628 patients diagnosed with DADA2 were included in the review to analyze the demographics, genotypes, and clinical characteristics.
Demographics
There were 221 (46.4% of patients with known sex) female patients, 255 (53.6%) male patients, and 152 patients whose sex was not specified.
Of 274 patients with reported ethnicity (43.6%), 137 were Caucasian (50%), 43 were South Asian (15.7%), 27 were East Asian (9.9%), 43 came from the Middle East (15.7%), 9 North African (3.3%), 9 Latin American (3.3%), 2 Jewish (0.7%), 2 African/Caucasian (0.7%), 1 African (0.4%), and 1 African American (0.4%).
The mean age of disease onset for 425 patients (67.7%) for whom it was reported was seven years. 33 reported patients (7.8%) had an age of onset ranging between 18 and 59.2,9,20,96–105 In 20 of these, the adult presentation was with stroke or another neurological manifestation.
Genetics
The notations of the patients’ mutations in the ADA2 gene were standardized according to the NM_001282225.2 transcript.
The pathogenic variants were reported for 495 patients (78.8%). 277 patients had a homozygous variant, 205 compound heterozygous, 12 patients had one heterozygous variant with an unknown second mutation, and one patient had both homozygous and heterozygous deletions. There were 82 missense mutations, 28 frameshift mutations, 9 splice site mutations, 7 nonsense mutations, 3 duplications, 18 deletions, 2 start loss mutations, 1 deletion-insertion mutation, and 1 unspecified intronic mutation. Figure 2 and supplementary Table S1 present the genetic characteristics in detail.
Clinical characteristics
Neurological manifestations
Among the reviewed patients, 316 (50.3%) had at least one reported neurological event throughout the course of the disease. The mean age of onset of neurological manifestation was 7.2 years (range: 0–36 years). 245 patients (77.5% of all neurological manifestations) had at least one cerebrovascular accident (CVA), including 115 ischemic, 61 hemorrhagic strokes, and five transient ischemic attacks; 88 patients (35.9%) had multiple stroke episodes. 34 patients presented with neuropathy (19 patients with mononeuropathies and 15 patients with polyneuropathies). Other neurological involvements included focal neurological deficits (such as cranial nerve paralysis, decreased/increased tendon reflexes, upper motor neuron signs, numbness, extremity weakness, sensory loss in the lower extremity) (n = 9), ophthalmological findings (such as strabismus, loss of vision) (n = 2), convulsions (n = 5), headache, including migraines (n = 4), aspecific findings like dizziness and amnesia (n = 2). In addition, cerebral atrophy (n = 4), white matter changes (n = 2), radiographic findings of brain anomaly (n = 1), and five patients with unspecified neurological findings were reported. The spectrum of neurological symptoms in patients with DADA2 is shown in Fig. 3.
For 18 patients (5.7% of patients with neurological involvement), a neurological event was the first manifestation of DADA2 [2, 13, 21, 23, 24, E6-E14]; for two of them [2, 13], it was the only manifestation of the disease. However, the majority of patients initially presented with a variety of hematological, immunodeficient, and vascular manifestations, such as recurrent fever, weight loss, recurrent upper airway infection, livedo racemosa or reticularis, skin and oral aphthous ulcers, Raynaud phenomenon, arterial hypertension, myocarditis, abdominal pain, diarrhea, hepatosplenomegaly, myalgia, arthritis, alopecia, hypogammaglobulinemia, cytopenia, testicular, mesenteric, pancreatic, splenic, and renal infarcts.
22 patients (3.5% of all the reviewed patients) had neurocognitive disorders (Fig. 4) [1, 8, 13, 21, 97, E9, E15-E21]. These included isolated cognitive impairment, isolated memory disturbance, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), isolated persistent irritability, and isolated difficulties in concentration. Most of the patients were reported to have only one type of neurocognitive disorders; only those diagnosed with ASD also had ADHD, and one patient with memory disturbance also had difficulties in concentration. The age of the disease onset of the patients with neurocognitive disorders ranges from 0 to 14 years, with the mean age of 4.3 years.
MRI findings of 146 patients were available (Table 1) [1, 2, 10, 13, 16, 20–24, 96, E1, E4-E7, E9-E11, E13-E15, E17-E19, E21-E51]. Other diagnostic reports for neurological involvement included computer tomography [2, E4, E52-E54], angiographic investigation (reveals arterial stenosis, aneurysms) [1, 2], nerve conduction study, and needle electromyography [E55] (both considered to serve as non-specific diagnostic tools of neuropathies in DADA2). According to the review of neuroimaging results, the most common CNS lesion during DADA2 is ischemic stroke, with most common localizations in the brain stem, thalamus, basal ganglia, internal capsule, and other deep cerebral structures, representing the pathological involvement of deep perforating arteries. Lacunar stroke cases comprise 62.7% of the available MRI findings, of which 90.2% were located in the deep gray matter or brain stem. Vascular wall enhancement of small perforating arteries has also been reported [E32], but may be under-represented because of the absence of vessel-wall-imaging sequences in studies. We note that the described imaging findings are based on MRI, in general, the preferred imaging modality in children because of its absence of ionizing radiation and its ability to demonstrate both subtle and marked intracranial pathology. As, in theory, this may have led to an underrepresentation of more marked intracranial pathology that may have caused patients not to receive an MRI but only a CT, we performed a sensitivity analysis by including also the findings of the patients that only received CT (n = 4). Because all these patients demonstrated intracranial hemorrhage, this would have increased the percentage of macroscopic intracranial hemorrhage from 11–12%.