POLG-Related Disorders

POLG-related disorders are a group of rare genetic conditions that affect the mitochondria. Mitochondria are parts of a cell that help turn the energy we get from food iinto energy that the body can use. They are also important in the communication between body parts and creating other materials the body needs. Mitochondrial conditions can cause a variety of signs and symptoms in many parts of the body, particularly those that use a lot of energy like muscles and the brain. The gene POLG provides instructions to make the important protein called polymerase gamma (pol gamma). Pol gamma is the only protein of its kind (ie polymerase) that is responsible for correcting spelling errors made as the mitochondrial DNA (mtDNA) undergoes its own replication. If there are any changes in POLG, the “spelling checker” will not work. Mistakes will remain in the mtDNA, leading to multiple deletions or overall reduction in the amount of mtDNA copies.

POLG-related disorders are a group of conditions whose signs and symptoms can overlap and vary widely. These conditions were discovered and named before scientists knew they were caused by changes in the same gene. POLG-related disorders are sometimes discussed together as a group, and are sometimes discussed as individual disorders. The named disorders are now considered more “historic” and what is considered more important to our understanding of these conditions is the age of onset of symptoms and the presence or absence of epilepsy (seizures).

• Alpers-Huttenlocher syndrome (Alpers syndrome, or AHS)
• ataxia neuropathy spectrum (ANS)
• childhood myocerebrohepatopathy spectrum (MCHS)
• mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)
• myoclonic epilepsy myopathy sensory ataxia (MEMSA)
• chronic progressive external ophthalmoplegia (CPEO)
• progressive external ophthalmoplegia (PEO)
• Leigh syndrome
• Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis (SANDO)
• Mitochondrial Recessive Ataxia Syndrome (MIRAS)

POLG

• Autosomal dominant
• Autosomal recessive
• De Novo

POLG-related disorders are inherited genetic conditions, meaning they are passed down in a family. People usually have two copies of the POLG gene, one inherited from each parent.

The vast majority of POLG-related disorders occur when there are changes on both copies of the POLG gene (autosomal recessive inheritance). Someone who has a change on only one copy of the POLG gene is called a carrier, and they usually do not have any medical symptoms, because the other copy is normal. If both parents are carriers, there is a 1 in 4 chance with each pregnancy that their child will have a POLG-related disorder.

However, there are times when having a change on only one copy of the POLG results in symptoms (autosomal dominant inheritance). If one parent carries a copy of an autosomal dominant POLG change, there is a 1 in 2, or 50% chance with each pregnancy that their child would also have the same change in POLG.

Currently, we have a very good understanding of which exact mutations cause autosomal recessive POLG disorders and which cause autosomal dominant POLG disorders.

Both males and females can have POLG-related disorders.

The true prevalence of POLG-related disease is likely underestimated, as it is often underdiagnosed due to its highly variable clinical presentation, even among people with the same mutation. The estimated birth prevalence is approximately 1:10,000. Both autosomal recessive and autosomal dominant inheritance patterns exist, although autosomal dominant forms are rare and typically mutation specific.

Both Male and Female

POLG-related disorders cause a range of signs and symptoms. These may differ greatly, even among members of the same family, so always check with your provider if new symptoms appear or you are concerned. people can begin to show signs and symptoms of POLG-related disorders as a baby or late into adulthood. Signs and symptoms may vary widely.

A study from 2020 reviewed the clinical features of 155 people with POLG-related conditions, divided by age. In people who started to show symptoms under 12 years old, the most common features were liver disease (87%), seizures (84%) and feeding difficulties (84%). For people who started to show symptoms between ages 12 and 40, the biggest features were uncontrolled movement called ataxia (90%), loss of feeling or a ‘pins and needles’ sensation in hands and feet called peripheral neuropathy (84%), and seizures (71%). For people who started showing symptoms over age 40, a drooping eyelid called ptosis (95%), a specific eye condition called progressive external ophthalmoplegia (89%) and uncontrolled movement called ataxia (58%) were the most common features reported. Overall, people who showed signs and symptoms earlier in life had more clinical features, and people with seizures were more severely affected. (Hikmat 2020)

Please see the following factsheets for more information about the signs and symptoms of each condition:

• Alpers-Huttenlocher syndrome (Alpers syndrome, or AHS)
• ataxia neuropathy spectrum (ANS)
• childhood myocerebrohepatopathy spectrum (MCHS)
• mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)
• myoclonic epilepsy myopathy sensory ataxia (MEMSA)
• chronic progressive external ophthalmoplegia (CPEO)
• progressive external ophthalmoplegia (PEO)
• Leigh syndrome
• Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis (SANDO)
• Mitochondrial Recessive Ataxia Syndrome (MIRAS)

A diagnosis of a POLG-related disorder is established by performing a genetic test to look for changes in the gene POLG. Depending on the age of the patient and the concern for different symptoms, a doctor may suggest many different types of examinations and tests. Please see the following factsheets for more information about the types of evaluations and tests that may be done:

• Alpers-Huttenlocher syndrome (Alpers syndrome, or AHS)
• ataxia neuropathy spectrum (ANS)
• childhood myocerebrohepatopathy spectrum (MCHS)
• mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)
• myoclonic epilepsy myopathy sensory ataxia (MEMSA)
• chronic progressive external ophthalmoplegia (CPEO)
• progressive external ophthalmoplegia (PEO)
• Leigh syndrome
• Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis (SANDO)
• Mitochondrial Recessive Ataxia Syndrome (MIRAS)

POLG-related disorders are not included on newborn screening panels. If there is a known family history of a POLG-related disorder, or if a parent is a known carrier, prenatal testing can be performed on amniotic fluid (the fluid surrounding a baby) or chorionic villi (a specific part of the placenta). Results interpretation of this testing is complicated and genetic counseling is recommended.

POLG-related disorders are not included on newborn screening panels. If there is a known family history of a POLG-related disorder, or if a mother is a known carrier, prenatal testing can be performed on amniotic fluid (the fluid surrounding a baby) or chorionic villi (a specific part of the placenta). Results interpretation of this testing is complicated and genetic counseling is recommended.

No

Before beginning any treatment or therapy, please consult with your physician.

There is currently no FDA-approved therapy for any POLG-related disorder. Treatment and management of POLG-related disorders are symptomatic and supportive. Individuals living with a POLG-related disorder typically work with several healthcare providers regularly based on their symptoms.

The FDA has recommended that people with POLG-related disorders avoid medications called Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®). These medications increase the risk of liver damage or failure in people with POLG-related disorders. Doctors may recommend that people with POLG-related disorders avoid other medications that can damage the mitochondria or recommend careful monitoring while on these medications. Recommendations may change over time. Visit https://mitopatients.org/list-of-medicines/ to learn more.

Carefully review all medications with your doctor.

Please see the following factsheets for more information about the treatment and management of each condition:

• Alpers-Huttenlocher syndrome (Alpers syndrome, or AHS)
• ataxia neuropathy spectrum (ANS)
• childhood myocerebrohepatopathy spectrum (MCHS)
• mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)
• myoclonic epilepsy myopathy sensory ataxia (MEMSA)
• chronic progressive external ophthalmoplegia (CPEO)
• progressive external ophthalmoplegia (PEO)
• Leigh syndrome
• Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis (SANDO)
• Mitochondrial Recessive Ataxia Syndrome (MIRAS)

The POLG Foundation: https://polgfoundation.org/. Other resources for individual conditions can be found in their respective factsheets.

Connecting with others impacted by a rare disease allows for vital information to be shared about day-to-day life, prevents isolation, and gives hope. Please contact MitoAction for peer support opportunities at 888-MITO-411 or email mito411@mitoaction.org.

Other resources we recommend are:

• New Patient Kit for Mitochondrial Conditions
• Planning and Preparation
• Monthly Expert Series
• Energy in Action Podcast