Ethylmalonic encephalopathy is a rare and severe inherited disorder. It primarily affects the body’s nervous system, blood vessels, and gastrointestinal tract, with symptoms often appearing at birth or within the first few months of life. As a type of encephalopathy, the condition alters brain function and structure, leading to progressive neurological problems. This disorder is very uncommon, though it appears more frequently in individuals of Mediterranean or Arab descent.
Underlying Genetic and Metabolic Causes
Ethylmalonic encephalopathy is an autosomal recessive disorder. This means that for a child to be affected, they must inherit two non-working copies of a particular gene—one from each parent. Individuals who carry only one copy of the mutated gene are considered carriers; they do not show signs of the condition but can pass the gene to their children. When both parents are carriers, there is a one-in-four chance with each pregnancy that the child will develop the disorder.
The specific gene responsible for this condition is the ETHE1 gene. This gene provides the instructions for producing an enzyme called ETHE1, which functions within the mitochondria—the energy-producing centers of our cells. The primary job of the ETHE1 enzyme is to help detoxify hydrogen sulfide, a substance that becomes toxic at high concentrations.
When mutations occur in the ETHE1 gene, the resulting enzyme is either absent or unable to function correctly. This failure obstructs the detoxification pathway for hydrogen sulfide. Consequently, hydrogen sulfide accumulates to dangerous levels inside the mitochondria, disrupting their ability to produce energy and causing widespread cellular damage. This toxic buildup is also associated with the accumulation of ethylmalonic acid, for which the condition is named.
Clinical Signs and Symptoms
The effects of ethylmalonic encephalopathy on the nervous system are progressive. Infants with the condition show significant developmental delays, failing to reach milestones like sitting up or crawling. In many cases, there is also developmental regression, where a child loses skills they had previously acquired. A common finding is hypotonia, or weak muscle tone, which contributes to difficulties with movement and feeding, and seizures are also frequent.
Vascular problems are a distinctive feature of the disorder and result from increased fragility of the blood vessels. This leads to recurrent petechiae, which are tiny, pinpoint-sized red or purple spots on the skin caused by minor bleeding. Purpura, which are larger patches of bleeding under the skin, may also appear. Another characteristic sign is acrocyanosis, a persistent bluish discoloration of the hands and feet resulting from poor circulation.
Chronic and severe gastrointestinal issues are a major component of the condition. Persistent, watery diarrhea is a nearly universal symptom and can lead to significant challenges with nutrition and hydration. This chronic diarrhea begins early in life and is often one of the first signs that draws medical attention.
The Diagnostic Process
The diagnostic process begins with a clinical evaluation based on the characteristic combination of symptoms. Healthcare providers may suspect the disorder in an infant presenting with developmental delays, hypotonia, a rash of petechiae, and chronic diarrhea. The presence of acrocyanosis further strengthens this suspicion and prompts more specific laboratory investigations.
Laboratory testing is a central part of confirming the diagnosis. A urine organic acid analysis is one of the primary tests performed, revealing elevated levels of ethylmalonic acid and methylsuccinic acid. Blood tests that analyze the acylcarnitine profile may also show distinctive abnormalities. These biochemical markers are direct consequences of the underlying metabolic disruption.
While clinical signs and biochemical tests are highly suggestive, the definitive diagnosis is achieved through molecular genetic testing. This involves sequencing the ETHE1 gene to identify the specific mutations responsible for the disorder. Confirming the presence of two disease-causing mutations solidifies the diagnosis. Physicians may also use an MRI scan to assess structural changes in the brain.
Management and Therapeutic Approaches
Currently, there is no cure for ethylmalonic encephalopathy, so treatment focuses on managing symptoms and the underlying metabolic problem. The primary medical intervention involves a combination therapy designed to counteract the toxic effects of hydrogen sulfide buildup. This often includes metronidazole, an antibiotic that helps reduce hydrogen sulfide produced by gut bacteria, and N-acetylcysteine (NAC) to support detoxification pathways.
In addition to targeting hydrogen sulfide, treatment includes supplements to support mitochondrial function. Coenzyme Q10 and L-carnitine are two such supplements commonly provided to patients. These substances are intended to help the mitochondria work more efficiently and withstand the damage caused by the toxic environment within the cells.
Supportive care is another fundamental aspect of managing the condition and improving quality of life. Physical therapy is used to address hypotonia and help with motor skills, while occupational therapy can assist with daily living activities. Nutritional support is necessary to manage the chronic diarrhea and ensure adequate growth. Despite these interventions, the prognosis is generally poor, with most affected children surviving only into early childhood.