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.
Keywords: Anticipation; Diabetes; Hypertriglyceridaemia; LMNA; lipodystrophy.
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