Identification of Potential Clusters of Signs and Symptoms to Prioritize Patients' Eligibility for AADCd Screening by 3-OMD Testing: An Italian Delphi Consensus.

Introduction: AADCd is an ultrarare, underdiagnosed neurometabolic disorder for which a screening test (3-OMD dosing on dried blood spot (DBS)) and targeted gene therapy (authorized in the EU and the UK) are available. Therefore, it is mandatory to raise awareness of presenting symptoms and signs among practitioners. Delivering scientifically sound information to promote screening of patients with the correct cluster of symptoms and signs would be critical. Materials and Methods: In light of the lack of sound evidence on this issue, expert opinion level of evidence was elicited with the Delphi method. Fourteen steering committee members invited a panel of 29 Italian experts to express their opinions on a series of crucial but controversial topics related to using 3-OMD DBS as a screening method in AADCd. Clusters of symptoms and signs were divided into typical or atypical, depending on age groups. Inclusion in newborn screening programs and the usefulness of a clinical score were investigated. A five-point Likert scale was used to rate the level of priority attributed to each statement. Results: The following statements reached the highest priority: testing pediatric patients with hypotonia, developmental delay, movement disorders, and oculogyric crises; inclusion of 3-OMD dosing on DBS in neonatal screening programs; development of a clinical score to support patients' selection for 3-OMD screening; among atypical phenotypes based on clinical characteristics of Italian patients: testing patients with intellectual disability and parkinsonism-dystonia. Discussion. Clusters of symptoms and signs can be used to prioritize testing with 3-OMD DBS. A clinical score was rated as highly relevant for the patient's selection. The inclusion of 3-OMD dosing in newborn screening programs was advocated with high clinical priority.

Management, treatment, and clinical approach of Sydenham's chorea in children: Italian survey on expert-based experience.

Sydenham's chorea (SC), an autoimmune disorder affecting the central nervous system, is a pivotal diagnostic criterion for acute rheumatic fever. Primarily prevalent in childhood, especially in developing countries, SC manifests with involuntary movements and neuropsychiatric symptoms. Predominantly occurring between ages 5 and 15, with a female bias, SC may recur, particularly during pregnancy or estrogen use. The autoimmune response affecting the basal ganglia, notably against dopamine, underlies the pathophysiology. Clinical management necessitates an integrated approach, potentially involving immunomodulatory therapies. To address discrepancies in SC management, a survey was conducted across Italy, targeting specialists in neurology, pediatrics, child neuropsychiatry, and rheumatology. Of the 51 responding physicians, consensus favored hospitalization for suspected SC, with broad support for laboratory tests and brain MRI. Treatment preferences showed agreement on oral prednisone and IVIG, while opinions varied on duration and plasmapheresis. Haloperidol emerged as the preferred symptomatic therapy. Post-SC penicillin prophylaxis and steroid therapy gained strong support, although opinions differed on duration. Follow-up recommendations included neuropsychological and cardiological assessments. Despite offering valuable insights, broader and more studies are needed in order to guide treatment decisions in this well-known yet challenging complication of acute rheumatic fever, which continues to warrant scientific attention and concerted clinical efforts.

Feeding and eating disorders in children and adolescents during the COVID-19 pandemic: real-word data from an observational, naturalistic study.

BACKGROUND: The COVID-19 pandemic had a substantial impact on the mental health of children and adolescents. The literature lacks large-scale research evaluating its consequences on teenagers with feeding and eating disorders (FED). This study aims to assess the impact of the COVID-19 pandemic on a population of patients of developmental age. METHODS: This single-center observational study compares two historical cohorts of children and adolescents diagnosed with FED, with a first consultation before (1st March 2018 to 31st October 2019) and during (1st March 2020 to 31st October 2021) pandemic. Demographic, clinical, nutritional, and treatment variables were assessed. RESULTS: We enrolled 479 patients (F=398, 83.1%), including 205 (F=161, 78.5% mean age 14.5±2.5, range 7.9-17.9 years) belonging to the first historical cohort and 274 (F=237, 86.5%; 14.4±2.1, range 6.5-17.9) to the second one (+33.7%). Increased mean new accesses/month (P=0.042) and a greater percentage of females (P=0.042) during the pandemic compared to the pre-pandemic period emerged. Physical hyperactivity (P=0.022) and suicidal behaviors (P=0.030) increased, while fewer patients required hospitalization (P=0.013). CONCLUSIONS: An increase in first visits for FED after the COVID-19 pandemic emerged, with females being the most affected. Physical hyperactivity and self-harming behaviors were intensified, while patients in need of hospitalization were reduced. Longitudinal studies are required.

Epilepsy after acute central nervous system complications of pediatric hematopoietic cell transplantation: A retrospective, multicenter study.

BACKGROUND: Acute central nervous system (CNS) complications are common and well described among pediatric patients undergoing haematopoietic cell transplantation (HCT). However, their long-term outcomes are not known. The aim of this study is to describe the incidence, characteristics, and risk factors of long-term epilepsy in pediatric patients with acute CNS complications of HCT. METHODS: This retrospective study included pediatric patients who developed acute CNS complications from autologous or allogeneic HCT between 2000 and 2022. Clinical, therapeutic and prognostic data including long-term outcomes were analyzed. A diagnosis of epilepsy was provided if unprovoked seizures occurred during follow-up. RESULTS: Ninety-four patients (63 males, 31 females, median age 10 years, range 1-21 years) were included. The most common acute CNS complications were posterior reversible encephalopathy syndrome (n = 43, 46 %) and infections (n = 15, 16 %). Sixty-five patients (69 %) had acute symptomatic seizures, with 14 (16 %) having one or more episodes of status epilepticus (SE). Nine patients (9.6 %) were diagnosed with long-term focal epilepsy during the follow-up (5-year cumulative incidence from the acute complication, 13.3 %). Acute symptomatic SE during neurological complications of HCT was associated with an increased risk of long-term epilepsy (OR=14, 95 % CI 2.87-68.97). CONCLUSIONS: A higher occurrence of epilepsy has been observed in our cohort compared to the general population. Acute symptomatic SE during HCT was associated with a higher risk of long-term epilepsy. Pediatric patients with CNS complications during HCT could benefit from specific neurological follow-up. Further studies are needed to characterize mechanisms of epileptogenesis in pediatric patients undergoing HCT.

The Role of Electroencephalography in Children with Acute Altered Mental Status of Unknown Etiology: A Prospective Study.

INTRODUCTION: Acute altered mental status (AAMS) is often a challenge for clinicians, since the underlying etiologies cannot always easily be inferred based on the patient's clinical presentation, medical history, or early examinations. The aim of this study is to evaluate the role of electroencephalogram (EEG) as a diagnostic tool in AAMS of unknown etiology in children. MATERIALS AND METHODS: We conducted a prospective study involving EEG assessments on children presenting with AAMS between May 2017 and October 2019. Inclusion criteria were age 1 month to 18 years and acute (<1 week) and persistent (>5 minutes) altered mental status. Patients with a known etiology of AAMS were excluded. A literature review was also performed. RESULTS: Twenty patients (median age: 7.7 years, range: 0.5-15.4) were enrolled. EEG contributed to the diagnosis in 14/20 cases, and was classified as diagnostic in 9/20 and informative in 5/20. Specifically, EEG was able to identify nonconvulsive status epilepticus (NCSE) in five children and psychogenic events in four. EEG proved to be a poorly informative diagnostic tool at AAMS onset in six children; however, in five of them, it proved useful during follow-up. CONCLUSIONS: Limited data exist regarding the role of EEG in children with AAMS of unknown etiology. In our population, EEG proved to be valuable tool, and was especially useful in the prompt identification of NCSE and psychogenic events.

CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy.

CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000-60,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype-phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder.

COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction.

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Efficacy and Safety of Pulse Intravenous Methylprednisolone in Pediatric Epileptic Encephalopathies: Timing and Networks Consideration.

Background: Epileptic encephalopathies (EE) are characterized by severe drug-resistant seizures, early onset, and unfavorable developmental outcomes. This article discusses the use of intravenous methylprednisolone (IVMP) pulse therapy in pediatric patients with EE to evaluate its efficacy and tolerability. Methods: This is a retrospective study from 2020 to 2023. Inclusion criteria were ≤18 years at the time of IVMP pulse therapy and at least 6 months of follow-up. Efficacy and outcome, defined as seizure reduction > 50% (responder rate), were evaluated at 6 and 9 months of therapy, and 6 months after therapy suspension; quality of life (QoL) was also assessed. Variables predicting positive post-IVMP outcomes were identified using statistical analysis. Results: The study included 21 patients, with a responder rate of 85.7% at 6 and 9 months of therapy, and 80.9% at 6 months after therapy suspension. Variables significantly predicting favorable outcome were etiology (p = 0.0475) and epilepsy type (p = 0.0475), with the best outcome achieved in patients with genetic epilepsy and those with encephalopathy related to electrical status epilepticus during slow-wave sleep (ESES). All patients evidenced improvements in QoL at the last follow-up, with no relevant adverse events reported. Conclusions: Our study confirmed the efficacy and high tolerability of IVMP pulse therapy in pediatric patients with EE. Genetic epilepsy and ESES were positive predictors of a favorable clinical outcome. QOL, EEG tracing, and postural-motor development showed an improving trend as well. IVMP pulse therapy should be considered earlier in patients with EE.

Olfactory bulb anomalies in KBG syndrome mouse model and patients.

ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Generation of two iPSC lines from Mowat-Wilson syndrome patients carrying heterozygous ZEB2 mutations.

ZEB2 is a protein-coding gene belonging to a very restricted family of transcription factors. ZEB2 acts mainly as a transcription repressor, is expressed in various tissues and its role is fundamental for the correct development of the nervous system. The best-known clinical picture associated with ZEB2 mutations is Mowat-Wilson syndrome, caused mostly by haploinsufficiency and characterized by possible multi-organ malformations, dysmorphic features, intellectual disability, and epilepsy. In this study we report the generation of IGGi004-A and IGGi005-A, iPSC clones from two patients carrying different heterozygous mutations in ZEB2, which can be used for disease modelling, pathophysiological studies and therapeutics testing.

Identification of the DNA methylation signature of Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.

The involvement of the adrenergic system in feeding and eating disorders. A systematic review.

BACKGROUND: Adrenergic dysregulation has been proposed as a possible underlying mechanism in feeding and eating disorders (FED). This review aims to synthesise the current evidence on the role of adrenergic dysregulation in the pathogenesis and management of FED. METHODS: A systematic review was conducted in MEDLINE, Cochrane Library, and Clinicaltrials.gov. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was adopted. Preclinical, clinical, and pharmacological studies assessing the adrenergic system in FED were included. RESULTS: Thirty-one out of 1415 recognised studies were included. Preclinically, studies on adrenaline's anorectic impact, receptor subtypes, and effects on hepatic function in rats show that catecholamine anorexia is primarily alpha-adrenergic, whereas beta-adrenergic anorexia can be obtained only after puberty, implying an impact of sexual hormones. Clinically, catecholamine levels may be higher in FED patients than in healthy controls (HC). Individuals with anorexia nervosa (AN) may show higher epinephrine-induced platelet aggregability response than HC. Pharmacological trials suggest that the alpha-2-adrenergic medication clonidine may not lower AN symptoms, but agents regulating the adrenaline-noradrenaline neurotransmission (bupropion, reboxetine, duloxetine, sibutramine) have been found to improve binge eating symptoms. CONCLUSION: Adrenergic dysregulation may be involved in the pathophysiology of FED. More research is needed to comprehend underlying mechanisms and treatment implications.

NFIA haploinsufficiency: case series and literature review.

Background: NFIA-related disorder (OMIM #613735) is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment and non-specific dysmorphic features. To date, fewer than thirty patients affected by this disorder have been described. Methods: Our study included three children with NFIA haploinsufficiency recruited from three medical genetics centers. Clinical presentations were recorded on a standardized case report form. Results: All patients presented a variable degree of intellectual disability. None of the individuals in our cohort had urinary tract malformations. Three novel mutations, c.344G>A, c.261T>G, and c.887_888del are reported here. Conclusion: NFIA haploinsufficiency can be suspected through careful observation of specific dysmorphisms, including macrocephaly and craniofacial abnormalities. Instrumental tests such as MRI and renal ultrasound provide further diagnostic clues, while genetic testing can confirm the diagnosis.

Anti-Inflammatory and Immunomodulatory Effect of High-Dose Immunoglobulins in Children: From Approved Indications to Off-Label Use.

BACKGROUND: The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy, in the treatment of IEI-related immune dysregulation disorders, according to labelled and off-label indications. Recent years have been dominated by a progressive imbalance between the gradual but constant increase in the use of immunoglobulins and their availability, exacerbated by the SARS-CoV-2 pandemic. OBJECTIVES: To provide pragmatic indications for a need-based application of high-dose immunoglobulins in the pediatric context. SOURCES: A literature search was performed using PubMed, from inception until 1st August 2023, including the following keywords: anti-inflammatory; children; high dose gammaglobulin; high dose immunoglobulin; immune dysregulation; immunomodulation; immunomodulatory; inflammation; intravenous gammaglobulin; intravenous immunoglobulin; off-label; pediatric; subcutaneous gammaglobulin; subcutaneous immunoglobulin. All article types were considered. IMPLICATIONS: In the light of the current imbalance between gammaglobulins' demand and availability, this review advocates the urgency of a more conscious utilization of this medical product, giving indications about benefits, risks, cost-effectiveness, and administration routes of high-dose immunoglobulins in children with hematologic, neurologic, and inflammatory immune dysregulation disorders, prompting further research towards a responsible employment of gammaglobulins and improving the therapeutical decisional process.

Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.