Congenital generalized lipodystrophy: identification of novel variants and expansion of clinical spectrum

Abstract

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.

Natural History of Congenital Generalized Lipodystrophy: A Nationwide Study From Turkey

“…Despite generalized lack of fat, patients with CGL1 had well preserved adipose tissues in the palms, soles, scalp and orbital region, as reported in a previous study (29). Although Haghighi et al (27) reported that bone cysts were noticed only in CGL1 patients in a very recent paper, we observed bone cysts both in patients with CGL1 and CGL2, which was in concordance with previous studies (30,31). On the other hand, mild mental retardation and hypertrophic cardiomyopathy were observed only in patients with CGL2.…”

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

“…The oldest patient, PERU1010 (age 7 years and 6 months) showed evidence of hypertriglyceridemia, diabetes mellitus, and mild liver function abnormalities, conditions frequently seen in patients with the Berardinelli–Seip syndrome [Van Maldergem et al, ; Van Maldergem, ; Haghighi et al, ]. The age of onset is unknown, she had no prior laboratory testing.…”

“…Metabolic abnormalities such as hypertriglyceridemia and insulin resistance are also characteristic features of these disorders [Prieur et al, ; Cortes and Fernandez‐Galilea, ; Patni and Garg, ]. CGL is usually caused by pathogenic variants in either the AGPAT2 or the BSCL2 genes, which are responsible for a milder CGL1 and a more severe CGL2 (Berardinelli–Seip syndrome), respectively [Van Maldergem et al, ; Agarwal et al, ; Haghighi et al, ]. A small number of patients with CAV1 mutations are reported in CGL3 [Kim et al, ] and PTRF mutations have been observed in CGL4 [Hayashi et al, ; Rajab et al, ].…”

“…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, ].…”

Lipodystrophy - A Rare Condition with Serious Metabolic Abnormalities

“…In fact, almost all patients that have African origin have the founder mutation in intron 4, c589-2A>G of one or both alleles [7,12]. In the past 5 years, several novel variants of AGPAT2 have been identified in CGL patients: c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316+1G>T; c.134C>A and c.216C>G [13]; c.514G>A [14]; c.685G>T, and c.514G>A [15]. In addition, a very rare case of dual mutations (c.493-1G>C and c.299G>A) in AGPAT2 was identified in two Chilean sisters [16].…”