Infantile Neuroaxonal Dystrophy

What Causes Infantile Neuroaxonal Dystrophy?

In most cases, INAD seems to be caused by an abnormal change (mutation) in a gene called the PLA2G6 gene. This gene carries instruction for making an enzyme vital in the break-down of fatty compounds within cells. The mutation impairs the body’s ability to produce the enzyme, and the lack of the enzyme, in turn, interferes with cells’ ability to function normally.

Scientists are not yet sure how the lack of the enzyme causes damage to nerve cells. Nerve cells in people with INAD have spherical swellings in their axons, long fibers responsible for transmitting nerve impulses. Affected nerve cells cannot communicate effectively with other cells in the muscles, eyes, and skin, leading to the symptoms of INAD.

Is Infantile Neuroaxonal Dystrophy Hereditary?

INAD 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 INAD. 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 Neuroaxonal Dystrophy Detected?

Infants with INAD typically appear to develop normally for the first few months after birth. At some point, usually after six months of age, babies with the disorder begin to show developmental delays in acquiring new motor and mental skills. They also start to lose the skills they’ve already developed.

These delays and regressions are usually the first noticeable symptoms of the disorder. General loss of muscle control, involuntary eye movements, and weak, floppy muscles are also common early signs.

How Is Infantile Neuroaxonal Dystrophy Diagnosed?

A doctor may suspect INAD 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
• Imaging scans such as magnetic resonance imaging (MRI) to look for the degeneration of brain tissue or accumulation of iron in the brain
• Ophthalmologic exam to look for the degeneration of the optic nerve
• Electroencephalogram (EEG) to look for seizure activity
• Tissue biopsies to look for characteristic swelling in nerve axons
• Genetic testing to look for the PLA2G6 mutations associated with INAD

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Infantile Neuroaxonal Dystrophy Treated?

INAD has no cure, and no treatment will reverse or stop the progression of symptoms. Instead, treatments aim to prevent complications, ease symptoms, and improve the child’s quality of life. A typical treatment plan may include:

• Medications to control muscle stiffness
• Medications to control seizures
• Feeding assistance
• Physical therapy
• Monitoring of vision and hearing impairments

Potential Treatments

Research is ongoing into therapies that could prove effective at treating INAD in the future. These potential therapies include:

• Enzyme replacement therapy (ERT)
• Gene therapy/gene replacement
• Gene editing

How Does Infantile Neuroaxonal Dystrophy Progress?

INAD usually progresses rapidly after symptoms appear. Loss of muscle control worsens, and cognitive decline is also rapid. Complications of the disorder are typically fatal between the ages of five and ten years.

Progressive symptoms of INAD include:

• Slowing development and loss of motor and cognitive skills
• Vision impairment or blindness
• Hearing loss
• Weak, floppy muscles that eventually become stiff and rigid
• Complete loss of mobility
• Difficulty swallowing and chewing
• Respiratory infections
• Dementia
• Loss of awareness of surroundings

How Is Infantile Neuroaxonal Dystrophy Prevented?

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

Infantile Neuroaxonal Dystrophy Caregiver Tips

• Caring for a child with INAD takes an enormous amount of physical and emotional strength. Trying to do it all yourself will put your own health at risk. Don’t hesitate to ask for help from family members and friends, and let them give you time away from caregiving whenever possible.
• Cherish the time you have with your child. Take time to process your grief, but don’t pass up the opportunity to relish the moments of joy when they happen.
• Find a community. The INADcure Foundation offers families living with INAD the opportunity to connect with other families and medical professionals who can help them with their questions and concerns about the disorder.

Infantile Neuroaxonal Dystrophy Brain Science

The PLA2G6 gene, which is mutated in most INAD cases, carries instructions for making an enzyme called an A2 phospholipase. The enzyme plays a role in breaking down a fatty compound called phosphatidylcholine inside cells. Scientists don’t know precisely how improper production of A2 phospholipase or accumulation of phosphatidylcholine affects nerve cells, but they suspect the abnormalities might impact the cell membrane.

The PLA2G6 mutations appear to lead to several distinctive features of INAD, including:

• Spheroid swelling in nerve axons
• Degeneration of the cerebellum, the part of the brain that controls muscle activity
• Abnormalities in brain tissue called white matter

Sometimes children with INAD exhibit abnormal accumulations of iron in a part of the brain called the globus pallidus. This kind of iron accumulation is also characteristic of other disorders, such as pantothenate kinase-associated neurodegeneration, Alzheimer’s disease, and Parkinson’s disease. Research is ongoing into a possible link between INAD and these disorders.

Infantile Neuroaxonal Dystrophy Research

Title: NBIAready: Online Collection of Natural History Patient-reported Outcome Measures

Stage: Recruiting

Principal investigator: Susan J. Hayflick, MD

Oregon Health & Science University

Portland, OR

This study aims to learn more about Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders. Data is being collected on three types of NBIA disorders:

Pantothenate Kinase-Associated Neurodegeneration (PKAN), PLA2G6-associated Neurodegeneration (PLAN), and Beta-propeller Protein-associated Neurodegeneration (BPAN). The study will (1) collect information about how symptoms and findings in NBIA change over time and (2) identify measures of NBIA that can be used in future clinical trials. In addition, participants will follow links to a secure website every six months for a period of 5-10 years to electronically complete a set of rating scales as related to their NBIA disorder.

Title: CoA-Z in Pantothenate Kinase-associated Neurodegeneration (PKAN)

Stage: Recruiting

Principal investigator: Allison Gregory, MS

Oregon Health & Science University

Portland, OR

The purpose of this study is to learn more about how people with the condition pantothenate kinase-associated neurodegeneration (PKAN) respond to a specialized study product. We are hoping to find out if the study product is safe, what effects, good and bad, the study product causes, and whether the study product changes certain measures of PKAN disease.

Title: A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy

Stage: Active

Study director:  Peter Milner, MD

University of California San Francisco, Benioff Children’s Hospital

San Francisco, CA

The purpose of this study is to evaluate the efficacy and safety of RT001 in patients with Infantile Neuroaxonal Dystrophy (INAD).

This is a single-arm open-label study with a structured observation of INAD patients treated with RT001. Enrolled subjects will undergo observation and testing to determine the effect of RT001 treatment. Fifteen eligible subjects will be treated with RT001 for long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics.