PolG disease is a mitochondrial disorder caused by mutations in the POLG gene[1]. It typically affects multiple organs, primarily the brain, nerves, muscles, and liver, and can affect vision due to involvement of brain structures[2,3]. It is also one of the most common inherited mitochondrial disease[4]. Up to 2% of those of Northern European decent may carry disease-causing POLG mutations[4], and the frequency of PolG disease is estimated to be 1 in 10,000[1]. Mutations may be autosomal recessive (meaning two mutations are required for disease expression) or autosomal dominant (meaning only one mutation is required for disease expression).
Signs of the disease can appear anywhere between infancy and late adulthood. Symptoms vary widely among affected individuals. As a result, PolG disease is sometimes divided into subtypes. These subtype rubric includes[2,3]:
- Alpers-Huttenlocher syndrome (initially labeled Alpers syndrome)
- Myocerebrohepatopathy (MCHS)
- Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
- Ataxia neuropathy spectrum (ANS)
- Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO)
- Mitochondrial recessive ataxia syndrome (MIRAS)
- Progressive external ophthalmoplegia (PEO and PEO+)
In general, earlier onset of PolG disease corresponds with more severe symptoms and poorer outcomes[2,3].
Available treatments for this disorder focus on symptom management and quality of life; medical research has yet to uncover a cure for PolG disease. The use of valproate (a common anticonvulsant medication) may result in irreversible liver failure.
PolG disease is caused by inherited mutations in the POLG gene[1]. Currently, over 200 disease-causing POLG mutations are known[5].
POLG mutations compromise the functioning of the enzyme responsible for mitochondrial DNA maintenance. Poor DNA maintenance reduces the amount of mitochondrial DNA present in the cell and/or introduces mutations in the mitochondrial DNA[6].
The primary symptoms of PolG disease depend on when it emerges[3].
For individuals with disease onset prior to age 12, the main symptoms are[3]:
- Seizures
- Cognitive regression
- Motor impairment
- Cortical visual loss
- feeding difficulties
- liver dysfunction
For individuals with disease onset between age 12 and 40, the primary symptoms are[3]:
- seizures
- impaired coordination (ataxia)
- peripheral neuropathy
For individuals with disease onset after age 40, the key symptoms are[3]:
- drooping eyelids (ptosis)
- paralysis of the muscles that control eye movement
- impaired coordination (ataxia)
- myopathy
- Parkinsonism
PolG disease can impact almost any organ. As such, symptoms may also include[2]:
- poor muscle tone
- developmental delay
- movement disorder
- weakness of the limbs
- depression
- anxiety
- headache
- hearing loss
- vision loss
- slurred speech (dysarthria)
- respiratory failure
- apnea
If your loved one has symptoms of PolG disease, their healthcare provider may perform or recommend the following to make a diagnosis[2]:
- molecular genetic testing for POLG mutation(s) is required to confirm the diagnosis
- brain-imaging such as computed tomography (CT) scan or magnetic resonance imaging (MRI) to look for changes in the brain associated with PolG disease
- Electroencephalogram (EEG or ‘brain wave’) testing
The following treatments can help manage the symptoms of PolG disease and improve life for affected individuals and their families[2]:
- anticonvulsant medications for seizures (although valproate must be avoided)
- pain medication and muscle relaxants for comfort
- small frequent meals or a feeding tube for nutritional support may be helpful and the ketogenic diet is sometimes used to help control seizures
- physical therapy for declining motor skills and muscle strength
- surgery or special glasses to correct drooping eyelids
- speech therapy for slurred speech
- breathing tube and/or artificial ventilation for respiratory failure
- CPAP or BiPAP for apnea
- Physical and occupational therapy for motor involvement
Because PolG disease is an inherited disorder, affected families should also receive genetic counseling.
Are there any clinical trials for PolG?
To see what trials you may qualify for, visit our Clinical Trials page – which also included a Clinical Trials Finder Tool. We also highly encourage you to join our patient registry, mitoSHARE, where we are actively recruiting PolG families.
What are the next steps if my loved one has PolG?
- Get Support
Connect with our Support & Education Team online, via email at support@umdf.org or phone at (888) 900-6486.
- Check our Clinical Trials Finder
Use our Clinical Trials Finder to see if you qualify for any clinical trials.
- Join our patient registry, mitoSHARE
We are actively recruiting PolG families to participate in our patient registry, mitoSHARE. Patient registries like mitoSHARE are an integral part in charting a course toward treatments and cures for PolG and other mitochondrial diseases. There are currently over 30 active mitochondrial disease clinical trials. Next generation patient registries like mitoSHARE are an integral part of expanding that number.
- Become an advocate
Ask your representatives to prioritize mitochondrial disease research and support via the UMDF Advocacy Center. We’ll send regular action items so you – and your friends and family – can let Congress know where we need their support. Click here to sign up.
- Join the conversation online
– UMDF Social Media Support Groups: Facebook Support Group
– UMDF News & Updates: Facebook | Twitter | Instagram | YouTube
- Get involved
Join the fight by giving your voice, generosity, time, or energy. Click here to see how you can help.
- Research & Funding: UMDF has provided more than $15 million in research funding to find treatments for diseases like PolG. UMDF advocacy has helped secure an additional $55 million in federal funding via the Department of Defense and National Institutes of Health. UMDF has
- Data: Over two decades ago, UMDF pioneered patient registries for the mitochondrial disease community. Today, our next generation patient registry, mitoSHARE, is helping chart a path toward the treatment and eventual cure of mitochondrial diseases.
- Patient Support: Thousands of families just like you depend upon UMDF for support and education on diseases like PolG. Attendance at our support meetings annually tops 7,000, including disease specific support meetings for families.
- Clinician Support: To help educate clinicians on diseases like PolG, we feature monthly Bench to Bedside clinician seminars, host the annual Mitochondrial Medicine Symposium, support the Mitochondrial Care Network, and educate clinicians on our Mito U platform.
- Research Studies: UMDF, in partnership with the PolG Foundation and Mito Foundation, has funded a study for PolG and PMM patients to help develop endpoints for future clinical trials. You can visit the UMDF Research page to see if the study is currently recruiting.
- Saneto RP, Naviaux RK. Polymerase gamma disease through the ages. Dev Disabil Res Rev. 2010;16(2):163-174. doi:10.1002/ddrr.105
- Cohen BH, Chinnery PF, Copeland WC. POLG-Related Disorders. 2010 Mar 16 [updated 2018 Mar 1]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 20301791.
- Hikmat O, Naess K, Engvall M, et al. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020;43(4):726-736. doi:10.1002/jimd.12211
- Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019;15(1):40-52. doi:10.1038/s41582-018-0101-0
- National Institute of Environmental Health Sciences. Human DNA Polymerase Gamma Mutation Database. Accessed August 3, 2023. https://tools.niehs.nih.gov/polg/
- Copeland WC. Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol. 2012;47(1):64-74. doi:10.3109/10409238.2011.632763