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

KIF1A-Related Research

A de novo low-frequency mosaic variant of KIF1A causes hereditary spastic paraplegia: A literature review

Just like a mosaic in art, we are composed of many, many smaller pieces – our bodies contain trillions of cells!As a single fertilized egg divides, replicates, and makes new types of cells and tissues, there is a small chance of a de novo (new) mutation in a new cell. As that cell replicates, it passes it on to its descendants. This means that some cells in the body have the mutation, and some don’t. We call this pattern a mosaic mutation.

Like the red pieces in this mosaic, mosaic mutations occur in some, but not all, of the cells in our bodies.

So what does this mean for the person? The presence or absence of symptoms depends on whether the cells carrying the mutation use that gene. For example, KIF1A is a neuron-enriched gene, which is why most symptoms relate to the nervous system.

Which cells have a mutation also impacts whether the mutation can be inherited. For this reason, mosaic mutations can be classified into three categories:

  • Gonadal mutations occur in some of the person’s egg or sperm cells; these may not cause symptoms in the parent, but can be transmitted to offspring who will have a copy of the mutation in every cell as they develop.
  • Somatic (soma ~ body) mutations occur in other parts of the body, and may cause symptoms but aren’t passed on to offspring.
  • Somatic-gonadal mutations affect both sperm/egg cells and other cells in the body; these may cause symptoms in the mosaic individual and be inherited by offspring.

In this week’s paper, researchers in Zhengzhou China identified a family in which three children, their father, and their aunt had hereditary spastic paraplegia and a mutation in KIF1A, while their uncle and grandparents had no symptoms. None of the family members had signs of epilepsy or intellectual disability.

Based on the inherited mutation, the researchers performed genetic sequencing on the children’s grandparents. They found that the grandmother, who did not have obvious symptoms, had a gonadal-somatic KIF1A mutation that was passed on.

Even though several family members shared the same mutation, they had different symptoms; the two daughters and aunt had mild symptoms, while the son and father had more severe symptoms. These differences may be due to different levels of KIF1A expression, sex differences, compensation by other proteins or a variety of other factors; more research needs to be done.

Rare Roundup

A First for Rett: FDA Approves Trofinetide for Treatment of Rett Syndrome!

In a huge victory for the rare disease community at large, the United States FDA has approved Acadia Pharmaceuticals’ trofinetide as the first approved treatment of Rett Syndrome in individuals two years of age or older.

Rett Syndrome is a developmental neurodegenerative disorder that impacts movement, communication, and sleep. There are roughly 4,500 diagnosed patients in the US alone; some members of our KAND community have been misdiagnosed with Rett Syndrome due to symptom overlap, but most cases of Rett Syndrome are caused by mutations in the Mecp2 gene.

Trofinetide is a synthetic analog of insulin-like growth factor (IGF-1), a hormone that promotes cellular growth metabolism and combats inflammation that can cause damage to neurons and the glial cells that support them. In Rett Syndrome patients, trofinetide improved “social communication, fine motor skills, and breathing.”

While Rett Syndrome can cause a broad range of symptoms and there may not be a universal treatment, this approval is a crucial first step to improving the lives of patients.

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