D-2-hydroxyglutaric aciduria 2

D-2-hydroxyglutaric aciduria 2 (D2HGA2) is a neurometabolic disorder caused by heterozygous mutations in the mitochondrial isocitrate dehydrogenase-2 (IDH2; 147650) gene on chromosome [7]. This condition has both mild and severe phenotypes, with the severe form presenting early infantile-onset epileptic encephalopathy and cardiomyopathy, while the mild form has a more variable clinical presentation [11].

The diagnosis of D-2-hydroxyglutaric aciduria 2 is based on the presence of excess D-2-hydroxyglutaric acid in the urine. This condition is one of the main types of 2-hydroxyglutaric aciduria, which is a group of neurometabolic disorders with a wide clinical spectrum ranging from severe neonatal presentations to progressive forms [8].

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) [5][9]. This condition is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the disorder.

It's worth noting that D-2-hydroxyglutaric aciduria 2 is caused by mutations in the IDH2 gene, which provides instructions for making enzymes that are found in mitochondria. Mitochondrial dysfunction can lead to a range of clinical symptoms and complications, including developmental delay, seizures, and cardiomyopathy.

References: [7] - Chromosome where the IDH2 gene is located [8] - Group of neurometabolic disorders with a wide clinical spectrum [9] - Main features of D-2-HGA [11] - Description of D-2-hydroxyglutaric aciduria 2

Signs and Symptoms of D-2-Hydroxyglutaric Aciduria Type II

D-2-hydroxyglutaric aciduria type II is a rare genetic disorder that causes progressive damage to the brain. The main features of this condition include:

• Delayed development: Children with D-2-HGA type II may experience delayed development, which can manifest as slow growth and development compared to their peers.
• Seizures: Seizures are a common symptom of D-2-HGA type II, and can range from mild to severe in intensity.
• Weak muscle tone (hypotonia): Individuals with D-2-HGA type II may experience weak muscle tone, which can lead to difficulties with movement and coordination.
• Abnormalities in the brain: The condition causes progressive damage to the brain, leading to abnormalities in the cerebrum, which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory.

According to [1], signs and symptoms of D-2-HGA type II may also include:

• Intellectual disability: Some individuals with D-2-HGA type II may experience intellectual disability.
• Muscular hypotonia: Weakness in the muscles can lead to difficulties with movement and coordination.
• Cerebral visual failure: In some cases, individuals with D-2-HGA type II may experience cerebral visual failure, which can affect their vision.

It's worth noting that [13] states that signs and symptoms of this disorder begin during infancy or early childhood, and the disorder worsens over time, usually leading to severe disability by early adulthood.

Diagnostic Tests for D-2-Hydroxyglutaric Aciduria

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

Recommended First-Tier Test

The recommended first-tier test for 2-hydroxyglutaric aciduria is a urine organic acids screen, which can be ordered as OAU / Organic Acids Screen, Random, Urine [8][9]. This test provides differentiation of the three subtypes of 2-hydroxyglutaric aciduria: D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and combined D,L-2-hydroxyglutaric aciduria [7].

Diagnostic Teams

A diagnostic team for D-2-hydroxyglutaric aciduria may include genetics, neurology, and other specialists. A primary care physician (PCP) can help in getting specialist referrals, ordering diagnostic tests, and coordinating providers as you build a healthcare team [10].

Treatment Options for D-2-Hydroxyglutaric Aciduria Type II

D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 gene. While there is currently no specific treatment for this condition, research has shown that certain medications can help manage its symptoms.

Enasidenib: A Promising Treatment Option

One such medication is enasidenib, a selective mutant IDH2 enzyme inhibitor. Studies have demonstrated its effectiveness in treating D2HGA2, with benefits including developmental gains, fewer acute medical interventions, and improved quality of life [7][14]. In one study, treatment with enasidenib led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids at doses of 50 mg per day [9].

Other Treatment Options

In addition to enasidenib, other treatments have been explored for managing the symptoms of D2HGA2. These include protein restriction, riboflavin, flavin adenine dinucleotide (FADH2), and levocarnitine chloride [6][8]. While these treatments may not be as effective as enasidenib, they can still provide some benefit in managing the condition.

Importance of Monitoring

It is essential to monitor liver function tests when using enasidenib for treatment of D2HGA2, as this medication can cause potential adverse effects [15].

In summary, while there is no specific cure for D-2-hydroxyglutaric aciduria type II, research has shown that certain medications such as enasidenib and other treatments like protein restriction and riboflavin can help manage its symptoms.

Differential Diagnosis of D-2-Hydroxyglutaric Aciduria

D-2-hydroxyglutaric aciduria is a rare neurometabolic disorder that can be challenging to diagnose. The differential diagnosis for this condition involves ruling out other disorders that present with similar symptoms.

• L-2-Hydroxyglutaric Aciduria: This is another type of 2-hydroxyglutaric aciduria, which can be differentiated from D-2-hydroxyglutaric aciduria by the presence of L-2-hydroxyglutaric acid in the urine and plasma. However, urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglutaric acid [1][6].
• Canavan Disease: This is a genetic disorder that affects the brain and can present with similar symptoms to D-2-hydroxyglutaric aciduria. However, Canavan disease typically involves brainstem involvement, which is not a characteristic of L-2-Hydroxyglutaric aciduria [9].
• Kearns-Sayre Syndrome: This is a mitochondrial disorder that can present with similar symptoms to D-2-hydroxyglutaric aciduria. However, Kearns-Sayre syndrome typically involves pigmentary retinopathy and cardiac conduction abnormalities, which are not characteristic of L-2-Hydroxyglutaric aciduria [5].
• HMGCoA Lyase Deficiency: This is a rare genetic disorder that can present with similar symptoms to D-2-hydroxyglutaric aciduria. However, HMGCoA lyase deficiency typically involves elevated levels of 3-methylglutaconic acid in the urine and plasma [5].

In order to establish a diagnosis of D-2-hydroxyglutaric aciduria, it is essential to demonstrate elevated levels of d-2-hydroxyglutaric acid in the urine and accumulation in plasma and CSF. Additionally, neuroradiological profiles can be used to differentiate between L-2- and D-2-hydroxyglutaric aciduria [3][4].

References: [1] M Kranendijk · 2012 · Cited by 312 [3] Diagnosis is confirmed by a large excretion of d-2-hydroxyglutaric acid in the urine and accumulation in plasma and CSF. [4] Distinct neuroradiological profiles are associated with L-2- and D-2-hydroxyglutaric aciduria, allowing a presumptive diagnosis prior to metabolic and genetic analysis. [5] by K Muthusamy · 2019 · Cited by 14 [6] Differential diagnosis. Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglurac acid. [9] Jul 22, 2024 — The absence of brainstem involvement in L-2-Hydroxyglutaric aciduria is an important differentiating feature.