Ethylmalonic encephalopathy

Title

Other Names:

Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria; Encephalopathy, ethylmalonic; Encephalopathy, petechiae, and ethylmalonic aciduria; Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria; Encephalopathy, ethylmalonic; Encephalopathy, petechiae, and ethylmalonic aciduria; EPEMA syndrome; EME See More

Categories:

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary 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]

Last updated: 10/7/2020

Symptoms 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]

Last updated: 10/7/2020

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.

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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

Showing of 25 |

Do you have more information about symptoms of this disease? We want to hear from you.

Last updated: 2/1/2021

Cause 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]

Last updated: 10/7/2020

Inheritance Inheritance

Ethylmalonic encephalopathy is inherited in an autosomal recessive pattern.^[5] All individuals inherit two copies of each gene. Autosomal means the gene is found on one of the numbered chromosomes found in both sexes. Recessive means that both copies of the responsible gene must be altered to have the condition.

People with autosomal recessive conditions inherit one alteration from each of their parents. The parents, who each have one gene alteration, are known as carriers. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, there is a 25% (1 in 4) chance to have a child with the condition.

Last updated: 10/7/2020

Diagnosis 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]

Last updated: 10/7/2020

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

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

Last updated: 10/7/2020

Statistics Statistics

There have been less than 100 cases of ethylmalonic encephalopathy reported in the medical literature. The exact number of people with this condition in unknown.^[1]

Last updated: 10/7/2020

Do you have updated information on this disease? We want to hear from you.

Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Related Diseases Related Diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
MADD and SCADD should be taken into account in the differential diagnosis of EE. Visit the Orphanet disease page for more information.

Learn More 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.

GARD Answers GARD Answers

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

Have a question? Contact a GARD Information Specialist.

References References

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.
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.
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.
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.
ENCEPHALOPATHY, ETHYLMALONIC; EE. Updated Sept. 22, 2016; https://www.omim.org/entry/602473.