12436 Madelung’S Multiple Symmetric Lipomatosis: A New Indication For Leptin Pathway Activation?
Authors: Foss de Freitas Maria Cristina , Dill Gomes Anabela , Schill Rebecca , Obua Bonje M , Kaba Diarratou , Verma Sneha , Celik Guler Merve , Gilio Donatella , Hoose Keagan , Soni Tanu , Chun Tae-Hwa , Burant Charles F , Cederna Paul , MacDougald Ormond A , Oral Elif A 
Published: October 2024

Disclosure: M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. Consulting Fee; Self; Aegerion Pharmaceuticals. A. Dill Gomes: None. R. Schill: None. B.M. Obua: None. D. Kaba: None. S. Verma: None. M. Celik Guler: None. D. Gilio: None. K. Hoose: None. T. Soni: None. T. Chun: None. C.F. Burant: None. P. Cederna: None. O.A. MacDougald: None. E.A. Oral: Advisory Board Member; Self; Regeneron Pharmaceuticals, Amryt. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Ionis Pharmaceuticals Inc., GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt.

Background: Multiple Symmetric Lipomatosis (MSL) or Madelung’s disease is a rare disorder with symmetric deposition of adipose tissue as non-encapsulated lipomas around the cervical neck region, upper torso and back, and lipoatrophy at the peripheral extremities. One reason for MSL is biallelic pathogenic variants involving at least one copy of R707W variant in Mitofusin 2 (MFN2) gene. Patients often present with metabolic problems including insulin resistance, fatty liver, and dyslipidemia. Given that patients with MFN2-related MSL also display low leptin concentrations, we investigated whether replacement of leptin ameliorates metabolic complications and the disfiguring lipomatosis. Methods: We treated four patients (2 brothers aged 18 and 22 and two unrelated women aged 56 and 60 with daily subcutaneous metreleptin (ML) injections. Treatment started at 2.5 mg daily in men and 5 mg in women, with a plan to titrate the dose every month up to 10 mg daily based on efficacy and weight. The primary endpoint was % change in trunk fat mass (TFM) at week 24 by DEXA. Metabolic and histopathological assessments were also carried out in the same time frame. Results: All patients experienced progressive reductions in the size of their lipomas with lipomas completely invisible in the younger male patients at W24. Consequently, TFM was significantly reduced with treatment (-38.5% from BL, p=0.01). Patients also had significant reduction (p &lt;0.05) in weight (-13.3%), waist circumference (-11.8%) and waist to hip ratio (-7.7%). Adipose tissue biopsies from all depots showed the presence of crown like structures (CLS)” and large variability in adipocyte size at BL, with improvement at W24. There were significant reductions in HbA1c (5.3±0.04% at BL to 4.9±0.2% at W24), fasting triglyceride (-38.6%) and AST levels (-41.6%) (p &lt;0.05). Insulin AUC (-60.6%), triglyceride AUC (-60.6%) and glucose AUC (-14.5%) from an OGTT were also reduced from BL to W24. At week 12 and W24 there were nominally significant reductions in total ceramides, consistent with a reduction in inflammation, likely due to the weight loss or reduction in insulin resistance accompanying ML treatment. ML was well tolerated, with all patients continuing treatment due to benefit. One patient experienced intermittent mild shivering within the first month (possibly related). All other adverse events were unrelated, nonserious and of mild to moderate intensity. Conclusion: Our data show a significant reduction in hypertrophic fat depots together with weight loss, metabolic improvement, and reduction in adipocyte inflammation in this small number of individuals with MSL. Given that there is no specific treatment for this disfiguring condition, we propose leptin pathway activation to be a rational, well-tolerated, and effective treatment for MSL. Future work will focus on molecular mechanisms and larger clinical trials.

Presentation: 6/3/2024