Science Saturday January 20, 2024January 20, 2024

#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dylan Verden of KIF1A.ORG summarizes newly published KIF1A-related research and highlights progress in rare disease research and therapeutic development.

KAND Resources

KAND is a complex disorder, and each patient may experience a wide variety of symptoms that require evaluation by different specialists. We’ve worked with lead specialists on the KOALA study to create informational resources on KAND symptoms; check out our Spasticity, Epilepsy, and Vision pages to learn more.

KIF1A-Related Research

Autosomal dominant neurodevelopmental disorders associated with KIF1A gene variants in 6 pediatric patients

Note: While the abstract and figures are available in English, the study was published in simplified Chinese, and translation software has been used to read the study for this summary.

One of the best ways to study a variable disorder like KAND is to look for similarities and differences across several patients with different variants. In this week’s article, researchers in Shanghai, China identified 6 children with KIF1A mutations and compared their symptoms to cases in the literature.

The Study

Two of the mutations addressed in this study, T99M and R254Q, are well-characterized in KAND, and observed symptoms aligned with other studies: T99M has severe consequences, including developmental delay and seizures. R254Q is a “milder” mutation that primarily causes motor symptoms associated with spastic paraplegia type 30 (SPG30).

The study also found three novel mutations:

• G109V caused developmental delay and motor symptoms without evidence of epilepsy at 18 months of age.
• L249V primarily caused motor symptoms at 2 years of age, including an abnormal walking gait and increased muscle tone in the legs. Other L249 mutations have been previously observed; L249Q and L249P mutations create different amino acids that seem to cause more severe symptoms than L249V. This highlights how even mutations in the same area of a protein can have different consequences.
• c.798+1G>A caused mild motor symptoms without other complications. The notation for this mutation is a little different from others, because it doesn’t just change a single amino acid. Instead, this is what is called a splicing mutation; it occurs at the boundary between coding DNA that is read into RNA and protein, and noncoding DNA that is excluded. These boundaries need to be “spliced” or specifically cut so RNA and proteins only contain coding DNA. This mutation caused improper splicing, and as a result the KIF1A is missing 66 amino acids and unlikely to function.

The authors followed up these observations by looking at the protein stability of KIF1A with T99M, R254Q, G109V, or L249V mutations; they found reduced stability for all mutations, indicating that they may compromise KIF1A structure or make it more easily degraded, preventing proper cargo transport.

With so many KIF1A mutations across our community, every new observation helps us get a better picture of this disease’s manifestations so we can accurately address symptoms.