Mitochondrial complex II deficiency is a condition that disrupts cellular energy production. Our cells contain mitochondria, which generate the energy necessary for the body to function. Within mitochondria, the electron transport chain is a series of protein complexes that produce energy. Mitochondrial Complex II, or succinate dehydrogenase (SDH), is a component of this chain and also participates in another energy-producing process called the Krebs cycle.
This enzyme complex oxidizes a molecule called succinate to fumarate. The electrons released are passed down the electron transport chain, contributing to the generation of adenosine triphosphate (ATP), the cell’s energy currency. When Complex II is deficient, this enzyme malfunctions, creating a bottleneck in energy production that results in an energy shortage within the cells.
The Genetic Basis of the Deficiency
Mitochondrial complex II deficiency is an inherited genetic disorder from mutations in nuclear DNA. The instructions for building the Complex II enzyme are encoded by the SDHA, SDHB, SDHC, and SDHD genes, which provide blueprints for its four protein subunits. Another gene, SDHAF1, creates a protein that helps assemble these subunits, and a mutation in any of these genes can prevent the enzyme from functioning correctly.
This error can cause a subunit to be misshapen, unstable, or absent, preventing the enzyme from functioning. The inheritance pattern for the condition varies. For forms affecting the nervous system, the pattern is often autosomal recessive, meaning an individual inherits a mutated gene from both parents, who are carriers without symptoms.
When mutations are in the SDHB, SDHC, or SDHD genes, the condition can be inherited in an autosomal dominant pattern. Inheriting one copy of the mutated gene is enough to increase the risk of developing certain tumors. This genetic difference explains the disorder’s varied presentation, from neurological disease to tumor predisposition.
Recognizing Signs and Symptoms
The clinical signs of this deficiency are varied, depending on which tissues are most deprived of energy. Because the brain has high energy demands, neurological symptoms are common. In infants and children, this can present as hypotonia (low muscle tone) that makes an infant seem “floppy,” along with developmental delays in motor skills and cognitive function.
Other neurological issues include seizures and movement disorders like dystonia, which causes involuntary muscle contractions. Brain imaging may reveal structural abnormalities, with some individuals developing a pattern of brain damage known as Leigh syndrome. This neurological disorder usually appears in the first year of life.
Muscle tissue is also impacted by the energy deficit, leading to myopathy, which causes weakness and fatigue. Individuals may experience exercise intolerance, where minor exertion leads to exhaustion and muscle pain. In some cases, this can cause rhabdomyolysis, a condition where muscle fibers break down and release their contents into the bloodstream.
Certain gene mutations create a predisposition for developing specific tumors. The most common are paragangliomas (tumors from nerve tissue) and pheochromocytomas (paragangliomas of the adrenal glands). This connection shows that Complex II dysfunction can lead to energy failure and uncontrolled cell growth in certain tissues.
The Diagnostic Process
Diagnosis begins with a clinical evaluation of symptoms and family medical history. A brain magnetic resonance imaging (MRI) scan is a common step to identify changes like the lesions associated with Leigh syndrome or brain tissue atrophy, which can point toward a mitochondrial disorder.
Biochemical tests on blood, urine, or cerebrospinal fluid look for metabolic markers, such as elevated lactic acid, that suggest a problem with energy production. These findings are not specific to Complex II deficiency and require more definitive testing.
A tissue biopsy, usually of muscle or skin, allows for an enzyme assay to directly measure Complex II activity. A reduction in its activity is a strong indicator of the deficiency. Final confirmation comes from genetic testing, which analyzes the patient’s DNA to identify the specific mutation in an SDH gene.
Management and Therapeutic Approaches
There is no cure for this deficiency, so treatment focuses on managing symptoms and providing supportive care. This requires a multidisciplinary team of specialists, including neurologists, geneticists, cardiologists, and therapists. The goal is to address the specific needs of each patient, which vary based on the condition’s severity and the organs affected.
Physical and occupational therapy are used to manage muscle weakness, improve motor skills, and maintain mobility. Medications may be prescribed to control neurological symptoms like seizures or movement disorders. Nutritional support is also considered to ensure patients receive adequate calories and nutrients.
Some patients are treated with a combination of vitamins and supplements, though their effectiveness is unproven and variable. Commonly used supplements include coenzyme Q10 (ubiquinone) and riboflavin (vitamin B2), which are molecules involved in the electron transport chain. The goal is that high doses might improve the function of the residual enzyme.
For individuals with mutations predisposing them to tumors, management is different. These patients require lifelong surveillance with periodic imaging and biochemical tests to monitor for paragangliomas and pheochromocytomas. If tumors are detected, they are managed by specialists with treatments like surgery or other targeted therapies.