ESPE2019 Poster Category 1 Fetal, Neonatal Endocrinology and Metabolism (to include Hypoglycaemia) (8 abstracts)
Idiopathic Ketotic Hypoglycemia (IKH) is the most common non-iatrogenic cause of hypoglycemia in children beyond infancy. The severity of the symptoms and frequency of hypoglycemic episodes may vary among the patients. The etiology of IKH is unclear; disturbances in gluconeogenesis, glycolysis and glycogenolysis were regarded as possible causes. Familial IKH recurrence is often observed, suggesting a genetic basis of glucose homeostasis dysregulation.
We aimed to investigate the possible molecular mechanisms of IKH condition.
Over the last 3 years, 114 children (48 females) were referred to the Endocrinology research center because of recurrent episodes of ketotic hypoglycemia. Investigations included measurements of serum glucose, liver transaminases, 3HOB, lactate, cortisol, insulin, pituitary hormones and acyl carnitine profile taken at the time of hypoglycemia (<3 mmol/l) and abdominal ultrasound. Additionally, genetic testing including ACAD9, ACADM, ACADS, ACADSB, ACADVL, ACAT1, AGL, AKT2, ALDOB, CPS1, CPT1A, CPT1B, CPT2, ETFA, ETFB, ETHE1, FBP1, G6PC, GBE1, GYS2, HADHA, HADHB, HMGCL, HMGCS2, HNF1A, INSR, MPI, MUT, NAGS, NPC1, NPC2, OTC, OXCT1, PCCA, PCCB, PCK1, PCK2, PDX1, PHKA2, PHKA2, PHKB, PHKG2, PPARG, PYGL, SLC22A5, SLC25A20, SLC37A4, and TANGO2 genes using the NGS technology has been carried out for 60 children.
The median age of hypoglycemia onset in our group was 4.75 y. The majority of patients had mild hypoglycemic symptoms such as irritability, confusion and dizziness. However, 26% presented with seizures and lethargy. 21 of 114 (18.4%) were diagnosed with pituitary hormones deficiency. Only 5 of 114 (4.4%) had biochemical abnormalities indicative for inborn metabolism errors, which were subsequently confirmed by genetic testing. It included fructose-1,6-bisphosphatase deficiency (n=1); 3-methylcrotonyl-CoA carboxylase deficiency (n=1); medium-chain acyl-CoA dehydrogenase deficiency (n=1); glycogenosis Ib (n=2). The rest 88 patients (37 females) were diagnosed with IKH. An NGS panel analysis was performed in 57 of them and revealed pathogenic hemizygous PHKA2 gene mutations in 4 children (7%). 18 patients were found to carry heterozygous pathogenic variants in following genes: PHKG2 (n=1); PHKB (n=2); OXCT1 (n=1); NCBI (n=1); INSR (n=2); HNF1A (n=1); GYS2 (n=1); FBP1 (n=1); ETFDH (n=1); CPS1 (n=1); ALDOB (n=1); AGL (n=1); ACADVL (n=2); ACADM (n=2).
To conclude: some cases of glycogen storage disease, especially its mild variants, may be misdiagnosed and labeled as IKH. Additional study is required to determine if some mutations are not detected because of the limitations of NGS method, or because the revealed heterozygous mutations in genes involved in glucose metabolism might be a predisposing factor for IKH development.
19 Sep 2019 - 21 Sep 2019