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).
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.
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 (
Disorders associated with persistent hyperinsulinemic hypoglycemia of infancy.
General Characteristics | |||
---|---|---|---|
PHHI due to K ATP channel mutation | Kir6.2: | Diffuse form: AR or AD; focal form: heterozygous paternal mutation, clonal loss of maternal 11p15.1 | ↑ Glucose requirement (up to 30.0 mg/kg/ min.); during hypoglycemia: ↓ ketone bodies, ↓ FFA (serum), insulin incompletely suppressed, normal blood gases and lactate, n/↑ ammonium, IGFBP-1 (<120.0 mg/mL), normal glucagon response |
Glucokinase activating mutations | AD | Heterozygous: familial mild non progressive hyperglycemia, gestational diabetes; homozygous: neonatal diabetes | |
HI/HA syndrome | AD | Hyperammonemia (100.0-200.0 μmol/L), usually asymptomatic, may be prominent early but may disappear later in childhood; often leucine-sensitive | |
Exercise-induced hyperinsulinemic hypoglycemia | AD | Children/adults with syncopal episodes after exercise | |
SCHAD deficiency | AR | Intermittent unpredictable hypoglycemia with seizures; ↑ C4-OH-carnitine, ↑ 3-OH-glutarate (urine) | |
Beckwith- Wiedemann syndrome | Chromosomal imbalance 11p15 | Hyperinsulinism (disappears in most patients within weeks); typical facial characteristics (macroglossia, ear creases, omphalocele, visceromegaly, hemihypertrophy) |
PHHI: persistent hyperinsulinemic hypoglycemia of infancy; AR: autosomal recessive; AD: autosomal dominant; ↑: elevated; ↓: low/decreased; FFA: free fatty acids; IGFBP-1: insulin-like growth factor-binding protein; HI/HA: hyperinsulinism-hyperammonemia; SCHAD: short-chain hydroxyacylCoA dehydrogenase; CA-OH-carnitine: 3-hydroxy-butyryl-carnitine; 3-OH-glutarate: 3-hydroxy-glutarate.
Hyperinsulinism-hyperammonemia syndrome is a con-sequence of a mutated
The
In our patient, the autosomal dominant syndrome, a mutation on the
We also performed genetic analyses on our patient’s 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 father’s (as well as his mother’s) genetic analyses results were normal.
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 ATP-sensitive potassium (KATP) channels in the pancreatic β-cell, preventing the cell membrane depolarization and insulin secretion [6]. The HI/HA patients with a