Optimization of the ketogenic metabolic bypass in a pediatric participant with a PFKFB1 defect and complex neurometabolic phenotype: a two-phase prospective case study

Background: PFKFB1 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1) is a bifunctional enzyme regulating hepatic glycolytic flux. No OMIM disease entity is currently associated with PFKFB1 variants, and the clinical literature is virtually nonexistent. We describe the first prospective interventional case study in a participant carrying a hemizygous PFKFB1 variant (p.Ser159Thr, ChrX:54984780A>T).

Case: A 14-year-old male with myoclonic epilepsy, a behavioral phenotype with a clinical diagnosis of autism spectrum disorder (ASD) — not confirmed by a standardized diagnostic tool — and recurrent symptomatic hypoglycemia aggravated by carbohydrate intake, carrying a hemizygous PFKFB1 variant inherited from his carrier mother. Genetic complexity includes two additional pathogenic variants (FAM21C p.E308* and SECISBP2L p.M506T) identified on initial exome sequencing (ISCIII 2017) and subsequently assessed as not relevant to the phenotype by the SpainUDP team and the Santiago de Compostela CSUR metabolic disease team.

Methods: Prospective two-phase case study, 40 days each (Phase I: standard bypass, days 1–40; Phase II: optimized bypass, days 41–80), with continuous glucose monitoring (CGM), systematic daily behavioral recording (0–10 scale with subscales), capillary ketonemia, and serial biochemical testing. Phase II incorporated a structured naturopathic and dietary intervention — ketogenic ratio adjustment, supplementation targeted to the PFKFB1 mechanism, and a structured MCT timing protocol — designed by the research team to optimize the metabolic bypass established in Phase I. Primary outcome: daily frequency of hypoglycemic episodes <65 mg/dL. Phase II was conducted during summer in Seville, Spain (ambient temperatures up to 42°C), documented as a confounding variable.

Results: Over 80 days of observation, days with maximal behavioral dysregulation (score ≥8) were absent in Phase II versus three episodes in Phase I (8% vs 0%). Days with optimal behavior (score = 0) increased from 22% to 35%. Morning fasting glucose decreased significantly (84.5 ± 13.0 vs 79.6 ± 8.2 mg/dL; p = 0.046). A statistically significant correlation was observed between behavioral score and mean ketones over the preceding three days (r = 0.43; p = 0.011), in contrast to the absence of correlation with same-day ketones (r = 0.04; p = 0.81). Hospital-grade MCT above 60 ml/day was associated with steatorrhea in 100% of Phase I episodes; this threshold was maintained with 0% violations in Phase II — the complete resolution of steatorrhea is one of the most direct clinically actionable outcomes of the naturopathic and dietary optimization. Protocol adherence was 100% for the MCT limit and 92% for the daily ≥2-hour nap. Rescue risperidone was used on 2/40 days in Phase I and 1/40 days in Phase II, compared with daily use during the prior glycogenosis-diet period.

Conclusions: These observations are consistent with greater behavioral stability and with resolution of steatorrhea under the optimized bypass protocol with structured naturopathic and dietary intervention, in the context of extreme summer heat. The temporal dissociation between ketone levels and behavioral outcome supports a model of cumulative oxidative stress rather than acute energy deficit. These data are hypothesis-generating and require confirmation in larger cohorts.