“Gluing” phenotypes together

Abstract

The identification of an increasing number of diseases caused by specific gene mutations is gradually bridging the gap between clinical and genetic diagnosis, paving the way to precise nosology, pathophysiologic characterization of diseases, and availability of potential treatments. In this way, discoveries have linked distinct clinical disorders to mutations in the same gene; and conversely, individual diseases were associated with several genetic determinants. This phenomenon, characterized by medical geneticists as “lumping and splitting,”1 provides an increased level of complexity when dealing with neurologic disorders with a genetic basis, hampering the diagnosis and delaying management of patients. GLUT1-associated disorders represent an excellent example of such complexity. The GLUT1/SLC2A1 gene encodes the glucose transporter type 1, the main glucose transporter across the blood–brain barrier. Impaired function of this transporter results in low CSF glucose concentrations in the presence of normoglycemia, the diagnostic hallmark of all GLUT1-related disorders.2 The first identified mutations in GLUT1 were heterozygous, and were linked causally to an epileptic encephalopathy with early onset (GLUT1 deficiency syndrome), characterized by intractable epilepsy in the first 2 years of life, …