Glucose Transporter Type 1 Deficiency Syndrome

CLINICAL CHARACTERISTICS

Glucose transporter type 1 deficiency syndrome (Glut1DS) is a disorder of brain energy metabolism. Glucose, the essential metabolic fuel for the brain, is transported into the brain exclusively by the protein glucose transporter type 1 (Glut1) across the endothelial cells forming the blood-brain barrier (BBB). Glut1DS results from the inability of Glut1 to transfer sufficient glucose across the BBB to meet the glucose demands of the brain. The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood. When first diagnosed in infancy to early childhood, the predominant clinical findings of Glut1DS are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and developmental delay. Subsequently children develop complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome. When first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings of Glut1DS are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability.

DIAGNOSIS/TESTING: The diagnosis of Glut1DS is established in a proband with suggestive clinical findings, hypoglycorrhachia documented by lumbar puncture, and a (usually) heterozygous pathogenic variant in identified by molecular genetic testing. Rarely, an individual with suggestive clinical findings and hypoglycorrhachia has biallelic pathogenic variants.

MANAGEMENT

Age-specific KDTs primarily provide a supplemental fuel, namely, ketone bodies, for brain energy metabolism. KDTs create chronic ketosis by largely replacing carbohydrates and proteins with lipids in varying ratios. In addition to educational programs to address the individual's needs, multidisciplinary care by specialists in neurology familiar with KDTs, physical medicine and rehabilitation, physical therapy, occupational therapy, speech and therapy, and clinical genetics and genetic counseling. Routinely scheduled evaluations with a neurologist (to determine response to KDTs and identify any new manifestations) as well as follow up per treating physical therapists, occupational therapists, and speech-language therapists. In individuals on KDTs: (1) avoidance of treatment of seizures with valproic acid, because it increases the risk of a Reye-like illness and may also inhibit glucose transport; (2) other anti-seizure medications (ASMs) including phenobarbital, acetazolamide, topiramate, and zonisamide may be relatively contraindicated as adjunctive treatment. It is appropriate to evaluate at-risk newborns, infants, and other relatives of a proband to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Early initiation of KDTs, ideally in infancy, results in better seizure control and improves long-term neurologic outcome.

GENETIC COUNSELING

Glut1DS is most commonly caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner. About 90% of individuals with Glut1DS have the disorder as the result of a pathogenic variant; about 10% of individuals have the disorder as the result of a pathogenic variant inherited from a parent. The degree of impairment in the transmitting parent may be mild or nonexistent; parental somatic mosaicism for the pathogenic variant may explain this observation. Each child of an individual with autosomal dominant Glut1DS has a 50% chance of inheriting the pathogenic variant and being clinically affected. Autosomal recessive inheritance has been reported in two families to date. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for Glut1DS are possible.