Congenital generalized lipodystrophy in an Indian patient with a novel mutation in BSCL2 gene

Abstract

Congenital generalized lipodystrophy (CGL) is an autosomal recessive metabolic syndrome with involvement of multiple organs. Mutations in BSCL2 are known to be associated with a severe form of CGL and mental retardation (MR). The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity in different ethnic groups. Studies in the Indian context are very few in this regard. We report here a detailed clinical analysis of a CGL case from infancy to adult hood. Interestingly, the patient was found to be homozygous for a novel BSCL2 mutation, but with normal intellectual development contrasting with the MR associated with BSCL2 mutation in CGL patients. The biochemical investigations at the time of diagnosis (9 months) included total cholesterol, total lipids, triglycerides, phospholipids, β-lipoprotein and free fatty acids, which were above normal limits. The clinical phenotype, viz. lack of subcutaneous fat, hepatosplenomegaly, cardiomegaly, and advanced bone age was also documented. The patient was found to be insulin resistant and diabetes mellitus was diagnosed by age 13 years. Ultrasonography of the ovaries at age 22 showed polycystic features with elevated levels of gonadotropins and negligible levels of serum leptin. For genetic analysis, direct DNA sequencing of BSCL2 was carried out and disclosed an 11-base-pair deletion in exon 6 (H217fsX272) resulting in a truncated protein. This is a novel mutation that contributes to CGL formation in a family of Indian origin and adds to the array of variants reported in this disorder. Moreover, the novel mutation is found to be associated with normal intellectual ability.

A Taiwanese Boy With Congenital Generalized Lipodystrophy Caused by Homozygous Ile262fs Mutation in the BSCL2 Gene

“…As described, mutations for CGL patients can be homozygous or compound heterozygous, and most of the BSCL2 mutations are nonsense or frameshift mutations that are expected to cause loss of function of the protein [9]. Reports from Japan, India, China and Taiwan [9,[13][14][15][16][17][18] indicate that BSCL2 is a major causative gene for CGL in Asian (Table). However, nearly 50% of CGL cases around the world have no sequence mutation in either AGPAT2 or BSCL2 [19].…”

High incidence of BSCL2 intragenic recombinational mutation in Peruvian type 2 Berardinelli–Seip syndrome

“…Since the initial identification of BSCL2 pathogenic variants as the causes of CGL2 [Magre et al, ], there have been a number of reports of BSCL2 disease‐causing variants from European, Middle Eastern, and Asian countries [Van Maldergem et al, ; Agarwal et al, ; Shirwalkar et al, ; Rahman et al, ; Schuster et al, ; Akinci et al, ; Haghighi et al, ]. While most identified pathogenic variants are null mutations, the result of either nonsense, indel, or splicing mutations, a small number of missense variants have also been reported in CGL2 [Van Maldergem et al, ].…”

Clinical and Mutational Features of Three Chinese Children with Congenital Generalized Lipodystrophy

“…It is unusual to have diabetes mellitus early in life in patients with CGL. Though metabolic abnormalities of hyperinsulinemia and insulin resistance are evident early in life, overt diabetes generally develops during the pubertal years or adulthood (5,6,7,8,17). In a report by Van Maldergem et al (5), among 24 patients with BSCL2, 16 were diagnosed to have diabetes.…”

“…Recently, a nationwide study from Turkey showed that the mean age of onset of diabetes in these patients was 16.5 years (8). CGL patients who were diagnosed as insulin resistant in infancy and who developed diabetes mellitus at puberty have also been reported (7,17). Consistently, serum insulin levels of patient 2 and patient 3 in our study were high, but they had not developed diabetes so far.…”

“…Affected individuals have severe hypertriglyceridemia, hyperinsulinemia, hepatomegaly, and often widespread acanthosis nigricans (4). Diabetes mellitus usually appears by the second decade or in adulthood (5,6,7,8). Additionally, hypertrophic cardiomyopathy is a classical late (second or third decade) complication (9,10) which has only been occasionally described in infancy or childhood (11,12,13,14).…”