Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18 F-deoxyglucose positron emission tomography ( 18 F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18 F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18 F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

Disproportionately fewer waitlisted Hispanics receive living donor kidney transplants (LDKTs) compared to non‐Hispanic whites. Northwestern Medicine's® culturally targeted Hispanic Kidney Transplant Program (HKTP) is associated with a significant increase in LDKTs among Hispanics. This multisite study assessed potential kidney recipients' and donors' and/or family members' perceptions of the HKTP's cultural components through semi‐structured interviews and validated surveys. Qualitative thematic analysis and descriptive statistics were performed. Thirty‐six individuals participated (62% participation rate) comprising 21 potential recipients and 15 potential donors/family (mean age: 51 years, 50% female, 72% preferred Spanish). Participants felt confident about the educational information because a transplant physician delivered the education and viewed the group format as effective. Participants felt that education sessions addressed myths about transplantation shared by Hispanics. Primary use of Spanish enhanced participants' understanding of transplantation. While few knew about living donation before attending the HKTP, most were “more in favor of” kidney transplantation (97%) and living donation (97%) afterward. Few reported learning about the HKTP from outreach staff and suggested leveraging community leaders to promote HKTP awareness. Our findings suggest the HKTP's cultural components were viewed favorably and positively influenced perceptions of kidney transplantation and living donation, which may help reduce transplant disparities in Hispanics. (Clinicaltrial.gov registration # NCT03276390, date of registration: 9‐7‐17, retrospectively registered).

Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4–6, 6.8–10 and 11–16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, β-ketopentanoate and β-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential.ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017.

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