Scientists suspect the mutation may have originated centuries ago in a common ancestor from Central Europe, probably in what is now Silesia, according to information released to the Polish Press Agency.

The disease results from a mutation in the PUS3 gene, which is responsible for producing the enzyme pseudouridine synthase 3. Researchers say the mutation, designated c.212A>G (p.Y71C), likely spread through a so-called founder effect. At least three of the patients outside Poland have documented Polish ancestors.

Researchers estimate that a child with PUS3 syndrome may be born in Poland on average once every one to two years. Some patients may remain undiagnosed, as the condition can be mistaken for disorders such as cerebral palsy or complications related to birth asphyxia.

The mutation is caused by the substitution of a single letter in the gene sequence. At position 212, guanine replaces adenine, producing an enzyme with an unstable structure that rapidly degrades at human body temperature. As a result, the efficiency of protein biosynthesis in cells is severely reduced.

Children with the condition develop a complex group of congenital disorders, including severe intellectual disability, developmental delay, absence of speech, short stature, microcephaly, internal organ defects, strabismus and extensive Mongolian spots. Some patients also develop epilepsy that can be resistant to treatment, while brain imaging may reveal additional abnormalities. The disease is progressive and neurodegenerative.

One of the affected children is Jerzy, the two-year-old son of PUS3 Foundation founder Jan Kieszczyński. Although he received an Apgar score of 10 at birth, developmental problems soon became apparent. Reduced muscle tone prevented him from moving normally and eating solid foods, and he missed key developmental milestones. His parents learned that a rare PUS3 mutation was responsible shortly after his first birthday.

Scientists believe gene therapy could offer a potential solution. The research is led by Professor Leszek Lisowski, a gene therapy specialist who heads a research unit at the Children’s Medical Research Institute in Sydney and collaborates with the Gene2Cure Foundation in the United States. The project also involves Professor Robert Śmigiel, head of the University Centre for Rare Diseases in Wrocław.

Researchers consider PUS3 syndrome a promising candidate for gene therapy because the gene is small enough to be inserted precisely into a viral vector. In the proposed treatment, a harmless AAV9 virus carrying a correct version of the PUS3 gene would enter cells and provide instructions enabling the body to produce the functional enzyme.

Laboratory studies on cells have already shown that introducing the correct gene can restore normal metabolism, raising hopes that neuroplasticity and developmental functions such as speech and movement could be partially recovered.

However, funding remains a major obstacle because the disease affects so few patients worldwide.

“Gene therapies are the most expensive drugs in the world. Drugs entering the market from pharmaceutical companies often exceed $3 million per dose. One dose is sufficient to cure this disease, but we are talking about over $3 million,” Professor Leszek Lisowski said.

“But creating the drug itself also requires a significant financial investment,” he added.

Developing the therapy is expected to take three to five years, and the total cost of the project — from laboratory work to treatment of patients — is estimated at about €5 million.

The PUS3 Foundation, which brings together families of affected children worldwide, is raising funds to support the research. A campaign is currently underway to collect €1 million to finance the first phase of work, including designing the viral vector, testing patient-derived cells, preclinical research and safety studies.

“A diagnosis of an ultra-rare genetic disease is a double sentence for a parent. On the one hand, we watch as the disease ruthlessly robs our child of their physical and intellectual abilities. On the other, we are faced with the realities of the medical business. For pharmaceutical companies, creating a drug for a dozen or so children worldwide is simply unprofitable. We were told that nothing can be done,” Jan Kieszczyński said.

Lisowski said early progress is crucial because of the progressive nature of the disease.

“The genetic diseases we are talking about, like PUS3, are progressive diseases (...) The sooner the better (...) These projects take a lot of time and require a lot of money. What we want to avoid is for this project's development to grind to a halt when the money runs out and be on hold while we are trying to raise more funds,” he added.

Joanna Morga (PAP)

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