This new disease prevents the production of antibodies

THE ESSENTIAL

• Doctors at the Children’s Hospital of Philadelphia have discovered a new form of rare disease in a 7-month-old baby with recurrent ear infections.
• Called PU.1 mutated agammaglobulinemia, it results in a mutation in the PU.1 gene, which usually helps in the production of B lymphocytes, cells essential for the production of antibodies.
• The little boy was able to benefit from a bone marrow transplant from his older brother, which allowed him to eventually produce his own B cells.

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Little Luke Terrio was around seven months old when his mother began to realize something was wrong. He had constant ear infections, had red spots on his face, and was tired all the time. Her development was stagnant and the antibiotics given to treat her frequent infections no longer worked.

Followed by a doctor at the Children’s Hospital of Philadelphia (CHOP), he then had a series of blood tests which revealed that Luke had no antibodies. At first, specialists thought the little boy may have had X-linked agammaglobulinemia, an immunodeficiency syndrome rare in children. However, as they continued to study Luke’s case, the CHOP research team realized that Luke’s disease was unlike any other disease described before.

A very rare mutation in the SPI1 gene

The doctors used whole exome sequencing to analyze Luke’s DNA. They then discovered the genetic mutation responsible for his condition, which prevents Luke and patients like him from making B lymphocytes, and therefore antibodies to fight infections. In a study published in the Journal of Experimental Medicine, they explain having named this disease agammaglobulinemia mutated PU.1 (PU.MA).

“It can be quite frightening for a family whose child has a mysterious illness, explains Neil D. Romberg, attending physician in the Allergy and Immunology Division of CHOP, lead author of the article. In this case, science has provided an explanation, thanks to many services from CHOP. Understanding the cause of Luke’s condition absolutely helped us know what direction to take his therapy. “

To identify the offending gene, CHOP researchers compared the entire exome sequences of 30 patients around the world born without B lymphocytes, the cells that produce the antibodies. In this group, they identified six patients, including Luke, who had a mutation in a gene called SPI1, which codes for the PU.1 protein. PU.1 helps B cells that develop in the bone marrow to open “doors” in their chromatin, a type of very compact DNA. Without PU.1, these doors remain closed, and B cells never form. The six PU.MA patients, ranging in age from 15 months to 37 years, each had different SPI1 mutations but in common had insufficient levels of PU.1, absent B cells, and therefore no antibodies. .

A beneficial bone marrow transplant

Since Luke’s condition was entirely new, there was no guide for his family or medical team to follow. After consulting with the research team, the family decided to have a bone marrow transplant in the hopes that the procedure would help them make their own B cells and antibodies. They quickly discovered that they had a perfect donor living under their own roof: Luke’s older brother, Jack, three and a half years old.

The transplant succeeded in making Luke produce his own B cells until they were able to create enough protective antibodies on their own. Luke continues to be protected against infection for the time being by the antibody infusions he receives every two weeks. “We call them his ninjas, Michelle, Luke’s mom, explains, describing the antibodies. We tell him that he doesn’t make his own ninjas, so he needs those ninja infusions to fight germs and keep him safe. ” Thanks to these “ninjas” and his brother’s donation of bone marrow, Luke is now an energetic 4-year-old boy who enjoys Transformers, fire trucks and riding bikes.

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