U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Ethylmalonic encephalopathy(EE)

MedGen UID:
355966
Concept ID:
C1865349
Disease or Syndrome
Synonyms: EE; Encephalopathy, petechiae, and ethylmalonic aciduria; EPEMA syndrome; Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria
SNOMED CT: Ethylmalonic encephalopathy (723307008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ETHE1 (19q13.31)
 
Monarch Initiative: MONDO:0011229
OMIM®: 602473
Orphanet: ORPHA51188

Disease characteristics

Excerpted from the GeneReview: Ethylmalonic Encephalopathy
Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of children die in the first decade. [from GeneReviews]
Authors:
Ivano Di Meo  |  Costanza Lamperti  |  Valeria Tiranti   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/602473
From MedlinePlus Genetics
Ethylmalonic encephalopathy is an inherited disorder that affects several body systems, particularly the nervous system. Neurological signs and symptoms include delayed development and the loss of previously acquired skills (developmental regression), weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels (the vascular system) is also affected. Children with this disorder often develop rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy.

The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood.  https://medlineplus.gov/genetics/condition/ethylmalonic-encephalopathy

Clinical features

From HPO
Ethylmalonic aciduria
MedGen UID:
355967
Concept ID:
C1865353
Finding
The concentration of ethylmalonic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Focal T2 hyperintense basal ganglia lesion
MedGen UID:
892349
Concept ID:
C4024926
Finding
A lighter than expected T2 signal on magnetic resonance imaging (MRI) of the basal ganglia. This term refers to a localized hyperintensity affecting a particular region of the basal ganglia.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Cytochrome C oxidase-negative muscle fibers
MedGen UID:
867360
Concept ID:
C4021724
Finding
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Elevated circulating butyrylcarnitine concentration
MedGen UID:
1787414
Concept ID:
C5539599
Finding
Concentration of O-butyrylcarnitine in the blood circulation above the upper limit of normal.
Elevated circulating thiosulfate concentration
MedGen UID:
1052481
Concept ID:
CN377906
Finding
The concentration of thiosulfate in the blood circulation is above the upper limit of normal.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
Petechiae are pinpoint-sized reddish/purple spots, resembling a rash, that appear just under the skin or a mucous membrane when capillaries have ruptured and some superficial bleeding into the skin has happened. This term refers to an abnormally increased susceptibility to developing petechiae.
Acrocyanosis
MedGen UID:
65138
Concept ID:
C0221347
Finding
Bluish discoloration of the skin of the hands or feet.
Abnormal retinal vascular morphology
MedGen UID:
870311
Concept ID:
C4024753
Anatomical Abnormality
A structural abnormality of retinal vasculature.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEthylmalonic encephalopathy
Follow this link to review classifications for Ethylmalonic encephalopathy in Orphanet.

Recent clinical studies

Etiology

Frusciante MR, Signori MF, Parmeggiani B, Grings M, Pramio J, Cecatto C, de Andrade Silveira J, Aubin MR, Santos LA, Paz AH, Wajner M, Leipnitz G
Cell Biochem Biophys 2023 Dec;81(4):683-695. Epub 2023 Aug 17 doi: 10.1007/s12013-023-01161-0. PMID: 37589888
Hanaford AR, Cho YJ, Nakai H
Orphanet J Rare Dis 2022 Jun 6;17(1):217. doi: 10.1186/s13023-022-02324-7. PMID: 35668433Free PMC Article
Kožich V, Stabler S
J Nutr 2020 Oct 1;150(Suppl 1):2506S-2517S. doi: 10.1093/jn/nxaa134. PMID: 33000152
Di Meo I, Lamperti C, Tiranti V
EMBO Mol Med 2015 Oct;7(10):1257-66. doi: 10.15252/emmm.201505040. PMID: 26194912Free PMC Article
Nowaczyk MJ, Lehotay DC, Platt BA, Fisher L, Tan R, Phillips H, Clarke JT
Metabolism 1998 Jul;47(7):836-9. doi: 10.1016/s0026-0495(98)90122-6. PMID: 9667231

Diagnosis

Horton A, Hong KM, Pandithan D, Allen M, Killick C, Goergen S, Springer A, Phelan D, Marty M, Halligan R, Lee J, Pitt J, Chong B, Christodoulou J, Lunke S, Stark Z, Fahey M
Cold Spring Harb Mol Case Stud 2022 Feb;8(2) Epub 2022 Mar 24 doi: 10.1101/mcs.a006193. PMID: 35165146Free PMC Article
Lim J, Shayota BJ, Lay E, Elsea SH, Bekheirnia MR, Tessier MEM, Kralik SF, Rice GM, Soler-Alfonso C, Scaglia F
J Child Neurol 2021 Sep;36(10):841-852. Epub 2021 Apr 26 doi: 10.1177/08830738211006507. PMID: 33900143
Tao Y, Han D, Li X, Wang L, Yue L, Huang C, Lu D, Li X
Clin Chim Acta 2020 Oct;509:8-17. Epub 2020 May 30 doi: 10.1016/j.cca.2020.05.051. PMID: 32485156
Bijarnia-Mahay S, Gupta D, Shigematsu Y, Yamaguchi S, Saxena R, Verma IC
Indian Pediatr 2016 Oct 8;53(10):914-916. doi: 10.1007/s13312-016-0959-0. PMID: 27771676
Rahman S
J Inherit Metab Dis 2013 Jul;36(4):659-73. Epub 2013 May 15 doi: 10.1007/s10545-013-9614-2. PMID: 23674168

Therapy

Tam A, AlDhaheri NS, Mysore K, Tessier ME, Goss J, Fernandez LA, D'Alessandro AM, Schwoerer JS, Rice GM, Elsea SH, Scaglia F
Am J Med Genet A 2019 Jun;179(6):1015-1019. Epub 2019 Mar 12 doi: 10.1002/ajmg.a.61104. PMID: 30864297Free PMC Article
Kılıç M, Dedeoğlu Ö, Göçmen R, Kesici S, Yüksel D
Metab Brain Dis 2017 Apr;32(2):293-296. Epub 2016 Nov 9 doi: 10.1007/s11011-016-9928-5. PMID: 27830356
Tiranti V, Zeviani M
Cold Spring Harb Perspect Biol 2013 Jan 1;5(1):a011437. doi: 10.1101/cshperspect.a011437. PMID: 23284046Free PMC Article
Di Meo I, Auricchio A, Lamperti C, Burlina A, Viscomi C, Zeviani M
EMBO Mol Med 2012 Sep;4(9):1008-14. Epub 2012 Aug 20 doi: 10.1002/emmm.201201433. PMID: 22903887Free PMC Article
Nowaczyk MJ, Lehotay DC, Platt BA, Fisher L, Tan R, Phillips H, Clarke JT
Metabolism 1998 Jul;47(7):836-9. doi: 10.1016/s0026-0495(98)90122-6. PMID: 9667231

Prognosis

Olivieri G, Martinelli D, Longo D, Grimaldi C, Liccardo D, Di Meo I, Pietrobattista A, Sidorina A, Semeraro M, Dionisi-Vici C
Orphanet J Rare Dis 2021 May 19;16(1):229. doi: 10.1186/s13023-021-01867-5. PMID: 34011365Free PMC Article
Bijarnia-Mahay S, Gupta D, Shigematsu Y, Yamaguchi S, Saxena R, Verma IC
Indian Pediatr 2016 Oct 8;53(10):914-916. doi: 10.1007/s13312-016-0959-0. PMID: 27771676
Dweikat I, Naser E, Damsah N, Libdeh BA, Bakri I
Metab Brain Dis 2012 Dec;27(4):613-6. Epub 2012 May 15 doi: 10.1007/s11011-012-9313-y. PMID: 22584649
Pigeon N, Campeau PM, Cyr D, Lemieux B, Clarke JT
J Child Neurol 2009 Aug;24(8):991-6. Epub 2009 Mar 16 doi: 10.1177/0883073808331359. PMID: 19289697
Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Sewell AC, Vianey-Saban C, Gregersen N
Neuropediatrics 2007 Apr;38(2):78-82. doi: 10.1055/s-2007-984447. PMID: 17712735

Clinical prediction guides

Kožich V, Schwahn BC, Sokolová J, Křížková M, Ditroi T, Krijt J, Khalil Y, Křížek T, Vaculíková-Fantlová T, Stibůrková B, Mills P, Clayton P, Barvíková K, Blessing H, Sykut-Cegielska J, Dionisi-Vici C, Gasperini S, García-Cazorla Á, Haack TB, Honzík T, Ješina P, Kuster A, Laugwitz L, Martinelli D, Porta F, Santer R, Schwarz G, Nagy P
Redox Biol 2022 Dec;58:102517. Epub 2022 Oct 18 doi: 10.1016/j.redox.2022.102517. PMID: 36306676Free PMC Article
Tao Y, Han D, Li X, Wang L, Yue L, Huang C, Lu D, Li X
Clin Chim Acta 2020 Oct;509:8-17. Epub 2020 May 30 doi: 10.1016/j.cca.2020.05.051. PMID: 32485156
Jamroz E, Paprocka J, Adamek D, Pytel J, Szczechowska K, Grabska N, Malec M, Głuszkiewicz E, Daab M, Wodołażski A
Folia Neuropathol 2011;49(1):71-7. PMID: 21455846
Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Sewell AC, Vianey-Saban C, Gregersen N
Neuropediatrics 2007 Apr;38(2):78-82. doi: 10.1055/s-2007-984447. PMID: 17712735
Grosso S, Mostardini R, Farnetani MA, Molinelli M, Berardi R, Dionisi-Vici C, Rizzo C, Morgese G, Balestri P
J Neurol 2002 Oct;249(10):1446-50. doi: 10.1007/s00415-002-0880-4. PMID: 12382164

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C4 and C5 +/- Other Acylcarnitines, Glutaric Acidemia II (GA-II) (MADD), 2022
    • ACMG Algorithm,
      American College of Medical Genetics and Genomics, Algorithm, Glutaric Acidemia II (GA-II)/ MADD, Riboflavin Metabolism Disorder, Ethylmalonic Encephalopathy: C4 and C5 elevated +/- other elevated acylcarnitines (AC), 2022
    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C4 Acylcarnitine, Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency, 2022

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...