The Spanish patient who has identified a new disease

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A team of doctors from the Virgen del Rocío Hospital in Seville and Sant Joan de Déu Hospital in Barcelona, and their respective research institutes (Irsdj and IBIS), has collaborated in the research that described from a Spanish patient a new minority disease associated with mutation in DOCK11.

For this, it has been necessary the work of years, together with other international reference centers, of genetic analysis of the patient and his family, as well as functional studies and work in experimental models, which are detailed in a study recently published in The New England Journal of Medicine.

However, this whole process of international collaboration begins at the moment when doctors who treat a patient with a clinical picture that does not fit any diagnosis decide to go a step further.

Because, as one of the specialists who participated in the discovery of this new disease acknowledges: "Without clinical suspicion, there is no diagnosis."

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Bless you.

Spanish researchers discover a new rare disease in a child with unexplained inflammation

• Editor: EFE Barcelona

Spanish researchers discover a new rare disease in a child with unexplained inflammation

Rare Disease Day.

"Neonatal screening makes a huge difference, as 70% of rare diseases appear in childhood"

• Writing: CRISTINA G. REAL Madrid

"Neonatal screening makes a huge difference, as 70% of rare diseases appear in childhood"

This is what Joan Calzada, from the Sant Joan de Déu Paediatric Rheumatology team and IRSJD researcher, comments, who highlights the importance of the clinical part in the process. "Only with the clinical suspicion that you are facing a new disease you probably will not be able to describe it, but without it, it is not possible to do so."

Experience in reference centres

The development of the ability to suspect that something does not fit is, above all: "A matter of experience: seeing many and many patients, which allows you to make connections between other cases you have treated or read about. Hence the importance of having reference centers and, especially, if it comes to rare diseases. "

In this case, the discovery of the new pathology began with a patient who was treated for the first time in the Virgen del Rocío, where the specialists of the Unit of Infectology, Rheumatology and Pediatric Immunology (with pediatricians Paula Sánchez Moreno and Marisol Camacho-Lovillo) found, after performing various analyzes, that his symptoms did not fit with those of any disease described.

"His symptomatology did not fit with any known immunodeficiency or autoinflammatory disease, so we contacted Professor Kaan Boztug, from the St. Anna Institute for Childhood Cancer Research and the Research Center for Molecular Medicine of the Austrian Academy of Sciences, in Vienna, to find out if they had references from other patients in the world who could be in the same situation to achieve a minimum of scientific evidence," says Olaf Neth, head of the Unit of Infectology, Rheumatology and Pediatric Immunology of the Seville hospital.

Functional studies and biological models corroborated the suspicion of being faced with a new entity, and allowed to determine the suspicion that the mutation detected in the DOCK11 gene could be related to the clinical picture of the child.

No previous connection to human disease

The gene, involved in regulating different cellular functions, had not previously been associated with any human disease. Previous studies had shown the importance of the protein produced by that gene for B cell development in mouse models. Researchers have now shown that, to some extent, B cells also do not develop properly in humans with DOCK11 deficiency, and at the same time, T lymphocytes are overactivated, which explains the state of persistent inflammation. "This constant inflammation can cause the accumulation of amyloid protein in the tissues, producing amyloidosis", adds Laia Alsina, head of the Allergy and Clinical Immunology Service at SJD Barcelona Children's Hospital, Irsjd researcher and coordinator of the Integrated Unit of Clinical Immunology SJD Barcelona Children's Hospital.

Olaf Nef also highlights the collaboration of the Pathological Anatomy Service of the Virgen del Rocío (specifically, doctors Rainiero Ávila Polo and Rocío Cabrera-Pérez) when carrying out all the genetic studies, functional tests and other determinations that the laboratories of Austria needed to continue with the study of the patient.

"Subsequently, the appearance in other foreign centers of new patients from different families with similar clinical pictures and also with mutations in the same gene has been the piece that completed the puzzle," adds the also head of the Congenital Alterations and Immunity group of the IBiS.

In fact, the publication of four patients from this group in NEJM coincided with that of another series of eight patients reported in the journal Blood, with Charlotte Boussard, from Paris Cité University (France) as the first signatory. That reinforced the solidity of the new entity's find.

New monogenic cause of actinopathy

Thus, the new disease is due to the abnormalities that the mutation in the DOCK11 gene produces in the cytoskeleton, the internal structure of the cells that gives them their shape and their ability to move. "The clinical manifestation is very variable," says Joan Calzada, in whose center the management of the patient continued, due to the transfer of the family to Barcelona.

"The expected phenotype of this disease, from what is known so far, is a boy – girls are only carriers – with persistent fever, acute elevation of inflammation markers, skin lesions, repeated infections and anemia. Secondary to the disease, due to the inflammatory action, growth retardation may occur, and if amyloidosis develops, renal, digestive or cardiac functions may be affected."

The disease falls within actinopathies, explains Joan Calzada, in which there is a failure in actin or other proteins important for the function of the cytoskeleton. "The clinical picture it generates is straddling primary immunodeficiencies and autoinflammatory diseases."

Until these patients, achinopathies were caused by variants in DOCK2 and DOCK8, among other genes. Now the DOCK11 gene is added, on the X chromosome, to the genetic causes of these alterations.

An editorial in NEJM accompanies the description of the disease, signed by Stuart Tangye of the Garvan Institute of Medical Research in Darlinghurst, Australia, and Isabelle Meyts of the University Hospitals of Leuven, Belgium.

The authors highlight as the main difference between the two series of published patients "the finding of autoantibodies in the 8 patients described by Boussard et al. but in none of the 4 patients described by Block et al". They add that although the platelets of the patients presented functional and morphological alterations, "no hemorrhagic phenotype was observed. Normocytic anemia with anisocytosis was detected in three patients, and one patient had erythroid hypoplasia of the bone marrow."

Bone marrow transplant

Of the series of four patients provided in the NEJM study, three have died. Researchers suspect that hematopoietic stem cell transplantation could be a therapeutic option. Also, since it is a monogenic disease, it would be plausible to use gene therapy. "However, these two options still need to be explored and much research is lacking. The important thing is that the description of this new entity broadens the spectrum of knowledge and may allow diagnosis in patients with inflammatory diseases whose cause is unknown", says Jordi Antón, head of the Paediatric Rheumatology Service of Sant Joan de Déu.