots, fruits, or even vegetables. This paper includes phytochemical screening of spices which have crucial role in the treatment of diabetis mellitus.