Haploinsufficiency determines the pattern of inheritance in patients with Glut1 deficiency. The rate of glucose uptake by the patient’s red blood cell is a surrogate for the degree of haploinsufficiency. “More than 90% of the patients we’ve seen have one normal allele and one null allele, and the red blood cell uptake assay has a value of about 50% compared with controls. In a smaller percentage—well below 10% at this point in time—we have identified some patients who have recessive mutations in the Glut1 gene.”
An Evolving Phenotype
Glut1 deficiency also is instructive in the context of rare diseases because its clinical phenotype changes during development. “Developmental delay, to a greater or lesser degree, affects 100% of these patients, as does developmental clumsiness and ataxia,” Dr. De Vivo said.
“This is a lifelong disability that these patients have,” he added. “The epileptic phenotype is largely limited to infancy. You see it in about 90% of the patients with Glut1 deficiency, and then it gradually subsides through childhood, adolescence, and into early adulthood. In contrast, the movement disorder, dominated principally by dystonia, emerges from late infancy and early childhood, up through adolescence, so that about 100% of patients with Glut1 deficiency known to exist demonstrate persistent or paroxysmal dystonia.”
Gene Therapy
“We have now started investigating more effective disease-modifying therapies to treat this condition, starting with experiments involving patients’ cultured human fibroblasts,” Dr. De Vivo said. Using gene therapy strategies in a mouse model, Dr. De Vivo and colleagues have restored Glut1 activity and totally mitigate the motor defect. By restoring Glut1 activity to the mouse model, the researchers were also able to increase the brain expression of Glut1 RNA and Glut1 protein and increase the CSF glucose concentrations from abnormally low values to the normal values of wild-type mice. “We have gotten to the point where we can effectively treat or cure the mouse model of this disease, and now we have to position ourselves to conduct equivalent studies in the human setting,” Dr. De Vivo said.
Take-Home Messages
“It is quite obvious from your own experience and certainly from my experience that rare diseases are common in neurology,” Dr. De Vivo said. “We now have a number of tools with which we can mitigate many of the neurologic phenotypes. Preconception carrier testing is an effective way to prevent untreatable recessive diseases. We can test for more than 100 untreatable recessive diseases, like Tay-Sachs disease, by preconception carrier testing and prevent these diseases from occurring.”
Expanded newborn screening could also make a large impact, “since it would increase the opportunities for proactive treatment of the presymptomatic infant. Early diagnosis and treatment is probably the most important aspect to approaching these patients, as is the case with phenylketonuria, particularly if you can identify the patients from the genotypic point of view before they become phenotypically affected.”
Finally, Dr. De Vivo noted that molecular-based gene therapy is now entering the clinic. “We can now explore the wonderful opportunities that are emerging for gene therapy to rescue the phenotype in our patients who develop neurologic symptoms,” he concluded.
—Glenn S. Williams