combined D-2- and L-2-hydroxyglutaric aciduria

Combined D-2- and L-2-hydroxyglutaric aciduria, also known as combined D,L-2-HGA, is a rare neurometabolic disorder that affects the brain and other tissues. It is characterized by the accumulation of both D-2-hydroxyglutarate and L-2-hydroxyglutarate in the body.

Symptoms:

• Severe neonatal epileptic encephalopathy
• Absence of developmental milestones
• Muscular weakness
• Intractable seizures
• Respiratory distress
• Early death, usually within the first years of life

Causes:

Combined D-2- and L-2-hydroxyglutaric aciduria is caused by mutations in the SLC25A1 gene, which encodes the mitochondrial citrate carrier (CIC). This gene mutation leads to a deficiency of the enzyme responsible for breaking down 2-hydroxyglutarate, resulting in its accumulation in the body.

Types:

There are three types of 2-hydroxyglutaric aciduria:

1. D-2-HGA
2. L-2-HGA
3. Combined D,L-2-HGA (the focus of this description)

Each type has distinct symptoms and characteristics, but combined D,L-2-HGA is the most severe form, often resulting in early death.

References:

• OMIM #615182
• Muntau et al. 2000

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Severe Early-Onset Epileptic Encephalopathy

Combined D-2- and L-2-hydroxyglutaric aciduria is characterized by severe early-onset epileptic encephalopathy, which means that affected individuals experience severe seizures and brain dysfunction from birth or shortly after. This condition is often associated with a lack of neurological developmental progress.

Common Features

The main features of this condition include:

• Neonatal Encephalopathy: Severe brain dysfunction present at birth
• Respiratory Insufficiency: Difficulty breathing, which can be life-threatening
• Developmental Delay: Significant delay in reaching developmental milestones
• Hypotonia: Weak muscle tone, making it difficult to move or maintain posture
• Early Death: Unfortunately, many affected individuals do not survive beyond early childhood

Additional Information

According to [11], combined D-2- and L-2-hydroxyglutaric aciduria is the third variant of 2-HGA, and its severe phenotype is characterized by neonatal encephalopathy, respiratory insufficiency, developmental delay, hypotonia, and early death. This condition is biochemically characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid.

References: [11] Muntau et al. (2000) - Combined D-2- and L-2-hydroxyglutaric aciduria: A severe phenotype with neonatal encephalopathy, respiratory insufficiency, developmental delay, hypotonia, and early death.

Combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a rare neurometabolic disorder that requires prompt diagnosis for effective management. The diagnostic tests for this condition typically involve the following:

• Urine analysis: Excess D-2-hydroxyglutaric acid in the urine is a key indicator of this condition [1]. This test can help establish the presence of the disorder.
• Magnetic Resonance Imaging (MRI): MRI findings, such as subependymal cysts, delayed cerebral maturation, and other brain abnormalities, are also characteristic of D/L-2-HGA [6].
• Genetic testing: Molecular genetic testing is available to detect single nucleotide and copy number variants in the 4 genes associated with 2-hydroxyglutaric aciduria, including the SLC25A1 gene [7, 8]. This test can help confirm the diagnosis.
• Blood tests: Blood samples may be taken for analysis, although this is not a primary diagnostic tool for D/L-2-HGA.

It's essential to note that these diagnostic tests should only be performed under the guidance of a qualified healthcare professional. A correct and timely diagnosis is crucial for providing appropriate care and management for individuals with combined D-2- and L-2-hydroxyglutaric aciduria.

References: [1] Combined D,L-2-HGA causes severe brain abnormalities that become apparent in early infancy [3]. [6] Diagnosis is established on the basis of excess D-2-hydroxyglutaric acid in the urine and MRI findings: subependymal cysts, delayed cerebral maturation, and other brain abnormalities [6]. [7] This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 4 genes associated with 2-hydroxyglutaric aciduria [7]. [8] Molecular genetic testing is available (SLC25A1 gene) [8].

Treatment Options for Combined D-2- and L-2-Hydroxyglutaric Aciduria

Combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a rare genetic disorder that requires prompt and effective treatment to manage its symptoms. While there is no specific cure for this condition, various drug treatments have been explored to alleviate its effects.

• Phenylbutyrate: A multiomics approach has revealed evidence for phenylbutyrate as a potential treatment for combined D,L-2-hydroxyglutaric aciduria [1]. This medication may help manage the symptoms of this condition.
• Citrate Supplements: Daily Na-K-citrate supplements have been successfully used to treat an affected patient, although no standardized treatment existed at that time [7].
• Enasidenib: In two children with combined D-2- and L-2-hydroxyglutaric aciduria, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. This medication was well-tolerated, with no side effects observed except for asymptomatic hyperbilirubinemia [13].

Management and Supportive Care

While these drug treatments may provide some relief from the symptoms of combined D-2- and L-2-hydroxyglutaric aciduria, management mainly involves control of seizures when they are present. The prognosis is generally poor, with early death often occurring in affected individuals [4].

References:

[1] A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2-hydroxyglutaric aciduria. [7] Mühlhausen et al. (28) successfully treated an affected patient with daily Na-K-citrate supplements, although no standardized treatment existed at that time. [13] In two children with combined D-2- and L-2-hydroxyglutaric aciduria, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids.

The differential diagnosis of combined D-2- and L-2-hydroxyglutaric aciduria involves a clinical evaluation of patients with unexplained developmental delay and/or other neurological dysfunction of unknown etiology, raising suspicion for a metabolic disorder.

Key Points to Consider:

• Clinical Evaluation: The first step in diagnosing combined D-2- and L-2-hydroxyglutaric aciduria is a thorough clinical evaluation of the patient. This includes assessing the patient's developmental delay, neurological dysfunction, and other symptoms.
• Metabolic Disorder Suspicions: If the clinical evaluation raises suspicion for a metabolic disorder, further testing may be necessary to confirm or rule out combined D-2- and L-2-hydroxyglutaric aciduria.

Diagnostic Considerations:

• Urinary Organic Acid Screening: Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglutaric acid. Therefore, further testing is necessary to confirm the diagnosis.
• Neonatal-Onset Encephalopathy: Combined D-2- and L-2-hydroxyglutaric aciduria can cause severe neonatal-onset encephalopathy, which may be a key diagnostic consideration.

References:

• [6] Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglutaric acid.
• [8] Distinct neuroradiological profiles are associated with L-2- and D-2-hydroxyglutaric aciduria, allowing a presumptive diagnosis.

It's essential to note that the differential diagnosis of combined D-2- and L-2-hydroxyglutaric aciduria requires a comprehensive evaluation by a qualified healthcare professional. If you suspect this condition in a patient, further testing and consultation with a specialist are necessary for an accurate diagnosis and treatment plan.