Abstract
Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide‐ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye‐head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS‐specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long‐term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.
Highlights
Glucose is the essential metabolic fuel for brain
This expert opinion was circulated to all authors for comments and revisions, surveys were circulated regarding controversial issues, and face-to-face consensus meetings were held during the 2nd European glucose transporter type 1 deficiency syndrome (Glut1DS) conference in East Grinstead, UK, on June 22, 2018, and the 8th biannual Glut[1] Deficiency Foundation Conference on July 11, 2019, and July 12, 2019 in Washington DC, USA Authors were instructed to cite peer-reviewed publications when available
The Glut1DS phenotype becomes protean with advancing age
Summary
Glucose transport across the blood-brain barrier (BBB) and astrocyte plasma membrane is exclusively facilitated by the glucose transporter type 1 (Glut[1]). A Glut[1] genetic defect would impair glucose transport across the BBB and into astrocytes, resulting in a cerebral “energy crisis” termed glucose transporter type 1 deficiency syndrome (Glut1DS) (for comprehensive review see[1]). Patients classically present with infantile-onset epilepsy, deceleration of head growth, impaired neurological growth and development, and complex movement disorders. Symptoms develop in an age-specific pattern: Paroxysmal eye-head movements and seizures are early presenting features in infancy. Developmental impairment becomes increasingly apparent and is followed by ataxia, paroxysmal exertion-induced dystonia, and further movement abnormalities that develop over time often becoming the major symptoms in adolescents and adult Glut1DS patients. The principal diagnostic tool is a lumbar puncture showing low CSF glucose and low to low-normal lactate
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