Alpers Disease

What Causes Alpers Disease?

Scientists don’t yet know precisely what causes Alpers disease. It is likely caused by an abnormal change (mutation) in a gene called the POLG gene, but some researchers believe the condition results from many different factors working together.

The POLG gene is responsible for producing a protein that plays a crucial role in building mitochondria, the cell structures that provide energy for the cell. Scientists think that if a mutation in the POLG gene leads to a deficiency in the vital protein, cells won’t have enough mitochondria to supply them with the energy they need to survive. The energy shortage may be especially problematic in cells with high energy demands, such as those in the brain, muscles, and liver.

Other scientists believe that POLG gene mutations are only part of a complex chain of circumstances leading to AD. Other theories for the disease’s cause include:

• Environmental factors that work in tandem with a genetic predisposition to produce the disease
• Proteins or other molecules that disrupt normal cell functions
• Defects in mitochondria

Is Alpers Disease Hereditary?

Mutations in the POLG gene seem to play at least some role in the development of AD, and those mutations sometimes may be inherited by a child from their parents. When the disease is inherited, it is passed on in an autosomal recessive pattern, meaning that a child must inherit two copies of the mutated POLG gene, one from each parent, for the disorder to develop.

The parents in these cases carry just one copy of the mutation, so they typically do not show any symptoms of AD themselves. When two parents both carry the mutated gene, they have a 25 percent chance of having a child with the disorder with each pregnancy. Fifty percent of the time, the pregnancy will produce a child who is a carrier like the parents. Twenty-five percent of the time, the child will not carry the mutation at all.

How Is Alpers Disease Detected?

The earliest signs of Alpers disease are often not specific to AD and may be similar to other disorders. Early symptoms can include:

• Low blood sugar caused by liver dysfunction
• Slowed growth or weight loss
• Spastic, jerking, or twitching muscles
• Neurological dysfunction associated with an infection

How Is Alpers Disease Diagnosed?

To diagnose Alpers disease, doctors will conduct physical exams and ask about the child’s medical and family history to rule out other possible causes for the symptoms. If the doctor suspects AD as a possibility, several specialized tests can help confirm a diagnosis:

• Genetic testing for POLG gene mutations.
• Testing of cell samples to look for abnormally low levels of mitochondria. This test will not detect the disease in its early stages.
• Imaging exams to look for signs of brain degeneration.
• Electroencephalography (EEG) to measure brain activity, which may be generally slower than usual or show a pattern indicating seizure activity.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Alpers Disease Treated?

Alpers disease has no cure. Alpers disease treatments focus on lessening the impact of symptoms, preventing complications, and improving the child’s quality of life.

Common Alpers disease treatments include:

• Physical therapy
• Anti-seizure medications
• Medications to treat muscle spasms and for pain relief
• Medications to treat infections

How Does Alpers Disease Progress?

Alpers disease is progressive, meaning it gets worse over time. No treatments will slow or stop the worsening of symptoms. Progression of the disease may include:

• Intellectual impairments that become more severe
• Loss of cognitive abilities such as memory and reasoning
• Loss of control of limbs
• Blindness caused by degeneration of the optic nerve
• Liver failure
• Seizures that don’t respond well to medications

Most children with AD don’t live past the age of 10. The most common causes of death include:

• Seizures
• Liver failure
• Cardiorespiratory failure caused by neurological symptoms

How Is Alpers Disease Prevented?

There is no known way to prevent Alpers disease. Parents with a family history of the disorder or who have had another child with AD are advised to consult a genetic counselor to assess their future risk.

Alpers Disease Caregiver Tips

• Be an active participant in your child’s medical care. Learn as much as you can about the disease so that you can ask informed questions and take the proper steps to improve your child’s quality of life.
• Take care of yourself. Caregivers for people with a progressive disease like AD are susceptible to mental and physical health problems if they don’t take care of themselves. Don’t feel guilty for needing occasional time away from the demands of caregiving, and don’t hesitate to ask for help from family and friends.
• Find sources of support. Organizations such as MitoAction and Alpers Awareness can guide you to educational resources, support groups, and contact with other people living with Alpers disease.

Some people with Alpers disease also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the issues commonly associated with AD:

• Many people with AD suffer from seizures.
• Some people with the disorder experience dementia.

Alpers Disease Brain Science

Alpers disease was first described in 1931 by Bernard Alpers as “diffuse progressive degeneration of gray matter of the cerebrum.” Alpers noted the patient in his study showed a loss of healthy tissue in the part of the brain that controls movement and other voluntary and cognitive functions. Later studies found abnormalities in the mitochondria of patients’ brain cells. However, it was unclear whether the mitochondrial abnormalities were the cause of brain degeneration or whether another factor caused both conditions.

The search for a cause of both conditions has led to the various theories of AD’s origin, including:

• Genetic triggers
• Mitochondrial defects caused by an infection or injury
• Metabolic disorders
• The involvement of prions (proteins that can cause defects in other cell proteins and thus spread disease-causing abnormalities)

Alpers Disease Research

Title:  A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy (MIT-E)

Stage: Recruiting

Principal Investigator: Richard Haas, Dr.

Rady Children’s Hospital UCSD

San Diego, CA

This is a parallel-arm, double-blind, placebo-controlled study with a screening phase that includes a 28-day run-in phase to establish baseline seizure frequency, followed by a 24-week, randomized, placebo-controlled phase. After completing the randomized, placebo-controlled phase, participants may enter a 48-week, long-term extension phase during which they will receive open-label treatment with vatiquinone.

Title: Mitochondrial Disease and Dysfunction in Neurological and Neurodevelopmental Disorders

Stage: Recruiting

Principal investigator:  Richard E Frye, MD, PhD

Phoenix Children’s Hospital

Phoenix, AZ

Mitochondria are essential for a wide range of functions in almost every cell in our body. Best known for their role in adenosine triphosphate (ATP) production, mitochondria are also closely involved in a wide variety of cell functions such as calcium buffering, redox regulation, apoptosis, and inflammation, and regulate metabolism through several mechanisms, including epigenetic changes. ATP produced is essential for many cellular systems. Thus, abnormal mitochondrial function can adversely affect cellular systems by several mechanisms.

Given the important role of the mitochondria in cellular function, individuals with classic mitochondrial disease demonstrate devastating symptoms, particularly in tissues that have high-energy demands such as the brain, muscles, gastrointestinal (GI) tract, and immune system. Mitochondrial dysfunction contributes to the pathophysiology of more common diseases, including psychiatric conditions, neurodegenerative disorders, neurological disorders including migraine and seizures, persistent systemic inflammation, cardiac disease, cancer, and diabetes. Mitochondrial dysfunction also affects a significant portion of individuals with autism spectrum disorder (ASD) and genetic syndromes associated with ASD.

One of our goals is to develop a Seahorse Analyzer method to measure individual variations in mitochondrial function, which can identify children with medical disorders and mitochondrial dysfunction without an invasive muscle biopsy. To establish comprehensive profiles of mitochondrial function for individuals with known neurological and neurodevelopmental disorders, we will compare blood, urine, and stool from these individuals to those of healthy, typically developing (TD) children. The relationship between mitochondrial function, development, and behavior will be assessed by performing standard developmental testing. In addition, in patients having a procedure that produces excess tissue, we will examine the mitochondrial function in that tissue and correlate it with findings from blood.

Title: Acute Infection in Mitochondrial Disease: Metabolism, Infection, and Immunity During the COVID19 Pandemic

Stage: Recruiting

Principal investigator:  Eliza M Gordon-Lipkin, MD

National Human Genome Research Institute (NHGRI)

Bethesda, MD

Infection is a major cause of morbidity and mortality in individuals with mitochondrial disease, frequently triggering metabolic decompensation, multiorgan dysfunction, and neurologic deterioration. In the context of the recent COVID19 pandemic, people with mitochondrial disease are at increased risk for severe disease and poor outcomes if infected. However, the mechanisms for this link between infection and clinical decline are incompletely understood. Given that people with mitochondrial disease are particularly susceptible to infection and may experience delayed recovery, we hypothesize that this is partly due to immune factors that influence host-pathogen interactions. The purpose of this protocol is to collect biological specimens to identify immune signatures that contribute to the phenotype of infection and outcomes in patients with mitochondrial disease who become ill during the COVID19 pandemic. To compare these cases with others of similar genetic backgrounds and environmental exposures, we will also collect specimens from family members. We will then examine how these signatures correlate with comprehensive quantifiable clinical measures throughout the course of the disease, from presenting symptoms through acute decompensation, stabilization, and convalescence. While this protocol is developed during the COVID-19 pandemic with a focus on a specific infectious pathogen, we hope that this study will extend beyond the pandemic in an effort to understand acute infectious illness in patients with mitochondrial disease more broadly. Additionally, it will serve as a remote adjunct to the NIH MINI Study, a natural history study focused on the immunophenotype of mitochondrial disease conducted at the NIH Clinical Center.