PracticeUpdate Conference Series - SSIEM 2018

Genetic Analysis Essential for Diagnosis of Glucose Transporter-1 Deficiency Syndrome Diagnosis of glucose transporter-1 deficiency syndrome (GLUT1DS) is incomplete without genetic analysis.

R esponse to ketogenic diet, drug-resistant epilepsy, and/or hypoglycorrhachia is not a pathognomonic marker for GLUT1DS. Genetic analysis is crucial for GLUT1DS classification. This conclusion, based on results of a sequencing study of 49 suspected cases of GLUT1DS, was presented at SSIEM 2018. The group of Belen Perez Gonzalez, PhD, of the Centro de Diagnóstico de Enfermedades Moleculares, Universidad Autónoma de Madrid, Spain, included 49 suspected cases of GLUT1DS with a cerebrospinal fluid glucose level ranging from 1.1–2.9 mmoL/L (glucose cerebrospinal fluid/ blood ratio 0.35–0.63). GLUT1DS is caused by a mutation in the SLC2A1 gene, which regulates the glucose transporter protein type 1 (Glut1). Glut1 is the principal glucose transporter across the blood-brain barrier. Cerebrospinal fluid from the 49 patients was sequenced for the SLC2A1 gene by Sanger sequencing combined with multiplex ligation- dependent probe amplification and/or NGS. Panel 1 was an in-house customized exome sequencing panel to capture the exome, including the entire sequence of SLC2A1. Panel 2 was an extended panel that included all known disease-associated genes described in the Online Mendelian Inheritance in Man database as of 2013. As expected, 27 patients, with variations in SLC2A1, were detected. The majority were de novo mutations, while five mutations were associated with maternal or paternal inheritance (missense variants). The mutational spectrum in SLC2A1 includes two large deletions, two small deletions, one duplication, and 22 nucleotide changes (19 likely missense, one nonsense, and two splice site mutations). Of the variants, 17 are novel, six are loss-of-function, and 11 are likely missense, including four with unknown

Belen Perez Gonzalez, PhD

significance following American College of Medical Genetics and Genomics guidelines. In 22 cases, no pathogenic mutations in SLC7A1 were detected. These 22 cases were analyzed further using panel 2, which allowed detection of pathogenic variants in five genes related to ion channels, transcription factors, or protein cellular trafficking. GLUT1DS cases worldwide number in the hundreds, though experts believe many patients remain undiagnosed. The exact prevalence is unknown. Most patients appear healthy at birth following uneventful pregnancies and delivery. Apgar scores are generally normal. GLUT1DS affects brain metabolism. More than 100 different types of mutations and deletions of this gene have been found in GLUT1DS patients. Impaired glucose transport associated with GLUT1DS often results in drug-resistant epilepsy, hypoglycorrhachia, speech and movement disorders, and developmental delays. Acquired microcephaly can occur. Not all patients experience all symptoms, especially with the milder phenotypes. Symptoms vary and may change and evolve over time.

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