Abstract
BACKGROUND AND PURPOSE: Glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1-DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. GLUT1-DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant. METHODS: We present clinical and genetic features of a five-generation family with GLUT1-DS. RESULTS: The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8-year-old proband, who also had drug-responsive absences associated with attention-deficit/hyperactivity disorder. His 52-year-old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core. CONCLUSIONS: Our study illustrates the extremely heterogenous phenotypes in familial GLUT1-DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1-DS.