Adenosine Deaminase 2: from the spectrum of phenotypes to ...• Normalized plasma ADA2 activity •...
Transcript of Adenosine Deaminase 2: from the spectrum of phenotypes to ...• Normalized plasma ADA2 activity •...
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Adenosine Deaminase 2: from
the spectrum of phenotypes to
the diagnosis and treatment
Gustavo C. SantoSeptember 2020
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Objetives
Describe the clinical presentation and the expansion of thespectrum phenotypes
PathophysiologyDiagnosis: genetics and plasma ADA2 activityTreatment
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Clinical manifestations in DADA2
Mutação em homozigotia Tyr453Cys no gene ADA2
Angiografia renal: múltiplas estenosese dilatações na pequenas artérias intra-renais
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• Abdominal pain• Distension and absence of bowel
movements• Underwent colostomy and ileostomy
constrution due to ileal stenosis• Histology examination of jejunum and
ileum revealing necrotizing inflammation of medium and small-sized arteries
Clinical manifestations in DADA2
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Skin Manifestations in our cohort
2002 2018
Skin Biopsy
Clinical manifestations in DADA2
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Immune dysregulation• Hypogammaglobulinemia
(IgM and IgG)• Transitional B cell
deficiency• Memory T cell deficiency
Expanding Phenotype of DADA2
Inflammatory/Vascular• Ischemic strokes• Fevers• Livedo Racemosa• PAN• Raynaud´s• Vasculitis/vasculopathy
Hematologic• Pure red cell aplasia• Bone marrow failure• Cytopenias
DADA2 in 2020
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Zhou et al. NEJM 2014
ADA2:• works as a growth factor• is important for the differentiation of
monocytes into macrophages
Pathophisiology of DADA2
Impaired M2 macrophage differentiation in DADA2
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Skewing toward proinflammatory M1 macrophages leads to accumulation of proinflammatory cytokines and tissue injury.
Pathophisiology of DADA2
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Elkan et al. NEJM 2014
Zhou et al. NEJM 2014
Cat Eye Syndrome Chromosome Region, Candidate 1 (CECR1) geneencoding
Adenosine Deaminase 2 (ADA2)
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2014
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2002/May…
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Patient 2 Patient 1Patient 3 Patient 4
p.T119A p.T119A
p.T119A
p.G142S
p. [(T119A);(G 142S)]
2018
p. [(T119A);(G 142S)]
p. [(T119A);(G 142S)]
2012-hemorrhagic
stroke
2018-Cerebellar ischemic
stroke
2013-hemorrhagic
stroke
mRS 6 mRS 5 mRS 1 mRS 3mRS 3
Livedo racemosa and skin lesion in the lower limbs
Stroke
Evolution: the natural history of one family
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Male, right lacunar stroke when he was 29 years-old
Since the age of 16:- livedo racemosa on lower limbs and trunk;- Recurrent and seasonal leg ulcerations, on the distal part of the legs
Patient 2
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Diagnosis
• Autosomal recessive loss-of-function mutation in ADA2 gene
• High clinical suspicion• Check for consanguinity!
• Plasma ADA2 activity• Genetic testing
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DADA2 in 2020
Not a rare disorder
Over 400 patients reported worldwide
152 confirmed at NIH
8 in Portugal (and 19 heterozygous…)
Estimation: 4.3 in 100,000 people have biallelic, predicted damaging mutations in ADA2
Missing patients from Africa, India, China, Japan, Australia and someof Europeancountries
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Genetics of DADA2
Highly polymorphic gene, over 300 variants in the coding part of the gene
Over 70 pathogenic variants, mostly missence
Copy number variations (CNVs): deletions/duplications
Non-coding mutations (splice variants)
Not all rare novel variants are associated with low ADA2 activity
genotype-phenotype correlations under investigation
Clinical variability seen in families and in patients with the same genotype
Reduced penetrance (modifying genetic or environmental factors)
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Therapies in DADA2 (no formal trials yet)
TNF inhibitors (etanercept, infliximab, adalimumab, golimumab, thalidomide)
- Are very effective in controlling inflammatory phenotype and in prevention of stroke
- Should be initiated ASAP
- IL-1 inhibitors are not efficacious
- Discontinue aspirin and/or anticoagulants
- May not be effective in patients with immunological/hematological presentation
- Some reports showed that it may help with lymphopenia/ hypogammaglobulinemia
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Therapies in DADA2
TNF inhibitors (etanercept, infliximab, adalimumab, golimumab, thalidomide)
Hematopoietic Stem Cell Transplantation
Gene therapy ( clinical trials expected in 6-8 years)
Enzyme replacement (less likely)
Key points:• HSCT represents and effective and
definitive treatment for DADA2 (butimportant caveats)
• Normalized plasma ADA2 activity• HSCT can cure the immunological,
hematological and vascular phenotype ofDADA2 with 100% survival at a medianfollow-up of 18 months
15 patients
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Summary
DADA2 is a potentially fatal monogenic loss-of-function disease described in 2014;
Since the original description of childhood vasculitis, more than 400 cases have been reported, greatly expanding the phenotype;
Given the pleiotropic presentations and different age of onset, the disease span multiple different specialities and is probably underdiagnosed;The pathophysiology is largely unknown and the diagnostic accuracy of more affordable biochemical testing are being established.
TNF inhibitors are effective in suppressing systemic inflammation; probably not in other phenotypes
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Summary
Estudo genético para DADA2 é ainda o gold standard mas:
- Perante a suspeita clínica deve pedir-se o doseamento da actividadeenzimática da ADA2 em laboratório credível ( e se diminuída solicitarestudo genético);
- Evitar – sempre que possível - estudos genéticos em painel
- Participar na construção de uma base de dados nacional destesdoentes