6887 Unraveling the Natural History of Lipodystrophy Syndromes with LD LYNC: Time to Development of Important Comorbidities

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Abstract Disclosure: M. Celik Guler: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. Speaker; Self; Amryt. M. Yosef: None. S. Khalatbari: None. D. Kaba: None. M. Ashmus: None. D. Guler: None. D. Gilio: None. A. Dill Gomes: None. D.S. Rosenberg: None. T. Neal: None. B. Tuska: None. M. Brush: None. M. Hwang: None. B. Tracey: None. M. Okawa: None. B. Brite: None. C. Richison: None. I. Yildirim Simsir: None. B. Akinci: Advisory Board Member; Self; Amryt. Consulting Fee; Self; Regeneron Pharmaceuticals, Alnylam Pharmaceuticals, Amryt, AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, Third Rock Ventures. R.J. Brown: Grant Recipient; Self; Pfizer. Research Investigator; Self; Regeneron Pharmaceuticals, Amryt. 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, Ionis Pharmaceuticals Inc., Fractyl, GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Background: Lipodystrophy (LD) syndromes represent a group of rare diseases, genetic or acquired, characterized by deficiency or abnormal distribution of adipose tissue with comorbidities such as diabetes, hypertriglyceridemia, cardiovascular disorders, and liver diseases. Natural history data, including comparisons between disease subtypes, are limited to retrospective chart reviews. We are now conducting a prospective, international, comprehensive registry study to unravel the natural history of important comorbidities (LD Lync study; ClinicalTrials.gov # NCT03087253). Methods: This analysis reports on 267 patients with LD (M/F: 19/81%, age range: 6-75 years). All participants are followed up yearly. Clinical and demographic data are summarized by either median [IQR], or frequencies (%) for the overall and subgroups. For generalized lipodystrophy (GL) versus partial lipodystrophy (PL) comparisons, as well as for the most common genetic subgroups, the time to diagnosis of complications was analyzed using Kaplan-Meier curves and defined as the median age of occurrence (in years and interquartile range). Results: At baseline, hypertriglyceridemia was the most common comorbidity (76.6%), followed by diabetes (72.1%), fatty liver disease (69.1%), and hypertension (49.1%). Pancreatitis was identified in 22.1% of patients, and cirrhosis in 7.5%. The median age at diagnosis of diabetes was 16 [14-32] years in GL and 35 [25-50] years in PL (p<0.0001), while the median age of hypertriglyceridemia was 20 [15-26] years in GL and 30 [22-49] years in PL (p<0.0001). The median age at diagnosis of diabetes (16 [14-24] vs 35 [25-46] years), hypertriglyceridemia (17 [14-23] vs 30 [20-42] years) and hepatic steatosis (22 [16-40] vs 40 [26-57] years) was earlier in congenital generalized lipodystrophy (CGL) than in familial partial lipodystrophy (FPLD) (p<0.0001 for all comparisons). The median age of the first cardiac condition was similar between CGL and FPLD: 31 [21-36] and 37 [24-53] years, respectively. More time and events are needed to obtain accurate estimates for pancreatitis and kidney disease. There was no statistically significant difference between GL and PL in the median age of first hospitalization. Seven (2.6%) patients died during follow-up. The causes of death were multiorgan failure (due to acute pancreatitis), aspiration pneumonia, acute respiratory failure (due to hemophagocytic lymphohistiocytosis), stage-4 endometrial cancer, myocardial infarction, and decompensated cirrhosis. Conclusion: Our data show that patients with LD have a substantial risk of comorbidities, with younger age of onset of diabetes, hypertriglyceridemia, and hepatic steatosis in GL compared to PL. The registry is well-positioned to be an important resource for understanding the differences in trajectories and impact of novel medications designed to modify disease course. Presentation: 6/1/2024

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