1. Glucose transporter‐1 deficiency syndrome with extreme phenotypic variability in a five‐generation family carrying a novel SLC2A1 variant.
- Author
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Giugno, Alessia, Falcone, Elena, Fortunato, Francesco, Sammarra, Ilaria, Procopio, Radha, Gagliardi, Monica, Bauleo, Alessia, de Stefano, Laura, Martino, Iolanda, and Gambardella, Antonio
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PHENOTYPIC plasticity , *HIPPOCAMPAL sclerosis , *DISABILITIES , *GENETIC variation , *NEUROLOGICAL disorders - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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