KIF1A-Associated Neurological Disorder (KAND)

KAND is a group of rare neurological disorders in children caused by variants (mutations) in the KIF1A gene, which plays an important role in the nervous system. Children with KAND have developmental delays and varied neurological symptoms. Some forms of KAND are mild, while others can be life-threatening. KAND is a degenerative disease, meaning it causes a loss of functioning over time.

Because it is so rare, there is still much to learn about KAND. Families are our best partners in advancing our understanding of this condition. Currently, several hundred people worldwide are known to have KAND, but the true number is believed to be higher.

KAND has a wide spectrum of symptoms and severity, depending on the nature of the variation on the KIF1A gene. More than 100 different KIF1A variants have been identified. However, it’s important to note that even two patients with the same genetic variant can have different symptoms.

KAND can resemble and is sometimes misdiagnosed as other conditions like cerebral palsy, Rett syndrome, or Charcot-Marie-Tooth disease. Its most common symptoms include:

• Intellectual disability, including developmental, speech, and language delays
• Epilepsy
• Problems with muscle strength, coordination, reflexes, and balance. These can include:
  • Hypotonia or low muscle tone. Children may feel limp in your arms, have trouble holding up their heads, or have weakness in leg or shoulder muscles.
  • Spastic paraplegia, muscle tightness (spasticity) or weakness that gets worse over time and can cause trouble walking.
  • Clumsiness, a lack of coordination and balance.
  • Other movement disorders (involuntary movements or difficulty coordinating movements).
• Slurred speech or difficulty swallowing or chewing
• Peripheral neuropathy (pain, tingling, numbness, or weakness in the hands or feet, caused by nerve damage)
• Vision loss, optic nerve atrophy, strabismus, cataracts, or other vision problems
• Autism and/or attention deficit hyperactivity disorder.

Usually the KIF1A variants that lead to KAND occur spontaneously and are not inherited; these are called de novo (new) variants. Less commonly, children can inherit KIF1A variants from one or both parents.

KIF1A encodes a protein of the same name, part of a group of proteins called kinesins. It serves as a molecular “motor,” transporting cargo (like nutrients and other molecules needed for nerve cell function) up and down nerve fibers. Variants in KIF1A can disrupt this transport in different ways, impairing nervous system function. For example, KIF1A may not attach well to the cargo, or it may fall apart structurally and be unable to travel. But other research suggests that the KIF1A protein can sometimes build up in cells and become toxic.

KAND can be definitively diagnosed with DNA sequencing of a group of genes or whole exome sequencing, a type of genetic test that looks across the genome. It can identify a variety of variants in the “spelling” of the KIF1A gene as well as deletions and duplications of DNA that affect KIF1A’s function. Sequencing can also rule out KAND by finding variations in other genes that explain the child’s symptoms.

Currently there is no cure for KAND, but its symptoms can be alleviated through a variety of interventions. The KAND program at Boston Children’s, led by Dr. Wendy Chung, offers care tailored to each child’s symptoms. This typically includes:

• Regular testing to assess spasticity, mobility, coordination, and balance
• Brain assessments, which may include a brain MRI to monitor for cerebral atrophy and an electroencephalogram (EEG) to test for or monitor epilepsy
• A neuropsychology evaluation to assess developmental milestones and cognitive abilities
• Medications for specific symptoms, such as gabapentin for peripheral neuropathy, baclofen or botox injections for muscle spasticity, and anti-seizure medications for epilepsy
• Speech and feeding therapies
• Physical therapy
• Occupational therapy
• Special education referrals

We often recommend that children with KAND see an orthopedist, who can prescribe orthotics and devices to improve mobility, and a neuro-ophthalmologist who can examine the child’s eyes and look for optic nerve atrophy and cataracts. We also offer genetic testing and counseling for family members.

Researchers at Boston Children’s are working to develop drugs that can correct certain KIF1A variants. This work is in the early stages.

KAND has a wide spectrum of severity. Some children may have only spasticity or tingling in the hands and feet and live to adulthood, while others may have severe, life-threatening seizures and live for only a few years.

Because KAND is neurodegenerative, it gets worse over time. Children born with severe KAND may never achieve milestones such as crawling, while children born with milder KAND may lose abilities like vision or mobility as time progresses.

The Chung Lab at Boston Children’s has evaluated more than 200 individuals affected by KAND. In 2017, in collaboration with the patient group KIF1A.org, the lab launched a two-part natural history study that is following children over time to track their symptoms and medical data. The goal is to better understand the features of KAND, develop better care guidelines, and lay the groundwork for future clinical treatment trials.

• ASCEND, part 1 of the study, involves online interviews and surveys. Families are asked to upload their child’s full genetic testing report with their exact KIF1A variant and diagnosis, and, if possible, the child’s medical records.
• KOALA (KIF1A Outcome measures, Assessments, Longitudinal And endpoints Study) is an extension of ASCEND that began in 2022. This study involves in-person visits with standardized assessments of children’s motor function, neurocognitive and neuropsychological status, seizure activity, and vision. Researchers will also collect blood and urine samples and photos and videos to track physical changes.

For more information on the natural history study, email ASCENDstudy@childrens.harvard.edu.

Experimental drugs

Dr. Chung and her colleagues are also studying KIF1A variants in the lab, using stem cell lines derived from patients and animal models to better understand how different variants affect the function of neurons (nerve cells) and to test potential treatments. The lab is using this information to develop individualized treatments for KAND using a family of drugs called antisense oligonucleotides (ASOs). These drugs are specially designed to mirror a child’s specific KIF1A variant and suppress, bypass, or modify it.

One ASO, tested in a single child to date, reduced her frequency of falling, improved her quality of life, and increased her independence. Dr. Chung hopes to offer this and other ASOs to additional children with KAND in the future.