title: A novel mutation in GLUD1 causing hyperinsulinism-hyperammonemia in a patient with high density of homozygosity on microarray: a case report.
abstract: BACKGROUND
  Hyperinsulinism-hyperammonemia syndrome is the second most common cause of congenital hyperinsulinism and is easily treated with diazoxide; however, the symptoms in our patient were very difficult to control with typical medical therapy. To the best of our knowledge, neither our patient's mutation, nor a case of hyperinsulinism-hyperammonemia presenting with dysmorphic features and intrauterine growth restriction has previously been reported.
  
  
  METHODS
  We describe a 2-year-old Hispanic girl with an unusual presentation of dysmorphic features and intrauterine growth restriction who was later found to have hyperinsulinism-hyperammonemia syndrome. Chromosomal microarray analysis revealed no copy number variants but demonstrated a high density of noncontiguous regions of homozygosity consistent with limited outbreeding. Sequencing of her GLUD1 gene revealed a previously undescribed mutation of cytosine to thymine at position 1519 resulting in an amino acid change of histidine to tyrosine at position 507. Although no functional studies were performed, function prediction tools in combination with our patient's phenotype support the hypothesis that the mutation is deleterious. Despite treatment with a maximum dose of diazoxide (15 mg/kg/day), phenobarbital (8.5 mg/kg/day divided twice daily) and a protein-restricted diet, she has global developmental delay, and continues to have seizures and recurrent episodes of hypoglycemia.
  
  
  CONCLUSIONS
  It remains unclear if her clinical presentation can be solely explained by hyperinsulinism-hyperammonemia syndrome or is the result of an undiagnosed recessive disorder related to her homozygosity. It is our hope that clinicians may learn from our patient when formulating treatment plans for refractory cases of hyperinsulinism-hyperammonemia and avoid the morbidities associated with delayed diagnosis and treatment.
authors.affiliation: USF Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Odom
authors.affiliation: Department of Pediatrics, USF Health South Tampa Center for Advanced Healthcare, 2 Tampa General Circle, Tampa, FL, 33606, USA.|USF Department of Neurology, 12901 Bruce B Downs Blvd, MDC 55, Tampa, FL, 33612, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Gieron-Korthals
authors.affiliation: Department of Pediatrics, USF Health South Tampa Center for Advanced Healthcare, 2 Tampa General Circle, Tampa, FL, 33606, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Shulman
authors.affiliation: Department of Pediatrics, USF Health South Tampa Center for Advanced Healthcare, 2 Tampa General Circle, Tampa, FL, 33606, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Newkirk
authors.affiliation: Greenwood Genetic Center, 101 Gregor Mendel Circle, Greenwood, SC, 29646, USA.
authors.forename: Eloise
authors.initials: E
authors.lastname: Prijoles
authors.affiliation: Department of Pediatrics, USF Health South Tampa Center for Advanced Healthcare, 2 Tampa General Circle, Tampa, FL, 33606, USA. asanche6@health.usf.edu.
authors.forename: Amarilis
authors.initials: A
authors.lastname: Sanchez-Valle
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation; D005969:Glutamate Dehydrogenase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy / Q000235:genetics*; D007003:Hypoglycemia / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human
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