P420: GM3 synthase deficiency: Case report of an atypical presentation

Conclusion:The clinical phenotype of NR4A2-related disorder is likely much broader and more heterogeneous than original suspected.Introduction: NR4A2 encodes an orphan transcription factor in the steroid-thyroid hormone-retinoid receptor family.Few pathogenic variants in NR4A2 have been reported in patients with heterogenous neurodevelopmental disorders.This case series expands the clinical spectrum of NR4A2-related disorders.Case Presentation: Patient 1 is a 20-year-old female with hypertension, bilateral polycystic kidneys, reactive hypoglycemia, developmental delays, intellectual disability, autism spectrum disorder, mild craniofacial dysmorphism, and benign Rolandic epilepsy in remission.She has a normal EGD and gastric emptying study, normal renal function (eGFR > 100 mL/min/1.73m 2 ), low free T4, normal brain MRI, and a negative hereditary renal disease gene panel.Further workup revealed Mayo Class 1B kidney volumes and a normal chromosomal microarray (CMA).Exome sequencing (ES) revealed a de novo pathogenic frameshift variant in NR4A2 (c.174dup, p.S59Qfs*33).She has received multidisciplinary care.Her seizures have been in remission since age 9, and her hypertension is well controlled on her current regimen.Patient 2 is an 18-year-old female with developmental delays, dyslexia, hypotonia, reactive hypoglycemia, nocturnal seizures, postural orthostatic tachycardia syndrome (POTS), mild craniofacial dysmorphism, and joint hypermobility complicated by recurrent dislocations requiring shoulder reconstruction.She has borderline low potassium, low growth hormone, high 24h urine cortisol, low-normal ACTH, and high triglycerides (non-fasting due to hypoglycemic intolerance).Further workup revealed normal plasma amino acids, urine organic acids, and plasma acylcarnitine profile.CMA was negative and ES revealed multiple VUS.ES re-analysis in 2024 resulted in reclassification of a heterozygous de novo splice site variant in NR4A2 as likely pathogenic (c.1361+1G>A, predicted disruption of GT donor site).Renal ultrasound to screen for renal cysts has been ordered but not yet completed.This patient also receives multidisciplinary care.Recently, she has required two reconstructive left shoulder surgeries as a consequence of repeated dislocation.Her seizures improved following initiation of carb-controlled diet and potassium supplementation, and she has been seizure free for the past year.