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Mafalda Melo1, José Paulo Monteiro2, Ana Pereira3, Laura Vilarinho4, Diana Antunes1, Ana Cristina Ferreira5

1 - Genetic Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - Pediatrics Department, Child Development Center Torrado da Silva, Hospital Garcia d’Orta, Almada, Portugal
3 - Germano de Sousa Group, Centro de Medicina Laboratorial, Polo Tecnológico de Lisboa, Lisboa, Portugal.
4 - Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, National Institute of Health Dr Ricardo Jorge, Porto, Portugal
5 - Reference Center of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal

- Poster em 16º Simposio Internacional da Sociedade Portuguesa de Doenças Metabólicas, Virtual, 11-13 novembro de 2020

Background: Glycerol kinase deficiency (GKD, MIM 307030) is a rare X-linked disorder that may occur as an isolated form caused by a pathogenic variant in GK gene, or as part of Xp21 contiguous gene syndrome involving GK and NR0B1 genes with or without DAX1, IL1RAPL, and DMD genes. Individuals with isolated GKD may be asymptomatic (only detected by pseudo hypertriglyceridemia) or symptomatic with episodes of vomiting, acidosis and lethargy that may progress to coma. Individuals with complex GKD may also have features of congenital adrenal hypoplasia, Duchenne muscular dystrophy, or developmental delay.
Case Report: Our case is a 6 year-old boy, the second child of non-consanguineous parents, followed in metabolic and neurology outpatient clinic for hypertriglyceridemia and borderline psychomotor development. He had no history of adrenal crisis, no dysmorphic features, no muscle symptoms, and normal creatine kinase. At 4 years of age, after a mild infection, he was admitted for vomiting, somnolence and dehydration. Laboratory analysis showed marked metabolic ketoacidosis (pH 7.07, pCO2 18 mmHg, HCO3- 8.9 mmol/L, urinary ketones 80 mg/dL) with normal glycaemia. Intravenous fluids and bicarbonate were initiated and the patient progressively improved. Organic acids analysis in crisis showed elevated 3-hydroxybutyric acid, 2-hydroxybutyric acid, 2-hydroxyisovaleric acid, and high levels of glycerol. Glycerol was confirmed in plasma outside crisis (25.5 μmol/L). GK gene sequencing revealed a previously unreported hemizygous variant in exon 3 (c.213_214del, p.Cys72Ter), classified as likely pathogenic. This nonsense variant results in a premature stop codon at amino acid 72, which originates a truncated protein.
Comments: Our patient presentation suggested the isolated GKD diagnosis, since he had metabolic ketoacidosis episodes, glycerolemia and hypertriglyceridemia, without manifestations of Xp21 contiguous gene deletions, such as dysmorphic features, motor deficiency (DMD gene) or adrenal insufficiency (NR0B1 gene). GK gene sequencing confirmed our clinical hypothesis. In GKD patients, genetic analysis is important to identify the underlying molecular mechanism, which is critical for patient management, prognosis and genetic counseling.