SNOMEDCT: 723307008; ORPHA: 51188; DO: 0060640;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.31 | Ethylmalonic encephalopathy | 602473 | Autosomal recessive | 3 | ETHE1 | 608451 |
A number sign (#) is used with this entry because of evidence that ethylmalonic encephalopathy (EE) is caused by homozygous or compound heterozygous mutation in the ETHE1 gene (608451), which encodes a mitochondrial matrix protein, on chromosome 19q13.
Ethylmalonic encephalopathy (EE) is an autosomal recessive severe metabolic disorder of infancy affecting the brain, gastrointestinal tract, and peripheral vessels. The disorder is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Brain MRI shows necrotic lesions in deep gray matter structures. Death usually occurs in the first decade of life (summary by Drousiotou et al., 2011).
Burlina et al. (1991) first described ethylmalonic encephalopathy as a syndrome characterized by developmental delay, acrocyanosis, petechiae, and chronic diarrhea. Laboratory studies showed ethylmalonic and methylsuccinic aciduria and lactic acidemia. However, in vitro activities of short chain acyl-CoA dehydrogenase (SCAD; 606885) and 2-methyl-branched chain acyl-CoA dehydrogenase, 2 enzymes whose deficiencies could theoretically produce the biochemical findings observed in ethylmalonic encephalopathy, were found to be normal (Burlina et al., 1994).
Nowaczyk et al. (1998) reported the cases of 2 sibs with ethylmalonic encephalopathy and central nervous system malformations. The girl had primary tethered cord. Her younger brother, who was evaluated at the age of 4 years because of a similar phenotype (episodic ataxia, chronic diarrhea, and acrocyanosis), had cerebellar tonsillar ectopia (Chiari I malformation).
Tiranti et al. (2004) stated that since the initial report no more than 30 cases of ethylmalonic encephalopathy had been described worldwide, leading to the assumption that the disorder is very rare. However, the actual incidence of the condition may be significantly underestimated because the biochemical phenotype may be incorrectly attributed to other metabolic disorders.
Drousiotou et al. (2011) reported 3 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy. The first patient presented at age 2.5 months with feeding difficulties, failure to thrive, petechiae, and ecchymosis. She was floppy with severe head lag and microcephaly, and showed poor responses to auditory and visual stimuli. Deep tendon reflexes were exaggerated, and there was sustained clonus and bilateral Babinski sign. She subsequently developed chronic diarrhea and seizures. Brain MRI revealed multiple bilateral loci of high intensity in the basal ganglia on T2-weighted images. She showed neurologic regression and was 5.5 years old at the time of the report. Her older brother died at age 6 months of a presumably similar disorder. Ultrasound of the brain showed hyperechogenicity of gyri and sulci. No tissues were available for confirmation of diagnosis. A girl from a second family was born prematurely at 36 weeks' gestation and presented at age 6 months with feeding difficulties, hypotonia, and global developmental delay. She later developed diarrhea, petechiae, ecchymosis, and seizures, and brain MRI showed abnormal signals in the basal ganglia and thinning of the corpus callosum. She died at age 8 months from cardiopulmonary arrest. Laboratory studies of all 3 patients showed increased serum lactate and butyrylcarnitine, and increased urinary ethylmalonic acid, methylsuccinate, and thiosulfate. Western blot analysis from 2 patients showed complete absence of the ETHE1 protein.
Pigeon et al. (2009) described a pair of monochorionic dichorionic twin sisters with EE. Both patients were born in the breech position and had severe neonatal hyperbilirubinemia. Both presented with psychomotor delay at 15 months of age. Patient 1 had truncal hypotonia and progressive pyramidal symptoms with dystonia and spasticity. During an episode of gastroenteritis at 3.5 years of age, she developed status epilepticus and decreased consciousness. At 10 years of age, she had severely impaired intellectual development, a pyramidal syndrome affecting all 4 limbs, and pseudobulbar palsy. Patient 2 had mild metabolic acidosis during an episode of gastroenteritis at 3.5 years of age. At 10 years of age, she had truncal hypotonia, scoliosis, and mildly to moderately impaired intellectual development. Laboratory testing showed increased urine ethylmalonic acid in both patients.
Kitzler et al. (2019) reported a 19-year-old man with EE who presented at 10 years of age with a long-standing history of spastic paraplegia, dysarthria, and Arnold-Chiari malformation. At 16 years of age, he developed acute trismus and worsening spasticity in the setting of an upper respiratory tract infection. Laboratory testing at that time showed elevation of C4 carnitine and moderately elevated ethylmalonic acid on urine organic acids. Brain MRI showed abnormal signal in the basal ganglia and cerebellum, and MRS showed a corresponding lactate peak. He presented again at 17 years of age with metabolic decompensation, encephalopathy, focal seizures, and fever. Laboratory testing showed elevated levels of lactate, thiosulfate, and acylcarnitines C4 and C5.
Govindaraj et al. (2020) reported a patient with EE who presented at 7 months of age with emesis, altered consciousness, seizures, developmental regression, and hyperammonemia. A brain MRI showed abnormal signal in the dorsal pons. He gradually recovered after this episode, but starting at 3 years and 10 months of age, he had regression of all developmental domains. At 52 months of age, he had contractures, spasticity, dystonia, and chorea.
Kashima et al. (2023) reported a boy with EE who presented at 19 months of age with developmental delay, mild hyperammonemia, and a wide-based gait. Laboratory testing showed elevated C4 acylcarnitine and a small amount of ethylmalonic acid. At 3 years and 5 months of age, he had abnormal speech articulation and dystonia. A brain MRI was normal. At 4 years and 8 months of age, he did not have spasticity or dystonia and had improved speech articulation.
Platt et al. (2023) described clinical features of 70 patients with ethylmalonic encephalopathy, including their 2 patients and 68 patients identified through a literature search. Symptom onset ranged from 1 day to 192 months of age, with first symptoms including diarrhea, developmental delay, hypotonia, petechiae, acrocyanosis, poor feeding, spastic paraparesis, seizure, and/or trismus. Among the 70 patients, 67 had psychomotor retardation, 57 had hypotonia, 57 had developmental delay, 53 had pyramidal signs, 28 had seizures, 27 had spastic paraparesis, 16 had episodic coma, and 17 had dystonia. Other common symptoms included gastrointestinal symptoms, such as failure to thrive and chronic diarrhea, and vascular symptoms, such as petechiae and acrocyanosis. Notably, patients with a relatively milder phenotype compared to those with a more severe phenotype had lower ethylmalonic acid levels and lower C4 acylcarnitine levels.
Viscomi et al. (2010) treated a 29-month-old Italian boy with ethylmalonic encephalopathy with metronidazole and N-acetylcysteine, a precursor of sulfide-buffering glutathione. The therapy was designed to act against accumulation of toxic hydrogen sulfide. Over the next 8 months, the patient showed increased body weight, a decrease and then disappearance of diarrhea, petechiae, and acrocyanosis, and marked neurologic improvement, with decreased seizures, less severe hypotonia, reversion of brain atrophy, and a reduction in leukodystrophy, although lesions in the neostriatum become more evident. Biochemical abnormalities also lessened. Treatment of 4 additional patients showed similar clinical, biochemical, and MRI improvements. The clinical treatment was performed after Viscomi et al. (2010) obtained favorable results in an Ethe1 -/- mouse model.
Kitzler et al. (2019) reported a patient with EE who presented at 17 years of age with metabolic decompensation, encephalopathy, focal seizures, and fever. Laboratory testing showed elevated levels of lactate, thiosulfate, and acylcarnitines C4 and C5. He was treated with N-acetylcysteine, metronidazole, and continuous renal replacement therapy, which resulted in improved metabolic and clinical status.
The transmission pattern of EE in the families studied by Tiranti et al. (2004) was consistent with autosomal recessive inheritance.
By a combination of homozygosity mapping, integration of physical and functional genomic datasets, and mutational screening, Tiranti et al. (2004) identified the ETHE1 gene (608451) as the site of mutations causing EE. They demonstrated that the ETHE1 protein is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.
In 14 patients with ethylmalonic encephalopathy, Mineri et al. (2008) identified homozygosity for mutations in the ETHE1 gene (see, e.g., 608451.0006 and 608451.0007). At the time of the report, 11 patients were deceased; age of death ranged from 18 months to 3 years. Three patients were alive at 6 months, 7 years, and 13 years, respectively.
In 2 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy, Drousiotou et al. (2011) identified 2 different mutations in the ETHE1 gene (608451.0007 and 608451.0008). One was compound heterozygous for the mutations, whereas the other was homozygous for 1 of the mutations.
Pigeon et al. (2009) identified compound heterozygous mutations in the ETHE1 gene (L185R, 608451.0008 and Q27K, 608451.0009) in a pair of Yugoslavian identical twins with ethylmalonic encephalopathy. Functional studies in patient cells were not performed.
Kitzler et al. (2019) identified homozygosity for the Q27K mutation in the ETHE1 gene in a 19-year-old patient with ethylmalonic encephalopathy. The mutation was identified by Sanger sequencing of the gene, and both parents were shown to be mutation carriers. Functional studies in patient cells were not performed.
Govindaraj et al. (2020) identified a homozygous mutation (D165H; 608451.0010) in the ETHE1 gene in an Indian boy with ethylmalonic encephalopathy. The mutation was identified by whole-exome sequencing. Respiratory chain activity testing in patient muscle demonstrated an isolated defect of complex IV activity. ETHE1 protein was reduced in patient muscle tissue, as were proteins associated with respiratory chain complexes I, II, and IV.
In a 4-year-old boy with ethylmalonic encephalopathy, Kashima et al. (2023) identified a homozygous mutation in the ETHE1 gene (D196N; 608451.0011). The mutation was identified by whole-exome sequencing. Functional studies in patient cells were not performed.
Platt et al. (2023) reviewed the biallelic mutations that had been identified in the ETHE1 gene in 45 patients with ethylmalonic encephalopathy. Thirty-two patients had homozygous mutations, and 13 patients had compound heterozygous mutations. Thirty individual mutations were identified, with the most common being R163Q, deletion of exon 4, and R163W.
In a review of clinical features and ETHE1 mutations identified in 70 patients with EE, Platt et al. (2023) noted that a milder clinical phenotype was associated with homozygosity for the R163W (608451.0001), R163Q, and Q27K (608451.0009) mutations and compound heterozygosity for the Q27K and L185R (608451.0008) mutations.
With few exceptions, reported patients with ethylmalonic encephalopathy have been of Mediterranean (Garcia-Silva et al., 1997; Grosso et al., 2002) or Arab (Ozand et al., 1994) extraction.
Tiranti et al. (2009) found that Ethe1-null mice developed the cardinal features of ethylmalonic encephalopathy, including poor growth, reduced motor activity, early death, low cytochrome c oxidase (COX) in muscle and brain, and increased urinary excretion of ethylmalonic acid. Both mutant mice and humans with the disorder excreted massive amounts of thiosulfate in the urine, and there was an accumulation of thiosulfate and hydrogen sulfide (H2S) in mutant mouse tissue. Hydrogen sulfide is powerful inhibitor of COX and short-chain fatty acid oxidation, and has vasoactive and vasotoxic effects. The findings suggested that ethylmalonic encephalopathy is a disease associated with impaired catabolism of inorganic sulfur leading to accumulation of hydrogen sulfide in key tissues. The toxic effects of this accumulation can account for several features, including ethylmalonic aciduria, COX deficiency, microangiopathy, acrocyanosis, and chronic diarrhea. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1-null mice, but it was markedly increased by ETHE1 overexpression in HeLa cells and E. coli. These findings indicated that ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.
Burlina, A. B., Dionisi-Vici, C., Bennett, M. J., Gibson, K. M., Servidei, S., Bertini, E., Hale, D. E., Schmidt-Sommerfeld, E., Sabetta, G., Zacchello, F., Rinaldo, P. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. J. Pediat. 124: 79-86, 1994. [PubMed: 8283379] [Full Text: https://doi.org/10.1016/s0022-3476(94)70257-8]
Burlina, A., Zacchello, F., Dionisi-Vici, C., Bertini, E., Sabetta, G., Bennett, M. J., Hale, D. E., Schmidt-Sommerfeld, E., Rinaldo, P. New clinical phenotype of branched-chain acyl-CoA oxidation defect. (Letter) Lancet 338: 1522-1523, 1991. [PubMed: 1683940] [Full Text: https://doi.org/10.1016/0140-6736(91)92338-3]
Drousiotou, A., DiMeo, I., Mineri, R., Georgiou, T., Stylianidou, G., Tiranti, V. Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches. Clin. Genet. 79: 385-390, 2011. [PubMed: 20528888] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01457.x]
Garcia-Silva, M. T., Ribes, A., Campos, Y., Garavaglia, B., Arenas, J. Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria. Pediat. Neurol. 17: 165-170, 1997. [PubMed: 9367300] [Full Text: https://doi.org/10.1016/s0887-8994(97)00048-9]
Govindaraj, P., Parayil Sankaran, B., Nagappa, M., Arvinda, H. R., Deepha, S., Jessiena Ponmalar, J. N., Sinha, S., Gayathri, N., Taly, A. B. Child neurology: ethylmalonic encephalopathy. Neurology 94: e1336-e1339, 2020. [PubMed: 32111695] [Full Text: https://doi.org/10.1212/WNL.0000000000009144]
Grosso, S., Mostardini, R., Farnetani, M. A., Molinelli, M., Berardi, R., Dionisi-Vici, C., Rizzo, C., Morgese, G., Balestri, P. Ethylmalonic encephalopathy: further clinical and neuroradiological characterization. J. Neurol. 249: 1446-1450, 2002. [PubMed: 12382164] [Full Text: https://doi.org/10.1007/s00415-002-0880-4]
Kashima, D. T., Sloan-Heggen, C. M., Gottlieb-Smith, R. J., Barone Pritchard, A. An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant. Am. J. Med. Genet. 191A: 1614-1618, 2023. [PubMed: 36891747] [Full Text: https://doi.org/10.1002/ajmg.a.63176]
Kitzler, T. M., Gupta, I. R., Osterman, B., Poulin, C., Trakadis, Y., Waters, P. J., Buhas, D. C. Acute and chronic management in an atypical case of ethylmalonic encephalopathy. JIMD Rep. 45: 57-63, 2019. [PubMed: 30349987] [Full Text: https://doi.org/10.1007/8904_2018_136]
Mineri, R., Rimoldi, M., Burlina, A. B., Koskull, S., Perletti, C., Heese, B., von Dobeln, U., Mereghetti, P., Di Meo, I., Invernizzi, F., Zeviani, M., Uziel, G., Tiranti, V. Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. (Letter) J. Med. Genet. 45: 473-478, 2008. [PubMed: 18593870] [Full Text: https://doi.org/10.1136/jmg.2008.058271]
Nowaczyk, M. J. M., Blaser, S. I., Clarke, J. T. R. Central nervous system malformations in ethylmalonic encephalopathy. Am. J. Med. Genet. 75: 292-296, 1998. [PubMed: 9475600]
Ozand, P. T., Rashed, M., Millington, D. S., Sakati, N., Hazzaa, S., Rahbeeni, Z., Al Odaib, A., Youssef, N., Mazrou, A., Gascon, G. G., Brismar, J. Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy. Brain Dev. 16 (suppl.): 12-22, 1994. [PubMed: 7726376] [Full Text: https://doi.org/10.1016/0387-7604(94)90092-2]
Pigeon, N., Campeau, P. M., Cyr, D., Lemieux, B., Clarke, J. T. Clinical heterogeneity in ethylmalonic encephalopathy. J. Child Neurol 24: 991-996, 2009. [PubMed: 19289697] [Full Text: https://doi.org/10.1177/0883073808331359]
Platt, I., Bisgin, A., Kilavuz, S. Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype. Neurol. Sci. 44: 3827-3852, 2023. [PubMed: 37458841] [Full Text: https://doi.org/10.1007/s10072-023-06904-8]
Tiranti, V., D'Adamo, P., Briem, E., Ferrari, G., Mineri, R., Lamantea, E., Mandel, H., Balestri, P., Garcia-Silva, M.-T., Vollmer, B., Rinaldo, P., Hahn, S. H., Leonard, J., Rahman, S., Dionisi-Vici, C., Garavaglia, B., Gasparini, P., Zeviani, M. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am. J. Hum. Genet. 74: 239-252, 2004. [PubMed: 14732903] [Full Text: https://doi.org/10.1086/381653]
Tiranti, V., Viscomi, C., Hildebrandt, T., Di Meo, I., Mineri, R., Tiveron, C., Levitt, M. D., Prelle, A., Fagiolari, G., Rimoldi, M., Zeviani, M. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nature Med. 15: 200-205, 2009. Note: Erratum: Nature Med. 15: 220 only, 2009. [PubMed: 19136963] [Full Text: https://doi.org/10.1038/nm.1907]
Viscomi, C., Burlina, A. B., Dweikat, I., Savoiardo, M., Lamperti, C., Hildebrandt, T., Tiranti, V., Zeviani, M. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nature Med. 16: 869-871, 2010. [PubMed: 20657580] [Full Text: https://doi.org/10.1038/nm.2188]