Neurological phenotype of ADA2 deficient patients:a cohort study

BACKGROUND: Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported.METHODS: In this cohort study, we included patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands. We analyzed the frequency and recurrence rates of neurological manifestations before and after initiation of TNF-α inhibiting therapy.RESULTS: We included 29 patients with a median age at presentation of 5 years (IQR: 1-17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. TIA/ischemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischemic strokes occurred in 12 patients; one after initiation of TNF-α inhibiting therapy and one while switching between TNF-α inhibitors. None were large-vessel occlusion strokes. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischemic strokes and seldom recurred after initiation of TNF-α inhibiting therapy.CONCLUSIONS: Neurological manifestations, especially TIA/ischemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness among neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small-vessel ischemic stroke without an identified cause should be considered.</p

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