Glucose transporter‐1 deficiency syndrome with extreme phenotypic variability in a five‐generation family carrying a novel SLC2A1 variant

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.