D-2-hydroxyglutaric aciduria 1

D-2-Hydroxyglutaric Aciduria: A Rare Neurological Disorder

D-2-hydroxyglutaric aciduria, also known as D-2-HGA, is a rare and clinically variable neurological form of 2-hydroxyglutaric aciduria [1]. This condition is characterized by delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain [10].

Key Features:

• Delayed development
• Seizures
• Weak muscle tone (hypotonia)
• Abnormalities in the brain

Causes and Symptoms:

D-2-HGA is an inherited metabolic condition that is associated with progressive brain damage [3]. The cardinal clinical manifestations in both D2HGA subtypes are developmental delay, hypotonia, and seizures [9].

Prevalence and Diagnosis:

This condition is rare and affects a small number of people worldwide. Diagnosing D-2-HGA can be challenging, but it is often identified through genetic testing and analysis of urine samples for elevated levels of hydroxyglutaric acid [8].

References: [1] - The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain. [3] - D-2-alpha hydroxyglutaric aciduria is an inherited metabolic condition that is associated with progressive brain damage. [8] - 2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. [9] - The cardinal clinical manifestations in both D2HGA subtypes are developmental delay, hypotonia and seizures. [10] - The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain.

Common Signs and Symptoms of D-2-Hydroxyglutaric Aciduria

D-2-hydroxyglutaric aciduria is a rare neurometabolic disorder that can cause significant damage to the brain. The signs and symptoms of this condition can vary from person to person, but some common features include:

• Delayed Development: Children with D-2-HGA may experience delayed development, which can manifest as slow growth, delayed speech, or difficulty with motor skills.
• Seizures: Seizures are a common symptom of D-2-HGA, and can range from mild to severe. They may be triggered by various factors, such as fever, stress, or certain medications.
• Weak Muscle Tone (Hypotonia): Individuals with D-2-HGA often experience weak muscle tone, which can lead to difficulties with movement, balance, and coordination.
• Abnormalities in the Brain: The condition can cause abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory.

These symptoms can begin at any age, but are often first noticed during infancy or early childhood. As the disorder progresses, it can lead to severe disability by early adulthood.

References:

• [1] The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum) [4].
• [2] Clinical symptoms include developmental delay, epilepsy, hypotonia, and dysmorphic features [6].
• [3] The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, often, severe developmental delay [12].

Diagnostic Tests for D-2-Hydroxyglutaric Aciduria

D-2-hydroxyglutaric aciduria is a rare neurometabolic disorder that requires accurate diagnosis to ensure proper treatment. The diagnostic tests for this condition are crucial in identifying the presence of elevated D-2-hydroxyglutaric acid (D-2-HG) in the urine, plasma, and cerebrospinal fluid.

• Urine Organic Acids Test: This is the recommended first-tier test for 2-hydroxyglutaric aciduria, including D-2-hydroxyglutaric aciduria. The test detects elevated levels of D-2-HG in the urine [8].
• Next-generation sequencing: This genetic testing method can detect single nucleotide and copy number variants in four genes associated with 2-hydroxyglutaric aciduria, including D-2-hydroxyglutaric aciduria [7].
• Biochemical assessment: This test measures the levels of L-2-hydroxyglutaric acid in urine and cerebrospinal fluid, which is a key characteristic of L2HGA and D-2-hydroxyglutaric aciduria [15].

Diagnostic Teams

A diagnostic team for D-2-hydroxyglutaric aciduria may include:

• Genetics: Geneticists play a crucial role in identifying genetic mutations associated with the condition.
• Neurology: Neurologists are involved in assessing the neurological symptoms and signs of the disorder.

These diagnostic tests and teams work together to provide an accurate diagnosis of D-2-hydroxyglutaric aciduria, enabling healthcare providers to develop effective treatment plans for affected individuals.

Treatment Options for D-2-Hydroxyglutaric Aciduria Type I

D-2-hydroxyglutaric aciduria type I is a rare genetic disorder caused by mutations in the D2HGDH gene. While there is no specific cure, various treatment options can help manage the symptoms and improve quality of life.

• Enasidenib: This is a specific inhibitor that targets mutant mitochondrial isocitrate dehydrogenase 2 (IDH2). It has been approved by the FDA for the treatment of adult acute myeloid leukemia with IDH2 mutations. In children, enasidenib has shown benefits in reducing developmental delays and cardiomyopathy [3][4].
• Phenylbutyrate: This compound has been identified as a potential treatment for combined D,L-2-hydroxyglutaric aciduria through a multiomics approach [5]. However, its effectiveness in treating D-2-hydroxyglutaric aciduria type I is still being researched.
• Supportive and symptomatic measures: Since there is no specific treatment for L-2-hydroxyglutaric aciduria, supportive and symptomatic measures are recommended. This includes seizure control, which can be achieved through medication [15].

Other Therapeutic Approaches

In addition to the above treatments, other therapeutic approaches may be considered on a case-by-case basis. These include:

• Protein-restricted diet: A protein-restricted diet may be recommended to help manage symptoms.
• Riboflavin and carnitine supplements: Supplements of riboflavin and carnitine may also be prescribed to alleviate symptoms.

Important Note

It is essential to consult with a healthcare professional for personalized advice on managing D-2-hydroxyglutaric aciduria type I. They can help determine the best course of treatment based on individual needs and circumstances.

References:

[3] In a study of two children with D-2-hydroxyglutaric aciduria type II, enasidenib showed benefits in reducing developmental delays and cardiomyopathy [3].

[4] Enasidenib has been approved by the FDA for the treatment of adult acute myeloid leukemia with IDH2 mutations [10].

[5] Phenylbutyrate has been identified as a potential treatment for combined D,L-2-hydroxyglutaric aciduria through a multiomics approach [5].

Differential Diagnosis of D-2-Hydroxyglutaric Aciduria

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare neurological disorder characterized by elevated levels of D-2-hydroxyglutaric acid in the urine, plasma, and cerebrospinal fluid. The differential diagnosis of D-2-HGA involves identifying other conditions that may present with similar clinical features.

Key Conditions to Consider:

• Canavan disease: A genetic disorder that affects the brain's ability to break down a type of sugar called N-acetyl-aspartate (NAA). It can cause developmental delay, seizures, and muscle weakness.
• Kearns-Sayre syndrome (KSS): A rare mitochondrial disorder that affects the muscles and nervous system. It can cause progressive external ophthalmoplegia, heart block, and other systemic symptoms.
• 3-hydroxy-3-methylglutaryl-coenzyme (HMGCoA) lyase deficiency: A rare genetic disorder that affects the metabolism of certain amino acids and can cause developmental delay, seizures, and muscle weakness.

Clinical Features to Consider:

• Developmental delay or intellectual disability
• Seizures or epilepsy
• Muscle weakness or hypotonia
• Abnormal brain MRI findings

Diagnostic Approach:

The diagnosis of D-2-HGA is confirmed by the presence of elevated levels of D-2-hydroxyglutaric acid in the urine, plasma, and cerebrospinal fluid. A comprehensive diagnostic evaluation should include:

1. Clinical evaluation: A thorough medical history and physical examination to identify any systemic symptoms or signs.
2. Laboratory tests: Urinary organic acid screening, plasma amino acid analysis, and cerebrospinal fluid analysis to detect elevated levels of D-2-hydroxyglutaric acid.
3. Imaging studies: Brain MRI to rule out other structural abnormalities.

References:

• OMIM #600721
• [1] Bozaci AE, et al. (2023). Clinical and molecular characteristics of D-2-hydroxyglutaric aciduria type I. Eur J Hum Genet.
• [2] Kearns-Sayre syndrome. Orphanet Journal of Rare Diseases.

Note: The references provided are for informational purposes only and may not be comprehensive or up-to-date.