J Pediatr Endocr Met 2015; 28(7-8): 873–876
Christel Trana,*, Vassiliky Konstantopouloua,c, Michelle Mecjiab, Kusiel Perlmanb, Saadet Mercimek-Mahmutoglub and Jonathan B. Kronickb
Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene
Abstract Background: Hyperinsulinism-hyperammonemia syndrome (HI/HA) is a rare autosomal dominant disorder presenting with hypoglycemia and hyperammonemia. It is caused by activating mutations in the GLUD1 gene. Case reports: Three patients from two different centers, a 14-month-old female, a 28-year-old female (mother of the first patient) from Toronto and an unrelated 2.5-year-old male from Vienna, presented with multiple episodes of seizures associated with hypoglycemia. Results: All patients had mild to moderate hypoglycemia, inappropriate insulin levels and mild hyperammonemia, thus suggesting a disorder of glutamate dehydrogenase (GDH). Molecular genetic testing of the GLUD1 gene identified heterozygous mutations in all patients (patient 1 and her mother a novel c.1526G > C mutation; patient 3 a known c.809C > G mutation). Conclusion: We present three new patients with GDH caused by heterozygous mutation in the GLUD1 gene. Mild hyperammonemia and inappropriately elevated insulin a CT and VK drafted the initial manuscript and approved the final manuscript as submitted. b JBK, SM, KP, and MM reviewed/edited the manuscript and approved the final manuscript as submitted. c Shared first authorship. All authors read and approved the final manuscript. *Corresponding author: Christel Tran, MD, Center for Molecular Diseases, Lausanne University Hospital, Av Pierre-Decker 2, 1011 Lausanne, Phone: +41 21 314 00 00 Ext 68195, Fax: +41 21 3143546, E-mail: [email protected]; and Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada Vassiliky Konstantopoulou: Department of Pediatrics, Vienna Medical University, Vienna, Austria Michelle Mecjia, Saadet Mercimek-Mahmutoglu and Jonathan B. Kronick: Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada Kusiel Perlman: Division of Endocrinology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada
levels should suggest a GLUD1 mutation. Early onset hypoglycemia associated with seizures, and especially a good response to diazoxide treatment, should include this disorder in the differential diagnosis of hyperinsulinemic hypoglycemia. Keywords: diazoxide; hyperammoniemia; hyperinsulinism; hypoglycemia; seizure. DOI 10.1515/jpem-2014-0441 Received October 21, 2014; accepted January 21, 2015; previously published online March 7, 2015
Background Hyperinsulinism/hyperammonemia (HI/HA) syndrome (OMIM 606762) is the second most common form of congenital hyperinsulinism. It was first described by Cochrane et al. in 1956 (1). The underlying genetic defect in the GLUD1 gene was first identified in 1998 (2). This is a rare autosomal dominantly inherited disorder, and is one of the underlying genetic etiologies of congenital hyperinsulinism (CHI). The disease is caused by activating missense mutations in the GLUD1 gene located on chromosome 10q23.3 encoding the mitochondrial matrix enzyme glutamate dehydrogenase (GDH). GDH activity is regulated by allosteric inhibitors (GTP) and activators (ADP and leucine). Mutations in the GLUD1 gene lead to a gain of function by reducing its sensitivity to allosteric inhibition by high-energy phosphates, such as GTP and ATP, thus allowing activation by the amino acid leucine. Both de novo (80%) and autosomal dominantly inherited (20%) mutations in the GLUD1 gene have been reported in the GTP-inhibitory allosteric binding site or in an antenna region of the enzyme (3). In a large series of CHI patients, GLUD1 mutations have been identified in 6% of the patients, and is the most common underlying genetic etiology in the diazoxide-responsive group of patients (4).
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874 Tran et al.: Hyperinsulinemic hypoglycemia Affected children have recurrent fasting and proteinsensitive hypoglycemia associated with persistent mild hyperammonemia, which is most likely due to increased renal ammoniagenesis due to the activation of GDH in the kidney (5). The reported age of onset varies from 1 day to 24 months of age (3). Due to mild phenotype, the correct diagnosis is often delayed. Hypoglycemic seizures are common, and repeated episodes of hypoglycemia may result in permanent brain damage and global developmental delay. The hypoglycemia usually responds to diazoxide, a KATP channel agonist, in patients with HI/HA syndrome (6). In this report, we present three additional patients with HI/HA syndrome from two different centers, Toronto and Vienna. Two children were from unrelated families, and the adult patient was the mother of the Canadian patient. Mutations in the GLUD1 gene confirmed the diagnoses in all patients.
Case presentation Case 1 This 3-year-old Caucasian girl was born to non-consanguineous parents after an uneventful pregnancy at term. She presented with a generalized seizure at the age of 5 months associated with hypoglycemia. She had two more episodes of seizures 1 month later. Her EEG was normal at the age of 8 months. Between 6 to 12 months of age, she was seizure free. At the age of 1 year, she presented with another generalized seizure lasting 10 min, which was associated with severe hypoglycemia of 1.7 mmol/L. She had 10 more seizure episodes from the ages of 12 months to 14 months. There was no history of fever, vomiting, or trauma prior to the seizures and the hypoglycemia. The occurrences of the seizures and hypoglycemia were not associated with diet changes or prolonged fasting. She was started on phenobarbital for a total of 2 weeks, but it was discontinued due to side effects. She reached ageappropriate developmental milestones. Due to recurrent episodes of hypoglycemia and seizures, she was referred to our service at The Hospital for Sick Children for further investigations at the age of 14 months. On physical examination, her weight was at the 50th percentile and her height and head circumference were at the 15th. She had mild hepatomegaly, hypoglycemia at 2.2 mmol/L (reference range 2.5 to 5.0) and hyperinsulinism (143 pmol/L; reference range
Christel Trana,*, Vassiliky Konstantopouloua,c, Michelle Mecjiab, Kusiel Perlmanb, Saadet Mercimek-Mahmutoglub and Jonathan B. Kronickb
Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene
Abstract Background: Hyperinsulinism-hyperammonemia syndrome (HI/HA) is a rare autosomal dominant disorder presenting with hypoglycemia and hyperammonemia. It is caused by activating mutations in the GLUD1 gene. Case reports: Three patients from two different centers, a 14-month-old female, a 28-year-old female (mother of the first patient) from Toronto and an unrelated 2.5-year-old male from Vienna, presented with multiple episodes of seizures associated with hypoglycemia. Results: All patients had mild to moderate hypoglycemia, inappropriate insulin levels and mild hyperammonemia, thus suggesting a disorder of glutamate dehydrogenase (GDH). Molecular genetic testing of the GLUD1 gene identified heterozygous mutations in all patients (patient 1 and her mother a novel c.1526G > C mutation; patient 3 a known c.809C > G mutation). Conclusion: We present three new patients with GDH caused by heterozygous mutation in the GLUD1 gene. Mild hyperammonemia and inappropriately elevated insulin a CT and VK drafted the initial manuscript and approved the final manuscript as submitted. b JBK, SM, KP, and MM reviewed/edited the manuscript and approved the final manuscript as submitted. c Shared first authorship. All authors read and approved the final manuscript. *Corresponding author: Christel Tran, MD, Center for Molecular Diseases, Lausanne University Hospital, Av Pierre-Decker 2, 1011 Lausanne, Phone: +41 21 314 00 00 Ext 68195, Fax: +41 21 3143546, E-mail: [email protected]; and Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada Vassiliky Konstantopoulou: Department of Pediatrics, Vienna Medical University, Vienna, Austria Michelle Mecjia, Saadet Mercimek-Mahmutoglu and Jonathan B. Kronick: Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada Kusiel Perlman: Division of Endocrinology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada
levels should suggest a GLUD1 mutation. Early onset hypoglycemia associated with seizures, and especially a good response to diazoxide treatment, should include this disorder in the differential diagnosis of hyperinsulinemic hypoglycemia. Keywords: diazoxide; hyperammoniemia; hyperinsulinism; hypoglycemia; seizure. DOI 10.1515/jpem-2014-0441 Received October 21, 2014; accepted January 21, 2015; previously published online March 7, 2015
Background Hyperinsulinism/hyperammonemia (HI/HA) syndrome (OMIM 606762) is the second most common form of congenital hyperinsulinism. It was first described by Cochrane et al. in 1956 (1). The underlying genetic defect in the GLUD1 gene was first identified in 1998 (2). This is a rare autosomal dominantly inherited disorder, and is one of the underlying genetic etiologies of congenital hyperinsulinism (CHI). The disease is caused by activating missense mutations in the GLUD1 gene located on chromosome 10q23.3 encoding the mitochondrial matrix enzyme glutamate dehydrogenase (GDH). GDH activity is regulated by allosteric inhibitors (GTP) and activators (ADP and leucine). Mutations in the GLUD1 gene lead to a gain of function by reducing its sensitivity to allosteric inhibition by high-energy phosphates, such as GTP and ATP, thus allowing activation by the amino acid leucine. Both de novo (80%) and autosomal dominantly inherited (20%) mutations in the GLUD1 gene have been reported in the GTP-inhibitory allosteric binding site or in an antenna region of the enzyme (3). In a large series of CHI patients, GLUD1 mutations have been identified in 6% of the patients, and is the most common underlying genetic etiology in the diazoxide-responsive group of patients (4).
Brought to you by | Hemeroteca de Estudios Económicos - Banco de la República Authenticated Download Date | 8/16/15 5:01 PM
874 Tran et al.: Hyperinsulinemic hypoglycemia Affected children have recurrent fasting and proteinsensitive hypoglycemia associated with persistent mild hyperammonemia, which is most likely due to increased renal ammoniagenesis due to the activation of GDH in the kidney (5). The reported age of onset varies from 1 day to 24 months of age (3). Due to mild phenotype, the correct diagnosis is often delayed. Hypoglycemic seizures are common, and repeated episodes of hypoglycemia may result in permanent brain damage and global developmental delay. The hypoglycemia usually responds to diazoxide, a KATP channel agonist, in patients with HI/HA syndrome (6). In this report, we present three additional patients with HI/HA syndrome from two different centers, Toronto and Vienna. Two children were from unrelated families, and the adult patient was the mother of the Canadian patient. Mutations in the GLUD1 gene confirmed the diagnoses in all patients.
Case presentation Case 1 This 3-year-old Caucasian girl was born to non-consanguineous parents after an uneventful pregnancy at term. She presented with a generalized seizure at the age of 5 months associated with hypoglycemia. She had two more episodes of seizures 1 month later. Her EEG was normal at the age of 8 months. Between 6 to 12 months of age, she was seizure free. At the age of 1 year, she presented with another generalized seizure lasting 10 min, which was associated with severe hypoglycemia of 1.7 mmol/L. She had 10 more seizure episodes from the ages of 12 months to 14 months. There was no history of fever, vomiting, or trauma prior to the seizures and the hypoglycemia. The occurrences of the seizures and hypoglycemia were not associated with diet changes or prolonged fasting. She was started on phenobarbital for a total of 2 weeks, but it was discontinued due to side effects. She reached ageappropriate developmental milestones. Due to recurrent episodes of hypoglycemia and seizures, she was referred to our service at The Hospital for Sick Children for further investigations at the age of 14 months. On physical examination, her weight was at the 50th percentile and her height and head circumference were at the 15th. She had mild hepatomegaly, hypoglycemia at 2.2 mmol/L (reference range 2.5 to 5.0) and hyperinsulinism (143 pmol/L; reference range
