3-Methylcrotonyl-CoA carboxylase deficiency

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3-Methylcrotonyl-CoA carboxylase deficiency
Other names3MCC deficiency, 3-methylcrotonylglycinuria, MCC deficiency, MCCD
Methylcrotonyl coenzyme A.svg
Skeletal formula of methylcrotonyl coenzyme A
Specialty Medical genetics

3-Methylcrotonyl-CoA carboxylase deficiency also known as 3-Methylcrotonylglycinuria is an inborn error of leucine metabolism and is inherited through an autosomal recessive fashion. [1] 3-Methylcrotonyl-CoA carboxylase deficiency is caused by mutations in the MCCC1 gene, formerly known as MMCA, or the MCCC2 gene, formerly known as MCCB. MCCC1 encodes the a-subunits of 3-methylcrotonyl-CoA carboxylase [2] while MCCC2 encodes the b-subunits. [3] The clinical presentation of 3-Methylcrotonyl-CoA carboxylase deficiency is varied, even within members of the same family. [4]

Contents

Manifestations of 3-Methylcrotonyl-CoA carboxylase deficiency range from asymptomatic [5] to neonatal onset with extreme neurological symptoms [6] and even fatal cases. [7] 3-Methylcrotonyl-CoA carboxylase deficiency is diagnosed by increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in the urine. 3-hydroxyisovalerylcarnitine is often found in both the urine and blood.

The diagnosis of 3-Methylcrotonyl-CoA carboxylase deficiency is confirmed by decreased enzyme activity in fibroblasts or white blood cells. [8] Although no treatment options have been proven to help manage 3-Methylcrotonyl-CoA carboxylase deficiency [9] proposed treatments include L-carnitine supplements, [10] glycine administration, [11] biotin supplements [4] and dietary restriction of leucine. [12] 3-Methylcrotonyl-CoA carboxylase deficiency is the most common organic aciduria detected by newborn screening programs in Australia, [13] North America, [14] and Europe. [15]

Signs and symptoms

Those with 3-Methylcrotonyl-CoA carboxylase deficiency typically display normal development until 6 months to 3 years old when patients present with an acute episode. These acute episodes are typically brought on by increased protein load [16] or intercurrent infections. [7] During metabolic crisis, moderate hyperammonemia, [7] hypoglycemia, and metabolic acidosis have been noted. [17] There is a broad spectrum of clinical manifestations ranging from cardiomyopathy, developmental delays, [4] leukodystrophy, necrotizing encephalopathy, respiratory failure, hypotonia, [6] cerebral palsy and failure to thrive. [17] Carnitine deficiency is found in about 50% of cases. [18]

Over 90% of those diagnosed with 3-Methylcrotonyl-CoA carboxylase deficiency by newborn screening remain asymptomatic. The medical abnormalities that present in the few who do show symptoms are not always clearly related to 3-Methylcrotonyl-CoA carboxylase deficiency. [5] Manifestations of 3-Methylcrotonyl-CoA carboxylase deficiency vary even among family members who share a common environment and genetics. [4]

Genetics

The MCCC1 and MCCC2 genes make protein subunits that come together to form an enzyme called 3-methylcrotonyl-CoA carboxylase. This enzyme plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the fourth step in processing leucine. If a mutation in the MCCC1 or MCCC2 gene reduces or eliminates the activity of 3-methylcrotonyl-CoA carboxylase, the body is unable to process leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, damaging the brain and nervous system. This condition is inherited in an autosomal recessive pattern. [19]

Diagnosis

3-Methylcrotonyl-CoA carboxylase deficiency is diagnosed by the detection of organic acids in urine using gas chromatography or mass spectrometry and analysis of the blood by liquid chromatography-tandem mass spectrometry. [20] 3-Methylcrotonyl-CoA carboxylase deficiency is characterized by increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine levels in the urine. The acylcarnitines profile shows elevated concentrations of 3-hydroxyisovalerylcarnitine as well as an increased ratio of 3-hydroxyisovalerylcarnitine to propionylcarnitine. [3]

Since genotype isn't predictive of phenotype, [5] DNA testing isn't necessary. However, DNA analysis may help confirm 3-Methylcrotonyl-CoA carboxylase deficiency when the diagnosis is uncertain. [9]

3-hydroxyisovalerylcarnitine is also elevated in other metabolism disorders such as 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, biotinidase deficiency, multiple carboxylase deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency and malonic aciduria. 3-Methylcrotonyl-CoA carboxylase deficiency is differentiated by the lack of other urine metabolites and by measuring the activity of 3-methylcrotonyl-CoA carboxylase, biotinidase, and other biotin dependant carboxylases. [12]

Screening

It is one of the 29 conditions currently recommended for newborn screening by the American College of Medical Genetics. [21]

Treatment

Symptoms can be reduced through avoidance of leucine, an amino acid. Leucine is a component of most protein-rich foods; therefore, a low-protein diet is recommended. Some isolated cases of this disorder have responded to supplemental biotin; [22] this is not altogether surprising, consider that other biotin-related genetic disorders (such as biotinidase deficiency and holocarboxylase synthetase deficiency) can be treated solely with biotin. Individuals with these multiple carboxylase disorders have the same problem with leucine catabolism as those with 3-methylcrotonyl-CoA carboxylase deficiency. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Biotin</span> Chemical compound (vitamin B7)

Biotin (also known as vitamin B7 or vitamin H) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name biotin, borrowed from the German Biotin, derives from the Ancient Greek word βίοτος (bíotos; 'life') and the suffix "-in" (a suffix used in chemistry usually to indicate 'forming'). Biotin appears as a white, needle-like crystalline solid.

<span class="mw-page-title-main">Methylmalonic acidemias</span> Medical condition

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.

<span class="mw-page-title-main">Medium-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Medium-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid oxidation that impairs the body's ability to break down medium-chain fatty acids into acetyl-CoA. The disorder is characterized by hypoglycemia and sudden death without timely intervention, most often brought on by periods of fasting or vomiting.

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">3-Hydroxy-3-methylglutaryl-CoA lyase deficiency</span> Medical condition

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, (HMGCLD) also known as HMGCL deficiency, HMG-CoA lyase deficiency, or hydroxymethylglutaric aciduria, is an uncommon autosomal recessive inborn error in ketone body production and leucine breakdown caused by HMGCL gene mutations. HMGCL, located on chromosome 1p36.11's short arm, codes for HMG-CoA lyase, which aids in the metabolism of dietary proteins by converting HMG-CoA into acetyl-CoA and acetoacetate.

<span class="mw-page-title-main">Systemic primary carnitine deficiency</span> Medical condition

Systemic primary carnitine deficiency (SPCD) is an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane. Carnitine is an important amino acid for fatty acid metabolism. When carnitine cannot be transported into tissues, fatty acid oxidation is impaired, leading to a variety of symptoms such as chronic muscle weakness, cardiomyopathy, hypoglycemia and liver dysfunction. The specific transporter involved with SPCD is OCTN2, coded for by the SLC22A5 gene located on chromosome 5. SPCD is inherited in an autosomal recessive manner, with mutated alleles coming from both parents.

<span class="mw-page-title-main">Biotinidase deficiency</span> Medical condition

Biotinidase deficiency is an autosomal recessive metabolic disorder in which biotin is not released from proteins in the diet during digestion or from normal protein turnover in the cell. This situation results in biotin deficiency.

<span class="mw-page-title-main">3 hydroxyisobutyric aciduria</span> Medical condition

3 Hydroxyisobutyric aciduria is a rare metabolic disorder in which the body is unable to metabolize certain amino acids. This causes a toxic buildup of specific acids called organic acids in the blood, tissues, and urine. The precise underlying cause remains unknown. Some cases may be caused by mutations in the ALDH6A1 gene and inherited autosomally recessively.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

2-Methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive metabolic disorder. It causes the body to be unable to process the amino acid isoleucine properly. Initial case reports identified individuals with developmental delay and epilepsy, however most cases identified through newborn screening have been asymptomatic.

β-Hydroxybutyric acid Chemical compound

β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).

<span class="mw-page-title-main">Propionyl-CoA carboxylase</span>

Propionyl-CoA carboxylase (EC 6.4.1.3, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA.

Methylcrotonyl CoA carboxylase is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid.

Biotinidase, also known as biotinase, is an enzyme that in humans is encoded by the BTD gene.

<span class="mw-page-title-main">Biotin deficiency</span> Medical condition

Biotin deficiency is a nutritional disorder which can become serious, even fatal, if allowed to progress untreated. It can occur in people of any age, ancestry, or of either sex. Biotin is part of the B vitamin family. Biotin deficiency rarely occurs among healthy people because the daily requirement of biotin is low, many foods provide adequate amounts of it, intestinal bacteria synthesize small amounts of it, and the body effectively scavenges and recycles it in the kidneys during production of urine.

<span class="mw-page-title-main">Methylcrotonyl-CoA</span> Chemical compound

3-Methylcrotonyl-CoA is an intermediate in the metabolism of leucine.

Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

β-Hydroxy β-methylbutyryl-CoA Chemical compound

β-Hydroxy β-methylbutyryl-coenzyme A (HMB-CoA), also known as 3-hydroxyisovaleryl-CoA, is a metabolite of L-leucine that is produced in the human body. Its immediate precursors are β-hydroxy β-methylbutyric acid (HMB) and β-methylcrotonoyl-CoA (MC-CoA). It can be metabolized into HMB, MC-CoA, and HMG-CoA in humans.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. However, the methylmalonic acid levels exceed those of malonic acid. CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII). Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

References

This article incorporates public domain text from The U.S. National Library of Medicine

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  2. ↑ Baumgartner, Matthias R.; Almashanu, Shlomo; Suormala, Terttu; Obie, Cassandra; Cole, Robert N.; Packman, Seymour; Baumgartner, E. Regula; Valle, David (February 15, 2001). "The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency". Journal of Clinical Investigation. 107 (4). American Society for Clinical Investigation: 495–504. doi: 10.1172/jci11948 . ISSN   0021-9738. PMC   199271 . PMID   11181649.
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  22. ↑ Baumgartner, Matthias R.; Dantas, M.Fernanda; Suormala, Terttu; Almashanu, Shlomo; Giunta, Cecilia; Friebel, Dolores; Gebhardt, Boris; Fowler, Brian; Hoffmann, Georg F.; Baumgartner, E. Regula; Valle, David (2004). "Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency: Evidence for an Allele-Specific Dominant Negative Effect and Responsiveness to Biotin Therapy". The American Journal of Human Genetics. 75 (5): 790–800. doi:10.1086/425181. PMC   1182108 . PMID   15359379.
  23. ↑ Thomsen, Jákup Andreas; Lund, Allan Meldgaard; Olesen, Jess Have; Mohr, Magni; Rasmussen, Jan (2014). "Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?". JIMD Reports. Vol. 21. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 79–88. doi:10.1007/8904_2014_393. ISBN   978-3-662-47171-5. ISSN   2192-8304. PMC   4470948 . PMID   25732994.

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