Electroclinical features and phenotypic differences in Adenylosuccinate lyase deficiency: long term follow-up of seven patients from four families and appraisal of the literature

Objective: Adenylosuccinate lyase (ADSL) deficiency is a rare inherited metabolic disorder, with a wide phenotypic presentation classically grouped in three types (neonatal, type I and type II). We aim to better delineate the pathological spectrum, focusing on electroclinical characteristics and phenotypic differences of patients with ADSL deficiency. Patients and methods: Seven patients, from four different families, underwent serial EEG, clinical assessment, and neuroimaging. We also performed a systematic review of the cases published in the literature summarizing the available clinical, neurophysiological, and genetic data. Results: We report seven previously unreported ADSL deficiency patients with long-term follow up (10-34 years). From the literature review, we collected 81 previously reported cases. Of the included patient population, 58 % (51/88) were classified as ADSL deficiency type I, 28% (25/88) as type II and 14% (12/88) as neonatal. The most frequently reported pathogenic variants are p.R426H homozygous (19 patients), p.Y114H in compound heterozygosity (13 patients) and p.D430N homozygous (6 patients). In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures. EEG features seems to display common pattern and developmental trajectories: i) poor general background organization with theta-delta activity ii) hypsarrhythmia with spasms, usually ACTH-responsive, iii) generalized epileptic discharges with frontal or frontal temporal predominance, iv) epileptic discharges activation in sleep with an altered sleep structure. Imaging features present consistent findings of cerebral atrophy with frontal predominance, cerebellar atrophy, and white-matter abnormalities among the three types. Significance: ADSL deficiency presents variable phenotypic expression which severity could be partially attributed to residual activity of the mutant protein and although a precise phenotype-genotype correlation was not yet feasible, we delineated a common pattern of clinical, neuroradiological and neurophysiological features.