2023-08-23 00:02:09
A team of hospital doctors Virgin of the Roco of Seville y Sant Joan de Du in Barcelonaand their respective research institutes (Irsdj and IBIS), has collaborated on research that described a new minority disease associated with a mutation in a Spanish patient. DOCK11.
For this, it has been necessary to work for years, together with other international reference centers, on genetic analysis of the patient and his family, as well as functional studies and work on experimental models, which are detailed in a study recently published in The New England Journal of Medicine.
However, this whole process of international collaboration It begins at the moment when some doctors who care for a patient with a clinical picture that does not match any diagnosis decide to go a step further.
Because, as recognized by one of the specialists who participated in the discovery of this new disease: “Without clinical suspicion, there is no diagnosis.”
As he comments to Joan Calzada, from the Pediatric Rheumatology team at Sant Joan de Du and a researcher at the Irsjd, who highlights the importance of the clinical part of the process. “Only with the clinical suspicion that you are dealing with a new disease, you will probably not be able to describe it, but without it, it is not possible to do so.”
Experience in reference centers
The development of the ability to suspect that something does not fit is, above all: “matter of experience: see lots and lots of patients, which allows you to make connections between other cases you have treated or read about. Hence the importance of having centers of reference and, especially, when dealing with minority diseases”.
In this case, the discovery of the new pathology began with a patient who He was treated for the first time at the Virgen del Rocowhere specialists from the Infectious Diseases, Rheumatology and Pediatric Immunology Unit (with pediatricians Paula Sanchez Moreno y Marisol Camacho Lovillo) found, after carrying out various analyses, that their symptoms did not match those of any disease described.
“His symptoms did not fit with any known immunodeficiency or autoinflammatory disease, so we contacted Professor Kaan Boztugfrom 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 might be in the same situation to achieve a minimum amount of scientific evidence,” says Last Nethhead of the Infectology, Rheumatology and Pediatric Immunology Unit of the Seville hospital.
The functional studies and the biological models corroborated the suspicion of being before a new entity, and made it possible 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 the regulation of different cell functions, had not previously been associated with any human disease. Previous studies had shown the importance of the protein produced by this gene for the development of B cells in mouse models. Researchers have now shown that, to some extent, B cells also do not develop properly in humans with B deficiency. DOCK11and at the same time, the 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,” he adds. Laia Alsinahead of the Allergy and Clinical Immunology Service of the Sant Joan de Du Barcelona, researcher at the Irsjd and coordinator of the Integrated Unit of Clinical Immunology Hospital Sant Joan de Du-Hospital Clnic de Barcelona.
Olaf Nef also highlights the collaboration of the Virgen del Roco Pathology Service (specifically, doctors Rainier Vila Polo y Roco Cabrera-Prez) when carrying out all the genetic studies, functional tests and other determinations that the Austrian laboratories 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 completes the puzzle“adds the also head of the IBiS Congenital Alterations and Immunity group.
In fact, the publication of four patients from this group in NEJM coincided with that of another series of eight patients reported in Blood magazine, with Charlotte Boussard, from Pars Cit University (France) as the first signatory. That reinforced the strength of the finding of the new entity.
New monogenic cause of actinopathy
Thus, the new disease is due to abnormalities that the mutation in the gen DOCK11produces in the cytoskeleton, the internal structure of cells that gives them their shape and ability to move. “The clinical manifestation is highly variable,” says Joan Calzada, whose center continued to manage the patient, due to the family moving to Barcelona.
“He phenotype From what is known up to now, the expected condition for this disease is a child -girls are only carriers- with persistent fever, acute elevation of inflammatory 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 function may be affected.”
The disease falls within the actinopathies, explains Joan Calzada, in which a failure of actin or other proteins important for cytoskeletal function. “The clinical picture that it generates straddles primary immunodeficiencies and autoinflammatory diseases.”
Until these patients, acinopathies were caused by variants in DOCK2 and DOCK8, among other genes. Now the DOCK11 gene, on the X chromosome, is added to the genetic causes of these alterations.
And editorial at NEJM accompanies the description of the disease, signed by Stuart Tangye, from the Garvan Institute for Medical Research in Darlinghurst (Australia) and Isabelle Meyts, from the Leuven University Hospitals (Belgium).
The authors highlight as the main difference between the two published series of 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 marrow.
bone marrow transplant
Of the series of four patients reported 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 terapia gnica. “However, these two options still have to be explored and a lot of research is needed. The important thing is that the description of this new entity broadens the spectrum of knowledge and can allow diagnosis in patients with inflammatory diseases whose cause is unknown”, points out Jordi Antn, head of the Sant Joan de Du Pediatric Rheumatology Service.
#Spanish #patient #identify #disease