silybin The SLC A mutations identified in both families
The SLC45A1 mutations identified in both families appear to be hypomorphic given that they resulted in a reduction but not abolition of intracellular glucose transport by SLC45A1 in our in vitro assay. It is tempting to speculate that recessive mutations causing a more severe dysfunction of the transporter would not be compatible with life or would result in a different and more dramatic phenotype. Heterozygous variants in the cerebral glucose transporter GLUT1 (or SLC2A1) also cause ID and epilepsy.2, 12, 13 Variants in the GLUT1 transporter appear to be haploinsufficient or hypomorphic in that they decrease glucose uptake in silybin to 37%–72% of that of controls. There is a correlation between the decrease in glucose uptake and clinical severity. Complete loss of GLUT1 function has not been reported in humans. As we postulated for SLC45A1, a more severe reduction of GLUT1-dependent glucose transport might likewise compromise postnatal survival.
The classic features of cerebral GLUT1 transporter deficiency include a combination of early-onset drug-resistant infantile seizures, neurodevelopmental delay, acquired microcephaly, complex movements disorders, spasticity, and ataxia (also see GeneReviews in the Web Resources). The phenotypic spectrum of GLUT1 transporter deficiency has expanded with the recognition of variants causing, for example, predominant ataxia or dystonia without seizures, paroxysmal exercise-induced dyskinesia with or without epilepsy, and a spectrum of epilepsy syndromes such as early-onset absence epilepsy, myoclonic astatic epilepsy, focal seizures, and infantile spasms. (also see GeneReviews in the Web Resources). Our affected individuals share clinical features associated with the GLUT1-deficiency phenotype, such as focal epilepsy and developmental delay or ID; however, they lack many features associated with the classic GLUT1 deficiency (such as a dystonia, ataxia, and microcephaly) or non-classic GLUT1-deficiency phenotype (such as paroxysmal movement disorder, early-onset absence epilepsy, or myoclonic astatic epilepsy). Furthermore, the hypoglycorrhacchia observed in over 90% of individuals with GLUT1 deficiency, characterized by low CSF glucose (<60 mg/dL) and a low ratio of CSF to serum glucose (<0.4), was not documented in the one individual who was tested from our cohort. This individual had normal CSF glucose and a normal ratio of CSF to serum glucose (0.7).
The ketogenic diet is a specific and effective treatment for GLUT1-related epilepsy, given that ketone bodies use a different transporter to cross the BBB and thus provide the brain with the only known fuel alternative to glucose for metabolism. The administration of a modified Atkins diet for 6 months at the age of 16 years did not improve the control of seizures in individual A.II-3 or her behavior. Nevertheless, the effectiveness of the ketogenic and/or modified Atkins diet in individuals with SLC45A1 mutations warrants further investigation because it could represent a potential specific treatment.
In summary, we have identified homozygous missense mutations in the cerebral glucose transporter SLC45A1 in four individuals with moderate to severe ID, epilepsy, and neuropsychiatric features from two families. We provide functional evidence that these missense mutations result in decreased intracellular glucose transport by SLC45A1. Together, our data suggest that autosomal-recessive mutations in SLC45A1 result in ID and epilepsy. SLC45A1 is thus the second cerebral glucose transporter, in addition to GLUT1, to be involved in human disease and implicated in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and exploration of potential targeted treatment options.
Conflicts of Interest
Acknowledgments This research was supported by a grant from the Fondation Jeanne et Jean-Louis Lévesque (to J.L.M). M.S. holds a Clinician-Scientist award from the Fonds de recherche du Québec – Santé. We thank the members of the massively-parallel-sequencing team at McGill University and Genome Quebec Innovation Center for their exome capture and sequencing service. We also thank the members of the bioinformatic-analysis team of Réseau de Médecine Génétique Appliquée du Québec (Alexandre Dionne-Laporte, Dan Spiegelman, Edouard Henrion, and Ousmane Diallo) for the primary analysis of the exome sequencing data.