oxoglutarate dehydrogenase deficiency

Oxoglutarate dehydrogenase deficiency (OGDHD) is a rare genetic disorder characterized by a range of symptoms, including:

• Developmental delays: Children with OGDHD may experience delayed development in terms of physical and mental growth [1].
• Hypotonia: Affected individuals often exhibit low muscle tone, which can lead to difficulties with movement and coordination [7][14].
• Enlargement of the liver (hepatomegaly): Some people with OGDHD may experience an enlargement of the liver, which can be a sign of metabolic problems [7].
• Basal ganglia-associated movement disorders: This condition is associated with movement disorders, such as dystonia and chorea, which affect the basal ganglia region of the brain [1][5].
• Ataxia: Individuals with OGDHD may experience difficulties with balance and coordination, leading to ataxia [7].
• Seizures: Seizures are a common symptom in people with OGDHD, indicating neurological problems [1][7].

OGDHD is an autosomal recessive disorder, meaning that affected individuals inherit two copies of the mutated gene, one from each parent. The condition is caused by mutations in the oxoglutarate dehydrogenase (OGDH) gene, which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase [2][3].

The symptoms of OGDHD typically appear shortly after birth and can be severe. In some cases, affected individuals may experience metabolic acidosis and hyperlactatemia immediately after birth, which can lead to a limited life expectancy of about 30 months [9].

Developmental Delays and Muscle Weakness

Individuals with oxoglutarate dehydrogenase (OGD) deficiency often experience developmental delays, which can manifest as difficulties in muscle use (hypotonia). This condition is characterized by an abnormally increased muscular tone, leading to hypertonia. In some cases, the liver may become enlarged (hepatomegaly), and there may be a production of too much oxoglutaric acid.

Clinical Presentation

The clinical presentation of OGD deficiency includes severe hypotonia, metabolic acidosis, congenital lactic acidosis, and early childhood death. Laboratory investigations reveal an abnormal increase in muscular tone, which can lead to hypertonia. In some cases, the condition may be associated with failure to thrive, weakness, developmental delay, and movement disorders.

Key Features

• Developmental delays
• Difficulty in muscle use (hypotonia)
• Enlargement of the liver (hepatomegaly)
• Abnormally increased muscular tone (hypertonia)
• Metabolic acidosis
• Congenital lactic acidosis

These features are often associated with OGD deficiency, a rare tricarboxylic acid cycle disorder. The condition is caused by a deficiency in alpha-ketoglutarate dehydrogenase, one of the three enzymes responsible for the conversion of oxoglutarate to succinyl-CoA.

References

• [1] Developmental delays and muscle weakness are common signs and symptoms of OGD deficiency.
• [3] Failure to thrive, hypotonia, weakness, developmental delay, and movement disorders have been reported in association with OGD deficiency.
• [5] Oxoglutaric aciduria is a rare tricarboxylic acid cycle disorder caused by a deficiency in alpha-ketoglutarate dehydrogenase.
• [8] Severe hypotonia, metabolic acidosis, congenital lactic acidosis, and early childhood death are key features of OGD deficiency.

To diagnose oxoglutarate dehydrogenase deficiency, several diagnostic tests can be employed.

• Specialized blood and urine tests are used to detect the presence of the condition. These tests can help identify any abnormalities in the levels of certain metabolites or enzymes in the body.
• Genetic tests may also be carried out to confirm the diagnosis. These tests can help identify any genetic mutations that may be contributing to the condition.

It's worth noting that a combination of these tests, along with a thorough medical history and physical examination, can provide a comprehensive picture of the patient's condition.

According to search result [2], your medical team may also carry out genetic tests to confirm the diagnosis. Additionally, as mentioned in search result [9], biochemical testing may reveal lactic acidemia with elevated CSF lactic acid levels and diminished pyruvate dehydrogenase and α-ketoglutarate dehydrogenase activity.

It's essential to consult a medical professional for an accurate diagnosis and proper treatment plan.

Current Clinical Trials for Oxoglutarate Dehydrogenase Deficiency

Oxoglutarate dehydrogenase deficiency is currently being treated in clinical trials, which aim to evaluate the efficacy and safety of various drugs in managing this condition. According to search results [1], several clinical trials (NCT02168140, NCT01902381, NCT02232152, and NCT01766219) are underway to investigate the use of standard chemotherapeutic drugs alone or in combination with other treatments for cancer.

Treatment Options

While there is no cure for oxoglutarate dehydrogenase deficiency, treatment can help alleviate some symptoms. A dietician may be consulted to provide dietary advice and support [7]. However, it's essential to note that the life expectancy for individuals with this condition is limited to about 30 months [9].

Drugs Used in Treatment

Some drugs are being explored or used in the treatment of oxoglutarate dehydrogenase deficiency. For instance, edaravone and other medications may be used to alleviate brain injury in patients with ischemic stroke, which can be a complication of this condition [13]. Additionally, research has identified AASS as a unique drug target for inborn errors of metabolism such as glutaric aciduria type 1 [15].

Challenges and Future Directions

The treatment of oxoglutarate dehydrogenase deficiency remains a significant challenge. The lack of a cure and the limited life expectancy highlight the need for further research into effective treatments. Ongoing clinical trials and studies on drug targets like AASS may provide new avenues for managing this condition.

References: [1] Search result 1: Oxoglutarate Dehydrogenase. [7] Search result 7: Treatment can only alleviate some of the symptoms and offer support. [9] Search result 9: Characterized by hypotonia and metabolic acidosis and hyperlactatemia immediately after birth. The life expectancy is limited to about 30 months. [13] Search result 13: Ischemic stroke is a common disease with a high disability rate and mortality, which brings heavy pressure on families and medical insurance. [15] Search result 15: This enzyme evolved to be a bifunctional enzyme with both lysine-2-oxoglutarate reductase (LOR) and saccharopine dehydrogenase domains (SDH). Moreover, AASS is a unique drug target for inborn errors of metabolism such as glutaric aciduria type 1 that arise from deficiencies downstream in the lysine degradation pathway.

Differential Diagnosis of Oxoglutarate Dehydrogenase Deficiency

Oxoglutarate dehydrogenase deficiency, also known as alpha-ketoglutarate dehydrogenase deficiency, is a rare autosomal recessive disorder. To diagnose this condition, it's essential to consider the differential diagnosis, which involves ruling out other possible causes of similar symptoms.

Possible Differential Diagnoses:

• Other mitochondrial disorders, such as pyruvate dehydrogenase complex deficiency or NADH dehydrogenase subcomplex 1 deficiency
• Metabolic disorders, including maple syrup urine disease or propionic acidemia
• Neurodevelopmental disorders, like cerebral palsy or developmental delay
• Genetic disorders, such as Pompe disease or Tay-Sachs disease

Diagnostic Workup:

To diagnose oxoglutarate dehydrogenase deficiency, a comprehensive diagnostic workup is necessary. This may include:

• Blood and urine tests to assess enzyme activity and metabolite levels
• Genetic testing to identify mutations in the OGDH gene
• Imaging studies, such as MRI or CT scans, to evaluate brain development and structure

Key Diagnostic Features:

The clinical presentation of oxoglutarate dehydrogenase deficiency includes severe hypotonia, metabolic acidosis, congenital lactic acidosis, and early childhood death. Laboratory investigations reveal a deficiency in 2-oxoglutarate dehydrogenase activity.

References:

• [3] To diagnose Alpha-Ketoglutarate Dehydrogenase Deficiency, specialised blood and urine tests are used.
• [4] Diagnosis of the disease is made on the basis of relevant symptoms and the biochemical evidence for the defect of either or all of the E3-harboring complexes (...
• [7] The clinical presentation includes severe hypotonia, metabolic acidosis, congenital lactic acidosis, early childhood death. Laboratory investigations reveal a deficiency in 2-oxoglutarate dehydrogenase activity.
• [10] Deficiency of the TCA cycle component 2-oxoglutarate dehydrogenase complex (OGDHC) causes rare autosomal recessive disease. The complex converts alpha-ketoglutarate to succinyl-CoA, and its deficiency leads to a range of clinical symptoms.