Test Id : MMPP

This test is not the recommended initial screening test for evaluating patients with suspected mitochondrial disorders, organic acidurias, and ketone body disorders. For these purposes, the preferred tests for first-tier assessment are OAU / Organic Acids Screen, Random, Urine; AAQP / Amino Acids, Quantitative, Plasma; and ACRN / Acylcarnitines, Quantitative, Plasma.

Analytes from LAPYP / Lactate Pyruvate Panel, Plasma are included in this test. If ordered together, LAPYP may be canceled.

Collection Container/Tube:

Preferred: Green top (sodium heparin)

Acceptable: Green top (lithium heparin)

Submission Container/Tube: Plastic vial

Specimen Volume: 0.5 mL

Collection Instructions: Centrifuge and aliquot plasma into plastic vial.

If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.

0.1 mL

Monitoring patients with mitochondrial disorders, organic acidurias, and ketone body disorders

Mitochondrial metabolites occur as physiologic intermediates in a variety of metabolic pathways. Mitochondrial diseases, organic acidurias, and ketone disorders are groups of disorders in which one or more of these pathways are blocked, resulting in a deficiency of normal products and an abnormal accumulation of intermediate metabolites in the body. In some conditions, these excess metabolites are observed in abnormal plasma concentrations.

Mitochondrial disorders vary widely in both clinical presentation and age of onset. Patients commonly present with neurologic and myopathic features. In addition, patients may experience involvement of multiple organ systems with features such as myopathy, ophthalmoplegia, ptosis, cardiomyopathy, sensorineural hearing loss, optic atrophy, pigmentary retinopathy, diabetes mellitus, encephalomyopathy, seizures, and stroke-like episodes.

Organic acidurias typically present with either an acute life-threatening illness in early infancy or unexplained developmental delay with intercurrent episodes of metabolic decompensations in later childhood. Organic acidurias should be considered when patients present with severe and persistent metabolic acidosis of unexplained origin, elevated anion gap, and severe neurologic manifestations, such as seizures. Other findings, especially during acute episodes of metabolic decompensations, may include elevated ketones in urine or plasma, hyperammonemia, hypoglycemia, and lactic acidemia.

Ketone disorders include disorders of impaired ketone body metabolism and disorders of ketogenesis. Ketones are converted as an energy source when either carbohydrate reserves are depleted or excessive fatty acids are present. Clinical symptoms of ketone body metabolism disorders include episodes of ketoacidosis, vomiting, dehydration, and lethargy with increased risk of symptoms during periods of illness or fasting. Patients with disorders of ketogenesis experience hypoketotic hypoglycemic episodes that may result in long-term sequelae including seizure disorders, intellectual disability, and white matter changes in the brain. Treatment for ketone disorders involves avoidance of fasting and management of acute symptoms.

A diagnostic workup for mitochondrial disorders, organic acidurias, and ketone body disorders includes analysis of urine organic acids (OAU / Organic Acids Screen, Random, Urine), plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma) and plasma acylcarnitines (ACRN / Acylcarnitines, Quantitative, Plasma) as recommended first-tier tests for assessment. While the mitochondrial metabolites panel complements this work up and provides additional context, this test should not be used in isolation for diagnostic purposes.

LACTIC ACID

< or = 4000.0 nmol/mL

2-HYDROXYBUTYRIC ACID

< or = 124.0 nmol/mL

3-HYDROXYBUTYRIC ACID

< or = 700.0 nmol/mL

PYRUVIC ACID

< or = 350.0 nmol/mL

cis-ACONITIC ACID

< or = 9.0 nmol/mL

CITRIC ACID

< or = 250.0 nmol/mL

3-HYDROXYPROPIONIC ACID

< or = 12.4 nmol/mL

3-HYDROXY-2-METHYLBUTYRIC ACID

< or = 2.5 nmol/mL

3-HYDROXYISOVALERIC ACID

< or = 15.4 nmol/mL

SUCCINIC ACID

< or = 10.0 nmol/mL

FUMARIC ACID

< or = 5.0 nmol/mL

3-METHYLGLUTACONIC ACID

< or = 1.6 nmol/mL

MALIC ACID

< or = 20.0 nmol/mL

2-KETOBUTYRIC ACID

< or = 16.0 nmol/mL

2-KETOISOVALERIC ACID

< or = 35.0 nmol/mL

ACETOACETIC ACID

< or = 350.0 nmol/mL

3-METHYL-2-KETOVALERIC ACID

< or = 70.0 nmol/mL

2-KETOISOCAPROIC ACID

< or = 70.0 nmol/mL

2-METHYLCITRIC ACID

< or = 1.0 nmol/mL

2-KETOGLUTARIC ACID

< or = 40.0 nmol/mL

An interpretive report based on pattern recognition is provided. The individual quantitative results support the interpretation of the mitochondrial metabolite profile but are not diagnostic by themselves.

The elevation of 3-hydroxyisovaleric acid can be explained by several differential diagnoses that cannot always be distinguished by the mitochondrial metabolite profile. Differential diagnoses will be noted in the interpretative comment.

For patients without a prior known diagnosis, abnormal results are typically not sufficient to conclusively establish a diagnosis of a particular disease. To verify a preliminary diagnosis based on a mitochondrial metabolite profile, independent biochemical or molecular genetic analyses are required.

3-hydroxyisobutyric acid can cause a false elevation in the quantitation of 3-hydroxybutyric acid. Patients affected by 3-hydroxyisobutyric aciduria may have falsely elevated 3-hydroxybutyric acid.

Gross elevations of methylmalonic acid may interfere with the quantitation of 3-hydroxyisovaleric and succinic acid. When observed, the report will include a comment indicating presence of interference.

Gross elevations of acetoacetic acid may interfere with the quantification of 3-methyl-2-ketovaleric acid. When observed, the report will include a comment indicating presence of interference.

1. Munnich A, Rotig A, Cormier-Daire V, Rustin P: Clinical presentation of respiratory chain deficiency. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed February 17, 2022. Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225086827

2. Robinson BH: Lactic acidemia: Disorders of pyruvate carboxylase and pyruvate dehydrogenase. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed February 17, 2022. Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225087140

3. Shoffner JM: Oxidative phosphorylation diseases. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019 Accessed February 17, 2022. Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225088339 

4. Mitchell GA, Fukao T: Inborn errors of ketone body metabolism. In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease McGraw-Hill Education; 2019. Accessed February 17, 2022. Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225087757

100 mcL of plasma specimen is spiked with a mixture of labeled internal standards following pentafluorobenzyl-oximation of keto acids. The samples are acidified and extracted into ethyl acetate. After evaporation, the dry residue is silylated with N,O,-bis-(trimethylsilyl) trifluoroacetamide with 1% trimethylchlorosilane and analyzed by capillary gas chromatography/mass spectrometry using selected ion monitoring with positive electron impact ionization and stable isotope dilution.(Unpublished Mayo method)

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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