A Patient with Congenital Generalized Lipodystrophy Due To a Novel Mutation in BSCL2: Indications for Secondary Mitochondrial Dysfunction

Abstract

Background: Congenital generalized lipodystrophy (CGL) results from mutations in AGPAT2, encoding 1-acyl-glycerol-3-phosphate-acyltransferase 2 (CGL1; MIM 608594), BSCL2, encoding seipin (CGL2; MIM 269700), CAV1, encoding caveolin1 (CGL3; MIM 612526) or PTRF, encoding polymerase I and transcript release factor (CGL4; MIM 613327). This study aims to investigate the genotype/phenotype relationship and search for a possible pathogenic mechanism in a patient with CGL.Design: Case report. Patients and Setting: A 7-day-old child of consanguineous Turkish parents presented with a generalized loss of subcutaneous fat. He had a strikingly enlarged liver, high serum triglycerides, and hyperglycaemia, suggestive for CGL.Results: A novel homozygous mutation in the acceptor splice site of exon 5 of the BSCL2 gene was found in the genome of the proband. This mutation causes a complex RNA splicing defect and results in two different aberrant seipin proteins, which were normally expressed and localized to the endoplasmic reticulum like wild type protein. Analysis of the patient's urine showed intermittent elevations of citric acid intermediates and persistently high concentrations of ethylmalonic acid, suggestive of a disturbance of the mitochondrial respiratory chain.Conclusion: Here we report abnormal urinary organic acid levels, indicative of mitochondrial dysfunction, in a patient with CGL resulting from a novel mutation in BSCL2. Our findings suggest for the first time an association between CGL and secondary mitochondrial dysfunction.

The Sodium–Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model

“…About half of the patients (54%) display abnormal electrocardiogram (ECG) with prolonged QT intervals and nonspecific T-wave abnormalities (18). It is not clear yet whether this cardiomyopathy is associated with ectopic myocardial lipid accumulation (19)(20)(21). Thus, the phenotype of lipodystrophic cardiomyopathy is poorly characterized, and the underlying molecular mechanism remains unknown.…”

Neonatal cardiac hypertrophy: the role of hyperinsulinism—a review of literature

“…In patients with congenital lipodystrophy, it is not fully understood whether the cardiomyopathy is the direct effect of the mutant gene, an effect of lipotoxic substances or the result of hyperinsulinemia. A causal relationship between hyperinsulinemia and CH in patients with BSCL2 mutations is suggested in two patients in whom CH improved or even regressed after correction of the hyperinsulinism [16,41].…”

“…H o w e v e r, i n hyperinsulinemic patients, it is frequently observed that CH results in a stiff heart with high diastolic filling pressure resulting in reduced stroke volume and in the case of severe CH leads to the development of heart failure secondary to left ventricular outflow tract obstruction [58,81]. In most of the hyperinsulinemic patients, the hypertrophy is asymptomatic and even reversible after normalization of insulin levels [24,30,41,82].…”

“…Additional therapies for hyperinsulinism were reported on trial basis or in individual cases. In one patient with BSCL2, Metformin treatment, a mitochondrial glycerophosphate dehydrogenase [107], resulted in normalization of cardiac hypertrophy [41]. Recombinant IGF-1 was administered in several patients with leprechaunism [108,109] and reported to stabilize severe obstructive cardiac hypertrophy in one patient [110].…”

How Research on Human Progeroid and Antigeroid Syndromes Can Contribute to the Longevity Dividend Initiative

“…These mutations result in variable expressions of striking losses of normal adipose tissue and abnormal accumulations of lipids in various viscera, including skeletal muscle, liver, and heart. In addition to the regional atrophy of subcutaneous tissues that is so common in normative aging, one also observe type 2 diabetes mellitus (Lawson 2009), cardiovascular lesions (Nelson et al 2013) often associated with lipid abnormalities, sometimes with multiple xanthomas (Machado et al 2013), psychomotor abnormalities (Wei et al 2013), and what some regard as secondary abnormalities of mitochondrial oxidative phosphorylation (Jeninga et al 2012). Gastrointestinal polyps, a common benign feature of normative aging, has also been observed (Agrawala et al 2014).…”