KIF1A-related disorders are a group of genetic disorders caused by one or more mutations in the KIF1A gene [1]. These mutations cause changes in the microtubule (MT) motor protein, disrupting the motor domain’s ability to transport specific synaptic vesicle precursors in axons, leading to KIF1A-Associated Neurological Disorder (KAND) [2].
Introduction
KAND is an ultra-rare genetic disorder that affects less than 500 people worldwide [3]. The disease is caused by a mutation(s) that disrupts the MT motor protein’s ability to transport synaptic vesicle precursors. KAND is both a neurodevelopmental and neurodegenerative disorder; while the progression of the disease varies from patient to patient, those with a KIF1A mutation often first develop symptoms in infancy or childhood [4]. Many factors contribute to the complexities of KAND, mutations can occur in a variety of locations along the KIF1A gene, and genetically it can present as an autosomal dominant variety, an autosomal recessive form, or through de novo variations [1].
So, what is a microtubule motor protein and why does it’s disruption cause such neurological diseases? Motor proteins carry cellular material throughout cells along a microtubule (MT). These motor proteins take several different forms, but the motor protein associated with KIF1A is classified in the kinesin-3 family [5]. KIF1A-related kinesin-3 transports critical cellular cargo that contributes to pre- and post-synaptic assembly, autophagic process, and neuron survival [6]. This motor protein carries and transports this critical cargo along the microtubule using it’s two motor domains, this movement is displayed in Figure 1. When a mutation occurs in the KIF1A gene, this motor protein’s motor domain can be disrupted resulting in failure to transport synaptic vesicles containing essential glycoproteins, which then results in neuron death. Due to this disruption in neuronal communication, pathogenic variations in KIF1A cause a number of different neurological symptoms.
Tell Me About This Rare Disease:
Genetic Basis: This disorder can be inherited as an autosomal dominant trait, an autosomal recessive trait, or may occur due to a sporadic mutation (de novo) [2]. Most frequently this disease occurs as a de novo or an autosomal dominant mutation [7]. KAND is caused by one or more variations in the KIF1A gene, locus 2q37.3 [8]. There is not one singular mutation that takes place to cause KAND. Instead, there are several different variations that can occur within the gene, most of which occur in the core motor domain, damaging the microtubule motor protein and causing a variety of phenotypic symptoms [9]. Some of these genetic variations and related disease severities can be seen below in Figure 3.
Clinical Presentation: KAND can present itself through a broad phenotypic spectrum of symptoms, with many patients first experiencing symptoms at birth or early childhood [11]. Some commonly found KAND symptoms include Hereditary Spastic Paraplegia (HSP), Optic Nerve Atrophy (ONA), Ataxia, Epilepsy, Hypotonia, Intellectual Disability, Cerebral Atrophy, Cerebellar Atrophy, Peripheral Neuropathy, Autism Spectrum Disorder (ASD), and Attention Deficit Disorder (ADD) [2] [4]. Most often, patients experience seizures.
Due to the complexity of this disease, it can be beneficial to look at the clinical presentation of the autosomal dominant variety, autosomal recessive forms, and de novo variations separately [1]. Some symptoms and related disorders commonly associated with the autosomal dominant form of this mutation are developmental delays, clumsiness, cerebellar atrophy, peripheral neuropathy, ptosis, facial diplegia, intention tremors, strabismus, nystagmus and ataxia [2]. Additionally, hypertonia, hyperreflexia, spasticity, and hyperreflexia have also been found to occur in some patients [2]. In an autosomal recessive inheritance, symptoms such as hereditary sensory neuropathy IIC and HSP may occur [2]. Lastly, KAND patients with de novo recessive mutations in the KIF1A gene, commonly linked to other comorbid conditions, may experience more harmful symptoms [2]. Clinical diagnoses and symptoms observed in patients with these de novo mutations in the motor domain of KIF1A have included intellectual disability, cerebellar atrophy, optic nerve atrophy, spastic paraplegia, and peripheral neuropathy [2].
Incidence: Although the exact incidence of KAND is unknown, it is averaged there are over 400 current patients worldwide [3].
Geographical Locale of Patients: A geographic or ancestral demographic pattern has not been found to be associated with KAND.
Brief History:
1991: KIF1A gene is discovered in C. elegans [12]
2016: KIF1A.org is launched by Luke and Sally Rosen [13]
2017: The Chung Lab at Columbia University launches the first Natural History of KAND and develops patient derived cell lines [14]
2017: The Jackson Laboratory develops mouse model for KIF1A [15]
2020: A Murdoch Children's Research Institute (MCRI) research study found two new mutations in the KIF1A gene that cause KAND [16]
2022: The n-Lorem Foundation dosed Susannah Rosen with the first mutation-specific experimental antisense oligonucleotide therapeutic designed to treat KAND [3]
The State of the Disease Today: There was not much known about KAND before 2016, but recent advances in whole genome sequencing have allowed scientists and patients alike to better understand the disease. This has allowed patients to receive more accurate diagnoses, with fewer patients experiencing a misdiagnosis of Rhett Syndrome, Charcot-Marie-Tooth disease, or other severe neurodevelopmental disorders [16] [17]. KAND patients and families have been at the forefront, spearheading awareness and pushing for research on KIF1A and possible KAND treatments.
What is it like to be a patient with this disease?
Who are the patients? Patients with KAND are mostly young children. A published natural history study of KAND in 117 individuals revealed that the mean age of individuals with KAND is 9.9 years, with a median age of 7.3 years. Individuals in this specific cohort ranged from 6 months to 39 years old [10], but there are reported cases of older KAND patients as well [18]. Life expectancy can vary from a few years to several decades depending on the location and severity of the mutation.
What do current treatment options look like? Currently, there are no effective cures or treatment options for patients with KAND. Due to this lack of a cure, patients with KAND must look to specialists for the treatment of individual symptoms. Current KAND patients may require services from neurologists, ophthalmologists, pediatricians, speech therapists, and an additional team of specialists depending on the severity of their KAND [2]. In 2022, the n-Lorem Foundation began treating Susannah Rosen with the first personalized antisense oligonucleotide treatment for KAND [3]. We are hoping ASO therapeutics like this one will be found effective, so more patients may be treated in the future.
Are there advocacy groups? Yes, KIF1A.ORG is a foundation to push forward research for KIF1A Associated Neurological Disorder (KAND) and to improve the lives of people affected by KAND. It was founded in 2016 by parents, Luke Rosen and Sally Jackson after their daughter, Susannah, was diagnosed with KAND [11].
Are there genetic tests? Yes, due to their complexity KIF1A-Associated Neurological Disorder can only be diagnosed through genetic testing. Mutations in the KIF1A gene can be identified by whole exome sequencing, which is a powerful sequencing method used to detect variants within a patient’s entire genome. Below is an example of a genetic report of a patient with a mutation in the KIF1A gene. In addition, KIF1A has been included in gene panels for epilepsy, ataxia, vision, and neuropathy.
How do Scientists and Clinicians Study this Disease?
Are there any (good) model systems for drug development? At the request of families affected by KIF1A-related diseases through a campaign led by KIF1A.org, the Jackson Laboratory has funded and developed several mouse models to support further KIF1A research [15]. In addition, KIF1A.ORG collaborated with Dr. Wendy Chung’s Lab at Columbia Medical Center and the Coriell Institute to create iPSC lines derived from patient samples, representing 5 disease-associated mutations for use by researchers [20]. For example, Neucyte is currently using some of these lines to create cellular models to model KAND for testing therapeutics [21]. Other models of KAND include a C. elegans model developed by Niwa lab at Tohoku University and a zebrafish model developed by the Chitnis lab at the National Institutes of Health [20].
Have natural history studies been done? Wendy Chung’s lab at Columbia Medical Center has previously published a natural history study of KAND in 117 individuals [10] and is continuing to collect this data from newly diagnosed patients [22]. Her group is also inviting patients to participate in an ongoing clinical endpoint study called the KOALA study to establish baseline disease metrics that can be used to assess the clinical benefits of new therapeutics [23].
Certain physicians or centers that are experts? Wendy Chung’s laboratory at Columbia Medical School studies rare diseases including KAND and has played an instrumental role in helping better understand KAND through their collaboration with KIF1A.ORG. They have since been awarded a four-year grant to study KIF1A in 2020 with the Vallee Lab at Columbia University and Gennerich Lab at Albert Einstein College of Medicine, both of which are experts in the biological mechanisms of motor proteins [24].
What are the major challenges in studying and curing this disease? One of the main challenges of curing KAND is the variability in pathophysiology and disease progression from patient to patient [2]. Because of the diversity of mutations in the KIF1A gene across KAND patients, the presentation of the disease in each patient can be studied by identifying the location of the mutation within the KIF1A gene. For example, a natural history study conducted by Wendy Chung’s laboratory at Columbia Medical Center found that more severe cases of KAND directly correspond to patients that have mutations in the gene that affect ATP and microtubule binding which are shown in Figure 3 [10]. The large size of the KIF1A gene (110.5 kB [25]), also makes it a difficult target for gene therapy options, for example, an rAAV vector has a packaging capacity of 4.8 kB [26].
The Cure Corner: What is needed for a cure?
What does an ideal therapeutic look like? As previously mentioned, there are no therapies readily available to treat KAND, and surgical treatment cannot cure KAND. Therefore, scientists and clinicians are looking at gene therapy options to treat these diseases [2]. It would be ideal to develop a therapeutic generally targeting KIF1A, however, due to the variation in KIF1A mutations and KAND from patient to patient, it might be necessary to develop personalized therapies for individual patients.
Are there companies already developing drugs? The n-Lorem Foundation has developed an antisense oligonucleotide therapeutic targeting Susannah Rosen’s specific KIF1A mutation and is working on developing therapeutics for other KIF1A mutations [3]. In addition, the Gennerich Lab at the Albert Einstein College of Medicine is working with Atomwise and their AI drug discovery platform to find small molecule therapeutics for KAND [21].
What are current therapies and treatments lacking? As mentioned previously, there is currently no cure for KAND. Current treatments for patients with KAND only manage symptoms related to the disease [27]. Ideally, there would be a therapeutic available that targets the genetic cause of KAND, rather than just downstream symptoms.
Could an RNA therapeutic fit the need? RNA therapeutics, specifically antisense oligonucleotides, have shown potential in knocking down mutant copies of a gene, but at this time have limitations for cases of loss-of-function. In late 2022, the n-Lorem Foundation treated Luke and Sally Rosen’s daughter Susannah with a personalized antisense oligonucleotide therapeutic. Since then, she has already seen improvement in her ability to stand up, speak, and focus her gaze [3]. We hope that she continues to see improvement so that other KAND patients can be treated with a similar RNA therapeutic in the future.
Conclusion
With the advent of whole genome sequencing and as it becomes more accessible, we can begin to understand much more about ourselves and the mutations we harbor. There is currently no treatment or cure for diseases related to KIF1A mutations, but advocates for KAND patients and their families alone have accomplished substantial feats through organization and advocacy. Research is ongoing and progressing quickly and it is our hope that soon there will be a therapeutic for every individual with a KIF1A mutation.
Thank you to Luke, Dylan, and the whole KIF1A.ORG family for taking the time to review our article prior to publication.
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