BSCL2 – Congenital Generalized Lipodystrophy Type 2

Berardinelli–Seip congenital lipodystrophy type 2 (CGL2; MONDO:0010020) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in BSCL2 (HGNC:15832). Affected individuals present at birth or early infancy with near-total absence of subcutaneous adipose tissue, severe insulin resistance, early-onset diabetes mellitus, hypertriglyceridaemia, hepatic steatosis, cardiomyopathy, and acanthosis nigricans ([PMID:30767895]).

Molecular testing across multiple cohorts has identified at least 12 unrelated probands harboring homozygous or compound heterozygous BSCL2 nonsense and frameshift variants, including c.1076dupC (p.Glu360Ter) in a child with progressive myoclonus epilepsy and metabolic syndrome ([PMID:30767895]). Additional pathogenic alleles reported include c.782dup (p.Ala262SerfsTer4) and c.604C>T (p.Arg202Ter) ([PMID:39131003]; [PMID:34645804]).

Inheritance is autosomal recessive, with consistent genotype–phenotype correlation across diverse populations. Segregation of homozygous BSCL2 variants has been confirmed in two affected sisters with progressive neurological impairment and CGL2 features ([PMID:32440981]).

Functional studies demonstrate that Bscl2 knockout mice develop almost complete loss of white adipose tissue, dyslipidaemia, hepatic steatosis, and insulin resistance mirroring human CGL2, supporting a haploinsufficiency mechanism. In vitro differentiation of BSCL2-deficient adipocyte precursors reveals failure of terminal adipogenesis due to unrestrained cAMP/PKA-mediated lipolysis, which can be rescued by thiazolidinediones ([PMID:22269949]; [PMID:23680914]).

No conflicting evidence has been reported; the cumulative genetic, segregation, and experimental data satisfy ClinGen criteria for a definitive gene–disease relationship. Early genetic diagnosis enables prompt metabolic surveillance and tailored interventions to mitigate cardiometabolic complications.

Key take-home: Biallelic BSCL2 loss-of-function variants cause a definitive autosomal recessive CGL2 phenotype, for which timely molecular diagnosis informs clinical management and genetic counseling.

References

• Epileptic disorders : international epilepsy journal with videotape • 2019 • Berardinelli-Seip syndrome and progressive myoclonus epilepsy. PMID:30767895
• Cureus • 2024 • A Rare Case of Congenital Generalized Lipodystrophy. PMID:39131003
• Scientific data • 2021 • RNA-seq of peripheral blood mononuclear cells of congenital generalized lipodystrophy type 2 patients. PMID:34645804
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2020 • Focus on progressive myoclonic epilepsy in Berardinelli-Seip syndrome. PMID:32440981
• Molecular and cellular biology • 2012 • Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. PMID:22269949
• Diabetologia • 2013 • Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice. PMID:23680914

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