Case Report: Twenty years of metreleptin therapy in congenital generalized lipodystrophy type 1: the longest reported follow-up to date.

Congenital generalized lipodystrophy (CGL) is a rare disorder marked by near-total loss of adipose tissue and severe metabolic disturbances due to leptin deficiency and the inability to store nutrients in adipose tissue effectively. Metreleptin is the only approved leptin replacement therapy for this condition. Here we present the >20-year follow-up of two sisters with CGL type 1 (AGPAT2 deficiency, OMIM# 608594), enrolled in early metreleptin trials. Clinical outcomes, adherence, immunogenicity, and pregnancies were assessed. Both cases showed rapid and sustained metabolic improvement after metreleptin initiation, allowing insulin discontinuation and triglyceride normalization. Menstrual cycles resumed within six months; allowing both to carry successful pregnancies while continuing metreleptin. Both cases experienced reduced treatment adherence over time, linked to psychological distress. One case developed both anti-drug antibodies and neutralizing activity through immune based assay after 14 years, but without significant clinical impact. In conclusion, these cases highlight both the sustained metabolic benefits of therapy and the complex challenges that may arise over time, such as antibody formation and difficulties in maintaining long-term adherence. Documentation of unmet medical needs can provide guidance and impetus for improved therapeutic approaches to achieve optimum quality of life.

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