The POLG gene provides instructions for making an enzyme known as polymerase gamma (Pol γ). This enzyme is located within mitochondria, structures found inside our cells. Mitochondria are often referred to as the “powerhouses” of the cell because they convert food into the energy the body needs to function. The proper functioning of the POLG gene and its enzyme is connected to maintaining the cell’s energy supply.
The Role of the POLG Gene in Mitochondrial Health
Mitochondria possess their own distinct genetic material, mitochondrial DNA (mtDNA), separate from the DNA found in the cell’s nucleus. Polymerase gamma, the enzyme produced by the POLG gene, is the only DNA polymerase active within mitochondria. It is responsible for maintaining this unique genetic blueprint by replicating mtDNA, ensuring new mitochondria receive a complete set of genetic instructions and continuity of energy production.
In addition to replication, polymerase gamma performs a proofreading function, correcting errors during the copying process. This exonuclease activity helps maintain the integrity of mitochondrial DNA, preventing the accumulation of mistakes. Without accurate function, mitochondrial DNA can become damaged or depleted, disrupting cellular energy supply and leading to various health issues.
The Spectrum of POLG-Related Disorders
Mutations in the POLG gene can disrupt the function of polymerase gamma, leading to a range of conditions known as POLG-related disorders. These genetic changes can cause a reduction in mitochondrial DNA copies (mtDNA depletion) or the accumulation of large deletions in mtDNA, impairing cellular energy production. The resulting symptoms and their severity vary significantly among individuals, reflecting a broad clinical spectrum.
One form is Alpers-Huttenlocher syndrome (AHS), which often appears in children between two and four years of age. This condition involves intractable seizures, progressive loss of mental and motor skills, and liver disease. Liver involvement can be delayed for years or decades after initial neurological symptoms, and fulminant liver failure may be triggered by certain medications.
Another condition is progressive external ophthalmoplegia (PEO), which causes weakness of the eye muscles, leading to drooping eyelids (ptosis) and difficulty moving the eyes. PEO can occur with or without other systemic symptoms, such as muscle weakness, hearing loss, or neurological problems like ataxia or parkinsonism. Spinocerebellar ataxia with epilepsy (SCAE) is characterized by problems with balance and coordination (ataxia), involuntary muscle jerks (myoclonus), and recurrent seizures. These neurological symptoms often present with varying degrees of cognitive impairment.
Inheritance of POLG Mutations
POLG-related disorders are genetic conditions passed down through families, with two primary patterns of inheritance. The specific inheritance pattern often influences the type and severity of the disorder an individual may experience.
Many POLG-related disorders, including Alpers-Huttenlocher syndrome and most forms of progressive external ophthalmoplegia, are inherited in an autosomal recessive manner. This means an individual must inherit a mutated copy of the POLG gene from both parents to develop the condition. Parents who carry one mutated copy are typically unaffected, serving as carriers who can pass the gene to their children. For each child of two carrier parents, there is a 25% chance of inheriting both mutated copies and being affected.
Conversely, some forms of progressive external ophthalmoplegia can follow an autosomal dominant inheritance pattern. In these cases, inheriting one mutated copy of the POLG gene from a single parent is sufficient to cause the disorder. If a parent has an autosomal dominant POLG mutation, each of their children has a 50% chance of inheriting the mutated gene and developing the condition. The age of onset and symptom severity can still vary significantly, even within the same family.
Diagnosis and Management of POLG Conditions
Diagnosing POLG conditions typically begins with a clinical evaluation of an individual’s symptoms, especially neurological issues, muscle weakness, and liver problems. The definitive diagnosis primarily relies on genetic testing to identify specific mutations within the POLG gene. Other supportive tests, such as brain imaging (MRI or CT scans), electroencephalograms (EEGs) to assess brain electrical activity, or muscle biopsies, can provide additional evidence and support clinical suspicion.
Currently, there is no cure for POLG-related disorders. Treatment focuses on managing symptoms and improving the individual’s quality of life. This supportive care involves a multidisciplinary medical team, including neurologists, geneticists, and other specialists, to address diverse symptoms. Management strategies may include anticonvulsant medications for seizures, physical therapy for muscle weakness, and nutritional support.
An important aspect of management is avoiding certain medications, such as valproic acid, a common anticonvulsant. Valproic acid can trigger severe liver failure in individuals with POLG mutations, especially in children. Therefore, medical professionals must screen for POLG mutations before prescribing this medication, particularly in young children with suspected mitochondrial disorders.