Mitochondrial diseases are disorders caused by the failure of mitochondria, the organelles responsible for generating most of the cell’s energy. Mutations in the POLG gene are the most frequent genetic cause of inherited mitochondrial conditions, leading to a spectrum of debilitating, multi-systemic illnesses. This condition is often referred to as POLG mitochondrial disease or a POLG-related disorder. The prevalence of pathogenic POLG variants is estimated to be approximately 1 in 10,000, and up to two percent of people of Northern European descent may carry a disease-causing mutation.
The Function of the POLG Gene and Disease Mechanism
The POLG gene provides instructions for the alpha subunit of DNA polymerase gamma (pol \(\gamma\)). This enzyme is the only DNA polymerase found within the mitochondria. Its primary job is to ensure the integrity of mitochondrial DNA (mtDNA) by replicating the genetic material and repairing damage.
A mutation in the POLG gene produces a flawed pol \(\gamma\) enzyme with impaired function, making it unable to efficiently copy or repair mtDNA. This leads to a decline in the quantity of mitochondrial DNA, known as mtDNA depletion, or the accumulation of multiple deletions and rearrangements within the mtDNA.
Since mtDNA integrity is necessary for producing proteins that drive cellular energy generation, this disruption causes mitochondrial dysfunction and a profound failure in energy production. Cells with the highest energy demands, such as those in the brain, nerves, muscle, and liver, are most susceptible to this energy deficit. This cellular failure ultimately causes the wide range of symptoms seen in POLG-related disorders.
The Wide Spectrum of POLG Disorders
POLG-related disorders are characterized by a continuous spectrum of overlapping clinical presentations. The age of onset generally correlates with disease severity, ranging from rapidly progressing, severe conditions starting in childhood to more gradual, milder forms appearing in late adulthood. This variability means the same genetic mutation can manifest as different clinical syndromes in different individuals.
Childhood-Onset Syndromes
The most severe childhood presentation is Alpers-Huttenlocher syndrome (AHS), typically beginning between the ages of two and four years. AHS involves a progressive encephalopathy (brain disease) characterized by refractory seizures that are difficult to control. Patients also experience psychomotor regression (loss of acquired mental and movement abilities) and cortical visual loss. A hallmark of AHS is liver involvement, ranging from dysfunction to fulminant liver failure. Another related early-onset condition is Childhood Myocerebrohepatopathy Spectrum, which similarly involves the muscles, brain, and liver, often presenting with hypotonia, muscle weakness, and feeding difficulties.
Adolescent and Adult-Onset Forms
In adolescents and adults, the presentation is often characterized by neurological symptoms grouped under the Ataxia Neuropathy Spectrum (ANS). Patients often experience impaired coordination (ataxia) due to cerebellar involvement. Peripheral neuropathy (damage to nerves outside the brain and spinal cord) also commonly manifests as weakness and sensory loss in the limbs. Other neurological features can include seizures and myoclonus (sudden, involuntary muscle jerks).
Late-Onset Progressive External Ophthalmoplegia
The mildest and most common adult-onset form is Progressive External Ophthalmoplegia (PEO), often presenting after age 40. This condition specifically affects the muscles controlling eye movement, leading to ptosis (drooping eyelids) and difficulty moving the eyes. PEO can occur as an isolated symptom, but it is often accompanied by other milder features, such as generalized muscle weakness (myopathy) and ataxia. The distinction between the various syndromes reflects the different patterns of organ system failure resulting from the underlying mitochondrial energy deficit.
Identifying POLG Disease: Diagnostic Methods
Diagnosis typically begins with clinical suspicion based on the patient’s multi-systemic symptoms, especially those involving the brain, muscle, and liver. Because symptoms are variable and overlap with many other neurological disorders, a definitive diagnosis relies on genetic confirmation. Molecular genetic testing identifies pathogenic variants within the POLG gene.
For most forms, including Alpers-Huttenlocher syndrome and recessive PEO, diagnosis requires identifying two disease-causing variants, one inherited from each parent. Autosomal dominant PEO, in contrast, is confirmed by detecting a single pathogenic variant. Genetic testing often involves sequencing the POLG gene, but clinicians increasingly use gene panels that test multiple mitochondrial DNA maintenance genes simultaneously.
Supporting evidence may come from neuroimaging, such as a brain MRI, which can reveal specific patterns of atrophy or lesions. An electroencephalogram (EEG) may document seizure activity. In some cases, a muscle biopsy may be performed to look for characteristic mitochondrial changes or multiple mtDNA deletions, common findings in adult-onset POLG disease.
Management and Supportive Care Strategies
Currently, there is no cure for POLG mitochondrial disease; treatment focuses on managing symptoms and providing supportive care to improve the patient’s quality of life. A multidisciplinary team, including neurologists, hepatologists, physical therapists, and nutritionists, is necessary to address the various affected organ systems. Supportive measures commonly include physical, occupational, and speech therapy to maintain motor skills, address muscle weakness, and assist with communication and swallowing.
Nutritional support is often a significant component of care, sometimes requiring feeding tubes or specialized diets. While anticonvulsant medications control seizures, valproate (valproic acid) is strictly contraindicated in POLG patients, particularly those with Alpers syndrome. This is because valproate can trigger or worsen severe, irreversible liver failure.
Some patients are prescribed supplements such as coenzyme Q10, although evidence for the effectiveness of these mitochondrial “cocktails” is mixed. Emerging therapies, such as nucleoside supplementation, are being investigated in clinical trials to potentially replenish depleted mitochondrial DNA building blocks. Diligent monitoring and avoidance of known mitochondrial toxins are paramount in the long-term management of this disorder.