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Disease Profile

Ethylmalonic encephalopathy

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

E88.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria; Encephalopathy, ethylmalonic; Encephalopathy, petechiae, and ethylmalonic aciduria;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary

Ethylmalonic encephalopathy (EE) causes damage to the brain, nerves, and blood vessels. Symptoms are present at birth and tend to get worse over time. These include low muscle tone, spasms of the arms and legs, seizures, and developmental delay. Blood vessel damage causes tiny red spots under the skin (petechiae) and blue discoloration in the hands and feet due to reduced blood flow (acrocyanosis). Chronic bloody diarrhea and difficulty swallowing leads to poor growth. EE is considered a lethal condition, and most people die in childhood. Ethylmalonic encephalopathy is caused by a variant in the ETHE1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on the symptoms, clinical exam, laboratory testing of blood and urine, and imaging studies of the brain. The result of genetic testing can be used to confirm the diagnosis. Treatment is focused on support and managing the symptoms.[1][2][3][4]

Symptoms

The following list includes the most common signs and symptoms in people with ethylmalonic encephalopathy. These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.

Symptoms may include:[1][4]

  • Low muscle tone (hypotonia)
  • Developmental delay
  • Intellectual impairment that gets worse over time
  • Injury to blood vessels
  • Red spots on the skin (petechiae)
  • Blue discoloration of the extremities (acrocyanosis)
  • Chronic diarrhea
  • Seizures

Symptoms of ethylmalonic encephalopathy are present from birth. The first symptom may be low muscle tone. Early development may be normal, but children with EE usually lose skills over time. Signs of blood vessel damage, such as red spots on the skin, usually appear in early childhood. People with EE develop spasms of the limbs and are often unable to walk without support. Swallowing difficulties and diarrhea lead to poor growth. Infectious illnesses can cause the neurological symptoms to get worse. Most people with EE die in childhood. EE is a variable disease and a few mild cases of this condition have been reported.[1][3]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Encephalopathy
0001298
Ethylmalonic aciduria
0003219
30%-79% of people have these symptoms
Abnormal basal ganglia MRI signal intensity
0012751
Abnormal pyramidal sign
0007256
Abnormality of extrapyramidal motor function
0002071
Acrocyanosis
Persistent blue color of hands, feet, or parts of face
0001063
Ataxia
0001251
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood

[ more ]

0002376
Diarrhea
Watery stool
0002014
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Lactic acidosis
Increased lactate in body
0003128
Neurodevelopmental delay
0012758
Petechiae
0000967
Retinal vascular tortuosity
0012841
Seizure
0001250
5%-29% of people have these symptoms
Abnormal brainstem MRI signal intensity
0012747
Percent of people who have these symptoms is not available through HPO
Abnormal retinal vascular morphology
Abnormality of retina blood vessels
0008046
Autosomal recessive inheritance
0000007
Chronic diarrhea
0002028
Cytochrome C oxidase-negative muscle fibers
0003688
Focal T2 hyperintense basal ganglia lesion
0007183
Global developmental delay
0001263
Muscular hypotonia
Low or weak muscle tone
0001252

Cause

Ethylmalonic encephalopathy is caused by the ETHE1 gene not working correctly. DNA changes known as pathogenic variants are responsible for making genes work incorrectly or sometimes, not at all.[5]

Diagnosis

Ethylmalonic encephalopathy is diagnosed based on the symptoms, clinical exam, laboratory tests of the blood and urine, and imaging studies of the brain. The results of genetic testing can help confirm the diagnosis.[1][2]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Newborn Screening

  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
  • The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.

Treatment

Treatment for ethylmalonic encephalopathy is focused on managing the symptoms. Treatment may include medications for seizures, physical therapy, and nutrition support.[3][4] 

Specialists involved in the care of someone with ethylmalonic encephalopathy may include:[1] 

  • Neurologist
  • Gastroenterologist
  • Orthopedist
  • Nutritionist
  • Physical therapist
  • Medical geneticist

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Ethylmalonic encephalopathy. This website is maintained by the National Library of Medicine.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Ethylmalonic encephalopathy. Click on the link to view a sample search on this topic.

References

  1. Di Meo I, Lamperti C, Tiranti V. 2017 Sep 21. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews. Ethylmalonic Encephalopathy. GeneReviews. Sept 21, 2017; https://www.ncbi.nlm.nih.gov/books/NBK453432.
  2. Govindaraj P, Parayil Sankaran B, Nagappa M, Arvinda HR, Deepha S, Jessiena Ponmalar JN, Sinha S, Gayathri N, Taly AB. Child Neurology: Ethylmalonic encephalopathy. Neurology. Mar 24, 2020; 94(12):e1336-e1339. https://pubmed.ncbi.nlm.nih.gov/32111695.
  3. Ersoy M, Tiranti V, Zeviani M. Ethylmalonic encephalopathy: Clinical course and therapy response in an uncommon mild case with a severe ETHE1 mutation. Mol Genet Metab Rep. Aug 28, 2020; 25:100641:https://pubmed.ncbi.nlm.nih.gov/32923369.
  4. Di Meo I, Lamperti C, Tiranti V. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches. EMBO Mol Med. Oct 2015; 7(10):1257-66. https://pubmed.ncbi.nlm.nih.gov/26194912.
  5. ENCEPHALOPATHY, ETHYLMALONIC; EE. Updated Sept. 22, 2016; https://www.omim.org/entry/602473.

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