GC×GC Detective Stories: Biomarkers, Biofuels, and Shape-Shifting Molecules

Philip Marriott, Renée Webster, and Konstantinos Kouremenos revisit three investigations in which an additional dimension of separation provided the information needed to solve three very different analytical mysteries

By
James Strachan
Frank van Geel
October 1, 2026
15 min

The Analytical Scientist

At a Glance

Category	Detail
Condition	Inborn Errors of Metabolism (IEM)
Key Mechanisms	Use of comprehensive two-dimensional gas chromatography (GC×GC) to identify biomarkers obscured in conventional separations.
Target Population	Newborns undergoing metabolic screening.
Care Setting	Clinical laboratories performing metabolic disorder diagnostics.

Key Highlights

GC×GC-TOFMS identified crotonylglycine as a novel urinary biomarker for HMGCS2 deficiency.
Conventional one-dimensional GC-MS failed to detect crotonylglycine due to coelution with adipic acid.
The urinary organic acid profile can be transient, complicating diagnosis during metabolic stability.
GC-MS remains the reference technique for urinary organic acid analysis.
Advances in chromatographic resolution have expanded the biomarker repertoire for diagnosing IEMs.

Guideline-Based Recommendations

Diagnosis

Use GC×GC to enhance detection of biomarkers in metabolic disorders.

Management

Monitor urinary organic acid profiles during episodes of metabolic decompensation.

Monitoring & Follow-up

Collect samples during acute presentations to avoid false negatives.

Risks

Transient urinary organic acid profiles may lead to misdiagnosis if not sampled appropriately.

Patient & Prescribing Data

Newborns screened for metabolic disorders.

Identification of specific biomarkers can guide treatment and management of IEMs.

Clinical Best Practices

Employ both GC-MS and LC-MS/MS in parallel for comprehensive metabolic analysis.
Utilize advanced chromatographic techniques to resolve complex mixtures.