Muthusamy, Kalpana

ABSTRACT Bardet‐Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.

Abstract Background Clinical nutrition (CN) is becoming increasingly complex because of the rising prevalence of chronic illness, cancer, and malnutrition‐related conditions such as short bowel syndrome and refeeding syndrome. Despite its clinical significance, nutrition education among US physicians remains limited. Simultaneously, large language model (LLM)–based artificial intelligence assistants (AIAs) have emerged as tools to support complex clinical decision‐making but remain largely untested in CN. Methods This retrospective study evaluated four LLM‐based AIAs—ChatGPT (OpenAI), OpenEvidence (OpenEvidence Inc), Gemini (Google, Google DeepMind), and Copilot (Microsoft Corporation)—using five complex CN cases from our nutrition support service. Each AIA was queried with patient‐specific CN questions. Responses were blinded and reviewed by five physician CN experts using an eight‐item assessment tool evaluating clarity, relevance, evidence, and clinical utility. Results All AIAs produced clinically appropriate responses, with Gemini scoring highest in relevance (4.04) and clarity (4.16). Overall satisfaction scores ranged from 3.08 (Copilot) to 3.84 (Gemini). Citation quality and originality of insights varied and were generally limited, and no consistent differences in performance were observed across the five cases among the four AIAs. Conclusion LLM‐based AIAs can reliably replicate expert reasoning in CN. Although not yet a source of novel clinical insights, the true potential of this approach may lie in its application among physicians without specialized expertise in CN, helping to bridge existing knowledge gaps in nutrition care. Presenting full clinical cases, as shown in this study, could support AIA‐enabled e‐consultation in the future, thereby addressing gaps in CN education.

Abstract Disclosure: D. Hassan: None. M. Salama: None. S. Kumar: None. K. Muthusamy: None. Background: Obesity is prevalent among individuals with Bardet-Biedl Syndrome (BBS), affecting approximately 72%-86% of patients. Setmelanotide, an MC4R agonist, is approved for the treatment of obesity in patients with BBS. It reduces hyperphagia and improves quality of life. However, the high cost of setmelanotide and the need for daily injections limit its use. Affordable and effective alternative pharmacotherapies are needed for managing obesity in patients with BBS. Here, we present a case of an adult with BBS who experienced significant weight loss following treatment with a combination of topiramate and phentermine. Clinical Case: A 29-year-old Hispanic female with BBS due to a homozygous BBS2 mutation (NM_031885.3, c.717+1G>T, GT donor) was evaluated for migraine. BMI was elevated at 42.5 kg/m², and obesity was complicated by obstructive sleep apnea, chronic respiratory failure requiring supplemental oxygen with activity, impaired fasting glucose (101 mg/dL; reference range [RR]: 70-100 mg/dL), and dyslipidemia (triglycerides: 252 mg/dL [RR: 30-150 mg/dL]; very low-density lipoprotein (VLDL): 50.4 mg/dL [RR: 8-30 mg/dL]; total cholesterol: 190 mg/dL [RR: 0-200 mg/dL]; high-density lipoprotein (HDL): 40 mg/dL [RR: 40-60 mg/dL]). She had polydactyly, retinal dystrophy, developmental delay and subclinical hypothyroidism. Topiramate was initiated at 25 mg and subsequently increased to 50 mg. At 31 years of age, BMI was 40.5 kg/m², and weight had decreased by 7.5 kg after two years of therapy with topiramate and lifestyle interventions. Phentermine 30 mg daily was added. She experienced a notable appetite-suppressing effect, reduced nighttime eating, fewer sugar cravings, and decreased stress-related eating. She was able to extend the duration of exercise with improved endurance. She reported constipation as a side effect but had no other intolerances. After three months of phentermine therapy, BMI decreased to 34.96 kg/m². Repeat metabolic profile revealed fasting glucose 70 mg/dL, HbA1c 5.5% (RR: 4.5-5.6%), triglycerides 204 mg/dL, VLDL 40.8 mg/dL, total cholesterol 175 mg/dL, HDL 38 mg/dL, and low-density lipoprotein (LDL) 96 mg/dL (RR: 70-100 mg/dL). Eight months after starting phentermine, BMI further decreased to 32.31 kg/m², reflecting a 25% total weight loss. Conclusion: This case report highlights the excellent weight loss response (25% total weight loss) and significant improvement in metabolic profile with phentermine and topiramate combination therapy in a patient with BBS. The effects of this combination therapy have not been formally studied in BBS, emphasizing the need for further research to evaluate the efficacy of conventional anti-obesity medications—used alone, sequentially, or in combination with setmelanotide—to optimize weight and metabolic outcomes. Keywords: Bardet-Biedl Syndrome, obesity, topiramate, phentermine, weight loss. Presentation: Sunday, July 13, 2025

Abstract Disclosure: D. Hassan: None. M. Salama: None. K. Muthusamy: None. A.M. Haqq: None. S. Kumar: None. Introduction: Bardet-Biedl syndrome (BBS) is a rare genetic condition characterized by obesity and considerable clinical and genetic heterogeneity. While cardiometabolic and endocrine comorbidities are commonly associated with BBS, data on their prevalence, particularly in children, remain limited. Objective: To assess the prevalence of cardiometabolic and endocrine comorbidities among pediatric and adult patients with BBS. Methods: This is a retrospective chart review of pediatric and adult patients with BBS evaluated in the outpatient setting at Mayo clinic. The cohort included individuals aged 0-50 years with either a clinical or genetic diagnosis of BBS, identified from January 1, 2000, onward. Demographic, anthropometric, phenotypic, and biochemical data were reviewed. Results: The study comprised 34 patients, including 9 children (median age 8 years (IQR: 3.5-11)) and 25 adults (median age 33.5 years (IQR: 27-42)). Females constituted 56% of the cohort and White individuals accounted for 76%. The median age at diagnosis of BBS was 9 years (IQR: 3-16). Phenotypic characteristics included retinal dystrophy in 33% of children and 92% of adults, polydactyly in 78% of children and 52% of adults, and learning disabilities in 56% of children and 52% of adults. Obesity was prevalent in 56% of children and 80% of adults. Among children, their median maximum BMI % of the 95th percentile was 149% (IQR: 136-163%). Adults had a a median maximum BMI of 50 kg/m² (IQR: 43-55). There was insufficient data to determine the onset of hyperphagia; however, the median age of obesity onset for the cohort was 7 years (IQR: 4-11). No cases of diabetes or prediabetes were identified among children, whereas 40% of adults were diagnosed with type 2 diabetes. Cardiometabolic characteristics included hypertension in 11% of children and 48% of adults, kidney dysfunction in 33% of children and 56% of adults. Dyslipidemia was noted in 22% of children and 44% of adults, with median triglyceride levels 133 mg/dL (IQR: 93-153) in children and 142 mg/dL (IQR: 120-200) in adults. No cases of cardiovascular disease were identified in children, whereas 8% of adults were diagnosed with the condition. Endocrine characteristics included hypothyroidism in 11% of children and in 24% of adults. Of the 34 patients, genotype data were available for 28 individuals (82%). The most prevalent genotype was BBS1, comprising 27% of the cases. This was followed by BBS2 and BBS10, which each accounted for 15% of the cohort. Genotypes BBS4, BBS6 (MKKS2), IFT172, and SCLT1 were each observed in 3% of the cohort. Conclusion: This study highlights the significant clinical, cardiometabolic, and endocrine burden associated with BBS across children and adults. These findings underscore the importance of early and comprehensive multidisciplinary management of BBS. Keywords: Bardet-Biedl syndrome, obesity, cardiometabolic, endocrine comorbidities. Presentation: Monday, July 14, 2025

Abstract There is limited data on the effect of antiobesity medications in individuals with Bardet-Biedl syndrome (BBS). Here, we present a case of an adult with BBS who experienced significant weight loss following treatment with a combination of topiramate and phentermine. A 31-year-old female with BBS, with homozygous pathogenic variant in the BBS2 gene, presented with obesity, dyslipidemia, and obstructive sleep apnea. At 29 years of age, her body mass index (BMI) was 43.3 kg/m2 (reference range 18.5-24.9 kg/m2), and she was initiated on 50 mg topiramate daily for migraine prophylaxis. With lifestyle modifications, BMI dropped to 40.5 kg/m2. Subsequently, phentermine 30 mg daily was added. Eight months after adding phentermine, BMI significantly decreased to 31.5 kg/m² (27% decrease in BMI), with improvement in glycemic and lipid parameters. She developed paranoia due to a social stressor prompting a brief hold of phentermine and resumption at a lower dose. This case highlights the weight loss response with phentermine and topiramate combination therapy in a patient with BBS. Further research is needed to explore the efficacy and safety of conventional antiobesity medications in isolation, as sequential or combination therapy to setmelanotide, to most effectively impact weight and metabolic burden in patients with BBS.

Abstract The widespread use of statins for cardiovascular diseases has unveiled a new subset of inflammatory myopathy, immune-mediated necrotizing myopathy (IMNM). We describe below an unusual case of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy. A 64-year-old male individual with type 2 diabetes, hyperlipidemia, and coronary artery disease presented with progressive proximal muscle weakness and pain for 3 months. He took atorvastatin 40 mg for 4 years, which was discontinued due to elevated liver enzymes and resumed treatment with rosuvastatin 5 mg later due to worsening hyperlipidemia. Physical examination showed significant weakness of the hip, shoulder girdle, and biceps/triceps. Creatinine kinase (CK) was found to be 232.48 µkat/L (13 921 IU/L) (normal: 0.833-5.133 µkat/L; 50-308 IU/L). Electromyography and left vastus lateralis muscle biopsy showed findings of myonecrosis. Anti-HMGCR assay was strongly positive with antibodies > 200 chemiluminescent units (CU) (normal: 0-20 CU). He was started on prednisone followed by human-immunoglobulin (IVIG) which led to a decline in CK. Statin-induced necrotizing autoimmune myopathy (SINAM) is an exceptionally rare side effect of statins. Although statins come with a good side-effect profile, one should be aware of marked, persistent elevations in muscle enzyme levels. Prompt confirmation with antibody levels, drug discontinuation, and early initiation of immunosuppression can lead to good outcomes.

The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired β-cell function and with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects, with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele. Subjects were studied on two occasions, 3 years apart, using an oral 75-g glucose challenge. The oral minimal model was used to quantitate β-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in subjects with the TT genotype. This was accompanied by impaired postchallenge glucagon suppression but appropriate β-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede β-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes. Article Highlights

Abstract Context Interventions targeting hypoglycemia in people with diabetes are important for improving quality of life and reducing morbidity and mortality. Objective To support development of the Endocrine Society Clinical Practice Guideline for management of individuals with diabetes at high risk for hypoglycemia. Methods We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence. Results We included 149 studies reporting on 43 344 patients. Continuous glucose monitoring (CGM) reduced episodes of severe hypoglycemia in patients with type 1 diabetes (T1D) and reduced the proportion of patients with hypoglycemia (blood glucose [BG] levels <54 mg/dL). There were no data on use of real-time CGM with algorithm-driven insulin pumps vs multiple daily injections with BG testing in people with T1D. CGM in outpatients with type 2 diabetes taking insulin and/or sulfonylureas reduced time spent with BG levels under 70 mg/dL. Initiation of CGM in hospitalized patients at high risk for hypoglycemia reduced episodes of hypoglycemia with BG levels lower than 54 mg/dL and time spent under 54 mg/dL. The proportion of patients with hypoglycemia with BG levels lower than 70 mg/dL and lower than 54 mg/dL detected by CGM was significantly higher than point-of-care BG testing. We found no data evaluating continuation of personal CGM in the hospital. Use of an inpatient computerized glycemic management program utilizing electronic health record data was associated with fewer patients with and episodes of hypoglycemia with BG levels lower than 70 mg/dL and fewer patients with severe hypoglycemia compared with standard care. Long-acting basal insulin analogs were associated with less hypoglycemia. Rapid-acting insulin analogs were associated with reduced severe hypoglycemia, though there were more patients with mild to moderate hypoglycemia. Structured diabetes education programs reduced episodes of severe hypoglycemia and time below 54 mg/dL in outpatients taking insulin. Glucagon formulations not requiring reconstitution were associated with longer times to recovery from hypoglycemia, although the proportion of patients who recovered completely from hypoglycemia was not different between the 2 groups. Conclusion This systematic review summarized the best available evidence about several interventions addressing hypoglycemia in people with diabetes. This evidence base will facilitate development of clinical practice guidelines by the Endocrine Society.

AbstractContextIndividuals with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. Management of hyperglycemia in these patients is challenging.ObjectiveTo support development of the Endocrine Society Clinical Practice Guideline for management of hyperglycemia in adults hospitalized for noncritical illness or undergoing elective surgical procedures.MethodsWe searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence.ResultsWe included 94 studies reporting on 135 553 patients. Compared with capillary blood glucose, continuous glucose monitoring increased the number of patients identified with hypoglycemia and decreased mean daily blood glucose (BG) (very low certainty). Data on continuation of insulin pump therapy in hospitalized adults were sparse. In hospitalized patients receiving glucocorticoids, combination neutral protamine hagedorn (NPH) and basal-bolus insulin was associated with lower mean BG compared to basal-bolus insulin alone (very low certainty). Data on NPH insulin vs basal-bolus insulin in hospitalized adults receiving enteral nutrition were inconclusive. Inpatient diabetes education was associated with lower HbA1c at 3 and 6 months after discharge (moderate certainty) and reduced hospital readmissions (very low certainty). Preoperative HbA1c level < 7% was associated with shorter length of stay, lower postoperative BG and a lower number of neurological complications and infections, but a higher number of reoperations (very low certainty). Treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors in hospitalized patients with type 2 diabetes and mild hyperglycemia was associated with lower frequency of hypoglycemic events than insulin therapy (low certainty). Caloric oral fluids before surgery in adults with diabetes undergoing surgical procedures did not affect outcomes (very low certainty). Counting carbohydrates for prandial insulin dosing did not affect outcomes (very low certainty). Compared with scheduled insulin (basal-bolus or basal insulin + correctional insulin), correctional insulin was associated with higher mean daily BG and fewer hypoglycemic events (low certainty).ConclusionThe certainty of evidence supporting many hyperglycemia management decisions is low, emphasizing importance of shared decision-making and consideration of other decisional factors.