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Deficiency of 2-methylbutyryl-CoA dehydrogenase(ACADSB)

MedGen UID:
355324
Concept ID:
C1864912
Disease or Syndrome
Synonyms: 2-methylbutyric aciduria; 2-methylbutyryl-CoA dehydrogenase deficiency; 2-methylbutyrylglycinuria; ACADSB; Acyl-CoA Dehydrogenase, Short/Branched Chain Deficiency; SBCAD deficiency; Short branched-chain acyl-CoA dehydrogenase deficiency
SNOMED CT: Deficiency of 2-methylbutyryl-CoA dehydrogenase (444838008); Deficiency of 2-methylbutyryl-coenzyme A dehydrogenase (444838008)
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): ACADSB (10q26.13)
 
HPO: HP:0020147
Monarch Initiative: MONDO:0012392
OMIM®: 610006
Orphanet: ORPHA79157

Definition

2-Methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (Sass et al., 2008). [from OMIM]

Additional description

From MedlinePlus Genetics
Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency (also known as 2-methylbutyryl-CoA dehydrogenase deficiency) is a rare disorder in which the body is unable to process proteins properly. Normally, the body breaks down proteins from food into smaller parts called amino acids. Amino acids can be further processed to provide energy for the body. People with SBCAD deficiency cannot process a particular amino acid called isoleucine.

Most cases of SBCAD deficiency are detected shortly after birth by newborn screening, which identifies abnormal levels of certain compounds in the blood. In individuals with this condition, a compound called 2-methylbutyryl carnitine is elevated in the blood and another called 2-methylbutyrylglycine is elevated in the urine (2-methylbutyrylglycinuria).

Most people with SBCAD deficiency have no health problems related to the disorder. A small percentage of affected individuals develop signs and symptoms of the condition, which can begin soon after birth or later in childhood. The initial symptoms often include poor feeding, lack of energy (lethargy), vomiting, and irritability. These symptoms sometimes progress to serious health problems such as difficulty breathing, seizures, and coma. Additional problems can include poor growth, vision impairment, learning disabilities, muscle weakness, and delays in motor skills such as standing and walking.

It is unclear why some people with SBCAD deficiency develop health problems and others do not. Doctors suggest that in some cases, signs and symptoms may be triggered by infections, prolonged periods without food (fasting), or an increased amount of protein-rich foods in the diet.  https://medlineplus.gov/genetics/condition/short-branched-chain-acyl-coa-dehydrogenase-deficiency

Clinical features

From HPO
2-ethylhydracylic aciduria
MedGen UID:
1780879
Concept ID:
C5539431
Finding
An increased concentration of 2-ethylhydracylic acid in the urine.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
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.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
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.
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Apneic episodes in infancy
MedGen UID:
814310
Concept ID:
C3807980
Finding
Recurrent episodes of apnea occurring during infancy.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Hypothermia
MedGen UID:
5720
Concept ID:
C0020672
Finding
Reduced body temperature due to failed thermoregulation.
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVDeficiency of 2-methylbutyryl-CoA dehydrogenase
Follow this link to review classifications for Deficiency of 2-methylbutyryl-CoA dehydrogenase in Orphanet.

Recent clinical studies

Etiology

Knerr I, Weinhold N, Vockley J, Gibson KM
J Inherit Metab Dis 2012 Jan;35(1):29-40. Epub 2011 Feb 3 doi: 10.1007/s10545-010-9269-1. PMID: 21290185Free PMC Article
van Calcar SC, Gleason LA, Lindh H, Hoffman G, Rhead W, Vockley G, Wolff JA, Durkin MS
WMJ 2007 Feb;106(1):12-5. PMID: 17393751
Matern D, He M, Berry SA, Rinaldo P, Whitley CB, Madsen PP, van Calcar SC, Lussky RC, Andresen BS, Wolff JA, Vockley J
Pediatrics 2003 Jul;112(1 Pt 1):74-8. doi: 10.1542/peds.112.1.74. PMID: 12837870
Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD, Linck L, Pohowalla P, Sacks M, Kiss D, Rinaldo P, Vockley J
Pediatr Res 2000 Jun;47(6):830-3. doi: 10.1203/00006450-200006000-00025. PMID: 10832746
Gregersen N
J Inherit Metab Dis 1985;8 Suppl 1:65-9. doi: 10.1007/BF01800662. PMID: 3930843

Diagnosis

Knerr I, Weinhold N, Vockley J, Gibson KM
J Inherit Metab Dis 2012 Jan;35(1):29-40. Epub 2011 Feb 3 doi: 10.1007/s10545-010-9269-1. PMID: 21290185Free PMC Article
Sass JO, Ensenauer R, Röschinger W, Reich H, Steuerwald U, Schirrmacher O, Engel K, Häberle J, Andresen BS, Mégarbané A, Lehnert W, Zschocke J
Mol Genet Metab 2008 Jan;93(1):30-5. Epub 2007 Oct 22 doi: 10.1016/j.ymgme.2007.09.002. PMID: 17945527
van Calcar SC, Gleason LA, Lindh H, Hoffman G, Rhead W, Vockley G, Wolff JA, Durkin MS
WMJ 2007 Feb;106(1):12-5. PMID: 17393751
Matern D, He M, Berry SA, Rinaldo P, Whitley CB, Madsen PP, van Calcar SC, Lussky RC, Andresen BS, Wolff JA, Vockley J
Pediatrics 2003 Jul;112(1 Pt 1):74-8. doi: 10.1542/peds.112.1.74. PMID: 12837870
Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD, Linck L, Pohowalla P, Sacks M, Kiss D, Rinaldo P, Vockley J
Pediatr Res 2000 Jun;47(6):830-3. doi: 10.1203/00006450-200006000-00025. PMID: 10832746

Therapy

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
Sass JO, Ensenauer R, Röschinger W, Reich H, Steuerwald U, Schirrmacher O, Engel K, Häberle J, Andresen BS, Mégarbané A, Lehnert W, Zschocke J
Mol Genet Metab 2008 Jan;93(1):30-5. Epub 2007 Oct 22 doi: 10.1016/j.ymgme.2007.09.002. PMID: 17945527
Matern D, He M, Berry SA, Rinaldo P, Whitley CB, Madsen PP, van Calcar SC, Lussky RC, Andresen BS, Wolff JA, Vockley J
Pediatrics 2003 Jul;112(1 Pt 1):74-8. doi: 10.1542/peds.112.1.74. PMID: 12837870
Gregersen N
J Inherit Metab Dis 1985;8 Suppl 1:65-9. doi: 10.1007/BF01800662. PMID: 3930843

Prognosis

Porta F, Chiesa N, Martinelli D, Spada M
J Pediatr Endocrinol Metab 2019 Feb 25;32(2):101-108. doi: 10.1515/jpem-2018-0311. PMID: 30730842
Nguyen TV, Andresen BS, Corydon TJ, Ghisla S, Abd-El Razik N, Mohsen AW, Cederbaum SD, Roe DS, Roe CR, Lench NJ, Vockley J
Mol Genet Metab 2002 Sep-Oct;77(1-2):68-79. doi: 10.1016/s1096-7192(02)00152-x. PMID: 12359132

Clinical prediction guides

McCalley S, Pirman D, Clasquin M, Johnson K, Jin S, Vockley J
Mol Genet Metab 2019 Sep-Oct;128(1-2):57-61. Epub 2019 May 21 doi: 10.1016/j.ymgme.2019.05.008. PMID: 31133529Free PMC Article
Porta F, Chiesa N, Martinelli D, Spada M
J Pediatr Endocrinol Metab 2019 Feb 25;32(2):101-108. doi: 10.1515/jpem-2018-0311. PMID: 30730842
Nguyen TV, Andresen BS, Corydon TJ, Ghisla S, Abd-El Razik N, Mohsen AW, Cederbaum SD, Roe DS, Roe CR, Lench NJ, Vockley J
Mol Genet Metab 2002 Sep-Oct;77(1-2):68-79. doi: 10.1016/s1096-7192(02)00152-x. PMID: 12359132
Ensenauer R, Niederhoff H, Ruiter JP, Wanders RJ, Schwab KO, Brandis M, Lehnert W
Ann Neurol 2002 May;51(5):656-9. doi: 10.1002/ana.10169. PMID: 12112118

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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