The Diagnostic Process and Avoiding 'Look-Alikes'
At a Glance
Diagnosing D-glyceric aciduria requires more than finding high glycerate in urine. Specialized testing must identify the D form, followed by genetic confirmation of two disease-causing GLYCTK variants; the L form suggests a different disorder, primary hyperoxaluria type 2.
The path to a D-Glyceric Aciduria (DGA) diagnosis is rarely straightforward. Because the condition is not part of routine newborn screening for healthy infants, testing usually occurs when a child is evaluated for symptoms, when there is another metabolic concern, or during family testing [1].
Step 1: The Urine Organic Acid Analysis
The first clue is usually found through a urine organic acid analysis, a test ordered to evaluate unexplained symptoms. In individuals with DGA, this test will show a significantly increased level of a substance called glycerate [1][2].
However, seeing “high glycerate” on a lab report is only the beginning. Glycerate comes in two “mirror-image” forms: the D-form and the L-form. To standard laboratory tests, these two forms look identical [1].
Step 2: D-Glycerate vs. L-Glycerate
To confirm which form is present, a specialized laboratory must perform enantioselective analysis (often using gas chromatography) [1][2]. This acts like a pair of “3D glasses” that allows doctors to differentiate the two:
- The D-Form: Finding the D-form supports a diagnosis of DGA, related to the GLYCTK gene [1][3].
- The L-Form (Primary Hyperoxaluria Type 2): Finding the L-form points to a completely different condition called Primary Hyperoxaluria Type 2 (PH2), caused by a deficiency in the GRHPR enzyme [4]. Unlike DGA, PH2 often causes high levels of oxalate in the urine, which can lead to painful kidney stones or kidney damage [4].
Step 3: Genetic Confirmation
Once the D-form is identified, doctors use genetic testing to look for changes in the GLYCTK gene [3]. To confirm DGA, the testing should identify two pathogenic (disease-causing) variants—one inherited from each parent [3][2].
Geneticists often test the parents as well to confirm the variants are on opposite copies of the gene. It is important to know that finding a Variant of Uncertain Significance (VUS) does not confirm the disease; it means the laboratory does not have enough information to know if the variant causes a problem [2].
Clearing Up a Historical Misconception
In the past, older medical literature suggested that DGA caused Nonketotic Hyperglycinemia (NKH), a condition characterized by extremely high levels of the amino acid glycine [5]. This belief came from one of the very first children diagnosed with DGA in 1974, who had both high glycerate and severe neurological symptoms caused by high glycine [5].
Modern science has corrected this. Years later, researchers re-tested that original patient and discovered they actually had two separate genetic disorders: DGA and classic NKH (caused by an AMT gene mutation) [5].
What this means:
- DGA itself does not cause the severe glycine elevations seen in classic NKH [5].
- If lab work shows marked or persistent glycine elevations alongside DGA, it is a signal for your doctors to look for a second, alternative cause (such as an AMT or GLDC variant), rather than assuming it is part of DGA [5].
Glossary of Key Terms
| Term | Definition |
|---|---|
| Pathogenic Variant | A genetic change that is proven to cause a specific disease. |
| Variant of Uncertain Significance (VUS) | A genetic change whose impact on health is currently unknown. It is not proof of disease. |
| Enantioselective Analysis | A highly specialized lab test that distinguishes between right-handed (D) and left-handed (L) molecules. |
| Oxalate | A natural substance that, if elevated (as in L-glycerate conditions), can form kidney stones. |
Common questions in this guide
How is D-glyceric aciduria confirmed?
Does high glycerate in urine prove D-glyceric aciduria?
How is D-glyceric aciduria different from primary hyperoxaluria type 2?
Can a variant of uncertain significance confirm D-glyceric aciduria?
Does D-glyceric aciduria cause nonketotic hyperglycinemia?
Why might parents need genetic testing for D-glyceric aciduria?
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References
References (5)
- 1
Further evidence that d-glycerate kinase (GK) deficiency is a benign disorder.
Kalim A, Fitzsimons P, Till C, et al.
Brain & development 2017; (39(6)):536-538 doi:10.1016/j.braindev.2017.01.005.
PMID: 28190537 - 2
d-Glycerate kinase deficiency in a neuropediatric patient.
Sass JO, Behringer S, Fernando M, et al.
Brain & development 2020; (42(2)):226-230 doi:10.1016/j.braindev.2019.11.008.
PMID: 31837836 - 3
D-glyceric aciduria due to GLYCTK mutation: Disease or non-disease?
Kingma SDK, Steinbusch LKM, Aukema SM, et al.
Molecular genetics and metabolism reports 2024; (41()):101159 doi:10.1016/j.ymgmr.2024.101159.
PMID: 39619776 - 4
Severe child form of primary hyperoxaluria type 2 - a case report revealing consequence of GRHPR deficiency on metabolism.
Konkoľová J, Chandoga J, Kováčik J, et al.
BMC medical genetics 2017; (18(1)):59 doi:10.1186/s12881-017-0421-8.
PMID: 28569194 - 5
d-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence.
Swanson MA, Garcia SM, Spector E, et al.
Molecular genetics and metabolism 2017; (121(2)):80-82 doi:10.1016/j.ymgme.2017.04.009.
PMID: 28462797
This page explains how D-glyceric aciduria is diagnosed and how similar metabolic conditions are distinguished for educational purposes; it does not replace advice from your child’s metabolic or genetics team.