Clinical and laboratory data of a large series of patients with congenital generalized lipodystrophy

Nóbrega

et al. 2017

Bone

Self Cite

Context Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty in storing lipids in adipocytes, low body fat mass, hypoleptinemia, and hyperinsulinemia. Sclerostin is a product of SOST gene that blocks the Wnt/β-catenin pathway, decreasing bone formation and enhancing adipogenesis. There are no data about sclerostin in people with BSCL. Objective We aimed to evaluate serum sclerostin, bone mineral density (BMD), and L1-L4 Trabecular Bone Score (TBS) in BSCL patients, generating new knowledge about potential mechanisms involved in the bone alterations of these patients. Design, Setting, and Patients In this cross-sectional study, we included 11 diabetic patients with BSCL (age 24.7±8.1 years; 6 females). Sclerostin, leptin, L1-L4 TBS, BMD were measured. Potential pathophysiological mechanisms have been suggested. Results Mean serum sclerostin was elevated (44.7±13.4 pmol/L) and was higher in men than women (55.3±9.0 vs. 35.1±8.4 pmol/L, p=0.004). Median of serum leptin was low [0.9 ng/mL (0.5-1.9) ]. Seven out of 11 patients had normal BMD, while four patients had high bone mass (defined as Z-score>+2.5SD). Patients on insulin had lower sclerostin (37.3±9.2 vs. 52.6±13.4 pmol/L, p=0.05). The mean TBS was 1.402±0.106, and it was higher than 1.300 in nine patients. Conclusions Patients with lipoatrophic diabetes (BSCL) have high serum concentrations of sclerostin, normal or high BMD, and reasonable trabecular bone mass measured by TBS. This is the first report of high sclerostin and good bone microarchitecture (TBS) in BSCL patients.

“…In the Brazilian BSCL cohort, from the state of Rio Grande do Norte, there are very high prevalence rates of Type 2 as described previously [8] due to consanguineous marriages.…”

Section: Introductionmentioning

confidence: 80%

“…These patients are part of a cohort previously published [8]. The mean age was 24.7±8.1 years old, and there were six females.…”

Section: Resultsmentioning

confidence: 99%

Normal bone density and trabecular bone score, but high serum sclerostin in congenital generalized lipodystrophy

Nóbrega

et al. 2017

Bone

Self Cite

“…Globally, the most common mutation is the c.589-2A > G (rs116807569). In Brazil, the predominant CGL mutations are c.589-2A > G, c.317-588del, c.646A > T, and c.570C > A in the AGPAT2 gene [17][18][19]. Our historical relationship with Portugal and Africa during colonization and the previous description of the c.589-2A > G mutation in these locations suggest a founder effect (Fig.…”

Section: Discussionmentioning

confidence: 69%

Leu124Serfs*26, a novel AGPAT2 mutation in congenital generalized lipodystrophy with early cardiovascular complications

Júnior

Fernandes

et al. 2020

Diabetol Metab Syndr

Background: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by the near-total loss of subcutaneous adipose tissue soon after birth, resulting in ectopic fat deposition and severe metabolic disturbances. Most cases are caused by AGPAT2 or BSCL2 gene mutations. We aimed to report two unrelated CGL patients with a novel frameshift mutation in AGPAT2 (p.Leu124Serfs*26). Methods: Clinical features and laboratory were obtained by medical interview and medical records review. DNA was extracted, amplified and sequenced. Mutation Taster was used to estimate the potential biological impact of the AGPAT2 mutations on the protein function. Results: Patient 1: a 30-year-old woman with lipodystrophy phenotype at birth and diagnosis of diabetes at age 13 presented with severe hypertriglyceridemia and pancreatitis at age 17, hypertension and albuminuria at age 18, proliferative diabetic retinopathy with visual loss at age 25, and an acute myocardial infarction due to multivessel coronary disease during a hospitalization for forefoot amputation at age 29. At this time, she required hemodialysis due to endstage renal disease. Patient 2: a 12-year-old girl with lipodystrophy phenotype and hypertriglyceridemia detected in the first year of life and abnormalities in the global longitudinal strain, evaluated by speckle-tracking echocardiography last year. Molecular analysis identified a c.369_372delGCTC (p.Leu124Serfs*26) AGPAT2 mutation in both unrelated patients, a compound heterozygous mutation in Patient 1, and homozygous mutation in Patient 2. Conclusion: We describe two unrelated patients with type 1 CGL due to Leu124Serfs*26, a novel AGPAT2 frameshift mutation, presenting as early cardiovascular disease. These findings suggest an association between Leu124Serfs*26 and a more aggressive phenotype.

Biology of Reproduction

“…Berardinelli-Seip congenital lipodystrophy (BSCL) is an autosomal recessive disease accompanied by lipodystrophy, diabetes, and hypertriglyceridemia, but muscle hypertrophy is among the most common clinical features of BSCL [9][10][11][12]17]. This study revealed that seipin deficiency led to uterine smooth muscle hypertrophy in middle-aged mice but not in the prepubertal mice.…”

Section: Discussionmentioning

confidence: 92%

“…We have been studying the functions of seipin in reproductive systems using seipin-deficient Bscl2 −/− mice and identified roles of seipin in mammary gland development, vaginal opening, and spermatogenesis [11,12]. Since seipin deficiency is associated with muscle hypertrophy and diabetes [10,17], diabetes has been associated with impairment of uterine contractility [18], and uterine smooth muscle contractions are critical for parturition, it was hypothesized that seipin deficiency might affect the myometrium to influence parturition. This hypothesis was tested in seipin-deficient Bscl2 −/− adult female mice.…”

Section: Introductionmentioning

confidence: 99%

Seipin deficiency leads to defective parturition in mice†

Zowalaty

2017

Seipin is an integral endoplasmic reticulum membrane protein encoded by Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2/Bscl2) gene. Seipin deficiency results in lipodystrophy, diabetes, muscle hypertrophy, and male infertility in both human and mouse. Seipin function in female reproduction is unknown. Bscl2 −/− dams had normal embryo implantation and body weight gain during pregnancy but reduced delivery rates from 2nd to 4th pregnancies and reduced numbers of pups delivered from 1st to 4th pregnancies. Characterization of first pregnancy revealed increased gestation period and parturition problems, including uterine prolapse, difficulty in delivery, undelivered fetuses, and undelivered tissues in Bscl2 −/− females. Bscl2 −/− uterine weight was comparable to control at 3 weeks old but significantly increased with myometrial hypertrophy at 10 months old. In situ hybridization revealed relatively low level of Bscl2 mRNA expression in myometrium throughout pregnancy and postpartum but high level of expression in uterine luminal epithelium, suggesting that systemic effect (e.g. elevated glucose and insulin levels) rather than local seipindeficiency in myometrium might be a main contributing factor to myometrial hypertrophy. On near-term gestation day 18.5 (D18.5), Bscl2 −/− females had normal levels of serum progesterone and 17β-estradiol, indicating functional ovary and placenta. Proliferating Cell Nuclear Antigen (PCNA) staining showed minimal myometrial cell proliferation in both D18.5 Bscl2 +/+ and Bscl2uteri. There was strong LC3 immunostaining in Bscl2 +/+ and Bscl2 −/− peripartum myometrium and increased LC3 staining in Bscl2 −/− peripartum uterine luminal epithelium, suggesting a potential role of seipin in regulating autophagy in uterine luminal epithelium but not myometrium. This study demonstrates an association of seipin with myometrium and parturition. Summary SentenceOur findings that seipin deficiency in mice leads to myometrial hypertrophy and parturition problems reveal a novel in vivo function of seipin in parturition.