Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05300360 |
| Other study ID # |
TR-ADA-006 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 16, 2021 |
| Est. completion date |
August 16, 2022 |
Study information
| Verified date |
March 2022 |
| Source |
TRPHARM |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This observational study was designed as a prospective epidemiological screening study.
Patients who have applied to the centers participating in the study and who have previously
been clinically or pathologically diagnosed with PAP (Pulmonary alveolar proteinosis) will be
included in the study. Up-to-date data will be collected from patients who have agreed to
participate in the study, and a blood sample with DBS will be taken from patients. The blood
taken will be subjected to analysis for ADA metabolites. For patients with a high metabolic
test, the responsible researcher will advise on clarifying the diagnosis with a genetic test
other than the study. In case of formation of new information for each patient, consultation
will be provided by the responsible researcher. Thus, the prevalence of ADA enzyme deficiency
disease will be evaluated in patients diagnosed with PAP.
Description:
PAP (Pulmonary alveolar proteinosis) is a rare disease with a frequency of 0.36 per million.
As a result of intensive accumulation of surfactant components in the lungs, it leads to
respiratory distress at various levels. PAP has been frequently monitored among patients with
ADA enzyme deciency. Primary immunodeficiency diseases are a group of diseases that are
accompanied by chronic and/or recurrent bacterial, fungal, protozoal and viral infections
that develop as a result of primary or congenital immunodeficiency. The incidence dec in
society varies from 1/10,000 to 1/100,000. Combined immunodeficiencies account for 15-29% of
primary immunodeficiencies. Severe Combined Immunodeficiencies (SCID) are a heterogeneous
group of diseases caused by hereditary errors in genes involved in the development and/or
function of T, B, and sometimes NK cells, which cause serious dysfunction of the immune
system. The incidence is estimated at 1/100,000 live births in the United States. Although
the exact incidence of inbreeding is not known in our country, where inbreeding is common, it
is expected that those who show autosomal recessive transition will be more common,
especially. The recognition of these disorders by clinicians is important for reducing
long-term complications due to recurrent infections and preventing mortality with appropriate
treatment. The frequency of SCIDY in our country is unknown. Unlike in Europe and America,
SCID types, which are autosomal recessive in our country, are considered to be the most
common form due to the high rates of inbreeding. The ratio obtained by comparing the number
of live babies born in a year in Konya with the number of SCID cases diagnosed in the same
year in the Pediatric Immunology Clinic of the Meram Faculty of Medicine of Selcuk
University, the only primary immunodeficiency diagnostic center in the region, is 1/10,000.
This preliminary study shows that in our country this disease is much more common than in
Europe and America. To date, more than 20 genetic defects have been identified that cause
SCID. All known genetic defects disrupt the development of cells of the immune system,
causing combined immunodeficiency. One of them, the ADA defect, is also a metabolic disease,
due to which there is a lack of enzymes. ADA catalyzes the deamination of purine nucleosides
adenosine (Ado) and 2'-deoxyadenosine (dAdo), which are produced during the degradation and
transformation of RNA and DNA. ADA is a cleansing enzyme: it detoxifies purines. In ADA
deficiency, 2'-deoxyadenosine (dAdo) is phosphorylated and converted into deoxyadenosine
triphosphate (dATP). Accumulation of DATP disrupts DNA repair and replication. In ADA
deficiency, a high percentage of dATP accumulates, especially in erythrocytes and
lymphocytes. Increased levels of adenosine break down the wall of the lymphocyte. It inhibits
the development of lymphocytes in the thymus. A kind of lymphocyte intoxication occurs. It
leads to a severe form of lymphopenia. Approximately 10-20% of SCID are diagnosed as ADA
enzyme deficiency. It shows an autosomal recessive transition. Your gene is 20. it is
localized on the long arm of the chromosome.
Clinically, there are early and late onset types:
Classic-early onset ADA deficiency: Although normal at birth, patients present with
infections seen from the first months of life, resulting in death if left untreated. In
addition to the AKI table, neuro-developmental disorders, sensorineural hearing loss and/or
skeletal abnormalities have also been reported in these patients. Although hematopoietic stem
cell transplantation, enzyme replacement therapy and gene therapy are treatment approaches
that provide cure, early diagnosis determines the prognosis.
Late-onset ADA deficiency: Patients may present with recurrent infections, bronchiectasis,
autoimmunity, human papillomavirus (HPV) infections at an older age, even in adulthood.
Lymphopenia is an invariable finding. High IgE and eosinophilia may be observed. In these
cases, residual enzyme activity due to the type of mutation causes a late onset. This
phenotype accounts for 10-15% of all cases of ADA deficiency.
Patients with late-onset ADA enzyme deficiency appear in the form of case reports. in a study
in which the data of two patients were shared in Zurich in 1997, one patient had a history of
recurrent otitis and pulmonary infection, bronchiectasis, lymphopenia, and immunoglobulin E
elevation. The other patient, his cousin ADA, was diagnosed by chance while undergoing a bone
marrow scan due to enzyme deficiency. He had a history of recurrent tonsillitis.
In a study conducted by Hacettepe University published in 2018. The data of 13 ADA enzyme
deficient patients were evaluated and it was determined that 3 patients with late/delayed
diagnosis had ADA enzyme deficiency. A patient with a late diagnosis of ADA enzyme deficiency
was found to have recurrent pneumonia, bronchiectasis, and immunoglobulin E elevation.
In the study in which the data of a patient with a late onset ADA enzyme deficiency published
in Konya from our country in 2010 were shared, it was observed that the patient had a history
of resection of the lower left lobe due to bronchiectasis, lymphopenia and an increase in
immunoglobulin E.
Diagnosis: ADA enzyme deficiency is included in severe combined immunodeficiencies and is
observed with lymphopenia and infections. The diagnosis is made by measuring the activity of
the enzyme ADA in erythrocytes or lymphocytes in patients with suspected clinical and
laboratory features (such as lymphopenia, bronchiectasis). By mutation analysis, a gene
defect is shown. However, T-cell receptor excision circles (TREC) test is used for early
diagnosis. However, since the TREC test is found to be normal at birth in late-onset
patients, screening that leads patients to an early diagnosis can only be achieved by
measuring ADA metabolites.
In late-onset ADA deficiency, it is difficult to diagnose. Low awareness of the disease and
its symptoms usually results in these cases not being diagnosed, not being able to reach
effective treatment, permanent organ damage and patient loss. For this reason, diagnosis of
patients is very important in terms of quality of life, as well as vital importance.
Reason ADA enzyme deficiencies account for approximately 15% of severe combined
immunodeficiencies. In 15-20% of patients with ADA enzyme deficiency, ADA enzyme deficiency
is observed with a late diagnosis. Because of the inability of these patients to get a
diagnosis, their treatment is also inadequate. For the first time in our country, this study
aims to determine the diagnosis and obtain preliminary data on the prevalence of ADA disease
by looking at ADA metabolites in a group of adult patients diagnosed with PAP.
