Understanding HIKESHI-leukodystrophy.

HIKESHI-related hypomyelinating leukodystrophy — also known as HLD13, hypomyelinating leukodystrophy type 13, or simply HIKESHI leukodystrophy (OMIM #616881) — belongs to a broader 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.

To date, researchers have described three HIKESHI mutations confirmed to cause HHL in patients. Together, they show that while HHL primarily affects Ashkenazi Jews, the disease is not exclusive to that population:

• Val54Leu (V54L; c.160G>C) — the Ashkenazi Jewish founder mutation, first described in 2016, and the most common cause of HHL.
• Cys4Ser (C4S; c.11G>C) — identified in a Finnish patient in 2016.
• Phe2Val (F2V; c.4T>G) — described in 2024 in a child of Afghan descent.

The HIKESHI gene (previously 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 (V54L) mutation — disables this protein. Without functional HIKESHI, brain cells cannot protect themselves during fever, leading to massive cell death and the destruction of myelin.

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.

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.

In 2024, a peer-reviewed case report demonstrated that introducing a healthy copy of the HIKESHI gene into a patient's cells restored their ability to respond to heat stress. The patient's cells, which had been unable to transport HSP70 to the nucleus during fever-like conditions, regained that function once the working gene was delivered. The study, published in the American Journal of Medical Genetics, concluded that vector-mediated gene replacement may be an effective treatment approach for patients with this disorder. This is the most direct published evidence to date that a gene therapy for HHL is biologically feasible.

With proper funding, this proof-of-concept can be translated into a real treatment within 4–6 years through:

1. Preclinical studies in animal models
2. GMP manufacturing of the gene therapy vector
3. FDA-approved Phase I/II clinical trials
4. Approval through FDA's Orphan Drug pathway