Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder caused by mutations in AGPAT2 and Gng3lg. We screened for mutations in AGPAT2 and Gng3lg in 26 families with CGL and one family with Brunzell syndrome. We found mutations in either AGPAT2 or Gng3lg in all but four probands, including three novel mutations in AGPAT2, A712T (Lys215X), IVS3-1G-->C, and C636A (Phe189X). In three siblings with Brunzell syndrome, we identified a splice site mutation (IVS4-2A-->G) in AGPAT2, showing that AGPAT2 mutations can also cause Brunzell syndrome. Eighteen CGL patients from 15 families from the same region of northeastern Brazil were homozygous for a frameshift mutation (669insA of AF05149) in Gng3lg. Despite having the same mutation, the subjects had widely divergent clinical manifestations. In our subjects, there did not appear to be any distinguishing clinical characteristics between CGL subjects with AGPAT2 or Gng3lg mutations with the exception of mental retardation in carriers of Gng3lg. In summary, mutations in AGPAT2 and Gng3lg are approximately equally represented in CGL; despite harboring the same Gng3lg mutation, subjects may have widely divergent clinical manifestations, suggesting modifying influences of other genes and/or environment; and Brunzell syndrome may be caused by a mutation in AGPAT2.

IntroductionBerardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive disease that affects the development of adipocytes and leads to an inability to store fat in adipocytes. This study aimed to evaluate the life expectancy and the causes of death of patients with BSCL.MethodWe analyzed death certificates, and medical records of BSCL patients who died between 1997 and 2017. If the death certificate was incomplete or unavailable, we reviewed the medical records, and if they were not available too, we collected information from the patient's relatives to understand how the death happened. We calculated the potential years of life lost as a result of premature death.ResultsTwenty patients (12 female and 8 male) died between 1997 and 2017. The mean age at the time of death was 27.1±12.4 years (women 25.2±12.5 vs. men 29.9±12.6 years, p = 0.41). Life expectancy for the study population was 62.9±4.8 years. The potential number of years of life lost was 35.6±16.6 years. The causes of deaths were divided into three major groups: infections (7 patients, 35%), liver disease (7 patients, 35%), and other causes (acute pancreatitis, one patient; renal failure, three patients; sudden death/myocardial infarction, two patients). Three patients had pulmonary fibrosis.ConclusionBSCL led to premature death, cutting the patients’ lifespan by 30 or more years. The majority of these young patients died of liver disease or infection. Other studies are needed to understand better the mechanisms that predispose to infections, as well as to assess whether new therapies can alter the natural history of this disease.

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Background: Berardinelli-Seip syndrome (BSS) or Generalized Congenital Lipodystrophy often affects the cardiovascular system and also promotes metabolic abnormalities involving glycidic and lipid metabolisms.