Lipodystrophy, Congenital Generalized, Type 2

A number sign (#) is used with this entry because congenital generalized lipodystrophy type 2 (CGL2) is caused by homozygous or compound heterozygous mutation in the gene encoding seipin (BSCL2; 606158) on chromosome 11q12.

Biallelic mutation in the BSCL2 gene can also cause progressive encephalopathy with or without lipodystrophy (PELD; 615924), a severe neurodegenerative disorder.

Description

Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes (Garg, 2004).

For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Clinical Features

Van Maldergem et al. (2002) studied 70 affected individuals from 44 unrelated families with congenital generalized lipodystrophy. Forty-five patients from 24 families had BSCL2 and 21 patients from 17 families had BSCL1 (608594). Two European families had no BSCL2 mutations and did not show linkage to chromosome 9q34, indicating the existence of an additional locus, which the authors termed BSCLX. All subjects of African ancestry (35%) were in the BSCL1 group. Congenital onset of lipoatrophy occurred in 79.5% of patients with BSCL2 compared to 61% of other cases. Onset of diabetes was the same in all patients. All patients had skeletal muscle hypertrophy, and the prevalence of hypertrophic cardiomyopathy was approximately 20% in all groups. Seven of 45 (15%) BSCL2 patients died prematurely (range, 4 months to 35 years of age), compared to no premature deaths in patients with BSCL1. The most significant finding was an increased frequency of mild or moderate intellectual impairment in the BSCL2 group (78%) compared to BSCL1 (10%), yielding an odds ratio of 23.5. There was no correlation between site and type of seipin mutation and intellectual impairment. Van Maldergem et al. (2002) concluded that BSCL1 is a milder disease than BSCL2.

Simha and Garg (2003) compared whole-body adipose tissue distribution by magnetic resonance imaging (MRI) in 10 congenital generalized lipodystrophy patients, of whom 7 (6 females, 1 male) had CGL1 (608594) and 3 (2 males, 1 female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most subcutaneous, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in the palms, soles, orbits, scalp, and periarticular regions was noted in CGL2, whereas it was well preserved in CGL1 patients. The authors concluded that congenital generalized lipodystrophy patients with BSCL2 mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue.

Friguls et al. (2009) reported a 4-month-old Chinese boy with a severe form of congenital lipodystrophy caused by a homozygous truncating mutation in the BSCL2 gene (E189X; 606158.0016). He had hirsutism with dry, thick hair, enlarged hands and feet, and lipoatrophy affecting the trunk, limbs, and face. He also had hepatomegaly with steatosis, acute pancreatitis, insulin resistance, and low serum leptin. Cardiac examination revealed hypertension and an apical murmur, and ultrasound showed severe obstructive and asymmetric septal hypertrophic cardiomyopathy. Dietary management resulted in clinical improvement. Friguls et al. (2009) emphasized the early onset of severe cardiac disease in this patient.

Haghighi et al. (2016) compared the clinical features of 5 patients with genetically confirmed CGL1 and 5 with CGL2. All patients had generalized lipodystrophy and muscular hypertrophy, and most had hepatomegaly and splenomegaly. Additional features were found in both groups, but tended to be more frequent in patients with CGL2 than in those with CGL1; these features included acromegaloid appearance, large ears, triangular facies, acanthosis nigricans, increased insulin levels, elevated liver enzymes, hernias, and cardiomyopathy. Genital abnormalities and hypertriglyceridemia were found equally in both groups. Two CGL1 patients and 1 CLG2 patient had nephrolithiasis. Only 1 CGL1 patient had bone cysts, and only CGL2 patients had intellectual disability, hypertrichosis, and high-pitched voice.

Mapping

Using a genomewide scan of 9 BSCL families from 2 geographic clusters in Lebanon and Norway, Magre et al. (2001) identified a disease locus, designated BSCL2, within a 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13 (maximum multipoint lod score of 13.2). Five Lebanese families were homozygous for the same alleles at 9 contiguous markers within an interval spanned by markers D11S4076 to PYGM (608455), probably because of a founder effect. Among families clustered in the southwest region of Norway, Magre et al. (2001) found that affected family members were homozygous for 4 consecutive markers, D11S1765, D11S4076, CA10, and CA9, confirming a founder effect. Analysis of 20 additional BSCL families of various ethnic origins led to the identification of 11 families in which the disease cosegregated with the 11q13 locus; the remaining families provided confirmation of linkage to 9q34.

Molecular Genetics

In chromosome 11q13-linked families with congenital generalized lipodystrophy type 2, and in 3 isolated patients, Magre et al. (2001) identified mutations in the BSCL2 gene (606158.0001-606158.0012). Affected individuals were either homozygous for a specific mutation or compound heterozygous; all parents of unaffected sibs carried only 1 mutation.

Agarwal et al. (2002) pointed out that individuals with congenital generalized lipodystrophy type 2 who carry mutations in the BSCL2 gene tend to have mild mental retardation and cardiomyopathy, features not seen in families with congenital generalized lipodystrophy type 1 who have mutations in the AGPAT2 gene. Based on the high expression of seipin in brain and weak expression in adipocytes, Magre et al. (2001) suggested a primary defect in hypothalamic pituitary axis. Agarwal et al. (2002) suggested that different forms of congenital generalized lipodystrophy may be caused by disruption of different pathways.

Fu et al. (2004) screened for mutations in AGPAT2 and BSCL2 in 27 families with congenital generalized lipodystrophy. In 3 sibs with the features of congenital generalized lipodystrophy with cystic angiomatosis of long bones (a phenotype designated Brunzell syndrome) they identified a splice site mutation in AGPAT2 (603100.0002). Eighteen patients from 15 families from the same region of northeastern Brazil were homozygous for a frameshift mutation in BSCL2 (669insA; 606158.0006). Despite having the same mutation, the subjects had widely divergent clinical manifestations. The authors concluded that there did not appear to be any distinguishing clinical characteristics between subjects with congenital generalized lipodystrophy with AGPAT2 or BSCL2 mutations with the exception of mental retardation in carriers of BSCL2.

Ebihara et al. (2004) reported 4 Japanese patients with Berardinelli-Seip congenital generalized lipodystrophy. In 3 of them the same homozygous nonsense mutation in the BSCL2 gene was found (606158.0015); analysis of flanking microsatellite markers and single-nucleotide polymorphisms (SNPs) within the gene revealed common ancestry in which the mutation originated. No mutation in either the BSCL2 or the AGPAT2 (603100) gene was found in the fourth patient, whose phenotype was considered atypical of patients with mutation in either gene. The authors stated that this was the first report of gene and phenotype analysis of congenital generalized lipodystrophy in Japanese.

Population Genetics

Gedde-Dahl et al. (1996) stated that 5 of the 6 families studied by Seip and Trygstad (1996) came from adjacent rural 'municipalities' of southwestern Norway. Six patients from this area were born between 1951 and 1973, and none between 1974 and 1995. The absence of new cases might be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogic investigation showed that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural east Norwegian population. In general, males appeared to be less severely affected than females.