PracticeUpdate Conference Series - SSIEM 2018

hyperinsulinemic hypoglycemia; fatty acid oxidation defects; ketogenesis/ketolysis defects, glycogen storage diseases; disorders of carbohydrate metabolism (for example, fructose-1,6-biphosphatase deficiency; hereditary fructose intolerance); mitochondrial disorders; along with some congenital glycosylation defects; and some aminoacidopathies (eg, maple syrup urine disease). The establishment of a precise diagnosis allows targeting of specific nutritional and pharmacologic therapies. The clinical and biochemical pattern may suggest a specific disease category. Genetic heterogeneity of these conditions makes identification of a single candidate gene difficult, however. Classic molecular gene- by-gene analysis is time-consuming and expensive for the number and size of involved genes. Dr. Maiorana concluded that NGS provided a diagnosis in approximately 50% of patients in whom clinical and laboratory evaluation did not allow for identification of a single candidate gene.

NGS will not replace metabolic testing, central to establish biochemical phenotypeandguidepatient management and follow-up. NGS represents a tool to provide information on genotype- phenotype correlation. It offers diagnostic confirmation and facilitates diagnosis of complex disorders by reducing the number of tests or procedures. It facilitates decision making and fills the gaps in laboratory diagnosis. Furthermore, NGS allows genetic counseling for the family and provides recurrence risk and prenatal diagnosis in future pregnancies. Hypoglycemia is an important cause of morbidity in the pediatric population and is associated with a large number of inborn errors of metabolism. Multiple proteins with different functions (enzymes, transporters, transcription factors, and others) participate in the complex machinery of glucose homeostasis. Mutations in many genes lead to impairment of glucose homeostasis. These disorders comprise heterogeneous and rare genetic diseases with a variety of overlapping and often unspecific clinical and biochemical phenotypes, including

" NGS provided a diagnosis in

approximately 50% of patients in whom clinical and laboratory evaluation did not allow for identification of a single candidate gene. "

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SSIEM 2018 • PRACTICEUPDATE CONFERENCE SERIES 11