Intractable Absence Seizures in Hyperinsulinism-Hyperammonemia Syndrome

Intractable Absence Seizures in Hyperinsulinism-Hyperammonemia Syndrome

Pediatric Neurology 47 (2012) 119e122 Contents lists available at ScienceDirect Pediatric Neurology journal homepage: C...

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Pediatric Neurology 47 (2012) 119e122

Contents lists available at ScienceDirect

Pediatric Neurology journal homepage:

Case Report

Intractable Absence Seizures in Hyperinsulinism-Hyperammonemia Syndrome Kousuke Nakano MD a, *, Katsuhiro Kobayashi MD b, Yoshiyuki Okano MD c, Kazuyoshi Aso MD c, Yoko Ohtsuka MD b a

Department of Pediatrics, Matsuyama Red Cross Hospital, Matsuyama, Japan Department of Child Neurology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan c Department of Pediatrics, Graduate School of Medicine, Osaka City University, Osaka, Japan b

article information


Article history: Received 3 February 2012 Accepted 19 April 2012

A girl with intractable absence seizures and facial myoclonia at age 7 years was eventually diagnosed with hyperinsulinism-hyperammonemia syndrome because of hypoglycemia, hyperinsulinism, hyperammonemia, and the results of an oral L-leucine loading test. Her seizures occurred even during periods of relatively normal blood glucose levels, and were completely suppressed by diazoxide treatment only. Her diagnosis of hyperinsulinismhyperammonemia syndrome was confirmed by a loss of sensitivity of glutamate dehydrogenase for guanosine 50 -triphosphate. Genetic studies identified the I444M mutation in the GLUD1 gene, which encodes glutamate dehydrogenase. This case illustrates the complex relationship between seizures and hypoglycemia in hyperinsulinism-hyperammonemia syndrome that can create diagnostic difficulties. The possibility of hyperinsulinism-hyperammonemia syndrome should be considered in patients with refractory absence seizures with myoclonia. Ó 2012 Elsevier Inc. All rights reserved.


Case Report

Hyperinsulinism-hyperammonemia syndrome is a recently reported congenital disorder of glycometabolism [1,2]. Patients with hyperinsulinism-hyperammonemia syndrome present with chronic hypoglycemia attributable to a gain of function of glutamate dehydrogenase. Although patients with hyperinsulinism-hyperammonemia syndrome are reported to manifest frequent seizures that are not necessarily typical hypoglycemic seizures, detailed analyses of the epileptic seizures and the mechanisms of their occurrence have not yet been undertaken. We report on a patient with hyperinsulinism-hyperammonemia syndrome who had been treated for intractable absence epilepsy for many years, and who was successfully diagnosed and treated after referral to our hospital.

This female patient had manifested no episodes of hypoglycemia during the neonatal period, after an uneventful pregnancy and delivery. At age 15 months, she began to manifest afebrile, generalized convulsions several times a month. She was diagnosed with epilepsy at a local hospital, where the results of neuroimaging examinations and blood examinations were reportedly normal. The generalized convulsions decreased to once every few months with the administration of antiepileptic drugs, including sodium valproate. However, a new type of seizure with impaired consciousness and myoclonic movements of the eyelids and the corner of the mouth, lasting for approximately 10 seconds daily, began at age 7 years. She was referred to Okayama University Hospital at age 12 years and 7 months because of these refractory seizures. An electroencephalogram during her first visit indicated diffuse 3-4 Hz spike-wave bursts lasting about 5 seconds, induced by hyperventilation and associated with impaired consciousness with facial myoclonic movements. Because her absence seizures were refractory and their frequency fluctuated unnaturally, she was admitted to our hospital at age of 13 years and 3 months, so that the underlying disorders could be investigated. Her height was 142 cm (2.3 standard deviations) and her weight was 32 kg (1.8 standard deviations). Her grades at junior high school were low. An examination of her blood revealed slight liver dysfunction (aspartate aminotransferase, 47 IU/L; alanine aminotransferase, 76 IU/L), hyperammonemia (126 mmol/L ammonia), and hypoglycemia (54 mg/dL

* Communications should be addressed to: Dr. Nakano; Department of Pediatrics; Matsuyama Red Cross Hospital; 1 Bunkyouchou; Matsuyama 790-8524, Japan. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.04.019


K. Nakano et al. / Pediatric Neurology 47 (2012) 119e122

Figure 1. Ictal electroencephalogram of absence seizures. The patient manifested a seizure with impaired consciousness and facial myoclonic movements. The electroencephalogram revealed diffuse 3 Hz spike-wave bursts.

glucose). The concentration of sodium valproate in her blood was measured at 65.8 mg/mL, and phenytoin was measured at 8.2 mg/mL. An endocrinologic examination of her short stature revealed no abnormalities. The frequency of her absence seizures ranged from 1-10 times per day. Ictal electroencephalograms of her absence seizures revealed somewhat irregular, diffuse 3 Hz spike-wave bursts (Fig 1). According to her mother, the patient tended to manifest seizures after eating meals, particularly after eating eggs, which were a favorite food. Seizure frequency did not increase when she was hungry. While she was undergoing treatment at the local hospital, her family was informed once or twice that her blood glucose levels were slightly low. Because of her low blood glucose level at the time of admission as well as the information concerning her seizures, we repeatedly examined her blood glucose levels, and observed that they fluctuated between 30 and 70 mg/dL. Her seizures definitely began to increase 30 minutes after eating eggs, and her blood glucose levels decreased to approximately 30 mg/dL with a relatively high level of immunoreactive insulin, but with no other clinical signs of hypoglycemia. After receiving informed consent from the patient and her parents, we performed an oral L-leucine loading test. Thirty minutes after the intake of L-leucine (150 mg/kg), she demonstrated significant hypoglycemia, elevated immunoreactive insulin, and frequent seizures (Fig 2). She manifested no clinical signs of hypoglycemia except for seizures. We diagnosed her with hyperinsulinism-hyperammonemia syndrome on the basis of hypoglycemia, hyperinsulinism, hyperammonemia, and the results of the oral L-leucine loading test. After the initiation of diazoxide (at a maintenance dose of 100 mg/kg/ day), her blood glucose levels always exceeded 50 mg/dL, and her seizures disappeared on the second day of treatment. Her blood ammonia levels decreased to 60-90 mg/dL. She has manifested no seizures and no electroencephalographic epileptic discharges with diazoxide only, and has totally discontinued her antiepileptic drugs. Her grades improved significantly at senior high school, and she has entered college. Her height was 151 cm (1.4 standard deviations) at 19 years of age. Genetic studies

An Epstein-Barr virus-transformed lymphoblastoid cell line was established from our patient and from control subjects, and was used for enzymatic and molecular analyses. Various concentrations of guanosine

50 -triphosphate were added to the reaction mixtures for the allosteric effect of glutamate dehydrogenase. Her diagnosis of hyperinsulinismhyperammonemia syndrome was confirmed by the loss of sensitivity of glutamate dehydrogenase for guanosine 50 -triphosphate (Fig 3). The mutation in our patient comprised a heterozygous A-to-G transition at nucleotide position 1504 in exon 11, resulting in the replacement of isoleucine (ATA) by methionine (ATG) at codon 444 (I444M) in the GLUD1 gene, which encodes glutamate dehydrogenase [2].


In 1996, Zammarch et al. first reported on familial cases of hyperinsulinism-hyperammonemia syndrome [1]. Stanley et al. detected a GLUD1 gene mutation in patients with

Figure 2. Graph of L-leucine tolerance test. Thirty minutes after the intake of L-leucine (150 mg/kg), the patient manifested significant hypoglycemia, elevated immunoreactive insulin, and frequent seizures. The insulin/ glucose ratio was 0.7 from 30 minutes after intake onward (normal range, <0.4 ). The left ordinate measures blood glucose (mg/dL) and immunoreactive insulin (mU/mL), whereas the right ordinate measures the insulin/ glucose ratio.

K. Nakano et al. / Pediatric Neurology 47 (2012) 119e122

Figure 3. Glutamate dehydrogenase (GDH) activity with various concentrations of guanosine 50 -triphosphate (GTP). Graded concentrations (0.2-1.0 mM) of guanosine 50 -triphosphate were added, and glutamate dehydrogenase activity decreased in inverse proportion to the concentration of guanosine 50 -triphosphate. The activities of glutamate dehydrogenase in our patient and in a patient already diagnosed with hyperinsulinism-hyperammonemia syndrome (HI/HA) [9] attained higher levels than in a normal control subject.

hyperinsulinism-hyperammonemia syndrome in 1998 [3], and indicated that dysfunction in the regulation of glutamate dehydrogenase activity was the cause of this disorder. Patients with hyperinsulinism-hyperammonemia syndrome exhibit an acceleration of glutamate dehydrogenase activity because of the GLUD1 gene mutation. An acceleration of glutamate dehydrogenase activity leads to the activation of insulin secretion from b cells. Accelerated glutamate dehydrogenase also leads to excessive sensitivity to leucine, and leucine loading induces the decomposition of glutamate that leads to hypoglycemia because of activated insulin secretion. In contrast, hyperammonemia appears as a result of the suppression of ammonia metabolism in the urea cycle in liver cells under conditions of accelerated glutamate decomposition. Blood glucose examinations were performed at least once at the local hospital after the patient began to manifest frequent seizures, but her hypoglycemia was probably mild at the time and not thought to be related. After admission, persistent hypoglycemia and hyperammonemia were evident. Further important data involved the history of increase in seizure frequency after the consumption of highprotein food. By means of the L-leucine loading test, we could finally diagnose hyperinsulinism-hyperammonemia syndrome in this patient. Hypoglycemia with hyperinsulinism-hyperammonemia syndrome usually becomes apparent during infancy, sometimes in the neonatal period. Because our patient did not manifest definite signs of hypoglycemia in daily life, except for an increase in seizure frequency, the relationship between seizures and hypoglycemia was not suspected for many years. In regard to epilepsy in hyperinsulinism-hyperammonemia syndrome, Bahi-Buisson et al. reported that 14 of 22 patients with hyperinsulinism-hyperammonemia syndrome manifested epilepsy [4]. Among their 14 patients, nine exhibited absence seizures, which were associated with eyelid myoclonia in five patients. Three others manifested focal motor seizures, and two manifested generalized tonicclonic seizures. Bahi-Buisson et al. also reported on clinical seizures in familial cases involving a mother, her son, and her


two daughters with hyperinsulinism-hyperammonemia syndrome [5]. All three children manifested myoclonic absence seizures induced by photic stimulation during electroencephalogram examinations. Photosensitivity was not observed in the electroencephalograms of our patient. In 2005, Raizen et al. reported on the electroencephalogram features and clinical seizures of 14 patients with hyperinsulinism-hyperammonemia syndrome [6]. Nine of these 14 patients manifested epilepsy, and six demonstrated seizures even when their blood glucose levels were normal. Their seizures were characterized by myoclonic movements of the eyeballs or eyelids, with impaired consciousness. Ictal electroencephalograms revealed diffuse spike-wave complexes. Although the presence of eyelid myoclonia associated with absences suggests a diagnosis of Jeavons syndrome [7,8], the present patient did not exhibit the typical clinical findings of Jeavons syndrome because photosensitivity and eye-closure sensitivity were not evident. Twenty-four-hour continuous electroencephalogram monitoring in one patient confirmed that the seizures occurred during times of both normal blood glucose levels and hypoglycemia [6]. Seizures occurred slightly more often during times of hypoglycemia. The authors hypothesized that epilepsy with hyperinsulinism-hyperammonemia syndrome was attributable to brain damage caused by hypoglycemia or the brain dysfunction associated with the glutamate dehydrogenase abnormality in neurons. In regard to our patient, absence seizures with myoclonia occurred during times of both relatively normal blood glucose levels and hypoglycemia, in concordance with previously reported cases. On the other hand, we observed that persistent hypoglycemia played an important role in our patient’s seizures because they disappeared completely after the normalization of blood glucose levels via diazoxide (without antiepileptic drugs). Our patient may have been able to avoid the irreversible brain damage caused by her many years of persistent hypoglycemia. The relationship between seizures and hypoglycemia is complicated in cases of hyperinsulinism-hyperammonemia syndrome, and this complicated relationship can create difficulty in the diagnosis of hyperinsulinism-hyperammonemia syndrome. Our experience with this patient indicates that we should consider the possibility of this disorder when we encounter a patient with refractory absence seizures and myoclonia. Because the present patient demonstrated the newly identified I444M mutation and it is a private mutation, we have not yet clarified a genotype-phenotype correlation. Detailed analyses of epileptic seizures in more cases of hyperinsulinism-hyperammonemia syndrome will be necessary to clarify the mechanisms of occurrence of epileptic seizures in this disorder. References [1] Zammarchi E, Filippi L, Novembre E, Donati MA. Biochemical evaluation of a patient with a familial form of leucine-sensitive hypoglycemia and concomitant hyperammonemia. Metabolism 1996;45: 957e60. [2] Aso K, Okano Y, Takeda T, et al. Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome. Osaka City Med J 2011;57:1e9. [3] Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutation of the glutamate dehydrogenase gene. N Engl J Med 1998;338:1352e7.


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[4] Bahi-Buisson N, Rose E, Dionisi C, et al. Neurological aspects of hyperinsulinism-hyperammonemia syndrome. Dev Med Child Neurol 2008;50:945e9. [5] Bahi-Buisson N, El Sabbagh S, Soufflet C, et al. Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase. Seizure 2008;17:658e64. [6] Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, Kelly A. Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 2005;146:388e94.

[7] Jeavons PM. Nosological problems of myoclonic epilepsies in childhood and adolescence. Dev Med Child Neurol 1977;19:3e8. [8] Striano S, Capovilla G, Sofia V, et al. Eyelid myoclonia with absences (Jeavons syndrome): A well-defined idiopathic generalized epilepsy syndrome or a spectrum of photosensitive conditions? Epilepsia 2009;50(Suppl. 5):15e9. [9] Fujioka H, Okano Y, Inada H, et al. Molecular characterization of glutamate dehydrogenase gene defects in Japanese patients with congenital hyperinsulinism/hyperammonemia. Eur J Hum Genet 2001;9:931e7.