Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p.T10I mutation

Abstract

Lipodystrophies are a group of heterogeneous disorders characterized by the loss of adipose tissue and metabolic complications. The main familial forms of lipodystrophy are Congenital Generalized Lipodystrophy and Familial Partial Lipodystrophy (FPLD). FPLD may result from mutations in the LMNA gene. Besides FPLD, mutations in LMNA have been shown to be responsible for other inherited diseases called laminopathies. Here we describe the case of a 15-year-old girl who was referred to our service due to diabetes mellitus and severe hypertriglyceridemia. Physical examination revealed generalized loss of subcutaneous fat, confi rmed by DEXA (total body fat 8.6%). As the patient presented with pubertal-onset of generalized lipodystrophy and insulin resistance, molecular analysis of the LMNA gene was performed. We identifi ed a heterozygous substitution in exon 1 (c.29C>T) predicting a p.T10I mutation. In summary, we describe an atypical phenotype of lipodistrophy associated with a de novo appearance of the p.

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations

“…Patient P15 with pubertal-onset generalized lipodystrophy and severe insulin resistance was previously described (16). The heterozygous p.T10I (c.29COT) mutation in exon 1 was found in the proband but was absent in both of her parents.…”

“…Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety, an autosomal dominant condition characterized by gradual loss of adipose tissue from the extremities and trunk starting at the puberty. However, phenotypic heterogeneity in the pattern of body fat loss has been observed among the laminopathies (11,12,13,14,15,16,17). Therefore, in this study, we searched for LMNA mutations in patients with various forms of lipodystrophy.…”

Molecular insights into the premature aging disease progeria

“…In addition to the classical 1824C>T HGPS mutation, other heterozygous, homozygous or compound heterozygous mutations in LMNA have been reported, such as T10I, A57P, L59R, R133L, L140R, S143F, E145K, V169fsX176, D300N, E578V and R644C and c.412G>A (Kirschner et al 2005 ; Csoka et al 2004 ; Chen et al 2003 ; Caux et al 2003 ; Jacob et al 2005 ; Mory et al 2008 ; McPherson et al 2009 ; Doh et al 2009 ; Renard et al 2009 ; Doubaj et al 2012 ; Kane et al 2013 ), all causing atypical progeroid syndromes (APS). APS mutations affect similar tissues (bone, skin, hair and body fat) and cause similar pathologies (growth retardation, alopecia, tight skin and beaked nose) as classical HGPS, but the course and severity of the symptoms vary greatly (Garg et al 2009 ; Doubaj et al 2012 ).…”

LMNA‐associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset

“…A small, but growing, number of patients with progeria described in the literature have LMNA mutations that do not alter Lamin A processing, representing a second class of LMNA ‐linked progeria disorders [Caux et al, ; Chen et al, ; Eriksson et al, ; Csoka et al, ; Huang et al, ; Jacob et al, ; Kirschner et al, ; Van Esch et al, ; Verstraeten et al, ; Mory et al, ; Rodriguez et al, ; Zirn et al, ; Garg et al, ; Madej‐Pilarczyk et al, ; McPherson et al, ; Renard et al, ; Al‐Haggar et al, ; Doubaj et al, ]. The mutations that cause these disorders can be either dominant or recessive and can alter residues throughout the protein structure with no clear clustering in a single region of lamin A.…”