Adenosine Deaminase Deficiency Research Articles

Whole exome sequencing reveals a missense mutation in the ADA gene causing severe combined immune deficiency in a Pakistani family ADA gene mutation causing SCID

BACKGROUND & OBJECTIVE: Human adenosine deaminase deficiency, OMIM 102700 (ADA deficiency) is a genetic disorder which causes severe combined immunodeficiency (SCID). The enzyme adenosine deaminase is a housekeeping in nature and is involved in purine catabolism by catalyzing irreversible deamination of adenosine and deoxyadenosine. The SCID patients’ immune system is unable to fight off most of the bacterial and fungal infections due to profound lymphopenia (T-B-NK+). About 20% of the SCID patients are genetically homozygous for defective ADA gene. In our study we aimed to find out genetic variant in ADA gene in a family carrying severe combined immune deficiency. Objective in the current study is to unravel and characterize the molecular cause of the patient suffering from by birth SCID.
 METHODOLOGY: In the present study we enrolled a 6-month-old female SCID patient belonging to highly consanguineous Pakistani family. Patient clinical features included repeated chest infection with failure to thrive, fever and chronic diarrhea. Whole blood samples from patient, parents and healthy siblings were acquired in EDTA tubes. DNA was extracted from all the blood samples.
 RESULTS: Flowcytometry revealed lymphopenia (T-B-NK+) type of SCID. Whole Exome Sequencing (WES) identified a one nucleotide change (c.716G>A) in ADA gene exon 8. The segregation of the identified variant in the family was confirmed through Sanger Sequencing.
 CONCLUSION: In this study, we presented detailed clinical and genetic description of patient suffering from severe combined immune deficiency. The immunological and genetic findings presented in this study will facilitate early diagnosis of the disease. Segregation of the identified variant in the family members will also aid in genetic counseling the family.

Computational 3D structure prediction followed by molecular docking to reveal the novel drug targets against ADA

Adenosine deaminase (ADA) is a functional enzyme that transforms deoxyadenosine and adenosine into deoxyinosine and inosine respectively. ADA deficiency causes toxic purine degradation byproducts to build up in the body, which has a particularly negative impact on lymphocytes and results in adenosine deaminase-deficient severe combined immunodeficiency. Different in silico techniques including threading, ab initio and homology modeling for 3D structure prediction were applied for the prediction of ADA structures. Following the three-dimensional structure prediction analyses, an extensive computational assessment of all predicted structures for reliability was performed. The overall quality factor of the predicted ADA structures was observed 62.45% in the predicted 3D models. A Ramachandran plot was created, and 94.80% of the residues were found in the allowed and favored regions of the protein structure plot. The molecular docking analyses were performed in order to identify the potential therapeutic medication targets against ADA. The virtually examined molecules through a virtually high throughput screening may have the ability the regulation the ADA activity. The least binding energy was calculated through the molecular docking analyses and the energy values were observed -8.7 Kcal/mol. The binding residues (Lys-367, Glu-424, Asp-422, Phe-381, Ile-377, Ser-430 and Glu-374) were conserved in all the interactional analyses of the docked complexes. Finding the effective binding domain in a protein three-dimensional structure is crucial for understanding of its structural makeup and determining its functions.

Safety and efficacy of elapegademase in patients with adenosine deaminase deficiency: A multicenter, open-label, single-arm, phase 3, and postmarketing clinical study.

Adenosine deaminase (ADA) deficiency is an ultrarare inherited purine metabolism disorder characterized by severe combined immunodeficiency. Elapegademase-lvlr is a new pegylated recombinant bovine ADA used in enzyme-replacement therapy (ERT) for ADA deficiency. Therefore, replacement with the new drug may eliminate the infectious risks associated with the currently used bovine intestinal-derived product, pegademase. We conducted a multicenter, single-arm, open-label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 μmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 μmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints. A total of four patients (aged 0-25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164-169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase. This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug-related adverse events were reported (Trial registration: JapicCTI-163204).

Outcome of BCG Vaccination in ADA-SCID Patients: A 12-Patient Series.

Vaccination with Bacillus Calmette-Guérin (BCG) can be harmful to patients with combined primary immunodeficiencies. We report the outcome of BCG vaccination in a series of twelve patients affected by adenosine deaminase deficiency (ADA-SCID). BCG vaccination resulted in a very high incidence of complications due to uncontrolled replication of the mycobacterium. All patients who developed BCG-related disease were treated successfully and remained free from recurrence of disease. We recommend the prompt initiation of enzyme replacement therapy and secondary prophylaxis to reduce the risk of BCG-related complications in ADA-SCID patients.

A case series of ten plus one deficiency of adenosine deaminase 2 (DADA2) patients in Iran

BackgroundDeficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA.Case presentationWe introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients’ symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant.ConclusionsConsidering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. Case report and detailed description of the clinical course of diagnosis and treatment. The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

Clinical Symptoms, Laboratory Parameters and Long-Term Follow-up in a National DADA2 Cohort

Deficiency of adenosine deaminase-2 (DADA2) is an autosomal recessive autoinflammatory disease with an extremely variable disease presentation. This paper provides a comprehensive overview of the Dutch DADA2 cohort. We performed a retrospective cohort study in 29 ADA2-deficient patients from 23 families with a median age at inclusion of 26 years. All patients had biallelic pathogenic variants in the ADA2 gene. The most common clinical findings included cutaneous involvement (79.3%), (hepato)splenomegaly (70.8%) and recurrent infections (58.6%). Stroke was observed in 41.4% of the patients. The main laboratory abnormalities were hypogammaglobulinemia and various cytopenias. Patients presented most often with a mixed phenotype involving vasculopathy, immunodeficiency and hematologic manifestations (62.1%). In this cohort, malignancies were reported in eight patients (27.6%), of whom five presented with a hematologic malignancy and two with a basal cell carcinoma. Four patients developed hemophagocytic lymphohistiocytosis (HLH) or an HLH-like episode, of whom three passed away during or shortly after the occurrence of HLH. TNF-inhibitors (TNFi) were effective in treating vasculopathy-associated symptoms and preventing stroke, but were hardly effective in the treatment of hematologic manifestations. Three patients underwent hematopoietic cell transplantation and two of them are doing well with complete resolution of DADA2-related symptoms. The overall mortality in this cohort was 17.2%. In conclusion, this cohort describes the clinical, genetic and laboratory findings of 29 Dutch DADA2 patients. We describe the occurrence of HLH as a life-threatening disease complication and report a relatively high incidence of malignancies and mortality.

Finding a Quorum in Deficiency of Adenosine Deaminase 2 Management

Finding a Quorum in Deficiency of Adenosine Deaminase 2 Management

Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function.

Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate, and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunologic analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific CAR T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR T cells and reveal potential targets for improving CAR T-cell therapy.

Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China.

Adenosine deaminase (ADA) is a key enzyme in the purine salvage pathway. Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency. To date, few Chinese cases have been reported. We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children's Hospital and summarized the previously published ADA deficiency cases from China in the literature. Nine patients were identified with two novel mutations (W272X and Q202 =). Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients. The ADA genotype has a major effect on the clinical phenotype. Notably, a novel synonymous mutation (c.606G>A, p.Q202=) was identified in a delayed-onset patient, which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein. Furthermore, the patient showed γδT cells expansion with an increased effect or phenotype, which may be associated with the delayed onset of disease. In addition, we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency. Five patients died with a median age of four months, while two patients received stem cell transplantation and are alive. This study described the first case series of Chinese ADA-deficient patients. Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations in our patients. We identified a synonymous mutation that affected pre-mRNA splicing in the ADA gene, which had never been reported in ADA deficiency. Furthermore, we reported cerebral aneurysm in a delayed-onset patient for the first time. Further study is warranted to investigate the underlying mechanisms.

Ocular involvement in adult and paediatric patients with monogenic autoinflammatory diseases: a Spanish multicentre retrospective study.

Ophthalmologic involvement in monogenic autoinflammatory diseases has been explored mainly in paediatric patients. The aim of this study is to characterise ophthalmologic manifestations, therapeutic management and visual outcomes in a Spanish (UVESAI) cohort of adult/paediatric patients with monogenic autoinflammatory diseases. Multicentre and retrospective study of patients with monogenic autoinflammatory diseases and ocular involvement. Eye manifestations, structural complications, treatments used and visual outcomes were analysed, and compared with previous studies. Forty-six patients (44/2 adults/children; 21/25 adult/paediatric-onset) with monogenic autoinflammatory diseases [cryopyrin associated periodic syndromes (n=13/28.3%), mainly Muckle-Wells syndrome (MWS) (n=11/24%); familial Mediterranean fever (FMF) (n=12/26%); TNF receptor-associated periodic syndrome (TRAPS); (n=9/20%); Blau syndrome (n=8/17%); hyperimmunoglobulin D syndrome (HIDS) (n=2/4.3%), deficiency of adenosine deaminase-2 and NLRC4-Autoinflammatory disease] (one each) were included. Conjunctivitis (n=26/56.5%) and uveitis (n=23/50%) were the most frequent ocular manifestations. Twelve (26.1%) patients developed structural complications, being cataracts (n=11/24%) and posterior synechiae (n=10/22%) the most frequent. Conjunctivitis predominated in TRAPS, FMF, MWS and HIDS (mainly in adults), and uveitis, in Blau syndrome. Seven (8%) eyes (all with uveitis) presented with impaired visual acuity. Local and systemic treatment led to good visual outcomes in most patients. Compared with previous studies mainly including paediatric patients, less severe ocular involvement was observed in our adult/paediatric cohort. Conjunctivitis was the most common ocular manifestation in our TRAPS, FMF, MWS and HIDS patients, and uveitis predominated in Blau syndrome. Severe eye complications and poor visual prognosis were associated with uveitis. Adults with monogenic autoinflammatory diseases seem to exhibit a less severe ophthalmologic presentation than paediatric patients.

Comparison of disease phenotypes and mechanistic insight on causal variants in patients with DADA2

Deficiency of adenosine deaminase 2 (DADA2) results in heterogeneous manifestations including systemic vasculitis and red cell aplasia. The basis of different disease phenotypes remains incompletely defined. We sought to further delineate disease phenotypes in DADA2 and define the mechanistic basis of ADA2 variants. We analyzed the clinical features and ADA2 variants in 33 patients with DADA2. We compared the transcriptomic profile of 14 patients by bulk RNA sequencing. ADA2 variants were expressed experimentally to determine impact on protein production, trafficking, release, and enzymatic function. Transcriptomic analysis of PBMCs from DADA2 patients with the vasculitis phenotype or pure red cell aplasia phenotype exhibited similar upregulation of TNF, type I interferon, and type II interferon signaling pathways compared with healthy controls. These pathways were also activated in 3 asymptomatic individuals with DADA2. Analysis of ADA2 variants, including 7 novel variants, showed different mechanisms of functional disruption including (1) unstable transcript leading to RNA degradation; (2) impairment of ADA2 secretion because of retention in the endoplasmic reticulum; (3) normal expression and secretion of ADA2 that lacks enzymatic function; and (4) disruption of the N-terminal signal peptide leading to cytoplasmic localization of unglycosylated protein. Transcriptomic signatures of inflammation are observed in patients with different disease phenotypes, including some asymptomatic individuals. Disease-associated ADA2 variants affect protein function by multiple mechanisms,which may contribute to the clinical heterogeneity of DADA2.

Transcriptomic Approaches to Diagnosis of Inborn Errors of Immunity

Molecular diagnosis of inborn errors of immunity (IEI) leads to many benefits including more accurate prognosis, access to molecularly targeted therapies, and better informed genetic counseling for relatives and offspring. However, in practice, diagnostic testing is often limited to gene panels and clinical exome sequencing or rarely genome sequencing. As a result, treating physicians remain unable to identify a specific cause in the majority of suspected IEI patients using currently established technologies, even when a genetic cause is suspected based on similarly affected family members. Even once a diagnosis is made, selection of appropriate treatments provides additional challenges as response to immunomodulatory therapy is heterogeneous. Better strategies are needed to identify which groups of patients are most likely to benefit from different therapies. Determining the optimal diagnostic and therapeutic strategy requires a personalized approach bringing together expertise from multiple clinical specialties and basic scientists to apply new discoveries to patient care and improve outcomes for these complex patients. We hypothesize that adding transcriptomic profiling to existing genomic diagnostic approaches could help close these gaps, facilitating identification of the molecular diagnosis in a larger fraction of patients and monitoring the gene expression response to treatment. To test this, we plan to (1) deploy RNA sequencing of peripheral blood paired with DNA sequencing in a cohort of IEI patients with known (N = 10) IEIs representing a spectrum of disorders as classified by IUIS (e.g. X-linked SCID due to ILR2g, deficiency of adenosine deaminase 2, CD40L deficiency) to validate the pipeline for detecting known disorders, (2) apply the pipeline to a pilot cohort of participants with unknown disorders (N = 10) to assess diagnostic efficacy, and (3) perform longitudinal RNA sequencing in IEI patients undergoing treatment to understand predictors of treatment response. To date, we have obtained whole-blood total RNA from 5 participants (3 known, 2 unknown and pretreatment). In parallel, we have adapted the detection of RNA outliers pipeline (DROP) for local use to identify novel monogenic causes of IEI through detection of aberrant expression, aberrant splicing, and mono-allelic expression, and have tested the pipeline using publicly available, well-characterized datasets.

Early immune reconstitution in an infant with adenosine deaminase deficient severe combined immunodeficiency started on enzyme replacement therapy

Severe Combined Immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency is an inborn error of immunity resulting in the accumulation of adenosine and deoxyadenosine leading to a T-B-NK-phenotype. Enzyme Replacement Therapy with Elapegademase-IvIr is typically used as a bridge prior to undergoing definitive treatment with HSCT or HSC-GT.We report a full-term female infant born to Caucasian parents. Immediate newborn course was unremarkable. She had two borderline newborn screens (NBS) for SCID. There was no consanguinity or family history of immunodeficiency. Physical exam was normal except for absent tonsils. She had profound lymphopenia (Absolute Lymphocyte Count of 210 cells/mL), and initial lymphocyte enumeration showed low CD3 cells (169/mL), decreased CD19 cells (6/mL) and CD16/56+ cells (26/mL) consistent with a T-B-NK- SCID. There was no maternal engraftment. Immunoglobulin studies showed normal IgG (325) with low IgM and IgA. Mitogen proliferation to phytohemagglutinin (PHA) was significantly low (10,200 CPM).A SCID genetics panel revealed two pathogenic variants in ADA (p.Glu319fs and p.Arg149Trp). Biochemical testing confirmed absent ADA activity and elevated total deoxyadenosine nucleotides (dAXP) of 40.3% in RBCs (normally undetectable), consistent with the diagnosis of ADA-SCID. She was promptly started on ERT twice weekly and developed full immune reconstitution of her T-cells, B-cells and NK-cells after 21 days. At that time, her dAXP remained elevated at 10%. Her T-cell function also normalized (PHA 239,562 CPM).We report an infant with ADA-SCID who had two borderline NBS results and developed full immune reconstitution 3 weeks after starting ERT. This is unusual since thymopoiesis typically requires 60–90 days for T-cell reconstitution. While B and NK immune reconstitution typically occurs early, early T-cell numbers lag behind, especially while dAXP levels remain measurable. Both genetic variants in this patient are severe, but somatic mosaicism with reversion of the Arg149Trp point mutation might account for rapid T-cell recovery; further T-cell analysis is planned to assess this possibility. This child is the first case of SCID diagnosed in North Carolina following a borderline NBS, as opposed to abnormal, reinforcing the utility of highly-sensitive TREC thresholds for identification of at-risk infants. [Display omitted] [Display omitted]

E032 Deficiency of Adenosine Deaminase 2: a rare diagnosis in a case of suspected vasculitis

Abstract Background/Aims Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive condition first described in 2014 which is characterised by vasculitis, systemic inflammation, immunodeficiency and cytopenias. The vasculitis is difficult to differentiate from polyarteritis nodosa and typically presents with recurrent strokes. It can also affect the skin and present with livedo racemosa. Clinical presentation varies widely; from vasculitic manifestations which tend to present later in life to severe haematological abnormalities such as bone marrow failure which tend to present earlier in life. Treatment with TNF inhibitors reduces the risk of additional strokes and controls inflammation in the presence of vasculitis but is not very effective against bone marrow failure. Methods We present the case of a 44-year-old gentleman who was being investigated for possible vasculitis by the rheumatology team in view of a history of Raynaud’s, 20-year history of recurrent leg ulcers and a previous pontine infarct. He presented acutely to the emergency department with numbness below the midthoracic level, weakness of his lower limbs and hands and urinary retention. His symptoms had progressed over a period of a few hours. On examination power was 4/5 on the MRC power scale for shoulder abduction and elbow flexion, 2/5 for elbow extension, 3/5 for wrist extension and 1/5 for finger extension. Power was 1/5 on his lower limbs. Sensation to pain was reduced with a T6 sensory level. Proprioception and vibration sense were intact. Upper limb reflexes were brisk. Knee jerks and left ankle jerk were difficult to elicit. Plantars were downgoing. Cranial nerves were normal. Results Bloods showed a white cell count of 6.7x109/l, haemoglobin of 96g/l (microcytic), platelets of 243x109/l, creatinine 119μmol/l (baseline 85μmol/l) and CRP of 42.9mg/l. Vitamin B12 was 200ng/l and folate levels were 2.2μg/L. ANA, ANCA, cryoglobulins and hepatitis serology were negative. MRI brain showed a 4mm area of hyper-density in the left pons. MRI whole spine was unremarkable. CSF showed normal protein, white cell count and glucose level. The patient was transferred to a tertiary neurology centre and a diagnosis of anterior spinal cord infarction was made. A nerve biopsy was performed which showed evidence of vasculitis and he was pulsed with methylprednisolone and commenced on high dose oral steroids. Genetic testing showed a pathogenic mutation in the adenosine deaminase 2 gene. He is currently awaiting to commence treatment with TNF inhibitors. Conclusion We conclude that DADA2 is an important differential in a young patient with suspected vasculitis especially in the presence of infarction. Identification of DADA2 allows initiation of treatment with TNF inhibitors which reduces the risk of additional strokes. Disclosure M. Xenophontos: None. J. Gan: None. A.C. Seneviratne: None.

Deficiency of adenosine deaminase 2: a challenging differential diagnosis of polyarteritis nodosa.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that was first described in 2014. It is a monogenic disease that is caused by loss-of-function variants in the ADA2 gene. Deficiency of adenosine deaminase 2 involves small- and medium-sized vessels and its clinical presentations include polyarteritis nodosa (PAN)-like features such as livedoid rash, early-onset stroke, hypogammaglobulinemia, hematological abnormalities, and systemic inflammation. Early diagnosis and treatment of DADA2 are crucial as the clinical features could be potentially life-threatening but might be treatable. The first-line treatment of choice in DADA2 is tumor necrosis factor α inhibitors. We aimed to provide an overview of the known pathophysiology, clinical presentations, diagnosis, and treatment of DADA2. A clearer knowledge of DADA2 may help to better diagnose, manage, and improve the clinical outcome of DADA2 patients. However, further studies are required to investigate the genotype-phenotype associations and exact pathophysiology of DADA2.

A Cohort Study on Deficiency of ADA2 from China

PurposeDeficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China.MethodsA retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed.ResultsThirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel.ConclusionTo establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Updated Management Guidelines for Adenosine Deaminase Deficiency

Inherited defects in the adenosine deaminase (ADA) gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies. In recent years, there have been remarkable advances in the management of ADA deficiency. Most ADA-deficient patients can be identified by newborn screening for severe combined immunodeficiency, which facilitates early diagnosis and treatment of asymptomatic infants. Most patients benefit from enzyme replacement therapy (ERT). Allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor or HLA-matched family member donor with no conditioning is currently the preferable treatment. When matched sibling donor or matched family member donor is not available, autologous ADA gene therapy with nonmyeloablative conditioning and ERT withdrawal, which is reported in recent studies to result in 100% overall survival and 90% to 95% engraftment, should be pursued. If gene therapy is not immediately available, ERT can be continued for a few years, although its excessive cost might be prohibitive. The recent improved outcome of hematopoietic cell transplantation using HLA-mismatched family-related donors or HLA-matched unrelated donors, after reduced-intensity conditioning, suggests that such procedures might also be considered rather than continuing ERT for prolonged periods. Long-term follow-up will further assist in determining the optimal treatment approach for ADA-deficient patients.

Long-Term Immune Reconstitution in ADA-Deficient Patients Treated With Elapegademase: A Real-World Experience

ADAGEN®, a bovine-based enzyme replacement therapy (ERT) has been used to treat adenosine deaminase severe combined immune deficiency (ADA-SCID). In 2018, ADAGEN® was replaced by REVCOVI®, (elapegademase) a modified bovine recombinant protein. To determine the real-life long-term benefits of REVCOVI® in ADA- SCID. Data on ERT, infectious and non-infectious complications, and metabolic and immune evaluations were collected from 17 ADA-SCID treated for 6 months or more with REVCOVI®. Eleven patients had previously received ADAGEN® for 16 to 324 months while 6 patients were ERT-naïve. REVCOVI® was administered twice weekly at 0.4 mg/kg/week in ERT-naïve, while patients transitioning to REVCOVI® from ADAGEN® typically continued at the same frequency and equivalent dosing as ADAGEN®, resulting in significantly lower (p=0.007) total REVCOVI® dose in the transitioning group. REVCOVI® treatment in ERT-naïve group led to the resolution of many clinical and laboratory complications of ADA deficiency, while among the transitioning patients there were no new adverse effects. REVCOVI® treatment increased plasma ADA activity and decreased dAXP among most patients, effects that persisted throughout the 7-37 months treatment periods, except in 2 patients with incomplete adherence. Among some patients, after 0.5 to 6 months, injection frequency was reduced to once a week, while maintaining adequate metabolic profiles. All ERT-naïve infants treated with REVCOVI® demonstrated increased CD4+ T and CD19+ B cell numbers, although in most transitioning patients these counts remained stable but lower than normal. REVCOVI® is effective for the management of ADA-SCID.

Applications of Gene Therapy in Dentistry: A Review Article

AbstractGene therapy promises to possess a good prospect in bridging the gap between dental applications and medicine. The dynamic therapeutic modalities of gene therapy have been advancing rapidly. Conventional approaches are being revamped to be more comprehensive and pre-emptive, which could do away with the need for surgery and medicine altogether. The complementary base sequences known as genes convey the instructions required to manufacture proteins. The oral cavity is one of the most accessible locations for the therapeutic intervention of gene therapy for several oral tissues. In 1990, the first significant trial of gene therapy was overseen to alleviate adenosine deaminase deficiency. The notion of genetic engineering has become increasingly appealing as a reflection of its benefits over conventional treatment modalities. An example of how this technology may alter dentistry is the implementation of gene therapy for dental and oral ailments. The objective of this article is to examine the effects of gene therapy on the field of dentistry, periodontology and implantology. Furthermore, the therapeutic factors of disease therapy, minimal invasion, and appropriate outcome have indeed been taken into consideration.