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Isovaleryl-CoA dehydrogenase deficiency(IVA)

MedGen UID:
82822
Concept ID:
C0268575
Disease or Syndrome
Synonyms: Isovaleric acid CoA dehydrogenase deficiency; Isovaleric acidemia; Isovaleryl CoA carboxylase deficiency; IVA; IVD deficiency
SNOMED CT: Isovaleric acid-CoA dehydrogenase deficiency (87827003); Isovaleryl-CoA dehydrogenase deficiency (87827003); Isovaleric acidemia (87827003); Isovaleric acid CoA dehydrogenase deficiency (87827003); Isovaleryl-coenzyme A dehydrogenase deficiency (87827003)
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): IVD (15q15.1)
 
Monarch Initiative: MONDO:0009475
OMIM®: 243500
Orphanet: ORPHA33

Definition

Isovaleric acidemia (IVA) is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. It can present with severe neonatal ketoacidosis leading to death, but in milder cases recurrent episodes of ketoacidosis of varying degree occur later in infancy and childhood (summary by Vockley et al., 1991). [from OMIM]

Additional description

From MedlinePlus Genetics
Isovaleric acidemia is a rare disorder in which the body is unable to properly break down a particular protein building block (amino acid). The condition is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.

Normally, the body breaks down proteins from food into smaller parts called amino acids. Amino acids can be further processed to provide energy for growth and development. People with isovaleric acidemia have inadequate levels of an enzyme that helps break down a particular amino acid called leucine.

Health problems related to isovaleric acidemia range from very mild to life-threatening. In severe cases, the features of isovaleric acidemia become apparent within a few days after birth. The initial symptoms include poor feeding, vomiting, seizures, and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including seizures, coma, and possibly death. A characteristic sign of isovaleric acidemia is a distinctive odor of sweaty feet during acute illness. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.

In other cases, the signs and symptoms of isovaleric acidemia appear during childhood and may come and go over time. Children with this condition may fail to gain weight and grow at the expected rate (failure to thrive) and often have delayed development. In these children, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), infections, or eating an increased amount of protein-rich foods.

Some people with gene mutations that cause isovaleric acidemia are asymptomatic, which means they never experience any signs or symptoms of the condition.  https://medlineplus.gov/genetics/condition/isovaleric-acidemia

Clinical features

From HPO
Hyperglycinuria
MedGen UID:
107456
Concept ID:
C0543541
Disease or Syndrome
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
Cerebellar hemorrhage
MedGen UID:
488779
Concept ID:
C0149854
Pathologic Function
Hemorrhage into the parenchyma of the cerebellum.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Bone marrow hypocellularity
MedGen UID:
383749
Concept ID:
C1855710
Finding
A reduced number of hematopoietic cells present in the bone marrow relative to marrow fat.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Ketoacidosis
MedGen UID:
67434
Concept ID:
C0220982
Disease or Syndrome
Acidosis resulting from accumulation of ketone bodies.

Professional guidelines

PubMed

David J, Chrastina P, Pešková K, Kožich V, Friedecký D, Adam T, Hlídková E, Vinohradská H, Novotná D, Hedelová M, Al Taji E, Holubová A, Skalická V, Macek M, Gaillyová R, Votava F
Cent Eur J Public Health 2019 Jun;27(2):153-159. doi: 10.21101/cejph.a5441. PMID: 31241292

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5 Acylcarnitine, Isovaleric Acidemia, 2022

American College of Medical Genetics and Genomics, Algorithm, Isovaleric Acidemia: Increased C5 (isolated), 2022

Recent clinical studies

Etiology

Magner M, Almássy Z, Gucev Z, Kieć-Wilk B, Plaiasu V, Tylki-Szymańska A, Zafeiriou D, Zaganas I, Lampe C
Orphanet J Rare Dis 2022 May 10;17(1):190. doi: 10.1186/s13023-022-02332-7. PMID: 35538504Free PMC Article
Hawkes N
BMJ 2016 Mar 24;352:i1680. doi: 10.1136/bmj.i1680. PMID: 27012884
Van Calcar SC, Baker MW, Williams P, Jones SA, Xiong B, Thao MC, Lee S, Yang MK, Rice GM, Rhead W, Vockley J, Hoffman G, Durkin MS
Mol Genet Metab 2013 Sep-Oct;110(1-2):111-5. Epub 2013 Apr 15 doi: 10.1016/j.ymgme.2013.03.021. PMID: 23712021Free PMC Article
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Vockley J, Ensenauer R
Am J Med Genet C Semin Med Genet 2006 May 15;142C(2):95-103. doi: 10.1002/ajmg.c.30089. PMID: 16602101Free PMC Article

Diagnosis

D'Annibale OM, Koppes EA, Alodaib AN, Kochersperger C, Karunanidhi A, Mohsen AW, Vockley J
Mol Genet Metab 2021 Sep-Oct;134(1-2):29-36. Epub 2021 Aug 30 doi: 10.1016/j.ymgme.2021.08.012. PMID: 34535384Free PMC Article
Hawkes N
BMJ 2016 Mar 24;352:i1680. doi: 10.1136/bmj.i1680. PMID: 27012884
Vockley J, Ensenauer R
Am J Med Genet C Semin Med Genet 2006 May 15;142C(2):95-103. doi: 10.1002/ajmg.c.30089. PMID: 16602101Free PMC Article
Gibson KM, Lee CF, Hoffmann GF
Eur J Pediatr 1994;153(7 Suppl 1):S62-7. doi: 10.1007/BF02138780. PMID: 7957389
Gregersen N
Scand J Clin Lab Invest Suppl 1985;174:1-60. PMID: 3892650

Therapy

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Mol Genet Metab 2014 Jan;111(1):52-4. Epub 2013 Nov 19 doi: 10.1016/j.ymgme.2013.11.005. PMID: 24291264
Van Calcar SC, Baker MW, Williams P, Jones SA, Xiong B, Thao MC, Lee S, Yang MK, Rice GM, Rhead W, Vockley J, Hoffman G, Durkin MS
Mol Genet Metab 2013 Sep-Oct;110(1-2):111-5. Epub 2013 Apr 15 doi: 10.1016/j.ymgme.2013.03.021. PMID: 23712021Free PMC Article
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Wei CC, Lin WD, Tsai FJ, Wu JY, Peng CT, Tsai CH
Acta Paediatr Taiwan 2004 Jul-Aug;45(4):236-8. PMID: 15624372

Prognosis

Mütze U, Henze L, Gleich F, Lindner M, Grünert SC, Spiekerkoetter U, Santer R, Blessing H, Thimm E, Ensenauer R, Weigel J, Beblo S, Arélin M, Hennermann JB, Marquardt T, Marquardt I, Freisinger P, Krämer J, Dieckmann A, Weinhold N, Keller M, Walter M, Schiergens KA, Maier EM, Hoffmann GF, Garbade SF, Kölker S
J Inherit Metab Dis 2021 Jul;44(4):857-870. Epub 2021 Feb 7 doi: 10.1002/jimd.12364. PMID: 33496032
Lin Y, Chen D, Peng W, Wang K, Lin W, Zhuang J, Zheng Z, Li M, Fu Q
Clin Chim Acta 2020 Oct;509:25-29. Epub 2020 Jun 4 doi: 10.1016/j.cca.2020.06.010. PMID: 32505769
Zaki OK, Priya Doss C G, Ali SA, Murad GG, Elashi SA, Ebnou MSA, Kumar D T, Khalifa O, Gamal R, El Abd HSA, Nasr BN, Zayed H
Hum Mol Genet 2017 Aug 15;26(16):3105-3115. doi: 10.1093/hmg/ddx195. PMID: 28535199
Couce ML, Aldamiz-Echevarría L, Bueno MA, Barros P, Belanger-Quintana A, Blasco J, García-Silva MT, Márquez-Armenteros AM, Vitoria I, Vives I, Navarrete R, Fernández-Marmiesse A, Pérez B, Pérez-Cerdá C
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Urano K, Daimon T, Banno Y, Mita K, Terada T, Shimizu K, Katsuma S, Shimada T
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Clinical prediction guides

Lin Y, Chen D, Peng W, Wang K, Lin W, Zhuang J, Zheng Z, Li M, Fu Q
Clin Chim Acta 2020 Oct;509:25-29. Epub 2020 Jun 4 doi: 10.1016/j.cca.2020.06.010. PMID: 32505769
David J, Chrastina P, Pešková K, Kožich V, Friedecký D, Adam T, Hlídková E, Vinohradská H, Novotná D, Hedelová M, Al Taji E, Holubová A, Skalická V, Macek M, Gaillyová R, Votava F
Cent Eur J Public Health 2019 Jun;27(2):153-159. doi: 10.21101/cejph.a5441. PMID: 31241292
Dercksen M, Kulik W, Mienie LJ, Reinecke CJ, Wanders RJ, Duran M
Eur J Clin Nutr 2016 Oct;70(10):1123-1126. Epub 2016 Jun 22 doi: 10.1038/ejcn.2016.100. PMID: 27329611
Urano K, Daimon T, Banno Y, Mita K, Terada T, Shimizu K, Katsuma S, Shimada T
FEBS J 2010 Nov;277(21):4452-63. Epub 2010 Oct 1 doi: 10.1111/j.1742-4658.2010.07832.x. PMID: 21040472
Rhead WJ, Tanaka K
Proc Natl Acad Sci U S A 1980 Jan;77(1):580-3. doi: 10.1073/pnas.77.1.580. PMID: 6928646Free PMC Article

Recent systematic reviews

Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H
J Inherit Metab Dis 2014 Nov;37(6):889-98. Epub 2014 Jul 15 doi: 10.1007/s10545-014-9729-0. PMID: 25022222

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.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5 Acylcarnitine, Isovaleric Acidemia, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Isovaleric Acidemia: Increased C5 (isolated), 2022

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