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. 2026 Mar 3:7:26330040261427020.
doi: 10.1177/26330040261427020. eCollection 2026 Jan-Dec.

A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment

Anastasia Ambrose  1 , Morganne McCabe  1 , Shalini Bahl  2   3 , David Sinasac  4 , Thomas Snyder  5 , Saadet Mercimek-Andrews  6   7
Affiliations

A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment

Anastasia Ambrose et al. Ther Adv Rare Dis. .

Abstract

Background: Pyridoxine-dependent epilepsy (PDE) due to biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1) is an metabolic disease of lysine catabolism. Current standard treatment includes pyridoxine, arginine, and lysine- or protein-restricted diet. Pyridoxine treats seizures. Arginine and lysine- or protein-restricted diet decrease elevated α-aminoadipic semialdehyde (α-AASA) and Δ1- piperideine-6-carboxylate (P6C) levels to improve neurodevelopmental outcomes. We previously reported abnormalities in tricarboxylic acid (TCA) cycle and electron transport chain in PDE-ALDH7A1. We report a new patient with PDE-ALDH7A1 who did not show any improvements in neurodevelopment on the current standard therapy. We hypothesized that triheptanoin will provide substrate to TCA cycle and improve abnormal energy metabolism leading to improvements in neurodevelopmental outcome.

Objective: To treat this patient with triheptanoin to improve neurodevelopmental outcome.

Design: Due to complex I deficiency and lack of response to the current standard therapy, we applied triheptanoin novel therapy.

Methods: A 4-year-old male had compound heterozygous variants in ALDH7A1 and markedly elevated urine α-AASA. The goal dose of triheptanoin was 50% of the estimated energy requirement (EER). We assessed efficacy of triheptanoin using neuropsychological assessments. We measured 6-oxopipecolic acid using liquid chromatography tandem mass spectrometry.

Results: Triheptanoin was started at 10 mL/day. There was nausea up to 3 weeks after each dose increase, which has improved allowing us to increase triheptanoin gradually. The maximum actual dose of triheptanoin was 40% of EER. Cognitive composite score improved from 16% to 63% on treatment. All chemistry and biochemical investigations were normal. 6-oxopipecolic acid levels did not normalize. Triheptanoin treatment seemed to be safe and tolerated well.

Conclusion: Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.

Keywords: 6-oxo-pipecolate; ALDH7A1; developmental delay; neurodevelopmental outcome; pyridoxine-dependent epilepsy; triheptanoin.

Plain language summary

A new treatment for pyridoxine-dependent epilepsy: Treating energy deficiency in mitochondria and improving brain development with triheptanoin What is PDE-ALDH7A1? Pyridoxine-dependent epilepsy (PDE) is caused by genetic changes in the ALDH7A1 gene (PDE-ALDH7A1). This genetic condition involves breaking down lysine, a building block of proteins. The typical treatment for this condition requires giving pyridoxine (a vitamin), arginine and tryptophane (building blocks of proteins) and decreasing protein intake in daily diet. What was the aim of this study? We previously reported that people with PDE-ALDH7A1 have problems with energy production. A boy with PDE-ALDH7A1 had the typical treatment in the first year of life. Unfortunately, his walking, talking and understanding (cognitive abilities) did not get better on this typical treatment. We decided to try a new treatment using a special oil, if this new treatment will help his body to produce more energy, as we found in his muscle biopsy a slight energy deficiency. How was this boy treated? We started a special oil therapy, called triheptanoin. The dose of this special oil was increased gradually as much as he was able to tolerate. We used structured tools to assess progress in his walking, talking and understanding every year. He started gaining new skills and understanding better. His cognitive abilities raised from 16% to 63% using structured tools. Why is this study important? In some people with PDE-ALDH7A1, the typical treatment may not work well. Adding special oil to the treatment may help to improve people’s walking, talking and understanding.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
Percentages of composite and scaled scores of Bayley Scales of Infant and Toddler Development – III.
Figure 2.
Figure 2.
The goal and actual percentage of estimated energy requirement of triheptanoin treatment. EER, estimated energy requirement.
See this image and copyright information in PMC

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