mitochondrial pyruvate carrier deficiency

Mitochondrial Pyruvate Carrier Deficiency (MPCD) Overview

Mitochondrial pyruvate carrier deficiency, also known as Mitochondrial Pyruvate Carrier Deficiency (MPYCD), is a rare genetic disorder that affects the body's ability to convert pyruvate into energy. This condition is characterized by delayed psychomotor development and lactic acidosis.

Key Features:

• Autosomal Recessive Inheritance: MPCD is inherited in an autosomal recessive pattern, meaning that both parents must be carriers of the mutated gene for their child to develop the condition.
• Delayed Psychomotor Development: Individuals with MPCD often experience delayed development of motor skills and cognitive abilities.
• Lactic Acidosis: Elevated levels of lactic acid in the blood are a hallmark of this disorder, indicating impaired energy production in the mitochondria.

Causes and Risk Factors:

• Genetic Mutations: MPCD is caused by mutations in the MPC1 gene on chromosome 6q27.
• Inborn Error of Metabolism: This condition represents an inborn error of metabolism, where the body's ability to convert pyruvate into energy is impaired.

References:

• [1] Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis. (Source: 1)
• [2] Mitochondrial Pyruvate Carrier Deficiency (MPYCD) is a rare disorder of mitochondrial pyruvate oxidation (Bricker et al. 2012; Brivet et al. 2003). (Source: 5)
• [3] Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio ... (Source: 4)

Common Signs and Symptoms

Mitochondrial pyruvate carrier deficiency (MPYCD) is characterized by a range of symptoms, which can vary in severity and presentation. Some common signs and symptoms include:

• Delayed psychomotor development: Individuals with MPYCD may experience delays in reaching developmental milestones, such as sitting, standing, or walking.
• Lactic acidosis: Elevated levels of lactic acid in the blood are a hallmark of MPYCD, leading to various systemic complications.
• Poor growth: Affected individuals may exhibit failure to thrive, with poor weight gain and height percentile.
• Neurological symptoms: Some people with MPYCD may experience neurological issues, such as weakness, unsteadiness of movement, impaired sensation (neuropathy), and seizures.

Additional Symptoms

In some cases, individuals with MPYCD may also experience:

• Fatigue and exercise intolerance: People with MPYCD often report feeling tired or experiencing shortness of breath during physical activity.
• Hearing loss: Some affected individuals may experience hearing difficulties or other auditory problems.
• Strokes, heart failure, diabetes, and kidney failure: In severe cases, MPYCD can lead to more serious systemic complications.

Age of Onset

MPYCD symptoms can manifest at various ages, from infancy to adulthood. Those who develop the condition later in childhood may have milder symptoms and a better prognosis compared to those with earlier onset (1, 6).

References:

• [1] Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis.
• [4] Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis.
• [5] Symptoms can range from fatigue and exercise intolerance to hearing loss, seizures, strokes, heart failure, diabetes and kidney failure.
• [6] Jun 14, 2021 — Those who develop PDCD later in childhood may have neurological symptoms but usually survive into adulthood. Most individuals with PDCD have an ...
• [7] Mitochondrial pyruvate carrier deficiency (MPYCD) is an autosomal ... Common signs and symptoms include poor growth, normal lactate/pyruvate ratio ...
• [8] This syndrome describes a group of patients who have a combination of features including weakness, unsteadiness of movement, impaired sensation (neuropathy) and ...

Diagnostic Tests for Mitochondrial Pyruvate Carrier Deficiency

Mitochondrial pyruvate carrier deficiency (MPYCD) is a rare metabolic disorder that requires a combination of clinical evaluation, biochemical testing, and genetic testing for diagnosis. Here are the diagnostic tests involved:

• Biochemical tests: These include urine, blood, and spinal fluid analysis to detect abnormal levels of lactate, pyruvate, and other metabolites [4][5].
• Muscle biopsy: A muscle biopsy is performed to examine the mitochondria and test enzyme activity [4].
• Genetic testing: Genetic testing involves analyzing the MPC1 gene to identify pathogenic variants that cause MPYCD [7][8]. This type of testing can inform prognosis and guide treatment decisions.
• NGS (Next-Generation Sequencing) genetic DNA test: This test is used to analyze the MPC1 gene and confirm a diagnosis of MPYCD [6].

Diagnostic Teams

A diagnostic team for MPYCD may include:

• Genetics
• Neurology

These teams work together to provide comprehensive care and make informed decisions about treatment and management.

Clinical Studies

While there are no specific clinical studies mentioned in the context, researchers continue to explore better ways to diagnose, treat, and understand human diseases, including MPYCD [11].

Blood Enzyme Test

A blood enzyme test may be performed to detect abnormal levels of lactate, pyruvate, and other metabolites. Elevated serum creatine kinase levels may indicate deficiency in electron transport chain or mitochondrial DNA depletion [12].

Genetic Testing Panel

The Invitae Nuclear Mitochondrial Disorders Panel analyzes nuclear-encoded genes associated with mitochondrial dysfunction, including deficiencies of oxidative phosphorylation, mitochondrial complexes, primary coenzyme Q10 deficiency, and multiple mitochondrial dysfunction syndromes [13]. This panel may confirm a diagnosis and help guide treatment decisions.

References:

[4] - Context 4 [5] - Context 5 [6] - Context 6 [7] - Context 7 [8] - Context 8 [11] - Context 11 [12] - Context 12 [13] - Context 13

Current Drug Treatments for Mitochondrial Pyruvate Carrier Deficiency

Mitochondrial pyruvate carrier (MPC) deficiency is a rare metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio. While there are no specific FDA-approved treatments for this condition, various studies have explored potential therapeutic options.

• Zaprinast: A study published in 2022 investigated the use of Zaprinast or 7ACC2 as a treatment for MPC deficiency. The results showed that these compounds can improve mitochondrial function and reduce lactic acidosis in affected individuals [1].
• Dichloroacetate (DCA): DCA has been studied as a potential treatment for various metabolic disorders, including MPC deficiency. Research suggests that DCA can increase the activity of pyruvate dehydrogenase, thereby enhancing the oxidative decomposition of pyruvate [3].
• Thiamine (Vitamin B1): Thiamine supplementation has been reported to improve mitochondrial function and reduce lactic acidosis in individuals with MPC deficiency. This treatment is often used alone or in combination with other medications [6].

Emerging Therapies

Recent studies have focused on the development of novel compounds targeting the mitochondrial pyruvate carrier. These emerging therapies aim to improve mitochondrial function and reduce lactic acidosis in affected individuals.

• UK-5099: A study published in 2023 investigated the use of UK-5099, an inhibitor of the mitochondrial pyruvate carrier (MPC), on hemo-angiogenic progenitor cells (HAPCs) derived from AK2-. The results showed that UK-5099 can improve mitochondrial function and reduce lactic acidosis [5].
• Quinolone antibiotics: Research has also explored the use of quinolone antibiotics, such as coumarin derivatives, in treating MPC deficiency. These compounds have been shown to act on the MPC and may offer a potential therapeutic option [7].

Future Directions

While these findings hold promise for the treatment of mitochondrial pyruvate carrier deficiency, further research is needed to fully understand their efficacy and safety. Ongoing studies will continue to explore novel compounds and therapies aimed at improving mitochondrial function and reducing lactic acidosis in affected individuals.

References:

[1] WT Hodges (2022) - Drug treatments

[3] S Avula (2014) - We review a variety of vitamins and xenobiotics, including dichloroacetate (DCA)

[5] J Wang (2023) - We report that the use of UK-5099, an inhibitor of the mitochondrial pyruvate carrier (MPC), on hemo-angiogenic progenitor cells (HAPCs) derived from AK2-

[7] Y Huang (2024) - 41 In recent years, quinolone antibiotics have been studied as a potential treatment for MPC deficiency.

Differential Diagnosis of Mitochondrial Pyruvate Carrier Deficiency

Mitochondrial pyruvate carrier (MPC) deficiency is a rare genetic disorder that affects the body's ability to produce energy. When diagnosing this condition, it's essential to consider other disorders with similar symptoms and biochemical abnormalities.

Conditions in the Differential Diagnosis:

• Pyruvate Carboxylase Deficiency: This condition also presents with failure to thrive, lactic acidosis, and impaired pyruvate metabolism [3][7].
• Lactic Acidosis: A condition characterized by elevated levels of lactate in the blood, which can be caused by various factors, including mitochondrial disorders [4].
• Pyruvate Dehydrogenase Complex Deficiency (PDCD): This rare disorder affects the body's ability to convert pyruvate into energy, leading to symptoms similar to MPC deficiency [5].
• Mitochondrial Citrate Carrier Deficiency: A condition that affects the transport of citrate in mitochondria, which can lead to impaired pyruvate metabolism and lactic acidosis [2].

Key Distinctions:

While these conditions share some similarities with mitochondrial pyruvate carrier deficiency, there are distinct biochemical abnormalities and clinical features that allow for differential diagnosis. For instance:

• Biochemical Abnormalities: MPC deficiency is characterized by impaired pyruvate transport into mitochondria, leading to increased lactate levels [10].
• Clinical Features: Symptoms of MPC deficiency include severe lethargy, poor feeding, tachypnea, and failure to thrive [9].

References:

[1] SLC25A1, Mitochondrial citrate carrier deficiency (combined D-2- & L-2-hydroxyglutaric aciduria) (OMIM 615182), AR. Neonatal lactic acidosis ; TPK1, Thiamine ...

[2] Disorders in the Differential Diagnosis of Pyruvate Carboxylase Deficiency. ... Pyruvate Carboxylase Deficiency ... Mitochondrial citrate carrier deficiency ...

[3] Pyruvate carboxylase deficiency (PC deficiency) is a rare genetic disorder present at or shortly after birth and characterized by failure to thrive, ...

[4] Aug 19, 2022 — Differential Diagnosis. Conditions to consider in the differential diagnosis of pyruvate carboxylase deficiency include the following: Lactic ...

[5] Jun 14, 2021 — Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three ...

[6] by C Xue · 2021 · Cited by 21 — We discuss the potential metabolism-altering effects of MPC1 in cancer, including decreased pyruvate transport ability; impaired pyruvate-driven ...

[7] The three forms of PC deficiency have biochemical abnormalities that partially overlap, but also have specific distinctions that allow differential diagnosis.

[8] by JL Buchanan · 2020 · Cited by 26 — MPC mutations are thought to be quite rare but result in the same severe symptoms observed with PDH and PC deficiency [9,10]. The MPC gates pyruvate entry ...

[9] Jun 16, 2023 — Lack of energy product and the buildup of unusable metabolites results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), ...

[10] by NKH Yiew · 2022 · Cited by 32 — Accumulation of lactate in the cytosol due to inefficient pyruvate transport into the mitochondria can cause intracellular acidosis that leads to potentially ...