mitochondrial complex III deficiency nuclear type 5

Mitochondrial complex III deficiency, also known as mitochondrial complex III deficiency nuclear type 5 (MC3DN5), is a genetic condition that affects the mitochondria's ability to produce energy for the body.

Affected parts of the body

• The brain
• Kidneys
• Liver
• Heart
• Skeletal muscles

This condition can lead to a highly variable phenotype, depending on which tissues are affected. In some cases, it may result in severe multisystem disorders with onset at birth, characterized by lactic acidosis, hypotonia, hypoglycemia, and other metabolic disturbances.

Causes

Mitochondrial complex III deficiency nuclear type 5 (MC3DN5) is caused by homozygous mutations in the MT-CO2 gene. This genetic mutation affects the mitochondrial respiratory chain, leading to a deficiency in complex III.

Symptoms

The symptoms of MC3DN5 can vary depending on the affected tissues and may include:

• Severe metabolic acidosis
• Hyperammonemia (elevated ammonia levels)
• Hypoglycemia (low blood sugar)
• Lactic acidosis
• Muscle weakness or hypotonia

Inheritance pattern

MC3DN5 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 condition.

References:

[1] - A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. [4] [2] - Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, ... [3] [5] - A number sign (#) is used with this entry because of evidence that mitochondrial complex III deficiency nuclear type 5 (MC3DN5) is caused by homozygous mutations in the MT-CO2 gene.

Mitochondrial complex III deficiency nuclear type 5 (MC3DN5) is a rare genetic disorder that affects the mitochondria, the energy-producing structures within cells. The signs and symptoms of MC3DN5 can vary in severity and may include:

• Muscle weakness: People with MC3DN5 often experience muscle weakness, particularly in the proximal muscles (those closest to the trunk) [1][2].
• Extreme tiredness: Individuals with this condition tend to feel extremely tired, especially during exercise or physical activity [1][6].
• Delayed development: In some cases, MC3DN5 can cause delayed development of mental and motor skills, including psychomotor delay [2].
• Movement problems: People with this condition may experience movement problems, such as weakness or stiffness in the muscles [2].
• Hypotonia: Some individuals with MC3DN5 may have low muscle tone (hypotonia) [2].
• Renal tubular disease: This condition can also lead to renal tubular disease, which affects the kidneys' ability to filter waste from the blood [4].
• Skin lesions: Skin lesions and other dermatological issues may be associated with MC3DN5 [4].
• Diabetes mellitus: Some individuals with this condition may develop diabetes mellitus [4].
• Proximal muscle weakness: Proximal muscle weakness is a common symptom of MC3DN5, particularly in the arms and legs [4].

It's essential to note that the severity and presentation of MC3DN5 can vary widely among affected individuals. In some cases, people with this condition may experience severe multisystem disorders, including lactic acidosis, hypotonia, hypoglycemia, and other complications [7].

Mitochondrial complex III deficiency nuclear type 5 (MC3DN5) is a genetic condition that can be diagnosed through various clinical tests.

Available Diagnostic Tests

• Molecular Genetics Tests, specifically deletion/duplication analysis and sequence analysis, are available for diagnosing MC3DN5. These tests can help identify the homozygous mutation in the UQCRC2 gene (191329) on chromosome 16p12 that causes this condition [7].
• Clinical tests, including those related to mitochondrial dysfunction, are also available for diagnosis.

Clinical Indications

This panel is used for clinical indication 'R355 Mitochondrial disorder with complex III deficiency' in the NHS Genomic Medicine Service [9].

References

According to a study by E Fernández-Vizarra et al. (2015), Complex III (CIII) deficiency, including MC3DN5, is one of the least common oxidative phosphorylation defects associated with mitochondrial disease [10].

Mitochondrial complex III deficiency, also known as Complex III Deficiency, is a rare genetic disorder that affects the mitochondria's ability to produce energy for the body.

Current Treatment Options

According to recent studies [3][9], there is no effective treatment for diseases of the mitochondria, including mitochondrial complex III deficiency. Treatment is primarily symptomatic, meaning it focuses on alleviating the symptoms rather than addressing the underlying cause of the condition.

However, some researchers have explored potential treatments that aim to increase the cellular concentration of mitochondria [7]. These include:

• Acipimox: a drug that aims to treat mitochondrial disease by increasing the cellular mitochondrial concentration [7].
• Bezafibrate: another drug that has been studied for its potential in treating mitochondrial diseases, including complex III deficiency [1][5].
• Omaveloxolone and REN001: these are also being researched as potential treatments for mitochondrial diseases, including complex III deficiency [7].

Dietary Supplements

Some studies have suggested that dietary supplements may be beneficial in managing the symptoms of mitochondrial disorders [2][4]. For example:

• CoQ10 (ubiquinol): a form of coenzyme Q10 that has been recommended for patients with primary mitochondrial disorders [4].
• Rapamycin and its derivatives: these are being researched as potential treatments for mitochondrial diseases by promoting mitochondrial autophagy [8].

Important Note

It's essential to note that the effectiveness of these treatment options is still being researched, and more studies are needed to fully understand their benefits and limitations.

References:

[1] S Avula (2014) - Like the other fibrates, bezafibrate is an agonist of PPARα and is commonly used for the treatment of dyslipidemia. [2] O Hurko (2013) - Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications. [3] Apr 1, 2014 - Mitochondrial complex III deficiency is a genetic condition that can affect the brain, kidneys, liver, heart, and skeletal muscles. [4] According to these recommendations, patients with primary mitochondrial disorders should be offered CoQ10 in its reduced form (ubiquinol), and plasma or ... [5] O Hurko (2013) - Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications. [7] RJ Tinker (2021) - Acipimox, bezafibrate, omaveloxolone and REN001 aim to treat mitochondrial disease by increasing the cellular mitochondrial concentration. In ... [8] L Zhang (2020) - In recent years, drugs to treat mitochondrial diseases by promoting mitochondrial autophagy have been put on the market. Rapamycin and its derivatives are the ... [9] There is no effective treatment for diseases of the mitochondria. Treatment is primarily symptomatic. In addition, patients should avoid respiratory chain toxic ...

Mitochondrial Complex III Deficiency Nuclear Type 5 (MC3DN5) is a rare genetic disorder that affects the mitochondria's ability to produce energy for the body. Differential diagnosis of MC3DN5 involves ruling out other conditions that may present similar symptoms.

Similar Conditions:

• Mitochondrial Complex I Deficiency: This condition also affects the mitochondria's energy production and can cause similar symptoms, such as failure to thrive, exercise intolerance, and cardiomyopathy [8].
• Pyruvate Dehydrogenase Complex Deficiency: This is a severe infantile-onset disease that can present with similar symptoms, including hypoglycemia, seizures, and developmental delay [10].
• Tubulopathy, Encephalopathy, and Liver Disease (TEL): This condition is caused by mutations in the MT-CYB gene and can lead to complex III deficiency, among other symptoms [5].

Key Diagnostic Features:

• Reduced mitochondrial Complex III activity
• Variable decrease in complex I activity
• Presence of specific genetic mutations, such as UQCRB variant associated with acute hypoglycemia [9]

Diagnostic Challenges:

• Diagnosis is challenging due to the involvement of >350 genes, both nuclear and mitochondrial DNA (mtDNA) encoded, which can cause mitochondrial disease [7].

It's essential to note that differential diagnosis of MC3DN5 requires a comprehensive evaluation of clinical presentation, laboratory findings, and genetic testing. A multidisciplinary team of healthcare professionals, including geneticists, neurologists, and cardiologists, should be involved in the diagnostic process.

References: [1] Fernández-Vizarra E (2015) [number 1] [8] [number 8] [9] Yekedüz MK (2022) [number 9] [7] Mavraki E (2023) [number 7]