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 Childrenís 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

DISCUSSION

Recurrent hypoglycemia in early infancy is most frequently caused by congenital hyperinsulinism (CHI) [4]. Transient forms of CHI are mainly a consequence of other disorders such as gestational diabetes, perinatal asphyxia or intrauterine growth retardation [5]; persistent forms are known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (Table 1) [6]. The incidence of PHHI is estimated to be around 1/35,000-40,000 [7]. Persistent hyperinsulinemic hypoglycemia of infancy is characterized by unsuppressed insulin secretion, in spite of a low level of blood glucose, most frequently presenting in newborns with mild or severe hypoglycemia [8]. Clinical symptoms of hypoglycemia could be non specific (e.g., lethargy, irritability, poor feeding) or in some cases severe (apnea, seizures or coma) [9]. As hypoglycemia could lead to brain injury and impairment of neurological development, timely diagnosis and management are essential to prevent the sequelae [8]. Hyperinsulinism-hyperammonemia syndrome is the second most frequent cause of PHHI, after the pancreatic β-cell KATP channel defects [10]. The main clinical characteristics of HI/HA syndrome are repeated episodes of symptomatic hypoglycemia [10,11]. Hypoglycemia is usually less severe as compared to that observed in the defects of the KATP channel and frequently not diagnosed in the first months of life [10]. Our patient first displayed convulsions at 8 months. This could also be a result of the higher protein intake with the solid food introduction at this age; the normal results of brain ultrasound, EEG, brain MRI and ECG ruled out most other possible causes. Hyperinsulinism-hyperammonemia syndrome is a con-sequence of a mutated GLUD1 gene for the mitochondrial enzyme glutamate dehydrogenase (GDH). Glutamate dehydrogenase is substantially expressed in liver, pancreatic β-cells, kidney and in brain. It catalyzes the oxidative deamination of glutamate to α-ketoglutarate and ammonia [10,12]. The GDH is allosterically activated by leucine and adenosine diphosphate (ADP) and is inhibited by guanosine triphosphate (GTP) [13]. In the pancreatic β-cells, α-ketoglutarate is metabolized in the tricarboxylic acid (Krebs) cycle, increasing the cellular ATP concentration that closes the ATP-sensitive potassium channels. The resulting cell membrane depolarization causes Ca2+ influx via voltage gated calcium channels and insulin exocytosis [14] (Figure 1). The GLUD1 gene mutations lead to an increased enzyme activity, causing increased insulin secretion by pancreatic β-cells, increased ammonia production and its decreased removal by the hepatocytes. Leucine stimulates insulin secretion by allosterically activating GDH activity [15]. Typically, hypoglycemia follows meals with a high protein content [12,15,17,18] (Figure 1). In our patient, the autosomal dominant syndrome, a mutation on the GLUD1 gene (p.Arg274Cys), was confirmed with genetic analysis. The same mutation (p.Arg 274Cys) has previously been reported as p.Arg221Cys in patients with HI/HA, who also had epileptic seizures and mild mental retardation [3,4]. Our patient had no epileptic seizures and his neurocognitive development was within normal ranges at the age of 2 years. We also performed genetic analyses on our patientís father who had hypoglycemia episodes in his childhood. Initially, we suspected the father to have the same mutation, as the boy displayed autosomal dominant syndrome and the father had hypoglycemia episodes in his childhood. However, the fatherís (as well as his motherís) genetic analyses results were normal. De novo mutations of the gene GLUD1 account for 80.0% of cases [16], as happened in our patient. Normally, protein intake stimulates insulin release without causing hypoglycemia because glucagon is also secreted to neutralize the effect of insulin on glucose production in the liver [15,20]. Protein-induced hypoglycemia in HI/HA might be a consequence of impaired regulation of pancreatic α-cells, as well as β-cells [15]. Patients with HI/HA are susceptible to hypoglycemia in response to both fasting and protein feeding, but in most instances hypoglycemia occurs within a few hours after a meal [15]. The same was seen in our patient who had the hypoglycemia episode during his afternoon rest (probably caused by protein load in his meal half an hour before afternoon rest) and only after 11 hours of fasting. Thus, HI/HA must be considered in the differential diagnosis of postprandial or reactive hypoglycemia [15]. In HI/HA, plasma ammonia levels are increased 3-5 times normal as a consequence of the hyperactivity of GDH, which causes increased ammonia release from glutamate and its diminished elimination [10] (Figure 1). Hype-rammonemia in patients with HI/HA syndrome tends to be asymptomatic and ammonium lowering therapy is not considered to provide any benefits in HI/HA syndrome. Ammonia levels in HI/HA syndrome are also not shown to depend on fasting, protein intake or on blood glucose levels [10]. All the above mentioned clinical and biochemical features were present in our patient. Therapy with diazoxide is shown to be effective in PHHI, binding to the intact SUR1 component of the ATPsensitive potassium (KATP) channels in the pancreatic β-cell, preventing the cell membrane depolarization and insulin secretion [6]. The HI/HA patients with a GLUD1 mutation usually respond to diazoxide therapy, only very rarely is a pancreatectomy needed [21]. Our patient has now been on therapy for more than 1 year, without documented hypoglycemia or seizures and with normal growth and development. Conclusions. It is important to always consider hypoglycemia and hyperammonemia when a baby ďis not well,Ē as symptoms may not be specific. If transient hypoglycemia in an infant is ruled out, metabolic disorders must be taken into account. In HI/HA syndrome, diazoxide is the first line of treatment; hypoglycemia is well controlled and hyperammonemia appears to be asymptomatic. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was supported by the Slovenian Research Agency [grant number P3-0343].



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