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ACADM
acyl-CoA dehydrogenase medium chain
The ACADM gene encodes the medium-chain acyl-CoA dehydrogenase (MCAD) enzyme, which is vital for breaking down certain fats into energy within the body's cells. The ACADM gene provides instructions for creating the MCAD enzyme, a key component in cellular energy production.
ACADM is located on the short (p) arm of chromosome 1, at band 1p31.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ACADM gene, or acyl-CoA dehydrogenase medium chain, is a gene that codes for the medium-chain acyl-CoA dehydrogenase (MCAD) enzyme. This enzyme is crucial for the body's metabolic processes, specifically the breakdown of medium-chain fatty acids to produce energy.
Disruptions in ACADM gene function can lead to metabolic disorders due to the body's inability to process these fats effectively, particularly during periods of fasting or increased energy demand.
What the gene does
The ACADM gene directs the synthesis of the MCAD enzyme, which operates within the mitochondria, often referred to as the 'powerhouses' of the cell. The primary role of MCAD is in fatty acid oxidation, a multi-step biochemical pathway that metabolises fats and converts them into energy.
Specifically, the MCAD enzyme is necessary for processing medium-chain fatty acids. These fatty acids are derived from dietary intake and body fat stores, and they also result from the breakdown of larger fatty acids. Fatty acids are a significant energy source for vital organs such as the heart and muscles. During times when food intake is limited, fatty acids become an important alternative energy source for the liver and other tissues.
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Chromosome location
The ACADM gene is situated on chromosome 1, specifically at the position 1p31.1. This location refers to the short (p) arm of chromosome 1, within region 3, band 1, and sub-band 1. The gene's precise genomic address is vital for understanding its inheritance and potential associations with inherited conditions.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ACADM gene can alter the function of the MCAD enzyme, potentially leading to its reduced activity or complete absence. Over 80 distinct variants have been identified, with many resulting in single amino acid changes in the enzyme. These genetic changes can impair the body's capacity to metabolise medium-chain fatty acids.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1010A>C | p.Tyr337Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1012C>T | p.Gln338Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1034A>T | p.Asp345Val | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1040G>T | p.Gly347Val | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1042C>T | p.Arg348Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1042del | p.Arg348fs | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1045C>T | p.Arg349Ter | Pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1046G>A | p.Arg349Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1049_1055dup | p.Tyr352Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
c.1237C>A | p.Arg413Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Medium-chain acyl-coenzyme A dehydrogenase deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the ACADM gene are primarily associated with Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), an autosomal recessive metabolic disorder. This condition can also manifest as MCADD (atypical), presenting with varying severities and symptoms. Individuals with MCADD struggle to convert certain fats into energy, particularly during fasting or illness.
- MCADD (atypical)
- Medium-chain acyl-CoA dehydrogenase deficiency Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ACADM variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ACADM gene is included in several expert-curated panels within the UK's National Genomic Test Directory, as listed on PanelApp. It is a green-lighted gene for conditions such as Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic, as well as for broader categories like Acute rhabdomyolysis, Hyperammonaemia, and Undiagnosed metabolic disorders. It is also covered under the DDG2P and Likely inborn error of metabolism panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ACADM gene?
The ACADM gene provides instructions for the MCAD enzyme, which is essential for breaking down medium-chain fatty acids into energy within the body's cells, particularly in mitochondria.
What condition is most commonly associated with ACADM gene variants?
Variants in the ACADM gene are primarily associated with Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), an inherited metabolic disorder that affects the body's ability to process certain fats.
How does the MCAD enzyme contribute to energy production?
The MCAD enzyme facilitates fatty acid oxidation, a process that converts medium-chain fatty acids from food and body fat into a usable energy source for the heart, muscles, and other tissues, especially during periods of fasting.
References
- Maier EM, Gersting SW, Kemter KF. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Human molecular genetics. 2009. PMID: 19224950
- Hsu HW, Zytkovicz TH, Comeau AM. Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening. Pediatrics. 2008. PMID: 18450854
- Waddell L, Wiley V, Carpenter K. Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations. Molecular genetics and metabolism. 2006. PMID: 16291504
- Maier EM, Liebl B, Röschinger W. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Human mutation. 2005. PMID: 15832312
- Gregersen N, Andresen BS, Corydon MJ. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Human mutation. 2001. PMID: 11524729
- Wang SS, Fernhoff PM, Hannon WH. Medium chain acyl-CoA dehydrogenase deficiency human genome epidemiology review. Genetics in medicine : official journal of the American College of Medical Genetics. 1999. PMID: 11263545