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Background The CLN3 disease spectrum ranges from a childhood‐onset neurodegenerative disorder to a retina‐only disease. Given the lack of metabolic disease severity markers, it may be difficult to provide adequate counseling, particularly when novel genetic variants are identified. In this study, we assessed whether lymphocyte vacuolization, a well‐known yet poorly explored characteristic of CLN3 disease, could serve as a measure of disease severity. Methods Peripheral blood obtained from healthy controls and CLN3 disease patients was used to assess lymphocyte vacuolization by (a) calculating the degree of vacuolization using light microscopy and (b) quantifying expression of lysosomal‐associated membrane protein 1 (LAMP‐1), using flow cytometry in lymphocyte subsets as well as a qualitative analysis using electron microscopy and ImageStream analysis. Results Quantifying lymphocyte vacuolization allowed to differentiate between CLN3 disease phenotypes (P = .0001). On immunofluorescence, classical CLN3 disease lymphocytes exhibited abundant vacuole‐shaped LAMP‐1 expression, suggesting the use of LAMP‐1 as a proxy for lymphocyte vacuolization. Using flow cytometry in lymphocyte subsets, quantifying intracellular LAMP‐1 expression additionally allowed to differentiate between infection and storage and to differentiate between CLN3 phenotypes even more in‐depth revealing that intracellular LAMP‐1 expression was most pronounced in T‐cells of classical‐protracted CLN3 disease while it was most pronounced in B‐cells of “retina‐only” CLN3 disease. Conclusion Lymphocyte vacuolization serves as a proxy for CLN3 disease severity. Quantifying vacuolization may help interpretation of novel genetic variants and provide an individualized readout for upcoming therapies.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterised by deficient glucose transport over the blood‐brain barrier and reduced glucose availability in the brain. This causes epilepsy, movement disorders, and cognitive impairment. Treatment with ketogenic diet provides ketones as alternative energy source. However, not all GLUT1DS patients are on dietary treatment (worldwide registry: 77/181 [43%] of patients). The current 25‐year experience allows evaluation of effects and tolerability of dietary treatment for GLUT1DS. To this end, literature was searched up to January 2019 for individual case reports and series reporting (side) effects of dietary treatment for GLUT1DS. Upon aggregation of data for analysis, we identified 270 GLUT1DS patients with dietary treatment with a mean follow‐up of 53 months. Epilepsy improved for 83% of 230 patients and remained unchanged for 17%, movement disorders improved for 82% of 127 patients and remained unchanged for 17%, and cognition improved for 59% of 58 patients and remained stable for 40%. Effects on epilepsy were seen within days/weeks and were most pronounced in patients with early treatment initiation. Effects on movement disorders were noticed within months and were strongest in patients with higher cerebrospinal fluid‐to‐blood glucose ratio. Although side effects were minimal, 18% of 270 patients reported poor compliance. In individual patients, symptoms deteriorated upon low ketosis, poor compliance, or treatment discontinuation. Based on the good tolerability and strong favourable effect of dietary treatment on GLUT1DS symptoms, we advocate dietary treatment in all GLUT1DS patients and prompt diagnosis or screening to allow early treatment.