Infantile Refsum Disease

What Causes Infantile Refsum Disease?

IRD is caused by abnormal changes (mutations) in one of several different genes called PEX genes. These genes are responsible for the function of cell structures called peroxisomes. Mutations in any of the PEX genes can cause problems with the growth and function of peroxisomes.

Peroxisomes play a crucial role in the breakdown of toxic substances and fatty compounds that accumulate in cells as the result of normal metabolic processes. One of these substances is phytanic acid, a chemical found in some foods. When peroxisomes don’t function correctly, these substances build up inside cells and have damaging effects, especially in organs such as the eyes, liver, kidneys, bones, and brain.

Adult refsum disease also is characterized by an accumulation of excess phytanic acid but is caused by different gene mutations than those that cause IRD.

Is Infantile Refsum Disease Hereditary?

IRD is an inherited disorder. The condition is inherited in an autosomal recessive pattern. This means that a child needs to inherit two copies of the mutated gene, one from each parent, to develop IRD. If both parents carry one of the disorder-causing mutations, they have a 25 percent chance of having a child affected by the disorder with each pregnancy. In 50 percent of their pregnancies, the child will carry the mutation but not develop the condition. In 25 percent of pregnancies, their child will not carry the mutation and will not be able to pass the disorder-causing mutation to their children.

How Is Infantile Refsum Disease Detected?

It may be possible to diagnose IRD during pregnancy. If both parents are known to be carriers of PEX gene mutations, prenatal testing may be recommended to look for the biochemical signature of the disorder. Tests used to make the diagnosis include amniocentesis and chorionic villus sampling.

How Is Infantile Refsum Disease Diagnosed?

A doctor may suspect IRD if a child presents symptoms consistent with the disorder, and other potential causes of the symptoms can be ruled out. The diagnostic process may include:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Blood tests to look for elevated levels of the chemicals associated with IRD
• Imaging scans such as magnetic resonance imaging (MRI) to look for damage to brain tissue called white matter and liver abnormalities
• Genetic testing to look for the PEX gene mutations associated with IRD

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Infantile Refsum Disease Treated?

IRD has no cure, but some treatments may be able to manage symptoms and prevent complications. Common treatments and therapies include:

• Surgery to remove cataracts from the eyes
• Vitamin K supplements and primary bile acid therapy to improve liver function
• Hearing aids
• Feeding assistance
• Anti-seizure medications
• Avoidance of foods rich in phytanic acid, such as cow’s milk, dairy products, beef, lamb, and some seafood
• Ongoing monitoring of vision, hearing, and liver function

How Does Infantile Refsum Disease Progress?

IRD is progressive, and its symptoms worsen over time. Potential long-term effects include:

• Blindness
• Deafness
• Intellectual disability
• Fractures or bone problems caused by osteoporosis
• Nerve pain and loss of sensation
• Loss of coordination
• Liver failure

It is not uncommon for children with IRD to survive into adulthood. However, the disease is usually fatal in early adulthood.

How Is Infantile Refsum Disease Prevented?

There is no known way to prevent IRD. However, parents with a family history of the disorder or who have had another child with IRD are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Infantile Refsum Disease Caregiver Tips

• Understand your child’s unique experience with IRD. This disease differs from other Zellweger spectrum disorders, and the symptoms of IRD vary from case to case. Learn all you can about the disease so that you can better help your child with their unique challenges.
• Take care of yourself. Caring for a child with any progressive disease is a job that can jeopardize the caregiver’s health. Don’t be afraid to use any help offered by family and friends, and make time to tend to your own physical, mental, and emotional needs.
• Take advantage of the community of families like yours. The Global Foundation for Peroxisomal Disorders maintains a collection of informational and educational resources, links to assistance resources, and support groups.

Infantile Refsum Disease Brain Science

IRD and other Zellweger spectrum disorders can cause a variety of problems with brain development and function, including:

• Neuronal migration defects. These problems occur when brain cells don’t move (or migrate) to their proper location during early brain development. Typically, brain cells move from where they are first produced to the places where they will form different brain structures. However, sometimes, as in IRD, biochemical abnormalities interfere with this process, and structural brain defects result.
• Leukodystrophy. Brain and spinal cord cells called white matter are covered with a fatty material called myelin. Myelin protects the nerve cells and allows them to transmit signals to one another. Some disorders, including ZSDs, cause the breakdown of myelin, which leads to damage to white matter. This condition is called leukodystrophy. Neurological symptoms such as weak muscle tone and seizures may result.

Infantile Refsum Disease Research

Title: MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis

Stage: Recruiting

Principal investigator: Paul Orchard, MD

Masonic Cancer Center, University of Minnesota

Minneapolis, MN

This single-institution, phase II study is designed to test the ability to achieve donor hematopoietic engraftment while maintaining low rates of transplant-related mortality (TRM) using busulfan- and fludarabine-based conditioning regimens with busulfan therapeutic drug monitoring (TDM) for patients with various inherited metabolic disorders (IMD) and severe osteopetrosis (OP).

Title: Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)

Stage: Recruiting

Principal investigator: Nancy E Braverman, MD, MS

McGill University Health Center, Montreal Children’s Hospital

Montreal, Quebec

The Peroxisome Biogenesis Disorders (PBD) are a group of inherited disorders due to defects in peroxisome assembly causing complex developmental and metabolic sequelae. Despite advancements in peroxisome biology, the pathophysiology remains unknown, the spectrum of phenotypes poorly characterized and the natural history not yet systematically reported. We aim to define this population further clinically, biochemically, and genetically. The investigators will prospectively follow patients from Canada, the US and internationally, and collect data from medical evaluations, blood, urine, and imaging studies that would be performed on a clinical care basis. For patients who are unable to attend our clinic, we will collect all medical records and images since birth as well as subsequent records/images for the next five years or until the end of the study. Clinical data from medical records will be banked in our Peroxisomal Disorder Research Databank and Biobank. The investigators will use this information to identify standards of care and improve management.

Participants have the option to be seen in consultation at the McGill University Health Centre in Montreal, Canada, every year. This includes a consultation in Genetics, Nutrition, Neurology, and Ophthalmology (OCT and FAF exams). All medical records and images will be collected retrospectively and prospectively until the study’s end and entered anonymously in a database. Biospecimens will be collected to identify new biomarkers. Candidate drugs will be evaluated for recovery of peroxisome functions in cultured fibroblasts.

Title: Proxy-Reported Symptoms and Quality of Life Survey in Zellweger Spectrum Disorders

Stage: Completed

University of South Florida

Tampa, FL

The purpose of this study is to characterize the symptoms of Zellweger Spectrum Disorder (ZSD) and related peroxisome disorders and to assess the quality of life of family caregivers (parents, stepparents, legal guardians) of patients diagnosed with ZSD or a related peroxisome disorder. All family caregivers of patients enrolled in the Rare Diseases Clinical Research Network (RDCRN) Contact Registry diagnosed with ZSD or a related peroxisome disorder will be invited via email to participate in this study.