Clinical Guidance

No genotype-phenotype correlations are known to be associated with ETHE1 biallelic pathogenic variants.

Source: GeneReviews — "Ethylmalonic Encephalopathy"

Diagnostic Criteria

Suggestive Findings

Ethylmalonic encephalopathy (EE) should be suspected in an individual with the following clinical findings, preliminary laboratory findings, and brain MRI findings .

Clinical findings

• Global neurologic impairment

• Early-onset progressive psychomotor regression

• Seizures

• Dystonia

• Diffuse microvasculature injury

• Petechiae and/or purpura

• Orthostatic acrocyanosis

• Hemorrhagic suffusions of mucosal surfaces

• Chronic hemorrhagic diarrhea

Preliminary laboratory findings

Source: GeneReviews — "Ethylmalonic Encephalopathy"

Differential Diagnosis

Ethylmalonic acid is a dicarboxylic organic acid produced by the carboxylation of butyrate. Ethylmalonic encephalopathy (EE) should be included in the differential diagnosis of other forms of persistent ethylmalonic aciduria, including the following:

• Defects of beta-oxidation of fatty acids with similar clinical findings (e.g., vomiting, diarrhea, difficulty with feeding, and developmental delay) such as short-chain acyl-CoA dehydrogenase (SCAD) deficiency and 3-hydroxyacyl-CoA dehydrogenase (HADH) deficiency (OMIM 231530). Petechiae, purpura, and orthostatic acrocyanosis are specific to EE .

• Defects of the mitochondrial electron-transfer flavoprotein pathway or glutaric aciduria type II

• Some forms of respiratory chain deficiency

Source: GeneReviews — "Ethylmalonic Encephalopathy"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ethylmalonic encephalopathy (EE), the recommended evaluations following diagnosis (if not performed as part of the evaluation that led to the diagnosis) are as summarized in . Table 2. Recommended Evaluations Following Initial Diagnosis of Ethylmalonic Encephalopathy (EE)

Source: GeneReviews — "Ethylmalonic Encephalopathy"

Therapies Under Investigation

While clearance of circulating sulfide by a transplanted liver could be beneficial, to date only one instance of liver transplantation in EE has been reported . Although results were encouraging, follow up of this patient and experience with additional patients are necessary to determine therapeutic efficacy of liver transplantation in EE and possible relevance for national or state-mandated newborn screening, particularly in populations with relatively high prevalence of pathogenic variants. Possible future treatments include AAV-mediated gene therapy or liver transplantation . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Ethylmalonic Encephalopathy"

Surveillance Guidelines

Surveillance should be individualized based on symptoms and organs affected. Table 4. Recommended Surveillance for Individuals with Ethylmalonic Encephalopathy

Source: GeneReviews — "Ethylmalonic Encephalopathy"