Clinical Aspects of Glucose Transporter Type 1 Deficiency

Abstract

IMPORTANCE Case reports regularly document unique or unusual aspects of glucose transporter type 1 deficiency (G1D). In contrast, population studies from which to draw global inferences are lacking. Twenty-five years after the earliest case reports, this deficiency still particularly affects treatment and prognostic counseling.OBJECTIVE To examine the most common features of G1D. DESIGN, SETTING, AND PARTICIPANTSIn this study, data were collected electronically from 181 patients with G1D through a web-based, worldwide patient registry from December 1, 2013, through December 1, 2016. The study used several statistical methods tailored to address the age at onset of various forms of G1D, associated manifestations, natural history, treatment efficacy, and diagnostic procedures. These factors were correlated in a predictive mathematical model designed to guide prognosis on the basis of clinical features present at diagnosis. RESULTS A total of 181 patients with G1D were included in the study (92 [50.8%] male and 89 female [49.2%]; median age, 9 years; age range, 0-65 years). As previously known, a relatively large variety of common phenotypes are characteristic of the G1D syndrome, including movement disorders, absence epilepsy (typical and atypical), and myoclonic and generalized epilepsies. The 3 main novel results are (1) the feasibility of effective dietary therapies (such as the modified Atkins diet) other than the ketogenic diet, (2) the relatively frequent occurrence (one-fourth of cases) of white matter magnetic resonance imaging abnormalities, and (3) the favorable effect of early diagnosis and treatment regardless of treatment modality and mutation type. In fact, the most important factor that determines outcome is age at diagnosis, as reflected in a predictive mathematical model. CONCLUSIONS AND RELEVANCEThe results reveal several changing notions in the approach to G1D syndrome diagnosis and treatment, such as the perceived absolute requirement for a ketogenic diet, the assumed lack of structural brain defects, and the potential existence of genotype-phenotype correlations, all of which are contested by the registry data.

Glucose transporter type 1 deficiency syndrome and the ketogenic diet

“…The strong benefits of dietary treatment and the finding of higher efficacy upon treatment adherence in a previous review of GLUT1DS patients underscore the importance of compliance. 6 Although diets with lower fat-to-carbohydrate ratios were effective in treating epilepsy in our study, higher fat-to-carbohydrate ratios were previously positively correlated with efficacy. 6 Side effects were minimal, also when compared with KD treatment of epilepsy.…”

“…Positive effects of dietary treatment on GLUT1DS symptoms have been described in case reports and series, but larger studies are lacking, putatively due to the rareness of GLUT1DS and absence of alternative therapies . Combined with adherence difficulties, this might explain why not all GLUT1DS patients receive dietary treatment (worldwide registry: 77/181 [43%] of patients) . The current 25‐year experience with dietary treatment for GLUT1DS now allows extensive evaluation of treatment effects.…”

“…7,8 Combined with adherence difficulties, this might explain why not all GLUT1DS patients receive dietary treatment (worldwide registry: 77/181 [43%] of patients). 6 The current 25-year experience with dietary treatment for GLUT1DS now allows extensive evaluation of treatment effects.…”

Genetic mimics of cerebral palsy

“…If no pathogenic variant is identified, 3‐O‐methyl‐D‐glucose uptake in erythrocytes can be performed, with a value between 35% and 74% of control levels being diagnostic for the condition . Brain imaging is either normal or shows slight brain atrophy, whereas in up to one‐quarter of cases white matter abnormalities are detected, including focal or diffuse supratentorial hyperintensities, prominence of perivascular Virchow Robin spaces, and delayed myelination . Critically, the ketogenic diet or modified Atkins diet often leads to substantial symptom improvement …”

Synaptic energy metabolism and neuronal excitability, in sickness and health

“…Approximately 50% to 60% of patients become seizure free, indicating that 4‐carbon (C4) ketone bodies (acetoacetate and β‐hydroxybutyrate) can largely compensate for the glucose deficit in the GLUT1‐deficient brain. Less restrictive dietary treatments, such as the modified Atkins diet, have similar efficacy in controlling seizures to the ketogenic diet in these patients, with the advantage that they are usually better tolerated due to the lower fat content . The question is how these diets exert their anti‐seizure effect.…”