Researchers tested whether limiting certain amino acids in food could help three patients with ethylmalonic encephalopathy (EE), a rare genetic disorder that causes the body to produce too much of a toxic gas called hydrogen sulfide. The patients were already receiving standard treatments including medications and a liver transplant. When doctors added a special diet that restricted sulfur-containing amino acids, they saw only small improvements in blood markers in two patients and actually worsening in one patient. This suggests that while the diet idea is worth studying more, it may not be a major breakthrough for this serious condition.

The Quick Take

  • What they studied: Can a special diet that limits certain amino acids (building blocks of protein) help patients with a rare genetic disease that causes toxic gas buildup in their bodies?
  • Who participated: Three patients with ethylmalonic encephalopathy—a rare inherited metabolic disorder. Two had milder forms of the disease, and one had the severe form. All were already receiving standard medical treatments and had received liver transplants.
  • Key finding: The special diet produced only modest results: it reduced a key marker (butyrylcarnitine) by 8-10% in the two patients with milder disease, but actually increased it by 82% in the patient with severe disease. This suggests the diet alone has limited benefit.
  • What it means for you: If you or a family member has ethylmalonic encephalopathy, this research suggests that dietary changes alone are unlikely to be a major treatment solution. However, it may help slightly when combined with other treatments. More research is needed before doctors can recommend this diet as standard care.

The Research Details

This was a small, open-label study involving just three patients with ethylmalonic encephalopathy. An open-label study means both the doctors and patients knew they were receiving the dietary intervention—there was no control group for comparison. The researchers measured specific chemicals in the patients’ blood before and after introducing a diet that restricted methionine and cysteine (two amino acids containing sulfur) to 20-30 mg per kilogram of body weight per day. They tracked these measurements over time and also performed detailed metabolic testing to see how the diet affected the patients’ overall chemical balance.

The study was designed to test whether reducing the amount of sulfur-containing amino acids in the diet could lower the production of hydrogen sulfide inside the body. This was based on the idea that since the body makes some hydrogen sulfide from breaking down these amino acids, eating less of them might reduce toxic gas production. All three patients were already receiving standard treatments (antibiotics and medications) and had undergone liver transplants before starting the diet.

The researchers focused on measuring butyrylcarnitine, a chemical marker that indicates how well the body is handling the toxic byproducts of the disease. They also performed comprehensive metabolic testing to see if the diet changed the overall pattern of chemicals in the patients’ bodies.

This research matters because ethylmalonic encephalopathy is a serious genetic disease with limited treatment options. Most current treatments focus on reducing toxic gas produced by bacteria in the intestines or helping the liver detoxify the gas. This study explored a different approach—reducing the gas produced inside the body itself through diet. Understanding whether dietary changes can help is important because diet is something patients and families can control, unlike genetic factors. However, the small sample size and mixed results mean this study is really just a starting point for future research.

This study has important limitations to understand: it involved only three patients, which is very small and makes it hard to draw firm conclusions. There was no control group (patients receiving standard care without the diet) for comparison, so it’s unclear how much the diet itself contributed to any changes. The study was open-label, meaning both doctors and patients knew about the dietary intervention, which could influence how they perceived results. The patients were already receiving multiple treatments and had undergone liver transplants, making it difficult to isolate the effect of the diet alone. The mixed results—with some patients improving slightly while one got worse—suggest the diet’s effects are unpredictable and may depend on the severity of the disease.

What the Results Show

When the three patients started the sulfur-restricted diet, the results were disappointing and inconsistent. In the two patients with milder forms of the disease, blood levels of butyrylcarnitine (a key marker of disease activity) decreased by 8-10%, which is a small improvement. However, in the patient with the severe form of the disease, butyrylcarnitine levels actually increased by 82%—a significant worsening.

Before starting the diet, all three patients had already shown improvement from their standard medical treatments and liver transplants. The standard treatments had reduced butyrylcarnitine levels by 20-38% in all three patients. The additional benefit from the diet was much smaller—and in one case, harmful.

When researchers performed detailed metabolic testing (untargeted metabolomics), they found that the overall pattern of chemicals in the patients’ bodies remained largely unchanged after starting the diet. This suggests the diet did not substantially alter the underlying metabolic problems caused by the disease. The researchers measured seven different chemical markers related to the disease, and none showed major changes with the diet.

The study revealed that the modest response to the diet likely reflects the fact that the body produces hydrogen sulfide from multiple sources. While the diet reduced sulfur-containing amino acids from food, this only addresses one source of the toxic gas. The body also produces hydrogen sulfide from bacteria in the intestines, which is why patients continue to need antibiotics and other medications. The fact that the diet had minimal effect suggests that endogenous (internally produced) hydrogen sulfide from amino acid breakdown is not the main problem in this disease. The worsening seen in the severely affected patient raises concerns that dietary restriction might be harmful in more advanced cases, though the reason for this is unclear.

This study builds on existing knowledge that current treatments for ethylmalonic encephalopathy—including antibiotics (metronidazole), medications (N-acetylcysteine), and liver transplants—can provide meaningful improvements. The new finding is that adding a sulfur-restricted diet provides only minimal additional benefit beyond these established treatments. Previous research has focused on reducing the bacterial production of hydrogen sulfide or helping the liver detoxify it. This study is one of the first to systematically test whether reducing dietary sulfur-containing amino acids helps, making it a novel approach. However, the limited benefit suggests that future research should focus on improving existing treatments rather than relying on diet alone.

This study has several important limitations. First, it included only three patients, which is too small to draw reliable conclusions that would apply to all patients with this disease. Second, there was no control group—no patients receiving standard care without the diet—so it’s impossible to know how much the diet itself contributed to any changes. Third, all patients were already receiving multiple treatments and had undergone liver transplants, making it difficult to separate the diet’s effects from other treatments. Fourth, the study was open-label, meaning both doctors and patients knew about the intervention, which could bias how results were interpreted. Fifth, the patients had different disease severity levels, and the diet appeared to harm the most severely affected patient, suggesting the results may not apply equally to all patients. Finally, the study was relatively short-term, so long-term effects of the diet are unknown.

The Bottom Line

Based on this limited evidence, a sulfur-restricted diet should NOT be used as a primary treatment for ethylmalonic encephalopathy. Current standard treatments (medications, antibiotics, and liver transplants when needed) remain the main approaches. If a patient and their doctor are considering a sulfur-restricted diet as an addition to standard care, it should only be done under close medical supervision with regular monitoring of blood markers. The diet may provide a small benefit in patients with milder disease, but it may be harmful in patients with severe disease. More research is needed before this diet can be recommended as standard care. Confidence level: LOW—based on only three patients with mixed results.

This research is most relevant to patients with ethylmalonic encephalopathy and their families, as well as doctors who treat this rare disease. Genetic counselors and metabolic specialists should be aware of this research. The general public should understand that while this study tested an interesting idea, it did not produce results strong enough to change current treatment recommendations. Parents of children with this condition should continue following their doctor’s standard treatment plan rather than pursuing dietary restriction on their own.

If a patient were to try this diet under medical supervision, any potential benefits would likely appear within weeks to months, based on how quickly blood markers changed in this study. However, the small improvements seen (8-10% reduction) are modest and may not translate to noticeable clinical improvements in how the patient feels or functions. Long-term effects beyond the study period are unknown. Patients should not expect dramatic improvements from diet alone and should maintain all standard medical treatments.

Want to Apply This Research?

  • If a patient with ethylmalonic encephalopathy is working with their doctor to try a sulfur-restricted diet, they could track daily protein intake (grams per kilogram of body weight) and specific amino acid sources, along with weekly blood test results for butyrylcarnitine levels. This would help identify whether the diet is having any measurable effect.
  • A practical change would be to work with a dietitian to identify and limit high-methionine and high-cysteine foods (such as eggs, meat, dairy, nuts, and seeds) while maintaining adequate overall nutrition. Users could log meals and track which foods are consumed and in what quantities, comparing this to blood marker results over time.
  • Long-term monitoring should include regular blood tests (at least monthly) to measure butyrylcarnitine and other metabolic markers, combined with clinical assessments of symptoms and overall health. Users should track any changes in energy, neurological symptoms, or disease progression. This data should be reviewed regularly with their metabolic specialist to determine if the diet is providing any benefit and whether it should be continued.

This research describes a very small study (three patients) with mixed and modest results. It should NOT be used to make treatment decisions without consulting a qualified metabolic specialist or geneticist. Ethylmalonic encephalopathy is a serious genetic disease that requires professional medical management. Any dietary changes should only be made under close medical supervision with regular monitoring of blood markers and clinical status. This study does not provide evidence strong enough to recommend sulfur-restricted diets as standard treatment. Parents and patients should continue following their doctor’s established treatment plan. Always consult with your healthcare provider before making any changes to diet or medical treatment.