3-Methylglutaric Acid

3-Methylglutaric (3MG) acid is a C6 dicarboxylic organic acid linked to deficiencies in the leucine catabolic pathway enzymes 3-hydroxy-3-methylglutaryl CoA lyase (HMGCL) and 3-methylglutaconyl CoA hydratase (AUH). 

‍These deficiencies lead to the accumulation of 3MG acid and other metabolites like 3-methylglutaconic (3MGC) acid and 3-hydroxyisovaleric (3HIV) acid in urine.

Secondary 3MG aciduria occurs in disorders affecting mitochondrial energy metabolism, such as Barth syndrome and DNAJC19 gene mutations.  These conditions impair mitochondrial function, leading to the accumulation of 3MG acid via an alternate biosynthetic pathway called the "acetyl CoA diversion pathway."

Detecting 3MG acid through techniques like gas chromatography-mass spectrometry (GC-MS) or nuclear magnetic resonance (NMR) spectroscopy is crucial for diagnosing and differentiating between primary and secondary 3MG acidurias.  

Understanding these pathways aids in identifying genetic defects and managing metabolic disorders effectively.

What is 3-Methylglutaric Acid?  [1., 2.] 

3-Methylglutaric (3MG) acid is a notable C6 dicarboxylic organic acid linked to enzyme deficiencies in the leucine catabolic pathway.  It is excreted in the urine of individuals with deficiencies in either 3-hydroxy-3-methylglutaryl CoA lyase (HMGCL) or 3-methylglutaconyl CoA hydratase (AUH). 

Although 3MG CoA is not part of the leucine catabolic pathway, it likely forms via a side reaction involving the reduction of the α-β trans double bond in 3-methylglutaconyl CoA.  In these enzyme deficiencies, the accumulation of pathway intermediates leads to the production of 3MG acid, which is excreted in urine.

Primary 3MG aciduria arises from mutations in the leucine pathway enzymes, leading to increased excretion of 3MG acid along with other organic acids such as 3-methylglutaconic (3MGC) acid and 3-hydroxyisovaleric (3HIV) acid.  Secondary 3MG aciduria, however, occurs in various unrelated inborn errors of metabolism that compromise mitochondrial energy metabolism. 

These disorders, which include conditions like Barth Syndrome and mutations in the DNAJC19 gene, impair mitochondrial function, leading to the accumulation of 3MG acid via an alternate biosynthetic pathway termed the "acetyl CoA diversion pathway."

This pathway is initiated by defective electron transport chain function, which inhibits acetyl CoA entry into the TCA cycle, resulting in the synthesis of 3MG acid from acetyl CoA in five steps.  The accumulation of 3MG acid and its precursor, 3MGC acid, is indicative of disrupted mitochondrial energy metabolism, serving as a marker for various mitochondrial disorders. 

‍Detecting 3MG acid through gas chromatography-mass spectrometry (GC-MS) or nuclear magnetic resonance (NMR) spectroscopy is crucial for diagnosing and differentiating between primary and secondary 3MG acidurias. 

Understanding the metabolic pathways and enzyme deficiencies involved in 3MG aciduria helps in identifying the underlying genetic defects and managing these metabolic disorders effectively.

Metabolic Disorders Associated with Elevated 3-Methylglutaric Acid Levels  [1.] 

The accumulation of 3-methylglutaric acid (3-MG) in the body is a hallmark of several inherited metabolic disorders, collectively known as organic acidurias. These disorders are caused by genetic defects that impair specific enzymatic pathways, leading to the abnormal buildup of organic acids like 3-Methylglutaric Acid. 

Primary 3-Methylglutaric Acidurias  

Elevated levels of 3-methylglutaric acid are associated with a range of metabolic disorders, both primary and secondary.  Primary disorders involving 3-methylglutaric acid accumulation are caused by deficiencies in enzymes directly involved in the leucine catabolic pathway. 

These include 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency and 3-methylglutaconyl-CoA hydratase (AUH) deficiency. In these disorders, the block in leucine breakdown leads to the accumulation of upstream metabolites like 3-methylglutaric acid, 3-methylglutaconic acid, and 3-hydroxyisovaleric acid in the urine, a condition known as organic aciduria.

Secondary 3-Methyl Acidurias  [1., 3.] 

Elevated 3-methylglutaric acid levels can also occur in various inborn errors of metabolism associated with compromised mitochondrial energy metabolism, even when the leucine pathway is not directly affected. 

These secondary disorders include Barth syndrome (3-methylglutaconic aciduria type II) caused by TAZ gene mutations affecting mitochondrial phospholipid remodeling, as well as other types of 3-methylglutaconic aciduria (I, III, IV, V) linked to mitochondrial dysfunction. 

The proposed "acetyl-CoA diversion pathway" explains how defective mitochondrial function can lead to the synthesis of 3-methylglutaric acid from acetyl-CoA via a novel reaction sequence, even in the absence of a direct block in leucine catabolism.

Measuring elevated levels of 3-methylglutaric acid in the urine or other bodily fluids aids in the diagnosis of these inborn errors of metabolism, whether they are primary disorders directly affecting leucine breakdown or secondary disorders associated with mitochondrial energy metabolism defects. 

Proper identification of the underlying metabolic disorder is crucial for appropriate management and treatment strategies.

Laboratory Testing for 3-Methylglutaric Acid

Laboratory Test, Sample Collection and Preparation

Urine and plasma are the most commonly used specimens for this analysis. Proper sample collection, handling, and storage procedures are essential to ensure the integrity and reliability of the test results.

It is important to consult with the ordering provider prior to sample collection, as avoidance of certain foods or supplements may be recommended.  Fasting may also be recommended.

Interpretation of Test Results

Optimal Levels of 3-Methylglutaric Acid

Generally, falling within reference ranges for organic acids is recommended, although for many of these organic acids, a level towards the lower end of the reference range is considered optimal.  

It is essential to consult with the laboratory company used for their recommended reference range for 3-Methylglutaric Acid.  

One company reports the following reference range for 3-Methylglutaric Acid:  0.02 - 0.38 mmol/mol creatinine  [4.]

What Does Elevated 3-Methylglutaric Acid Mean? 

Elevated levels of 3-methylglutaric acid (3MG) are indicative of various metabolic disorders. Primary 3MG acidurias result from deficiencies in enzymes involved in the leucine catabolic pathway, specifically 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency and 3-methylglutaconyl-CoA hydratase (AUH) deficiency. 

These enzyme deficiencies block leucine breakdown, leading to the accumulation of 3MG acid, 3-methylglutaconic acid, and 3-hydroxyisovaleric acid in urine, a condition known as organic aciduria.

Secondary 3MG acidurias arise from inborn errors of metabolism associated with compromised mitochondrial energy metabolism, even when the leucine pathway is unaffected.  Conditions such as Barth syndrome (3-methylglutaconic aciduria type II), caused by TAZ gene mutations, and other types of 3-methylglutaconic aciduria (types I, III, IV, V) linked to mitochondrial dysfunction, fall into this category. 

The "acetyl-CoA diversion pathway" explains how defective mitochondrial function leads to the synthesis of 3MG acid from acetyl-CoA via a novel reaction sequence, independent of leucine catabolism.

‍Measuring elevated levels of 3MG acid in urine or other bodily fluids helps diagnose these metabolic disorders. Proper identification of the underlying disorder is crucial for appropriate management and treatment strategies.

What Does Low 3-Methylglutaric Acid Mean?

While elevated levels of 3-methylglutaric acid are associated with various metabolic disorders, low levels of this organic acid are generally not considered clinically significant. 

As a metabolite produced during the breakdown of the amino acid leucine, its presence in bodily fluids at low concentrations is expected in healthy individuals.

 3-Methylglutaric Acid Related Biomarkers

While 3-methylglutaric acid (3-Methylglutaric Acid) is a crucial biomarker for various metabolic disorders, it is often accompanied by other related biomarkers, often as part of an organic acid panel, that provide additional insights into the underlying metabolic pathways and aid in differential diagnosis.

Methylcitric Acid  [1.] 

Methylcitric acid is a metabolite that is closely related to 3-Methylglutaric Acid and is frequently elevated in patients with methylglutaconic aciduria and other organic acidurias. 

The accumulation of methylcitric acid is thought to result from the impaired metabolism of leucine and other branched-chain amino acids. 

Measuring methylcitric acid levels in conjunction with 3-Methylglutaric Acid can help differentiate between specific subtypes of methylglutaconic aciduria and other related disorders.

3-Hydroxyisovaleric Acid  [1.] 

3-Hydroxyisovaleric acid is another organic acid that is often elevated in patients with methylglutaconic aciduria and other organic acidurias. This biomarker is particularly useful in the diagnosis of 3-methylglutaconic aciduria, as it is a direct product of the deficient enzyme, 3-methylglutaconyl-CoA hydratase. 

Elevated levels of 3-hydroxyisovaleric acid, along with 3-Methylglutaric Acid, can provide a strong indication of this specific metabolic disorder.

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