Beyond the classic ketogenic diet: A systematic review of alternative and adjunctive therapies for GLUT1 deficiency syndrome.

BACKGROUND: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare, paediatric onset, neurometabolic disorder caused by impaired cerebral glucose transport, leading to chronic brain energy deficiency. The classic ketogenic diet (CKD) is its established cornerstone therapy but it is not universally effective, well tolerated or sustainable. A growing number of alternative and adjunctive therapies has been explored, but their clinical roles remain unclear due to the fragmented and heterogeneous nature of the evidence. OBJECTIVES: Systematic synthesis and appraisal of clinical evidence for non-ketogenic and adjunctive therapeutic strategies in paediatric GLUT1-DS with a focus on patients who are unable to initiate, maintain, or adequately respond to classic KD. METHODS: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov were searched from inception to November 2025. Eligible studies included paediatric patients with confirmed GLUT1-DS diagnosis receiving therapeutic interventions beyond the CKD. Outcomes included: seizure control, paroxysmal movement disorders, neurodevelopmental and functional measures, treatment tolerability, and quality of life. Owing to substantial clinical and methodological heterogeneity across studies, a narrative synthesis was performed. RESULTS: Twenty-two studies- involving 290 GLUT1-DS patients-were included, consisting of: randomized controlled trials, non-randomized interventional studies, observational studies, case series and case reports. Evaluated interventions included: modified Atkins diet (MAD) variants, triheptanoin, intravenous sodium lactate, acetazolamide, zonisamide, diazoxide, intermittent glucose administration, and combined dietary-pharmacologic approaches. MAD variants and acetazolamide were associated with the most consistently favourable clinical outcomes across the available studies. Triheptanoin showed conflicting efficacy. Evidence for lactate- and glucose-based strategies was limited to small, high-risk studies with narrow applicability. CONCLUSIONS: While CKD remains the reference standard for GLUT1-DS management, selected alternative and adjunctive therapies may offer clinically meaningful benefit in specific clinical contexts. The current evidence base, however, is limited. These findings support cautious and individualized use of alternative therapeutic strategies while highlighting the need for larger prospective studies and standardized outcome measures to better define their role in GLUT1-DS management.