Avoid common mistakes on your manuscript.
To the Editor: Genetic studies in fructose-1, 6-bisphosphatase deficiency (FBP1D) are scarce [1, 2]. We report a novel mutation in a developmentally normal, 2-y-old girl, born of a nonconsanguineous marriage, presenting with fever, vomiting, drowsiness, hepatomegaly, hypoglycemia, severe metabolic acidosis, hyperlactatemia (10.2 mmol/L), normal ammonia, and ketonuria. Neonatal period was unremarkable. One year back, she had a similar illness requiring dextrose and bicarbonate infusion. Tandem mass spectrometry (TMS) was normal. Clinical exome sequencing revealed a homozygous 3 base pair deletion in exon 3 of the FBP1 gene (chr9:g.94620363_94620365del; Depth: 156x) resulting in an in-frame deletion of amino acids (p.Glu99del; ENST00000415431.5). The FBP1 gene spans approx. 31 kb on chromosome 9q22.2-q22.3 and consists of 8 exons [1]. The observed variation was in the fructose-1-6-bisphosphatase N-terminal domain of the FBP1 protein, in the nonrepeated region. The p.Glu99del variant has not been reported in the 1000 genomes or in the genome aggregation database (gnomAD). Common variants in the Indian population are missense mutations - c.841G>A (p.Glu281Lys) in exon 8 and c.472C>T (p.Arg158Trp) in exon 6 [3]. Intragenic deletions in FBP1 are rare [2, 4].
FBP1D presents with episodic lactic acidosis and ketotic hypoglycemia, manifesting as hyperventilation, seizures, or coma. Triggers include fever, fasting, vomiting, infections, and excessive fructose ingestion. Half of children have hypoglycemia in the neonatal period, but mostly normal development [1]. Early, prolonged hypoglycemia may cause intellectual disability. Diagnosis is confirmed by identifying biallelic FBP1 pathogenic variants on molecular genetic testing or deficient FBP1 activity in liver or mononuclear white blood cells, the latter not widely available [1].
FBP1D should be suspected in children with episodic hypoglycemia, lactic acidosis, and ketosis. TMS is normal; elevated glycerol-3-phosphate in urine organic acid analysis is suggestive [1]. Molecular diagnosis helps in timely and accurate diagnosis of this rare but treatable disorder. Simple measures (avoiding triggers, timely admission, and dextrose infusion) can ensure a normal life for the child.
References
Bijarnia-Mahay S, Bhatia S, Arora V. Fructose-1,6-Bisphosphatase deficiency. 2019 Dec 5. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.
Santer R, du Moulin M, Shahinyan T, et al. A summary of molecular genetic findings in fructose-1,6-bisphosphatase deficiency with a focus on a common long-range deletion and the role of MLPA analysis. Orphanet J Rare Dis. 2016;11:44.
Bhai P, Bijarnia-Mahay S, Puri RD, et al. Clinical and molecular characterization of Indian patients with fructose-1, 6-bisphosphatase deficiency: identification of a frequent variant (E281K). Ann Hum Genet. 2018;82:309–17.
Lebigot E, Brassier A, Zater M, et al. Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients. J Inherit Metab Dis. 2015;38:881–7.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
None.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Samprathi, M., Sridhar, M., Adiga, R. et al. Novel Mutation with Fructose-1,6-Bisphosphatase Deficiency. Indian J Pediatr 88, 505 (2021). https://doi.org/10.1007/s12098-021-03694-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12098-021-03694-9