Mitochondrial complex II deficiency is a rare genetic disorder that affects how the body generates energy. Mitochondria, often called the “powerhouses” of cells, produce most of the body’s energy in the form of adenosine triphosphate (ATP), which fuels various cellular processes.
When Complex II, a specific part of this energy production system, is deficient, cells do not receive enough ATP. This leads to a range of health issues across different organ systems. The condition is uncommon, with about 61 genetically confirmed cases reported as of 2020, though other cases have been identified through biochemical and histological analyses.
Understanding Mitochondrial Complex II
Mitochondria produce ATP through oxidative phosphorylation, a process involving the electron transport chain (ETC) in the inner mitochondrial membrane. Complex II, also known as succinate dehydrogenase (SDH), is one of several protein complexes in the ETC. It plays a dual role in cellular energy production by linking the Krebs cycle with the electron transport chain.
In the Krebs cycle, Complex II helps convert succinate to fumarate, transferring electrons to the ETC. These electrons are then passed along the chain, contributing to ATP production.
When Complex II is deficient, this crucial step in both the Krebs cycle and the electron transport chain is impaired, reducing ATP production. This energy disruption can cause cellular dysfunction and damage, especially in tissues with high energy demands like the brain, muscles, and heart.
The deficiency is primarily caused by genetic mutations in nuclear DNA that encode Complex II subunits or its assembly factors. Mutations in genes such as SDHA, SDHB, SDHC, SDHD, and SDHAF1 can lead to this condition. These genetic changes are often inherited in an autosomal recessive pattern, meaning an individual receives a faulty gene copy from each parent.
Recognizing the Signs
Symptoms of mitochondrial complex II deficiency vary widely in severity and age of onset, even among family members. The condition can affect multiple organ systems, including the brain, peripheral nervous system, heart, liver, kidneys, and muscles.
Neurological symptoms are common, including developmental delays, intellectual disability, and movement problems like ataxia. Seizures and microcephaly (a smaller-than-expected head) are also observed, especially in severe cases. Some individuals may experience vision and hearing impairment.
Muscle weakness (myopathy) and exercise intolerance are frequent. Muscle pain and rhabdomyolysis (breakdown of muscle tissue) can occur. Heart problems, such as cardiomyopathy (heart muscle disease) and arrhythmias (irregular heartbeats), are also reported.
Kidney dysfunction, liver issues, and endocrine problems like diabetes can also arise. In infants, symptoms might include poor growth, feeding difficulties, and decreased muscle tone. The disorder is often progressive, meaning symptoms may worsen over time.
Identifying the Condition
Diagnosing mitochondrial complex II deficiency involves a thorough clinical evaluation based on an individual’s symptoms and family medical history. Given the varied presentation, a combination of signs affecting multiple organ systems often prompts suspicion of a mitochondrial disorder.
Preliminary tests include blood and urine analyses for biochemical markers of mitochondrial dysfunction. Elevated levels of lactic acid and pyruvate in blood or cerebrospinal fluid can indicate energy metabolism issues. Further investigation may involve a muscle biopsy, a procedure where a small sample of muscle tissue is taken for examination.
Muscle biopsies can reveal abnormalities like “ragged red fibers,” which are muscle cells with abnormal mitochondria. Enzyme activity assays on muscle tissue can also measure Complex II activity to determine if it is deficient. The most definitive diagnosis is made through genetic testing, which identifies mutations in relevant genes. Whole exome sequencing or specific gene panels, which analyze genes like SDHA, SDHB, SDHC, SDHD, and SDHAF1, are used to pinpoint the exact genetic changes. Genetic counseling is often recommended for affected individuals and their families to understand inheritance patterns and reproductive risks.
Managing Mitochondrial Complex II Deficiency
Currently, there is no cure for mitochondrial complex II deficiency, and management primarily focuses on supportive care and addressing symptoms. A multidisciplinary approach involving various medical specialists is employed to manage the diverse manifestations of the disorder.
Medications are often prescribed to control specific symptoms, such as anti-seizure medications for individuals experiencing seizures. Cardiac medications may be used to manage heart problems like cardiomyopathy or arrhythmias. Nutritional support and dietary modifications are also considered, with some individuals benefiting from supplements like coenzyme Q10 (CoQ10), riboflavin, and L-carnitine.
CoQ10 supplementation, often given in doses of 5-30 mg/kg/day divided into 2-3 doses, aims to support the electron transport chain and reduce oxidative stress. Riboflavin, typically administered at 100-400 mg/day, can be particularly helpful in some mitochondrial disorders by improving mitochondrial function. L-carnitine, at doses of 50-100 mg/kg/day, may also be used, especially if carnitine deficiency is present.
Physical, occupational, and speech therapies are important components of care to help improve functional abilities and enhance the overall quality of life. Regular monitoring of affected organ systems, including neurological, cardiac, ophthalmological, and muscular systems, is also performed to detect and manage complications early. While promising new therapies are being explored in research, such as mitochondria transplantation and gene therapy, these are still in experimental stages.