Roser Pons

Objective: To determine the genetic diagnostic yield, characterize the clinical and genetic landscape, and evaluate long‐term epilepsy, neurodevelopmental, and survival outcomes in a strictly defined cohort of neonatal‐onset developmental and epileptic encephalopathy (DEE). Methods: Retrospective multicenter observational study across tertiary epilepsy centers in Italy, Greece, and Spain. Sixty‐two full‐term neonates fulfilling ILAE 2022 criteria for DEE with seizure onset within the first 30 days of life and a minimum follow‐up of 18 months were included. All patients underwent next‐generation sequencing–based genetic testing. Genetic findings, clinical characteristics, and long‐term outcomes were systematically analyzed. Results: A molecular diagnosis was established in 82.2% of patients (51/62), identifying variants across 29 genes grouped, for descriptive purposes, into four broad categories according to principal biological role. First‐line whole‐exome sequencing achieved higher diagnostic yield than targeted gene panels (88.9% vs. 41.2%), although this comparison was influenced by differences in testing era and strategy. KCNQ2 variants were the most frequent genetic cause (29.4%), and several treatable metabolic disorders were identified. After a mean follow‐up of 11.9 years, 64.5% of patients had drug‐resistant epilepsy and mortality reached 17.7%. Seizure freedom was achieved in a subset of patients, particularly those with KCNQ2 ‐related DEE. Nevertheless, severe‐to‐profound intellectual disability affected 71.7% of evaluable patients and persisted even among those who became seizure‐free, suggesting that neurodevelopmental outcomes are influenced by factors beyond seizure burden, including the underlying genetic disorder and other disease‐related factors. However, the marked variability observed precludes any causal inference from these data. Significance: This large European cohort demonstrates a high genetic diagnostic yield in neonatal‐onset DEE, supporting first‐line whole‐exome sequencing as the preferred first‐tier genetic test. The persistence of severe neurodevelopmental impairment despite seizure control highlights the need for precision therapies targeting disease mechanisms in addition to seizure management. Plain Language Summary: We studied 62 newborns who developed severe epilepsy caused by genetic changes, following them for up to 25 years. We found a genetic cause in over 80% of cases, and genetic testing that reads the entire genetic code was far more effective than tests that only look at specific genes. Although seizures improved in some children over time, nearly all had lasting intellectual disability regardless of seizure control. This suggests that the underlying genetic condition may contribute substantially to brain development in addition to the effects of seizures, although our study cannot determine the relative contribution of each factor.

Newborn screening for primary immunodeficiencies and spinal muscular atrophy (SMA) enables early identification of infants at risk for severe disorders, facilitating timely treatment and improved outcomes. This study describes the first Greek experience with combined screening for T-cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and SMN1 using a single dried blood spot (DBS) sample. During 2026, 29.460 newborns were screened using a commercially available in vitro diagnostic kit. TREC and KREC were assessed semi-quantitatively, while SMA screening was based on qualitative detection of the SMN1 exon 7 target. Of these, 2.168 (7,36%) required duplicate retesting, with 481 requiring a second DBS sample. Among the 481 newborns for whom a second DBS card was requested, 469 cards were received. Of these, 446 were classified as negative, 13 remained inconclusive, 4 were referred for genetic/immunological confirmatory evaluation, 2 remained under immunological follow-up, and 4 demonstrated recovery on repeat testing. Confirmatory evaluation identified four clinically significant cases: two with SMA, one with severe T-cell lymphopenia associated with 22q11.2 deletion syndrome, and one with CHARGE syndrome. Several low TREC/KREC results normalized on repeat testing. This experience demonstrates the feasibility of combined screening and highlights the importance of appropriate follow-up and confirmatory evaluation.

Background/Objectives: Genomic sequencing can shorten the diagnostic pathway for selected symptomatic neonates and young infants, but evidence from such cohorts should not be extrapolated to population newborn screening. This study describes molecular findings and potential clinical implications in 25 unrelated patients younger than 6 months at referral with heterogeneous, predominantly neurological phenotypes and no established molecular diagnosis. Methods: The first 17 patients underwent whole-exome sequencing (WES), and the subsequent 8 underwent whole-genome sequencing (WGS) under sequential laboratory protocols; allocation was not randomized, and the study was not designed to compare platforms. Results: Pathogenic or likely pathogenic findings providing a definitive or likely molecular diagnosis were identified in 7/25 patients (28.0%; 95% confidence interval [CI], 14.3–47.6), including sequence variants, one 20q13.33 deletion, and mosaic trisomy 9. An additional RANBP2 variant was interpreted as a susceptibility-associated finding in a patient with infection-related encephalitis, yielding clinically relevant findings in 8/25 patients (32.0%; 95% CI, 17.2–51.6). Three definitive diagnoses involved disorders with established disease-specific management considerations; however, patient-level treatment changes, turnaround times, and outcomes were not systematically assessed. Conclusions: These findings support the diagnostic value of genomic testing in selected symptomatic neonates and young infants, while the small, heterogeneous cohort, sequential non-equivalent workflows, and incomplete outcome data preclude conclusions about comparative WES/WGS performance or population newborn screening.

Background/Objectives: To study the hypothesis that cognitive functions and learning skills are impaired in child/adolescent childhood cancer survivors (CCS). Secondary outcomes included psychosocial parameters and quality of life. Methods: This case–control study was conducted over four years (2017–2021) at the largest pediatric Aghia Sophia Children’s Hospital, in Greece. Eligible participants were children and adolescents in Greece. For CCS, ≥1 year should have elapsed from completion of cancer treatment. Assessments of neurocognitive function, learning and psychosocial skills and health-related quality of life (HRQoL) were performed with validated instruments (WISC-III, LAMDA software, Achenbach CBCL/6-18 and YSR, KIDSCREEN-52, respectively). Results: In total, 219 participants (47.49% males, mean age ± SD 11.72 ± 2.32 years), 70 CCS and 149 controls (matched for age, sex, family income), were included. Cases were CCS of acute lymphoblastic leukemia (n = 25)/brain tumors (n = 19)/lymphoma (n = 17)/nephroblastoma (n = 5)/Ewing sarcoma (n = 3)/rhabdomyosarcoma (n = 1). CCS had worse scores in full-scale Intelligence Quotient (FSIQ) (p = 0.004), verbal IQ (VIQ) (p = 0.005) and all its subscales, performance IQ (PIQ) (p = 0.021), and almost all learning parameters than controls. Attention, working memory, writing/visual–motor coordination, processing accuracy/speed, language acquisition/expression, all psychosocial scales, and HRQoL domains of mood and emotions, were negatively affected in CCS. Female CCS demonstrated lower FSIQ (p = 0.019) and VIQ (p = 0.014) than control females, whereas male CCS retained their total IQ unaffected. Among CCS, those with non-central nervous system (CNS) tumors, higher parental educational level or higher family income had significantly higher IQ than those with CNS tumors, lower parental educational level or lower family income, respectively. Conclusions: CCS in Greece carry a significant burden of cognitive and psychological morbidity. Cognitive/educational and psychosocial support to CCS is imperative.

Background: NKX2‐1 –related disorders result from heterozygous variants in NKX2‐1 , a gene crucial for brain, lung, and thyroid development. Although movement disorders, hypothyroidism, and neonatal respiratory distress are recognized, the full phenotype and genotype–phenotype relationships remain incompletely defined. Objectives: To delineate neurological, respiratory, and endocrine features across ages, characterize movement disorder trajectories – particularly chorea – and explore genotype–phenotype associations with clinical relevance. Methods: We conducted a multicenter, cross‐sectional study recruiting participants through referral clinicians and European networks. Standardized clinical and genetic data were captured in an electronic database and analyzed with descriptive and inferential statistics. Results: Sixty‐eight individuals (37 female; median age 16 years, range 2–60 years) were included. Motor delay was the commonest presenting feature (~60%); neonatal respiratory distress syndrome occurred in one‐third of cases. The brain–lung–thyroid triad was present in almost half. Chorea affected over 90% and began in early childhood; it was more frequent with single nucleotide variants than with deletions. Deletions are associated with better gross motor function. Frameshift or nonsense variants showed greater respiratory involvement, and variants in the exon‐3 homeobox region were associated with age‐related reduction of chorea. Neonatal respiratory distress predicted later respiratory symptoms. Greater abnormal involuntary movement severity correlated with poorer manual and gross motor function. Hypotonia and untreated hypothyroidism are associated with more severe chorea. Psychiatric comorbidity occurred in over one‐third of cases, mainly attention‐deficit/hyperactivity symptoms. Conclusions: This largest cohort to date shows early neurological onset, genotype‐specific outcomes, and frequent psychiatric comorbidity in NKX2‐1 ‐related disorders, refining clinical expectations and supporting genotype‐informed diagnosis, counseling, and management. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Parkinsonism in infancy is rare and is highly correlated with the presence of dystonia. Advances in treating and characterizing developmental and infantile degenerative parkinsonism have highlighted the need for a specialized assessment scale. Objective: The aim of this study was to design and validate a scale that effectively assesses parkinsonism‐dystonia in early life. Methods: The Infantile Parkinsonism‐Dystonia Rating Scale (IPDRS) was designed to capture the key clinical features of parkinsonism‐dystonia in early life. It consists of 28 items across three subscales: Non‐motor symptoms, Motor symptoms, and Dyskinesias. Thirty‐two patients with hypokinetic movement disorder were scored following a standardized protocol. Filmed motor examinations were analyzed independently by three pediatric movement disorders specialists to evaluate interrater reliability. Twenty additional patients with primary neurotransmitter disorders were scored, and nine of them were evaluated at baseline and after treatment. Psychometric validation was conducted. Results: A total of 52 patients were scored using the IPDRS. Mean age was 3.1 years (standard deviation [SD]: 2.0), and the mean IPDRS score was 40.8 (SD: 13.17). Internal consistency analysis demonstrated a Cronbach's α of 0.21 for Non‐motor symptoms subscale, 0.84 for Motor symptoms subscale, and 0.95 for Dyskinesia subscale. Kappa indexes exceeded 0.70 in seven items. Correlation coefficients for dystonia items with the Barry‐Albright‐Dystonia Scale ranged from 0.46 to 0.64. After treatment, all IPDRS scores changed significantly, with an effect size of 2.42. Conclusions: The IPDRS appears to be a reliable and valid tool for assessing parkinsonism in early life. Further validation studies with a larger sample size are needed to confirm these findings and complete the validation process. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes.