Understanding HIKESHI-leukodystrophy.
A rare, fatal genetic disease — and a roadmap to ending it.
What is leukodystrophy?
Leukodystrophies are a group of rare, progressive genetic disorders that affect the white matter (myelin) of the brain and nervous system. Myelin is the protective coating around nerve fibers that allows electrical signals to travel quickly between brain cells.
There are over 50 known types of leukodystrophy, each caused by a different genetic mutation. They typically appear in childhood and progressively worsen over time. Many leukodystrophies are fatal — but recent advances in gene therapy are bringing real hope.
The HIKESHI gene
HIKESHI (also known as C11ORF73) is a small but critical gene located on chromosome 11. It produces a protein that acts as a "shuttle" — transporting another protein called HSP70 into the cell's nucleus during heat stress, such as fever. HSP70 protects cells from damage when temperatures rise.
In HIKESHI-leukodystrophy, a single DNA letter change — the Val54Leu mutation — disables this protein. Without functional HIKESHI, brain cells cannot protect themselves during fever, leading to massive cell death and the destruction of myelin.
Why Ashkenazi Jews?
The Val54Leu mutation is what geneticists call a founder mutation — it originated in a small Jewish ancestral population centuries ago and spread as the community grew. Today, it is found almost exclusively in people of Ashkenazi Jewish descent.
HIKESHI-leukodystrophy joins the well-known list of Ashkenazi genetic conditions — including Tay-Sachs, Gaucher, and Canavan disease. Unlike these, it is not yet included in standard Ashkenazi genetic screening panels — meaning most carriers don't know they're at risk. Source: Int. J. Mol. Sci. 2025, 26, 6037.
Symptoms and progression
Children with HIKESHI-leukodystrophy typically appear healthy at birth. Symptoms emerge in infancy, often triggered by the first significant febrile illness: developmental regression, loss of motor skills, seizures, and progressive neurological decline.
Roughly half of affected children do not survive their first severe fever. Those who do face cumulative, irreversible neurological damage with each subsequent illness.
The path to a cure
Recent proof-of-concept gene therapy work in cell and animal models has shown that delivering a functional copy of the HIKESHI gene can restore the protein and protect brain cells from heat stress.
With proper funding, this proof-of-concept can be translated into a real treatment within 4–6 years through:
- Preclinical studies in animal models
- GMP manufacturing of the gene therapy vector
- FDA-approved Phase I/II clinical trials
- Approval through FDA's Orphan Drug pathway