Multigene NGS panels and metabolic profiling streamline diagnosis of rare FBPase deficiency
This review consolidates diagnostic strategies and molecular interpretation frameworks for fructose-1,6-bisphosphatase deficiency, a rare autosomal recessive disorder of gluconeogenesis. Investigators note that urinary organic acid analysis and plasma acylcarnitine profiling during hypoglycemic episodes are essential for distinguishing the condition from fatty acid oxidation disorders. The authors highlight targeted next-generation sequencing multigene panels as the preferred molecular diagnostic tool and propose a functional model for classifying FBP1 variants by protein stability, catalytic activity, and AKT signaling regulation. These insights provide clinical laboratories with a structured approach to variant interpretation and metabolic workup for rare inherited hypoglycemic disorders.
The original study
Fructose-1,6-bisphosphatase deficiency: the clinical characteristics, molecular consequences of FBP1 variants, and emerging non-canonical functions of FBP1.
- Authors
- Sakuma I, Shulman GI, Tanaka T
- Journal
- Endocrine journal
- Type
- Journal Article
- PMID
- 42816337
Original abstract
Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive disorder of gluconeogenesis caused by the biallelic pathogenic variants of FBP1. Recurrent episodes of hypoglycemia and lactic acidosis usually occur during childhood. Because the ketone levels during hypoglycemic attacks may vary in patients with FBPase deficiency, differentiation from fatty acid oxidation disorders can be challenging. A urinary organic acid analysis during hypoglycemic attacks, particularly the detection of glycerol and glycerol-3-phosphate, in conjunction with plasma acylcarnitine profiling, is useful for distinguishing between these disorders. Furthermore, targeted next-generation sequencing-based multigene panels for hypoglycemia and related inherited metabolic disorders have become increasingly valuable diagnostic tools in this field. At the molecular level, a useful working model is to interpret FBP1 variants along three functional dimensions: protein abundance/stability, catalytic activity, and non-canonical restraint of AKT signaling. Within this framework, many missense variants fall into two major classes: variants that preserve protein abundance, but impair the catalytic activity and variants that reduce both protein abundance and the catalytic activity through defective folding. Selected C-terminal variants additionally disrupt the AKT-regulatory scaffolding function. Emerging experimental evidence suggests that FBP1 influences hepatic lipid accumulation, fibrosis, and tumorigenesis through mechanisms beyond its canonical role in gluconeogenesis. This review summarizes the clinical features, diagnosis, genetics, and management of FBPase deficiency, with particular emphasis on the functional interpretation of FBP1 variants and the broader biological roles of FBP1.