Ethylmalonic encephalopathy (ORPHA:51188)
A rare, early-onset, progressive neurologic disease characterized by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities.
Epidemiology
More than 70 cases have been described in the literature so far.
Clinical description
The disease manifests at birth or in the first few months of life with neurological, intestinal and vascular manifestations. Neurological symptoms include progressive encephalopathy, developmental delay, hypotonia, seizures and movement disorders. MRI abnormalities include symmetric patchy T2-weighted signals in the basal ganglia, periventricular white matter and dentate nuclei, brain stem, and cerebellar white matter. In some instances, cortical atrophy and diffuse leukoencephalopathy are present. Common gastrointestinal signs are chronic hemorrhagic diarrhea and failure to thrive. Vascular lesions include petechial purpura and orthostatic acrocyanosis. Spastic tetraplegia may be present. In addition to increased excretion of EMA, methylsuccinic acid, thiosulphate and C4-C6-acylglycines (isobutyryl-, isovaleryl-, 2-methylbutyryl-, hexanoylglycine) may also be found in small, but elevated, amounts in the urine. Blood levels of lactic acid and C4-C5-acylcarnitines may be elevated.
Etiology
EE is inherited in an autosomal recessive manner and is caused by variants of the ETHE1 gene (chromosome 19q13), encoding a mitochondrial sulfur dioxygenase (SDO) involved in the catabolic oxidation of hydrogen sulfide (H2S) to sulfate.
Diagnostic methods
Diagnosis is based on clinical examination, urinalysis, blood test, brain MRI and genetic analysis. As a large number of different disease-causing variants 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 variants is clear if homozygosity (which should be confirmed by genotyping of the parents) or compound heterozygosity are present in the patient.
Differential diagnosis
In some cases, the urine and blood patterns identified in EE patients may resemble those seen in multiple acyl-CoA dehydrogenase deficiency (MADD or glutaric aciduria type 2) but in others they resemble those seen in short chain acyl-CoA dehydrogenase deficiency (SCADD), where the only abnormalities seen may be elevated EMA in urine with or without blood elevation of butyryl-carnitine. It seems, at least in severe cases, that the clinical picture of recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea 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 variant, molecular analysis should include sequencing of the SCAD gene (for variants 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 variants in patients with MADD).
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
At the moment, no treatment approved by the FDA or EMA exists. Treatment is primarily supportive including antispastic medications, muscle relaxants, and anti-seizure medication. L-carnitine, riboflavin and/or Q10 supplements, as well as other vitamin therapies, may improve energy metabolism and alleviate oxidative stress. N-acetylcysteine (NAC) in combination with metronidazole are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE. NAC, a cell-permeable precursor of glutathione, is the physiologic acceptors of the sulfur atom of hydrogen sulfide (H2S), which has deficient clearance in persons with EE. Metronidazole is an anaerobic bactericide, which can reduce the sulfide-producing bacterial load in the large intestine. Liver transplantation has been proposed and used in few cases with the aim to restore the liver ability to scavenge the most of the circulating H2S from intestinal blood.
Prognosis
The prognosis is generally poor: although milder chronic cases are known, most patients die before the age of 10 years.

                            Last update: 
                            July 2024


                            - Expert reviewer(s): 
                            Dr Ivano DI MEO  - Dr Valeria TIRANTI | EURO-NMD*


                                * European Reference Network