Diagnosis of inborn errors of metabolism

Organic acids are water-soluble compounds containing 1 or more

carboxyl groups as well as other functional groups (-keto, -hydroxy),

which are intermediate metabolites of all major groups of organic,

cellular components:  amino acids, lipids, carbohydrates, nucleic

acids, and steroids. Organic acidurias are a biochemically heterozygous

group of inborn errors of metabolism biochemically characterized by

the accumulation of metabolites that are either not present under normal

physiological conditions, (and that accumulate as a result of the

activation of alternative pathways in response to the loss of function of a

specific gene product), or pathological amounts of normal metabolites.

These disorders share a common natural history, which is the

occurrence of either acute life-threatening illness in early infancy or

unexplained developmental delay with intercurrent episodes of

metabolic decompensation in later childhood.

The incidence of individual inborn errors of organic acid metabolism

varies from 1:10,000 to >1:1,000,000 live births. Collectively, their incidence

approximates 1:3,000 live births. This estimate, however, does not include

other inborn errors of metabolism (i.e., amino acid disorders, urea

cycle disorders, congenital lactic acidemias) for which diagnosis and

monitoring also require organic acid analysis.  All possible disease

entities included, the incidence of conditions where informative organic

acid profiles could be detected in urine is likely to approach 1:1,000 live

births.

A situation of severe and persistent metabolic acidosis of unexplained

origin, elevated anion gap, and severe neurologic manifestations should

be considered strong diagnostic indicators of 1 of these diseases. The

presence of ketonuria, occasionally massive, provides an important clue

toward the recognition of disorders, especially in the neonatal period.

Hyperammonemia, hypoglycemia, and lactic acidemia are frequent

findings, especially during acute episodes of metabolic decompensation.

These abnormalities warrant immediate verification by urine organic acid

analysis using capillary gas chromatography-mass spectrometry (GC-MS).

An interpretive report will be provided.

An abnormal organic acid analysis is not sufficient to conclusively

establish a diagnosis of a particular disorder. It is strongly recom-

mended to seek confirmation by an independent method, typically

by in vitro enzyme assay (blood or cultured cells, tissue biopsy)

or molecular analysis. Rather than on individual abnormal values,

interpretation is based on pattern recognition and correlation of positive

and negative findings (for example, ketotic versus nonketotic dicarboxylic

aciduria).

When no significant abnormalities are detected, the organic acid

analysis is reported and interpreted in qualitative terms only. When

abnormal results are detected, a detailed interpretation is given,

including an overview of the results and of their significance, a

correlation to available clinical information, elements of differential

diagnosis, recommendations for additional biochemical testing, and

in vitro confirmatory studies (enzyme assay, molecular analysis),

name and phone number of key contacts who may provide these

studies at Mayo or elsewhere, and a phone number to reach one of

the laboratory directors in case the referring physician has additional

questions.

The diagnostic specificity of organic acid analysis under acute and

asymptomatic conditions may vary considerably.

Informative profiles may not always be detected in disorders where

the excretion of diagnostic metabolites is a reflection of the residual

activity of the defective enzyme, the dietary load of precursors, and the

anabolic/catabolic status of a patient.

In some cases, methods of higher specificity and sensitivity such as

acylcarnitine determination by tandem mass spectrometry and acyl-

glycine determination by GC-MS stable isotope dilution analysis can

effectively overcome the limitations of standard organic acid analysis

for the investigation of non-acutely ill patients.

1.   Goodman SI, Markey SP: Diagnosis of organic acidemias by gas

      chromatography-mass spectrometry. New York,  Alan R Liss, 1981

2.   Sweetman L:  Organic acid analysis. In Techniques in Diagnostic

      Human Biochemical Genetics. Edited by FA Hommes. Wiley-Liss,

      New York, 1991, pp 143-176

3.   Lehotay DC, Clarke JT:  Organic acidurias and related abnormalities.

      Crit Rev Clin Lab Sci 1995;32:377-429