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Ethylmalonic encephalopathy

Synonym(s) -
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • G31.8
  • C1865349
  • C535737
MedDRA -


Disease definition

Ethylmalonic acid encephalopathy (EE) is defined by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhoea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities.


Less than 40 cases have been described in the literature so far.

Clinical description

The disease manifests at birth or in the first few months of life. Spastic tetraplegia may be present. In addition to increased excretion of EMA, methylsuccinic acid and C4-C6-acylglycines (isobutyryl-, isovaleryl-, 2-methylbutyryl-, hexanoylglycine) may also be found in small, but elevated, amounts in the urine. Blood levels of C4-C6-carnitines (butyryl-, isobutyryl-, isovaleryl- and hexanoylcarnitine) may be elevated.


EE is caused by mutations in the ETHE1 gene (chromosome 19q13).

Diagnostic methods

Diagnosis depends on the clinical picture, the results of the biochemical work-up and, more recently, genotype analysis. As a large number of different disease-causing mutations have been identified, DNA sequencing of all seven exons of the ETHE1 gene is necessary for the molecular diagnosis. The diagnosis of EE due to ETHE1 mutations is clear if homozygosity (which should be confirmed by genotyping of the parents) or compound heterozygosity are present in the patient. In some cases, the urine and blood patterns identified in EE patients may resemble those seen in multiple acyl-CoA dehydrogenase deficiency (MADD or Glutaricaciduria type 2, see this term) but in others they resemble those seen in short chain acyl-CoA dehydrogenase deficiency (SCADD, see this term), where the only abnormalities seen may be elevated EMA in urine with or without blood elevation of butyrylcarnitine. It seems, at least in severe cases, that the clinical picture of recurrent petechiae, orthostatic acrocyanosis and chronic diarrhoea is specific for EE. However, more cases need to be identified before it can be determined whether milder cases of EE exist with clinical features like MADD or SCADD. In the absence of any detectable ETHE1 gene mutation, molecular analysis should include sequencing of the SCAD gene (mutations in which lead to SCADD) and, eventually, of the two electron transfer flavoprotein (ETFA and ETFB) genes and the ETFDH gene (one of which may carry mutations in patients with MADD).

Differential diagnosis

MADD and SCADD should be taken into account in the differential diagnosis of EE.

Antenatal diagnosis

Prenatal diagnosis of EE is possible in cases where the mutations on both chromosomes have been identified.

Genetic counseling

The disease is inherited in an autosomal recessive manner.

Management and treatment

Patients with EE have been treated more or less successfully with L-carnitine, riboflavin and/or Q10 supplements, as well as other vitamin therapies, which may improve energy metabolism and alleviate oxidative stress. As the function of the protein encoded by the ETHE1 gene is still not known, a more rational treatment remains to be developed.


The prognosis is generally poor: although milder chronic cases are known, most patients die before the age of ten years.

Expert reviewer(s)

  • Pr Niels GREGERSEN

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