ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 2.5 | DOI: 10.1530/ey.19.2.5


J Clin Endocrinol Metab. 2021 19;107(5):1346-1356. doi: 10.1210/clinem/dgab932. PMID: 34971397.

Brief Summary: This is a case report of a potentially new genetic disorder that causes hyperinsulinaemic hypoglycemia, protein sensitivity and high serum ammonia level (Hyperinsulinism/hyperammonemia syndrome (HI/HA) syndrome). Mutations in the solute the carrier family 25, member 36 (SLC25A36) may be a novel cause of HI/HA syndrome but more patients need to be identified.

Hyperinsulinism/hyperammonemia syndrome (HI/HA) is an autosomal dominant form of hyperinsulinism due to gain of function mutations in the GLUD1 coding for the mitochondrial enzyme glutamate dehydrogenase (GDH) (1). This is classically associated with protein sensitivity and an elevated serum ammonia level. Rarely there are patients with protein sensitivity and an elevated serum ammonia level but with no mutations in the GLUD1 gene, suggesting potentially other genetic mechanisms.

This paper describes 2 siblings who have biochemical findings of hyperinsulinism and high serum ammonia levels but no mutations in GLUD1. Instead these patients were found to have a homozygous splice site variant in solute the carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The authors were able to show that PNC2 impairment likely leads to a reduced mitochondrial GTP content, hence limiting GDH inhibition and hyperactivating insulin secretion pathway.

PNC2 seems to be a new player in the regulation of insulin secretion (2). PNC2 catalyzes the transport of guanosine phosphates (GNPs) in exchange for other nucleotides across the inner mitochondrial membrane, thus feeding the mitochondrial GTP pool. In glucose-stimulated pancreatic beta-cells, a defect in PNC2 may reduce mitochondrial GTP leading to an increase of glutamate oxidative deamination by glutamic dehydrogenase (GDH) and, consequently, a stimulation of TCA cycle activity and oxidative phosphorylation. These are interesting observations and it will be important to find more cases of patients with mutations in SLC25A36 and further understand the complex mechanisms of how GLUD1 is regulated.

References: 1. MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA; Hyperinsulinism/hyperammonemia Contributing Investigators. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001 Apr;86(4):1782–7. doi: 10.1210/jcem.86.4.7414. PMID: 11297618. 2. Casimir M, Lasorsa FM, Rubi B, Caille D, Palmieri F, Meda P, Maechler P. Mitochondrial glutamate carrier GC1 as a newly identified player in the control of glucose-stimulated insulin secretion. J Biol Chem. 2009 Sep 11;284(37):25004–14. doi: 10.1074/jbc.M109.015495. Epub 2009 Jul 7. PMID: 19584051; PMCID: PMC2757205.

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