Balkan Journal of Medical Genetics

HYPERINSULINISM-HYPERAMMONEMIA SYNDROME IN AN INFANT WITH SEIZURES
Strajnar A1, Tansek MZ2, Podkrajsek KT3,4, Battelino T2,5, Groselj U
*Corresponding Author: Assistant Professor Urh Groselj, M.D., Ph.D., Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000 Ljubljana, Slovenia. Tel: +386-1-5229270. Fax: +386-1-2320190. E-mail: urh.groselj@ kclj.si
page: 77

INTRODUCTION

The 8-month-old male patient was admitted to our hospital because of seizures. He was an only child of non consanguineous parents and the conception was not assisted. The pregnancy was normal. The father was followed at our department over 20 years ago during his childhood due to recurrent hypoglycemia episodes, often with collapses, which usually happened after eating protein rich food; however, no hypoglycemia episodes or any other health problems persisted into the father’s adulthood. The boy was born at term with normal birth parameters. Postnatally, the patient was healthy until this admission to the hospital. He was vaccinated according to the national program. His psychomotor development was apparently normal. On the day of admission, the mother found the child’s body jerking during his afternoon rest period. She tried to wake him but he was less alert. Then she saw him turn his eyes backwards. The body jerks lasted for 5 min. He also had difficulty breathing. The boy had his last meal half an hour before mother found him jerking. He had previously had two similar short episodes with twitches, always after afternoon rest, but they had ceased by themselves so parents had not sought any medical attention at those times. At the outpatient clinic, a doctor reported the boy did not respond to pain but had the sucking reflex. The oxygen saturation was 85.0%, breathing rate was 20/min., heart rate 166/min., blood sugar 2.8 mmol/L (50.0 mg/dL). At admission to the hospital, the oxygen saturation increased to 99.0% and the blood sugar level to 3.7 mmol/L (66.0 mg/dL) without therapeutic intervention. The child was still less responsive and his gaze was not fixed but after time he became alert and responded to all stimuli adequately. Jerking ceased. Somatic status was normal with no organomegaly. Nutritional status was also normal with body weight 7.92 kg (20 percentile), body height 71 cm (43 percentile) and head circumference 44 cm (25 percentile). Initial laboratory tests with lactate, pyruvate, cortisol, blood gases analysis, plasma amino acids, acylcarnitines, free fatty acids, urea and creatinine, ions, liver function tests, hemogram, C-reactive protein (CRP), were all in normal value ranges, with the exception of blood sugar and ammonia, which was 110.0 μmol/L (reference: ammonia values 9.0-33.0 μmol/L). Hospital Course. During the initial hospitalization, the boy was in a good mood and had a good appetite. He had normal stool. He had no seizures. Brain ultrasound, electroencephalogram (EEG), brain magnetic resonance imaging (MRI) and electrocardiogram (ECG) were normal. The laboratory tests revealed occasional hypoglycemia (the lowest value 2.2 mmol/L; 40.0 mg/dL) and persistent hy-perammonemia (in a range from 95.0 to 139.0 μmol/L). Insulin level was 2.31 mE/L (reference: insulin values 2.0-29.1 mE/L). During the first hospitalization, we also performed a fasting test and protein loading test. During the fasting test, hypoglycemia 2.3 mmol/L (42.0 mg/dL) was revealed after 11 hours of fasting. Blood ammonium was 100.0 μmol/L at that time, insulin level 2.0 mE/L and ketones 1.6 mmol/L. All other laboratory examinations were normal with the exception of adequate ketosis after fasting. We performed the protein-loading test [1] to exclude a possible urea cycle disorder. Two hours after the loading test with 35 g/m2 proteins, blood ammonium changed from 100.0 μmol/L to 142.0 μmol/L; other laboratory examinations were normal. During the second hospitalization after three weeks, we performed a therapeutic experiment with diazoxide 3 mg/kg, which prevented postprandial hypoglycemia but ammonia levels remained high (in a range from 114.0 to 148.0 μmol/L). Thus, the child was diagnosed with hyper- insulinism-hyperammonemia (HI/HA) syndrome and started treatment with 10.0 mg/kg diazoxide per day and protein restriction up to 1.2 g/kg per day to avoid the high protein meals. Later, no postprandial hypoglycemias were recorded. The patient’s growth and neurological development at the age of 2 years were within the normal ranges. Final Diagnosis. The clinical diagnosis of HI/HA syndrome was anticipated and genetic confirmation was provided with a next generation sequencing (NGS) panel test related to neonatal hypoglycemia. Nucleotide variant NM_005271.3: c.820C>T was detected in the GLUD1 gene, resulting in an arginine to cysteine amino acid substitution at the position 274 (NP_005262.1: p.Arg274Cys). The variant has previously been reported as p.Arg221Cys (as numbered by mature protein amino acids) in patients with HI/HA syndrome [2,3]. Therefore, genetic analysis results confirmed the autosomal dominant syndrome to be HI/HA. Interestingly, the mutation was not detected in his parents.

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