Summary about Disease
Succinate dehydrogenase (SDH) deficiency is a rare genetic disorder that disrupts cellular energy production. SDH is a crucial enzyme complex (Complex II) in the mitochondrial electron transport chain, which is essential for oxidative phosphorylation, the process by which cells generate ATP (the primary energy currency). A deficiency in SDH can lead to a variety of health problems due to impaired energy production. The effects can vary significantly depending on the specific gene affected, the severity of the deficiency, and the tissues most affected.
Symptoms
Symptoms of SDH deficiency are highly variable and depend on the specific mutation and tissues affected. Common symptoms include:
Neurological: Developmental delay, intellectual disability, seizures, hypotonia (low muscle tone), ataxia (poor coordination), leukoencephalopathy (disease affecting the white matter of the brain).
Muscular: Muscle weakness, exercise intolerance, myopathy (muscle disease).
Cardiac: Cardiomyopathy (disease of the heart muscle), heart failure.
Tumors: Increased risk of certain tumors, particularly paragangliomas and pheochromocytomas (tumors of the adrenal glands). Gastrointestinal stromal tumors (GISTs) and renal cell carcinomas are also associated.
Other: Failure to thrive, lactic acidosis (build-up of lactic acid in the body).
Causes
SDH deficiency is caused by mutations in genes that encode subunits of the succinate dehydrogenase enzyme complex (Complex II). These genes include:
SDHA
SDHB
SDHC
SDHD
SDHAF2 These mutations are typically inherited in an autosomal recessive manner (meaning both parents must carry a copy of the mutated gene for a child to be affected), except for *SDHAF2* mutations which follow autosomal dominant inheritance.
Medicine Used
There is no specific cure for SDH deficiency. Treatment focuses on managing symptoms and complications:
Supportive care: Physical therapy, occupational therapy, speech therapy to address developmental delays and motor skill deficits.
Seizure management: Anti-epileptic medications to control seizures.
Cardiac management: Medications for heart failure, such as diuretics, ACE inhibitors, or beta-blockers.
Tumor management: Surgical removal of tumors, radiation therapy, chemotherapy, or targeted therapies, depending on the tumor type and location.
Coenzyme supplementation: Riboflavin (Vitamin B2), a component of FAD which is a cofactor for SDH, may be used as a trial to improve enzyme function in some cases, though effectiveness varies. Other supplements, such as CoQ10, L-carnitine, and creatine, are sometimes used. However, evidence supporting their efficacy is limited.
Is Communicable
No, SDH deficiency is not communicable. It is a genetic disorder caused by mutations in specific genes and cannot be spread from person to person.
Precautions
Precautions for individuals with SDH deficiency primarily involve managing their specific symptoms and potential complications:
Regular monitoring: Regular check-ups with a physician, including neurological, cardiac, and oncological evaluations.
Avoidance of triggers: Avoiding activities that can exacerbate symptoms, such as strenuous exercise or prolonged fasting, which can trigger lactic acidosis.
Genetic counseling: Genetic counseling for affected individuals and their families to understand the inheritance pattern and risk of recurrence.
Medication awareness: Awareness of potential drug interactions and side effects, particularly medications that can affect mitochondrial function.
Tumor screening: Regular screening for paragangliomas, pheochromocytomas, and other associated tumors, especially in individuals with mutations in genes that predispose to tumor development (e.g., SDHB, *SDHD*).
How long does an outbreak last?
SDH deficiency is not an infectious disease and does not have "outbreaks." It is a chronic, lifelong condition. The symptoms and complications can vary in severity over time, but the underlying genetic defect persists throughout the individual's life.
How is it diagnosed?
Diagnosis of SDH deficiency involves a combination of clinical evaluation, biochemical testing, and genetic testing:
Clinical evaluation: Assessment of symptoms, medical history, and family history.
Biochemical testing: Measurement of succinate dehydrogenase activity in tissues (e.g., muscle biopsy, fibroblasts). Elevated levels of succinate and fumarate in urine or blood can also be suggestive. Lactate and pyruvate levels might also be elevated.
Genetic testing: Sequencing of the SDHA, *SDHB*, *SDHC*, *SDHD*, and *SDHAF2* genes to identify disease-causing mutations.
Imaging studies: MRI of the brain to assess for leukoencephalopathy or other neurological abnormalities. Cardiac imaging (echocardiogram) to evaluate heart function. Imaging studies (CT scan, MRI) to screen for tumors.
Timeline of Symptoms
The timeline of symptoms can vary greatly depending on the specific gene affected, the severity of the deficiency, and the tissues involved.
Infancy: Some individuals may present with symptoms in infancy, such as hypotonia, failure to thrive, developmental delay, or lactic acidosis.
Childhood: Other individuals may not develop symptoms until childhood, such as muscle weakness, exercise intolerance, seizures, or cognitive impairment.
Adulthood: In some cases, the first manifestation of SDH deficiency may be the development of a tumor, such as a paraganglioma or pheochromocytoma, in adulthood. Some individuals remain relatively asymptomatic for much of their lives, with symptoms only becoming apparent under periods of metabolic stress.
Important Considerations
Variable expressivity: The severity of symptoms can vary greatly, even among individuals with the same mutation.
Genetic counseling: Crucial for families to understand inheritance patterns and recurrence risks.
Multidisciplinary care: Requires a team of specialists, including neurologists, cardiologists, geneticists, oncologists, and metabolic specialists.
Early diagnosis and intervention: Can improve outcomes and quality of life.
Research: Ongoing research is focused on understanding the mechanisms of SDH deficiency and developing new therapies.
Family Screening: If a patient is diagnosed, other family members may need genetic testing to determine if they carry the mutated gene. This is especially important for SDHB, *SDHC*, *SDHD* and *SDHAF2* mutations due to the increased risk of paragangliomas and pheochromocytomas, some of which may be asymptomatic until screened for.