POLG-related disorders

What are POLG-related Disorders?

POLG-related disorders are a spectrum of conditions most commonly characterized by muscle weakness, seizures, and liver failure. POLG-related disorders are caused by harmful genetic changes (variants) in the POLG gene. The symptoms vary widely, ranging from infantile-onset seizures and liver failure to adult-onset eye weakness (ophthalmoplegia). Individuals in the same family can have different forms of POLG-related disorders. Additionally, some individuals may present with one form of POLG-related disorders and then, over time, develop symptoms of another form. The various conditions associated with the POLG gene are described below.

Alpers-Huttenlocher syndrome (AHS)

Alpers-Huttenlocher syndrome (AHS) is the most severe form of POLG-related disorders. The symptoms of AHS usually begin before age four. Individuals can have recurrent seizures that become difficult to treat over time. Progression of the condition also includes abnormal movements, loss of cognitive function, and liver disease.

Childhood myocerebrohepatopathy spectrum (MCHS)

The symptoms of childhood myocerebrohepatopathy spectrum (MCHS) usually begin before age three. Individuals typically have developmental delays or problems with memory and thinking, liver problems, build-up of lactic acid in the body, and muscle weakness (myopathy) with failure to thrive. Individuals may also experience regular vomiting, hearing loss, problems with the pancreas, and kidney problems (renal tubular acidosis).

Ataxia neuropathy spectrum (ANS)

Ataxia neuropathy spectrum (ANS) is a group of conditions that includes two specific ones: mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). Individuals with ANS may start experiencing symptoms anywhere from early childhood to adulthood. Symptoms include problems with balance and coordination (ataxia) and problems with nerve function (neuropathy). Some individuals will have seizures and changes to their brain structure. Other possible symptoms include blindness, sudden jerking of muscles (myoclonus), liver problems, depression, and headaches.

Autosomal recessive progressive external ophthalmoplegia (arPEO)

Symptoms of autosomal recessive progressive external ophthalmoplegia (arPEO) typically start in the teens or early adulthood. Symptoms include eye weakness that worsens over time and an inability to exercise for very long. Individuals with arPEO typically do not have other symptoms, but some individuals may go on to develop the ANS type of POLG-related disorders.

Myoclonic epilepsy myopathy sensory ataxia (MEMSA)

Symptoms of myoclonic epilepsy myopathy sensory ataxia (MEMSA) usually start in young adulthood. MEMSA includes a spectrum of symptoms, including muscle weakness (myopathy), which may present as exercise intolerance, seizures (epilepsy), and coordination or balance difficulties (ataxia).

Additional considerations for carriers

Some carriers of POLG-related disorders may have symptoms of autosomal dominant progressive external ophthalmoplegia (adPEO). Symptoms usually start in adulthood and may include weakness of the eye muscles that worsens over time and exercise intolerance. Individuals may also experience hearing loss, eye problems (cataracts), muscle weakness, facial muscle weakness, changes in their balance and coordination (ataxia), Parkinsonism, depression, and nerve problems (neuropathy). A subset of carriers may additionally experience premature ovarian failure and shrinking of the testicles. The risk for symptoms may depend on the type of harmful change an individual has, but the exact risk for symptoms in carriers is not yet well understood.

Some individuals with adPEO that only have one harmful change in the POLG gene may have a harmful change in another gene known as TWNK (digenic inheritance). There have only been a few cases of digenic inheritance reported with POLG-related disorders, and more evidence is needed to know the exact risks.

How common are POLG-related Disorders?

The incidence of autosomal recessive POLG-related disorders, which includes all forms of the condition besides adPEO, may be as high as 1 in 10,000 births. The AHS form of POLG-related disorders is reported to be 1 in 51,000.

How are POLG-related Disorders treated?

There is no cure for POLG-related disorders. Treatment is directed at managing an individual's specific symptoms and supportive care. This often means receiving care through a team of specialists. Individuals with the more severe AHS may need a feeding tube, breathing assistance, and often receive palliative care to make them more comfortable. Medications to control seizures, muscle relaxants, and pain medications are often used to treat symptoms. Individuals with POLG-related disorders may need to adjust their medication dosage to avoid harmful side effects.

What is the prognosis for an individual with POLG-related Disorders?

Individuals with the AHS and MCHS forms typically have a shortened lifespan due to the severity of their symptoms.

Individuals with ANS and MEMSA have a later disease onset, and the symptoms worsen slowly over time. Because the severity and progression of symptoms vary from person to person, the impact on life expectancy is specific to each individual.

ArPEO and adPEO are generally adult-onset disorders. The impact on life expectancy depends on if other symptoms develop over time.