The $SDHA$ gene provides the blueprint for a protein that is a fundamental piece of the cellular machinery responsible for energy production within the mitochondria. A mutation in the $SDHA$ gene disrupts the cell’s metabolic processes. This disruption can lead to the development of specific tumor types and, in certain cases, severe neurological disorders. Understanding the health risks associated with an $SDHA$ mutation requires recognizing the protein’s normal function as a gatekeeper of metabolism.
The Normal Role of SDHA in Cellular Energy Production
The $SDHA$ gene directs the production of a protein that is a core component of the Succinate Dehydrogenase (SDH) complex, also known as Mitochondrial Complex II. This protein complex is positioned in the inner membrane of the mitochondria, linking two central metabolic pathways. Its primary job is to ensure the continuous flow of energy that powers the cell.
The SDHA protein contains the binding site for flavin adenine dinucleotide (FAD), which facilitates the chemical reaction. The SDHA subunit catalyzes the conversion of succinate into fumarate. This conversion is a necessary step in the tricarboxylic acid (TCA) cycle, generating intermediate compounds for energy production.
The SDH complex also acts as Complex II in the electron transport chain (ETC), the final stage of energy generation. Electrons released during the succinate-to-fumarate conversion are transferred through the SDH complex into the ETC. This process supports oxidative phosphorylation, which creates the cell’s main energy currency, adenosine triphosphate (ATP).
The Metabolic Consequences of SDHA Dysfunction
A mutation in the $SDHA$ gene prevents the formation of a functional SDH complex, derailing the metabolic processes it controls. When the enzyme cannot convert succinate to fumarate, succinate concentration builds up inside the mitochondria. This excess succinate then spills into the cytoplasm, acting as a signaling molecule.
The accumulated succinate is referred to as an “oncometabolite” because it contributes to tumor development. It achieves this by inhibiting $\alpha$-ketoglutarate-dependent dioxygenases. These enzymes normally regulate gene activity, including the breakdown of Hypoxia-Inducible Factor ($\text{HIF-}\alpha$).
By blocking $\text{HIF-}\alpha$ breakdown, the excess succinate causes the protein to stabilize and accumulate, mimicking a state of low oxygen (hypoxia). This “pseudo-hypoxia” triggers the cell to activate genes that promote growth, cell division, and new blood vessel formation. This explains how a defect in a single metabolic enzyme can lead to the uncontrolled proliferation of cells.
Conditions Linked to SDHA Gene Mutations
The primary health risk associated with inheriting a single $SDHA$ mutation is the development of hereditary tumor syndromes. These are most commonly Paraganglioma (PGL) and Pheochromocytoma (PHEO), collectively known as PPGL. SDHA-linked PPGLs typically present as solitary neuroendocrine tumors, frequently located in the head, neck, or abdomen, including the adrenal glands.
The penetrance, or lifetime risk of developing a tumor, is estimated to be around 10% by age 70, which is lower compared to other related gene mutations. Individuals with an $SDHA$ mutation also face risk of developing Gastrointestinal Stromal Tumors (GISTs), which are tumors of the digestive tract, most often found in the stomach. These SDHA-deficient GISTs often arise in children or young adults.
A distinctly different condition linked to the $SDHA$ gene is Leigh Syndrome, a severe, progressive neurological disorder. This condition is associated with a complete loss of SDH function, occurring when an individual inherits mutations in both copies of the $SDHA$ gene. Leigh Syndrome usually presents in infancy with symptoms such as psychomotor regression, muscle weakness, and breathing difficulties, reflecting profound energy deficiency in the central nervous system.
Understanding Inheritance and Genetic Screening
$SDHA$ gene mutations linked to tumor syndromes are inherited in an autosomal dominant pattern. This means only one mutated copy of the gene is needed to carry the risk. However, tumor formation requires a “second hit,” where the remaining normal copy of the gene is lost or inactivated in a specific cell. This leads to the total loss of SDHA function and the accumulation of succinate.
Genetic screening for the $SDHA$ gene is performed using next-generation sequencing panels, which analyze several related genes simultaneously. Testing is recommended for individuals diagnosed with PPGL or GIST, or for asymptomatic relatives of known mutation carriers (cascade screening). Identifying the specific mutation allows for personalized monitoring and surveillance.
Proactive surveillance is recommended for individuals who test positive for an $SDHA$ mutation to detect tumors at an early, treatable stage. This surveillance often involves annual biochemical screening, measuring levels of catecholamine metabolites (like metanephrines) in the blood or urine. Regular radiological screening, such as Whole-Body Magnetic Resonance Imaging (MRI), is also utilized to scan for new tumor growth in the head, neck, and abdomen, often starting in the early teenage years.