Potential association of LMNA-associated generalized lipodystrophy with juvenile dermatomyositis

Abstract

BackgroundJuvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome.Case presentationA previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation.ConclusionsThis is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted.Electronic supplementary materialThe online version of this article (10.1186/s40842-018-0058-3) contains supplementary material, which is available to authorized users.

Use of bioinformatic analyses in identifying characteristic genes and mechanisms active in the progression of idiopathic thrombocytopenic purpura in individuals with different phenotypes

“…40 Another study identified a potential relationship between lamin A/C (LMNA)-associated generalized lipodystrophy and juvenile dermatomyositis. 41 On this basis we postulate that the observed high LMNA expression in the chronic ITP group in our study is closely related to disease progression. Furthermore, a familybased genetic study demonstrated that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and low expression of filamin A in megakaryocytes.…”

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

“…248 Some cases of juvenile FPLD2 have also been reported. 249,250 C-reactive protein (CRP) and free fatty acids are elevated in non-diabetic FPLD2 individuals. 251 Interestingly, LMNA knockout mice also lack insulin resistance, although they show features of FPLD2.…”

“…While FPLD2‐affected females are more likely to have diabetic physiology compared to FPLD2‐affected males, 247 it is also noted that FPLD2 females are prone to polycystic ovary syndrome (PCOS) and infertility 248 . Some cases of juvenile FPLD2 have also been reported 249,250 . C‐reactive protein (CRP) and free fatty acids are elevated in non‐diabetic FPLD2 individuals 251 .…”

PPARγ Gene as a Possible Link between Acquired and Congenital Lipodystrophy and its Modulation by Dietary Fatty Acids

“…The loss of fat usually begins in childhood or adolescence [1]. Most patients have related autoimmune diseases [8][9][10][11][12][13]. In certain au-toimmune diseases, the role of the PPARγ gene is essential to modulate inflammation.…”