ABC | Volume 114, Nº2, February 2020

Review Article Romano et al. Myocardial alterations in familial lipodystrophy Arq Bras Cardiol. 2020; 114(2):305-312 Figure 1 – Characteristics of patients with familial partial lipodystrophy. PanelAshows fat accumulation on the face and neck and panel B, fat accumulation in the perineal and intra-abdominal regions. normal fat distribution during childhood and begin to have progressive and variable loss of subcutaneous fat during puberty, typically from the extremities, and in varying degrees from the abdomen and chest. Many patients, especially females, show fat accumulation in the face, neck and perineal and intra-abdominal regions. (Figure 1) Excess fat accumulation in the dorsocervical (buffalo hump), supraclavicular and submental regions gives these patients a “cushingoid” appearance. In women, there may be masculinization, menstrual irregularity and high prevalence of polycystic ovary syndrome. 5 Five genes may be involved in the pathophysiology of this type of lipodystrophy, all leading to subcutaneous fat loss in the extremities. The most prevalent form of familial lipodystrophy is autosomal dominant type 2, the first familial partial lipodystrophy more formally described: FPLD2 (Familial Partial Lipodystrophy Type 2), also referred to as variant or Dunnigan Syndrome. This syndrome has a prevalence of 1 in 15 million people, affecting both genders equally. The patients develop several metabolic complications such as dyslipidemia, hypertriglyceridemia and diabetes. In addition, they may manifest varying degrees of myopathy, cardiomyopathy, and other conduction system abnormalities, thus proving to be a multisystem dystrophy. 6 FPLD2 is characterized by a mutation in the long arm of chromosome 1 (1q21-22) specifically involving lamins A and C or the LMNA gene. Commonly, the mutation that causes FPLD2 affects exon 8 (replacement of arginine by a neutral amino acid at position 482 - R482W), but other mutations in exon 8 and 11 (codon 644 - R644C) have already been described. 6,7 It has been shown that the LMNA R482Wmutation is more associated with muscle and cardiac abnormalities, such as muscular atrophy and dystrophy, cardiac hypertrophy and advanced atherosclerosis. 8 But the phenotypic differences associated with each specific mutation determinant of FPLD are yet to be elucidated. Numerous mutations spread throughout the LMNA protein give rise to diseases commonly called laminopathies that affect muscle, heart, fat, cartilage and bone tissues or lead to early aging syndromes. 9 A-type lamins include lamins A (LMNA) and C (LMNC) that arise from alternative splicing of RNA from the LMNA gene. These proteins are expressed in most cells, and they are located in the nuclear envelope and nucleoplasm and play a relevant role in directing the transcription of heterochromatin located on the periphery of the nucleus. 9 It is believed that the alteration of these proteins weakens the integrity and structure of the nuclear envelope, which would profoundly deteriorate the structure of the adipocyte nucleus, ultimately leading to premature cell death. In addition, it is known that A-type lamin is capable of interacting with transcription factors such as SREBP1 (Sterol Regulatory Element Binding Protein 1), which is involved in the differentiation of adipocytes. 6,7,9 Furthermore, it has been observed that type A and C-lamins bind to telomeric sequences, having a role in regulating telomere length. The main point common to all types of lipodystrophy is the total or almost total absence of adipose tissue, thus compromising the affected individual's storage of triglycerides and their metabolic activity. Before that, most patients clinically manifest muscular appearance, prominent superficial veins, 306