Homozygous LMNA p.R582H pathogenic variant reveals increasing effect on the severity of fat loss in lipodystrophy

Abstract

Background: Classical heterozygous pathogenic variants of the lamin A/C (LMNA) gene cause autosomal dominant 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.

Case presentation: Here, we report a patient with a lamin A specific pathogenic variant in exon 11, denoted LMNA (c.1745G > A; p.R582H), present in the homozygous state. Fat distribution was compared radiographically to an unrelated heterozygote LMNA p.R582H patient from another pedigree, a healthy female 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, the p.R582H LMNA variant in homozygous fashion 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, the 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 an additive effect of LMNA pathogenic 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.

Keywords: Generalized lipodystrophy; Homozygous; LMNA; Lamin A; Partial lipodystrophy.

Fig. 1

Patient pictures showing generalized fat loss. a: Near-total lack of adipose tissue and muscular appearance in the trunk. Arms are very muscular. Note that there is no fat accumulation in the neck. In contrast, subcutaneous fat is lost over shoulders and in the upper trunk. b: Subcutaneous fat is lost in the abdomen. Muscular appearance is remarkable. c: Arms are muscular with visible vessels and no subcutaneous fat. d: Subcutaneous fat is lost in the distal legs. Legs are muscular with prominent veins. e: Acanthosis nigricans and skin tags in the armpits associated with severe insulin resistance

Fig. 2

Comparison of fat distribution. The whole-body MRI confirms generalized fat loss in the patient who had a homozygous pathogenic variant in the LMNA gene. Adipose tissue is well preserved around mons pubis and external genital region similar to heterozygous LMNA R582H patient and typical FPLD2 patients while fat tissue loss is noted in a generalized pattern in the scalp, mammary gland, abdomen visceral/subcutaneous, and extremities. Fluid like signal is detected in the bone marrow. Supraclavicular subcutaneous fat was preserved, but the amount of fat was significantly decreased in contrast to heterozygous LMNA R582H and typical FLPD2. The liver was steatotic and diffusely enlarged. Fat loss is partial in heterozygous LMNA p.R582H carrier (Fig. 2b) affecting the limbs, abdomen, breasts and the lower part of the body which is similar to typical FPLD2, although more subcutaneous fat was observed in the upper part of the trunk, over the shoulders, and head and neck (Fig. 2b and d). Retroorbital fat is preserved in all patients. a: Fat distribution in the patient with homozygous LMNA pathogenic variant, R582H; b: Fat distribution in the patient with heterozygous LMNA pathogenic variant, p.R582H; c: Fat distribution in a healthy control (28 years old, female); d: Fat distribution in a 30-year-old female with typical FPLD2 caused by heterozygous LMNA pathogenic variant p.R482W (c.1444C > T); e: Fat distribution in a 30-year-old female with the classical CGL1 phenotype caused by homozygous AGPAT2 pathogenic variant p.C48X (c.144C > A). In each panel I. Whole-body T1-weighted imaging; II. Retroorbital, axial T1 weighted- imaging; III. Head and neck, axial T1 weighted-imaging; IV. Trunk, axial T1 weighted-imaging; V. Pelvic region, axial T1 weighted-imaging, VI. Upper leg, axial T1 weighted imaging; VII. Sole, axial T1-weighted imaging