Lab-grown mini brains reveal DHDDS disease mechanism, vitamin B3 shows promise

A pair of parents refused to accept what they'd been told: that their two children, diagnosed with a rare genetic disease called DHDDS, would simply have to wait for science to catch up. There was nothing to be done, they were told. The disease would progress. Their children would lose the ability to walk, to care for themselves. So instead of waiting, they reached out to researchers at the Icahn School of Medicine at Mount Sinai in New York, and that decision set in motion a chain of discovery that has now offered real hope to a handful of patients and opened a path toward understanding a condition that had seemed, until recently, entirely intractable.

DHDDS is a neurodegenerative disorder caused by mutations in a single gene. It announces itself in early childhood with tremors, seizures, and progressive problems with coordination and learning—a Parkinson's-like condition that worsens over time. It is extraordinarily rare, which means it has attracted little attention from pharmaceutical companies and even less from the medical establishment. Parents of affected children have historically been offered little more than sympathy.

Dr. Irena Muffels, a clinical genetics resident working in the Morava-Kozicz lab at Mount Sinai, and her colleagues took an unconventional approach. Rather than studying the disease in animal models or trying to extract tissue samples from the children's brains—an invasive and ethically fraught prospect—they grew miniature brain structures from the patients' own cells in the laboratory. These "mini-brains," tiny blobs of neural tissue cultivated in dishes, allowed the team to watch the disease unfold in real time. After four months, the structures showed clear signs of deterioration that mirrored what happens in actual patients.

The mechanism became visible under the microscope. The DHDDS gene normally helps produce dolichol, a small lipid molecule that acts as an anchor for sugar molecules. Those sugars are essential for building glycans—structures that function like antennae on proteins, allowing them to perform their intended roles. In the diseased mini-brains, dolichol production was severely diminished, and the glycans were malformed. But there was more. The reduction in dolichol disrupted the brain's lipid metabolism broadly, causing cholesterol to accumulate in astrocytes, the brain cells responsible for protecting neurons. This cholesterol buildup intensified over time, triggering mitochondrial dysfunction and starving the brain of energy. That progressive energy depletion, the researchers concluded, was why the disease worsened.

With the mechanism mapped, Muffels and her team collaborated with the biotech company Perlara to screen existing FDA-approved drugs and vitamins for therapeutic potential. One compound stood out: NMN, a naturally occurring form of vitamin B3, also known as nicotinamide mononucleotide. It rescued a yeast model of the disease. When tested in the patient-derived mini-brains, the results were striking. Word of the findings spread, and before the formal experiments were complete, some patients began ordering NMN online. Within a month, the improvements were unmistakable. Children who had been taking the supplement showed better walking ability, more energy, reduced tremors, and smoother movement. The disease seemed to be slowing.

Twelve patients are now taking NMN, and the research team has secured funding from CDG UK, a charity supporting those with congenital disorders of glycosylation, to launch an international clinical trial. Patients will take the supplement for a year, with assessments every three months. The appeal of NMN is difficult to overstate: it is cheap, widely available without prescription, and has no known serious side effects. Some patients have shown such dramatic improvement that observers could barely detect signs of the disease. Muffels, who has since returned to the Wilhelmina Children's Hospital in Utrecht, hopes to continue the work there and expand the trial internationally.

The path from desperate parents to a potential treatment took less than two years. The mini-brain technology proved decisive—it allowed researchers to see the disease unfold, to understand why it progressed, and to test interventions without waiting for the slow machinery of traditional drug development. The vitamin B3 finding is particularly significant because NMN has already shown promise in other mitochondrial and neurodegenerative conditions, suggesting that the mechanism discovered in DHDDS might unlock treatments for a broader class of rare metabolic disorders. For the families involved, the shift from hopelessness to possibility has been transformative. The trial is only beginning, but for the first time, there is something to hope for.