Liver and Brain Drive Separate Symptoms in Rare Inherited Epilepsy, Mouse Study Finds

A rare inherited disorder that causes devastating seizures in infancy has long puzzled physicians for a second reason: even when the seizures are brought under control, many patients continue to struggle with psychiatric and cognitive symptoms that shadow them for life. A new study from Johns Hopkins Medicine, published in the journal Science Advances, now offers a striking explanation for that split. Working with genetically engineered mice, the researchers found that the seizure susceptibility of pyridoxine-dependent epilepsy and its psychiatric manifestations arise from two entirely separate biological pathways — one rooted in the liver, the other in specialized cells of the brain. In a twist that has captured attention well beyond the rare-disease community, the team also showed that a compound found in broccoli sprouts could reverse the psychiatric-like symptoms in the mice, pointing toward a potential new avenue for treatment.

Pyridoxine-dependent epilepsy, or PDE, is caused by loss-of-function mutations in a gene called ALDH7A1. People with the disorder experience severe seizures that, remarkably, can be ameliorated by high doses of pyridoxine, better known as vitamin B6. That response has been the cornerstone of treatment for decades. Yet the vitamin does not solve everything. Psychiatric and cognitive symptoms can persist even after the seizures are controlled, leaving patients and families grappling with problems that the standard therapy does not touch. That clinical observation raised a fundamental question for the Johns Hopkins team: do those lingering symptoms arise through the same mechanism as the seizures, or through something else entirely?

To find out, the researchers engineered mice in which ALDH7A1 could be selectively removed from either the liver or from astrocytes, the star-shaped brain cells that help maintain the chemical environment surrounding neurons. This precision approach allowed the team to disentangle contributions from different organ systems in a way that a conventional whole-body knockout could not. The results were unambiguous. Mice lacking ALDH7A1 in their liver cells became more susceptible to seizures but did not develop the changes in mood and behavior seen in mice lacking the gene throughout the body. Conversely, mice lacking the gene specifically in astrocytes developed behavioral deficits without becoming any more prone to seizures.

The behavioral changes observed in the astrocyte-specific mice were detailed and telling. The animals showed depressive-like behavior, reduced motivation, passive coping and decreased self-care — a constellation of deficits that mirrors the psychiatric burden reported by people with PDE whose seizures are well managed. The researchers traced these changes to a disruption of the normal antioxidant defenses that help cells manage reactive molecules and maintain normal function. In the astrocytes lacking ALDH7A1, that protective machinery faltered, and the disruption was associated with reduced activity among neurons in the prelimbic cortex, a brain region known to be involved in regulating emotional behavior.

That mechanistic chain — gene loss in astrocytes, weakened antioxidant defenses, disturbed redox balance, altered neuronal activity in an emotion-regulating circuit — gave the team a concrete therapeutic target. Because antioxidant defenses can help maintain the balance of reactive molecules in cells, the researchers turned to sulforaphane, an antioxidant compound found in broccoli sprouts that is known to activate NRF2, a cellular pathway that helps protect cells from oxidative stress. When the researchers incorporated sulforaphane into the mice’s diet, it increased NRF2 levels in the ALDH7A1-deficient astrocytes, suggesting increased antioxidant protection and an improved redox balance within the affected brain cells.

Crucially, the compound’s effects were selective. Sulforaphane did not correct the increased seizure susceptibility associated with loss of ALDH7A1 throughout the body. That distinction, the researchers say, provided additional evidence that the psychiatric and seizure symptoms are driven by separate mechanisms, with the psychiatric changes linked to astrocytes in the brain and seizure susceptibility linked to dysfunction involving the liver. For a field that has often treated a genetic mutation as a single point of failure, the finding is a powerful demonstration that one gene can produce distinct disease processes in different tissues.

“An important implication of this work is that the symptoms we see in a rare neurological disorder do not necessarily have to come from the same place or through the same mechanism,” says Akira Sawa, M.D., director of the Johns Hopkins Schizophrenia Center and professor of psychiatry and behavioral sciences at Johns Hopkins Medicine. “In this case, we found that the liver and brain each make distinct contributions to the disease, which gives us a much clearer picture of how these symptoms arise.”

The separation of mechanisms also reframes how the psychiatric burden of PDE might be treated. Vitamin B6 remains the standard for controlling seizures, but sulforaphane could potentially be added to treatment to address the psychiatric symptoms associated with the disorder. “The fact that sulforaphane could improve the psychiatric phenotype while not preventing seizures was especially informative,” says Sawa. “It suggests that targeting the biology of the brain directly may be able to address psychiatric symptoms that persist even when the seizures themselves are controlled.”

The study adds to a growing body of evidence that neurological and psychiatric symptoms arising from the same genetic mutation can stem from distinct biological and metabolic processes. That principle may extend well beyond PDE. If a single inherited mutation can produce seizures through liver-centered metabolic dysfunction and mood and motivational deficits through astrocyte redox imbalance in the brain, then other neurodevelopmental and neuropsychiatric conditions may similarly harbor organ-specific mechanisms that have been blurred together under a single diagnosis. Dissecting those mechanisms, as this study did with tissue-selective genetic engineering, could open the door to therapies aimed at each pathway individually rather than at the gene in the abstract.

The researchers caution that much work remains before sulforaphane reaches the clinic. The findings provide a foundation for further study of the compound as a potential supplemental treatment for psychiatric symptoms associated with pyridoxine-dependent epilepsy, but future research will be needed to determine whether targeting astrocyte redox imbalance can improve these symptoms in people with the disorder. Mechanism-driven clinical trials of sulforaphane represent a potential next step, and any such trials would need to establish whether the NRF2 activation seen in mice translates safely and effectively to human patients. The federally funded study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. Researchers from the Johns Hopkins University School of Medicine departments of neuroscience, psychiatry and behavioral sciences, physiology, pharmacology and therapeutics, biomedical engineering and genetic medicine led the work, with collaborators from the National Institute on Drug Abuse Intramural Research Program, Heidelberg University and the University of Maine. For now, the study stands as a vivid example of how a humble broccoli-sprout compound, guided by rigorous mechanistic science, can illuminate the hidden architecture of a rare disease — and perhaps point the way toward treating the symptoms that medicine has long left behind.

Subject of Research: Distinct liver and brain mechanisms underlying seizures and psychiatric symptoms in pyridoxine-dependent epilepsy

Article Title: Study reveals both liver and brain pathways in differing symptoms of inherited metabolic disorder

Article References: Study reveals both liver and brain pathways in differing symptoms of inherited metabolic disorder. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: pyridoxine-dependent epilepsy, ALDH7A1, astrocytes, liver, sulforaphane, NRF2, oxidative stress, vitamin B6, seizures, psychiatric symptoms, Johns Hopkins, Science Advances