SUN-600 Presence of LMNA p.R582H Pathogenic Variant in Homozygous State Demonstrates Gene Dosage Effect on the Severity of Fat Loss in Lipodystrophy

Abstract

Background Classical heterozygous pathogenic variants of the lamin A/C (LMNA) gene cause familial partial lipodystrophy type 2 (FPLD2). However, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants, and a few patients have been associated with generalized fat loss. Clinical Case Here, we report a patient with lamin A specific pathogenic variant at exon 11 LMNA p.R582H present in homozygous state. Fat distribution was compared radiographically to a heterozygote LMNA p.R582H patient from another pedigree, female healthy control, a series of adult female subjects with congenital generalized lipodystrophy type 1 (CGL1, n = 9) and typical FPLD2 (n = 8). The whole body MRI of the index case confirmed near-total loss of subcutaneous adipose tissue with well-preserved fat in the retroorbital area, palms and soles, mons pubis, and external genital region. This pattern resembled the fat loss pattern observed in CGL1 with only one difference: strikingly more fat was observed around mons pubis and the genital region. Also, homozygous p.R582H LMNA variant was associated with lower leptin level and earlier onset of metabolic abnormalities compared to heterozygous p.R582H variant and typical FPLD2 cases. On the other hand, heterozygous LMNA p.R582H variant was associated with partial fat loss which was similar to typical FPLD2 but less severe than the patients with the hot-spot variants at position 482. Conclusions Our observations and radiological comparisons demonstrate a gene dosage effect of LMNA variants on the severity of fat loss and add to the body of evidence that there may be complex genotype-phenotype relationships in this interesting disease known as FPLD2. Although the pathological basis for fat loss is not well understood in patients harboring pathogenic variants in the LMNA gene, our observation suggests that genetic factors modulate the extent of fat loss in LMNA associated lipodystrophy.