Background Type-2 familial partial lipodystrophy (FPLD2) is a rare autosomal dominant lipodystrophic disorder due to mutations in LMNA encoding lamin A/C, a key epigenetic regulator. FPLD2 severity is determined by the occurrence of metabolic complications, especially diabetes and hypertriglyceridaemia. We evaluated the disease history and severity over generations.
Methods This retrospective study of the largest cohort of patients with FPLD2 reported to date investigates 85 patients from 24 families comprising three generations (G1: n=39; G2: n=41; G3: n=5).
Results Lipodystrophy appears with the same characteristics and at the same age in first generation (G1;18.6±1.5 years) and second generation (G2;15.9±0.8 years). Despite similar body mass index (23.7±0.6 vs 23.8±0.6 kg/m2), the mean delay between the onset of lipodystrophy and diabetes was far shorter in G2 (10.5±2.4 years) than in G1 (29.0±3.5 years) (p=0.0002). The same is true for the delay preceding hypertriglyceridaemia (G2: 4.5±1.4; G1: 19.3±3.2 years) (p=0.002), revealing an anticipation phenomenon. Observations in G3, and analysis within each family of disease history and diagnostic procedures, confirmed this result.
Conclusions This study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals.
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Contributors IJ, CVa, OL and CVi contributed to the conception and design of the work. All the authors contributed to the collection and interpretation of data: CVa, MCV and CVi were involved in patients care. IJ, CVi and OL were involved in genetic analyses.
IJ wrote the manuscript, which was revised critically by all authors. All the authors provided final approval of the submitted manuscript and agreed to be accountable for all aspects of the work. IJ is the guarantor of this article.
Funding This work was supported by Institute of Cardiometabolism and Nutrition (ICAN), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie (UPMC), Société Francophone du Diabète (SFD) and AFERO (Association Française d’Etude et de Recherche sur l’Obésité).
Competing interests None declared.
Patient consent All patients provided informed written consents for molecular diagnosis.
Ethics approval This study was approved by the Comité de Protection des Personnes Ile-de-France 5, Paris, France.
Provenance and peer review Not commissioned; externally peer reviewed.