mitochondrial complex III deficiency

Mitochondrial complex III deficiency is a genetic condition that affects several parts of the body, including the brain, kidneys, liver, heart, and skeletal muscles [1][2]. It is a severe multisystem disorder with onset at birth, characterized by lactic acidosis, hypotonia, hypoglycemia, failure to thrive, and other symptoms [3].

The condition can manifest in different forms, including fatal infantile encephalomyopathy, congenital liver disease, and progressive neurodegeneration [10]. Clinical features of mitochondrial complex III deficiency include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness, and other systemic problems [8].

Mitochondrial complex III deficiency is an autosomal recessive disorder, meaning that it is inherited in a recessive pattern and affects both males and females equally. The condition is caused by mutations in the genes that encode for the subunits of mitochondrial complex III, which is essential for the production of energy in cells [6].

In some cases, mitochondrial complex III deficiency can be associated with other conditions, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. The exact prevalence of mitochondrial complex III deficiency is unknown, but it is considered to be a rare condition [7].

Symptoms of Mitochondrial Complex III Deficiency

Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and muscles used for movement (skeletal muscles). The signs and symptoms of this condition usually begin in infancy but can appear later.

Common Symptoms:

• Poor growth
• Muscle weakness, muscle pain, or low muscle tone
• Vision and/or hearing loss
• Developmental delays or issues with cognitive development

Other Possible Symptoms:

• High levels of amino acids in urine (aminoaciduria)
• Brittle hair
• Decreased liver function
• Blocked bile flow from the liver
• Lactic acidosis (buildup of lactic acid in the body)
• Ketoacidosis (buildup of molecules called ketones in the blood)
• High blood pressure
• Ragged-red fibers (a characteristic feature of mitochondrial diseases)

Severity and Age of Onset:

The severity of mitochondrial complex III deficiency can vary greatly, ranging from mild to severe. Some individuals may experience symptoms that are not life-threatening, while others may have a more severe form of the condition that can be fatal in childhood.

References:

• [1] Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body... (Search result 3)
• [2] Symptoms of mitochondrial diseases vary based on the type and location of the affected cells. They can range from mild to severe... (Search result 2)
• [4] ...which summarizes the main symptoms and signs: growth retardation, aminoaciduria, cholestasis, iron overload, and early death (before 5 months of age). (Search result 4)
• [7] People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). (Search result 7)
• [13] Mitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood. (Search result 13)

Note: The references provided are based on the search results and may not be an exhaustive list of all relevant sources.

Diagnostic Tests for Mitochondrial Complex III Deficiency

Mitochondrial complex III deficiency can be diagnosed through various tests, which are essential for accurate diagnosis and treatment planning.

• Blood enzyme test: This test measures lactate and pyruvate levels in the blood. Elevated levels may indicate a deficiency of mitochondrial complex III [5].
• Serum creatine kinase (CK) test: If elevated, this test can suggest a deficiency of mitochondrial complex III [5].
• Exome sequencing, genome sequencing, and mitochondrial sequencing: These tests analyze nuclear DNA and mtDNA simultaneously to identify genetic mutations causing the condition [4].
• Exercise testing: This test is used for research purposes and as a clinical diagnostic tool for mitochondrial myopathy [8].
• Laboratory studies: Increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts can be detected through laboratory studies [9].

Other Diagnostic Methods

In addition to these tests, other methods may be used to diagnose mitochondrial complex III deficiency. These include:

• Review of medical and family history
• Complete physical examination
• Neurological examination
• Brain imaging: This test shows a pattern consistent with mitochondrial complex III deficiency [9]

Important Considerations

It is essential to note that the diagnosis of mitochondrial complex III deficiency requires a comprehensive approach, including a review of medical and family history, complete physical examination, neurological examination, and

Treatment Options for Mitochondrial Complex III Deficiency

Mitochondrial complex III deficiency, a genetic condition affecting energy production in cells, currently has no cure. However, various treatments aim to alleviate symptoms and improve quality of life.

• Metabolic therapies: Riboflavin, thiamine, biotin, co-enzyme Q10, carnitine, and the ketogenic diet are among the metabolic therapies that may be effective in treating mitochondrial complex III deficiency [1][3].
• CoQ10 supplementation: Coenzyme Q10 (CoQ10) has been shown to be an effective treatment option for patients with a rare congenital CoQ10 deficiency [8]. A phase 2 clinical trial evaluated the efficacy of CoQ10 in adult patients, demonstrating its potential as a therapeutic agent.
• Idebenone/ubiquinone: This compound can bypass complex I altogether and provide electrons directly to complex III or increase available substrate for complex II, potentially benefiting mitochondria with complex I deficiency [9].
• KH176 and succinate pro-drugs: These drugs have the potential to scavenge reactive oxygen species and may be beneficial in treating mitochondrial diseases.
• Vitamin K3 and vitamin C: A patient with mitochondrial myopathy due to complex III deficiency showed clinical improvement after treatment with vitamin K3 (menadiol sodium diphosphate) and vitamin C [10].

Emerging Therapies

Recent research has explored the potential of dietary supplements, exercise therapies, and emerging treatments in addressing mitochondrial diseases. These include:

• Dietary supplement therapies: Certain nutrients, such as arginine, may be beneficial in treating mitochondrial diseases [15].
• Exercise therapies: Exercise can have a positive impact on mitochondrial function and overall health.
• Emerging therapies: Research is ongoing to develop new treatments that target specific aspects of mitochondrial dysfunction.

Current Treatment Limitations

While these treatment options show promise, it's essential to note that current treatments for mitochondrial complex III deficiency are largely symptomatic and do not significantly alter the disease course. Further research is needed to develop more effective therapeutic strategies.

References:

[1] Ehinger et al., 2016 [3] Zhang et al., 2020 [8] CoQ10 clinical trial data [9] Idebenone/ubiquinone study findings [10] Vitamin K3 and vitamin C treatment outcomes [15] Arginine supplementation benefits

Mitochondrial complex III deficiency, also known as ubiquinone-cytochrome c oxidoreductase deficiency, has several differential diagnoses that can be considered in patients presenting with similar symptoms.

• Fatty acid oxidation defects: These are a group of disorders that affect the metabolism of fatty acids, which are an important source of energy for the body. Symptoms can include hypoglycemia, lactic acidosis, and liver dysfunction [1][2].
• Glycogen storage diseases (GSDs): GSDs are a group of inherited disorders that affect the metabolism of glycogen, a complex carbohydrate stored in the liver and muscles. Symptoms can include hypoglycemia, lactic acidosis, and muscle weakness [3].
• Mitochondrial oxidative phosphorylation defects: These are a group of disorders that affect the production of energy in cells through the process of oxidative phosphorylation. Symptoms can include hypoglycemia, lactic acidosis, and liver dysfunction [4].

It's worth noting that mitochondrial complex III deficiency is a rare disorder, and differential diagnoses should be considered based on the patient's clinical presentation and laboratory results.

References:

[1] Mori M (2015) Ophthalmologic and audiologic exams were normal. Differential diagnoses included fatty acid oxidation defects, GSDs, and mitochondrial oxidative phosphorylation defects [2]. [3] Fernández-Vizarra E (2015) A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure [4]. [5] Al Qurashi M (2022) A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure [6].