GLYCTK

The GLYCTK gene encodes glycerate kinase, an enzyme essential for breaking down certain sugars and amino acids involved in key energy-producing pathways. 

Mutations in GLYCTK can lead to D-glyceric aciduria, a rare autosomal recessive metabolic disorder characterized by neurological symptoms and elevated urinary D-glyceric acid.

What is GLYCTK (Glycerate Kinase)?

The GLYCTK gene provides instructions for making glycerate kinase, an essential enzyme that breaks down certain sugars and amino acids in the body. 

Located on chromosome 3p21.2, this gene produces multiple isoforms of the enzyme, some found in the mitochondria and others in the cytoplasm. The most common isoform is a 523-amino acid protein with a molecular mass of ~55.3 kDa.a

GLYCTK: An Enzyme Involved in Several Metabolic Pathways

Glycerate kinase catalyzes a chemical reaction that converts (R)-glycerate into 3-phosphoglycerate, a compound used in several critical metabolic pathways:

• Serine degradation
• Fructose metabolism
• Glycolysis and gluconeogenesis (to a lesser extent)

This reaction supports the body's ability to produce energy and break down sugars and amino acids.

Diseases Associated with GLYCTK Mutations

The primary disease associated with GLYCTK mutations is D-glyceric aciduria (DGA), a rare autosomal recessive metabolic disorder. 

Rarely, juvenile myoclonic epilepsy has also been reported in association with GLYCTK variants, though causality remains unclear. 

As of 2011, only 10 genetically confirmed DGA cases have been reported worldwide, underscoring its rarity and the importance of molecular testing in diagnosis.

D-Glyceric Aciduria

D-Glyceric Aciduria (DGA) is a rare inherited metabolic disorder caused by mutations in the GLYCTK gene, which encodes the enzyme glycerate kinase. 

This enzyme breaks down certain sugars and amino acids. When the enzyme doesn’t function properly, D-glyceric acid builds up in the body and is excreted in the urine, showing high levels of urinary D-glyceric acid. 

DGA is inherited in an autosomal recessive pattern and can manifest in a variety of symptoms. Some individuals may experience developmental delays, seizures, and microcephaly, while others may have only mild speech delays or develop normally.

Juvenile Myoclonic Epilepsy

Juvenile Myoclonic Epilepsy (JME) is a common type of epilepsy that usually starts between the ages of 12 and 18. It causes sudden, brief muscle jerks (called myoclonic seizures), most often in the morning after waking up. 

Some people also have full-body seizures (generalized tonic-clonic seizures) or short staring spells (absence seizures). Seizures can be triggered by things like lack of sleep, stress, or drinking alcohol. 

JME does not affect intelligence. 

It often runs in families and can be caused by changes in certain genes, including GABRA1 and EFHC1. The condition is usually passed down in an autosomal dominant pattern, but other genetic factors may also be involved.

When is GLYCTK Genetic or Enzyme Testing Relevant?

GLYCTK testing may be relevant in the following scenarios:

Suspected D-Glyceric Aciduria

Testing is recommended for individuals—especially infants or young children—who present with signs of D-glyceric aciduria, including:

• Developmental delay
• Intellectual disability
• Hypotonia (low muscle tone)
• Seizures (e.g., infantile spasms or tonic-clonic)
• Metabolic acidosis

Biochemical Evidence of Glycerate Kinase Deficiency

Urine organic acid analysis may reveal elevated D-glyceric acid, a key biomarker. Confirmatory enzyme activity assays using fibroblasts or liver cells can assess glycerate kinase function.

Family History or Carrier Screening

Genetic testing may be offered to relatives of affected individuals to identify carriers or assess reproductive risks.

Differential Diagnosis

GLYCTK testing can help distinguish D-glyceric aciduria from other metabolic or neurologic disorders with similar features, such as nonketotic hyperglycinemia (NKH) or hyperoxaluria type II.

Genetic Counseling

Genetic counseling is highly recommended before and after testing to interpret results, explain inheritance patterns, and discuss next steps.

GLYCTK Enzyme Activity Testing Procedure

D-glyceric aciduria is diagnosed through a combination of biochemical and genetic testing. 

The first step typically involves urine metabolite screening, where elevated levels of D-glyceric acid can be detected using targeted urine metabolomics (TUM).

This test distinguishes D-glyceric aciduria from similar conditions, such as L-glyceric aciduria, by evaluating oxalic acid levels, which remain normal in DGA.

Confirmatory testing may include enzyme activity assays. However, the glycerate kinase enzyme (D-glycerate-2-kinase) is unstable and can typically only be measured in liver tissue or specific cell models, limiting routine clinical use. 

Genetic testing—such as exome sequencing or a targeted metabolic gene panel—can identify biallelic pathogenic variants in GLYCTK, confirming the diagnosis.

What Do Low Levels of GLYCTK Enzyme Activity Mean?

Significantly reduced or absent enzyme activity, particularly when accompanied by elevated urinary D-glyceric acid, is diagnostic for D-glyceric aciduria, a rare autosomal recessive condition. In affected patients, enzyme activity is often less than 5% of normal.

GLYCTK Genetic Testing: Test Procedure and Interpretation

Testing for GLYCTK is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for GLYCTK genetic testing are considered to be without mutations that can alter the activity of the GLYCTK proteins.

What Do Specific GLYCTK Mutations Mean?

Identification of two pathogenic mutations (one on each gene copy) confirms the genetic diagnosis of D-glyceric aciduria. Known pathogenic variants include:

• c.1448delT (p.Phe483Serfs*2) – frameshift leading to early stop codon
• c.1478T>G (p.Phe493Cys) – missense mutation abolishing enzyme function
• c.1558delC (p.Leu520Cysfs*108) – frameshift with protein degradation

These mutations cause loss of enzyme function and are found across diverse populations.

Inheritance Pattern

D-glyceric aciduria follows an autosomal recessive pattern. Both parents must be carriers for a child to be affected.

Genotype-Phenotype Correlation

Clinical severity varies widely. Some individuals with biallelic mutations have profound developmental delays, while others may have milder or no symptoms. The relationship between specific mutations and outcomes is still under investigation.

What if No GLYCTK Mutations Are Found Despite Low Enzyme Activity?

In rare cases, individuals may show low glycerate kinase activity but no identifiable mutations through standard testing. Possible explanations include:

• Deep intronic mutations
• Large deletions or rearrangements not detected by sequencing

Further testing may be needed, such as whole genome sequencing or specialized assays.

Key Points for Clinicians

GLYCTK encodes glycerate kinase, which is critical for serine and fructose metabolism.

Deficiency leads to D-glyceric aciduria, a rare metabolic disorder with neurological symptoms and elevated urinary D-glyceric acid.

Diagnosis relies on biochemical testing, enzyme assays, and genetic sequencing.

The condition is autosomal recessive, and genetic counseling is recommended.

Clinical presentation can be highly variable, ranging from severe developmental delay to asymptomatic cases.

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