Developmental Delay Research Articles

Incidence of ophthalmic manifestations in congenital cytomegalovirus (CMV).

Congenital cytomegalovirus (CMV) infections are associated with eye manifestations, especially in patients with systemic disease. However, there are no ophthalmic screening guidelines for infants with congenital CMV. Retrospective review of pediatric patients (< 18 years old, 2010-2023) with a diagnosis of congenital CMV and at least 1 eye examination. Gestational age at birth, systemic findings, and ophthalmic findings at initial and final eye examinations were collected. Seventy-two patients (47% male) with congenital CMV underwent initial eye examination at 2.1 ± 2.9 years of age (median 0.3 years). Thirty-one patients (43%) only had one eye examination while 41 patients had follow-up (1 month-19 years). Fifty-two patients (72%) had systemic findings, most commonly hearing loss (50%), neurologic abnormalities (39%), and developmental delay (38%). Patients born < 36 weeks gestation (n = 15) had a higher rate of systemic findings, neurologic abnormalities, developmental delay, and intrauterine growth restriction compared to full-term patients. Twenty-four (33%) patients had ocular findings and all also had systemic manifestations. Strabismus (26%) and optic nerve abnormalities (17%) were most common. Only 2 patients (3%) were diagnosed with retinitis, which was detected at initial examination. One-third of patients with congenital CMV had ocular findings in conjunction with systemic manifestations. Retinitis was rare and detected on initial eye examination. While initial screening for retinitis is important, patients with systemic sequelae of congenital CMV are at risk for other eye manifestations and require continued follow-up.

Prevalence and Risk Factors of Developmental Delay among High-risk Preterm NICU Graduates – A Cross-Sectional Study

Prevalence and Risk Factors of Developmental Delay among High-risk Preterm NICU Graduates – A Cross-Sectional Study

Phenotypic variability in progressive encephalopathy with brain atrophy and thin corpus callosum: insights from two families.

The cytoskeleton, composed of microtubules, intermediate filaments and actin filaments is vital for various cellular functions, particularly within the nervous system, where microtubules play a key role in intracellular transport, cell morphology, and synaptic plasticity. Tubulin-specific chaperones, including tubulin folding cofactors (TBCA, TBCB, TBCC, TBCD, TBCE), assist in the proper formation of α/β-tubulin heterodimers, essential for microtubule stability. Pathogenic variants in these chaperone-encoding genes, especially TBCD, have been linked to Progressive Encephalopathy with Brain Atrophy and Thin Corpus Callosum (PEBAT, OMIM #604,649), a severe neurodevelopmental disorder. We report three cases from two consanguineous families with varying clinical presentations of PEBAT syndrome due to homozygous pathogenic variants in the TBCD. In Family 1, two siblings (F1C1 and F1C2) harboring the homozygous c.2314C > T, p.(Arg772Cys) variant exhibited severe neurodevelopmental regression, spastic tetraplegia, seizures, and brain atrophy. In contrast, Family 2, Case 3 (F2C3), with the homozygous c.230A > G, p.(His77Arg) variant, presented a milder phenotype, including absence seizures, slight developmental delay, and less pronounced neuroanatomical abnormalities. These findings contribute to the expanding phenotypic spectrum of PEBAT and suggesting that modifier genes or epigenetic factors may influence disease severity.

Assessment of glymphatic function and white matter integrity in children with autism using multi-parametric MRI and machine learning.

To assess glymphatic function and white matter integrity in children with autism spectrum disorder (ASD) using multi-parametric MRI, combined with machine learning to evaluate ASD detection performance. This retrospective study collected data from 110 children with ASD (80 exploratory, 43 validation) and 68 typically developing children (50 exploratory, 18 validation) from two centers. The automated diffusion tensor imaging along the perivascular space (aDTI-ALPS), fractional anisotropy (FA), cerebrospinal fluid volume, and perivascular space (PVS) volume indices were extracted from DTI, three-dimensional T1-weighted, and T2-weighted images. Intergroup comparisons were conducted using t-tests, Mann-Whitney U-test, and tract-based spatial statistics. Correlation analysis assessed the relationship between glymphatic function, white matter integrity, and clinical scales. Machine learning models based on MRI indices were developed using the AutoGluon framework. The PVS volume (p < 0.001) was larger, and aDTI-ALPS index (p < 0.001) was lower in children with ASD compared to typically developing children. FA values were reduced in the ASD group and positively correlated with aDTI-ALPS index. The aDTI-ALPS index correlated with ASD severity (r = -0.27, p = 0.02) and developmental delays (r = 0.63, p < 0.001). Mediation analysis indicated the aDTI-ALPS index partially mediated the relationship between white matter integrity and developmental delay. The MRI-based model achieved an area under the curve of 0.84 for ASD diagnosis. Analyzing glymphatic function and white matter integrity enhances understanding of ASD's neurobiological underpinnings. The multi-parametric MRI, combined with machine learning, can facilitate the early detection of ASD. Question How can multi-parametric MRI based on the glymphatic system improve early diagnosis of autism spectrum disorder (ASD) beyond the limitations of current behavioral assessments? Findings Glymphatic dysfunction and disruptions in white matter integrity were associated with clinical symptoms of ASD. Multi-parametric MRI with machine learning can improve early ASD detection. Clinical relevance Multi-parametric MRI, focusing on glymphatic function and white matter integrity, enhances the diagnostic accuracy of ASD by serving as an objective complement to clinical scales.

Compound heterozygous TMEM67 biallelic variants including a novel frameshift mutation in two Filipino adolescent siblings with Joubert syndrome.

Joubert Syndrome (JS) is a congenital cerebellar ataxia typically inherited in an autosomal recessive pattern, although rare X-linked inheritance can occur. It is characterized by hypotonia evolving into ataxia, global developmental delay, oculomotor apraxia, breathing dysregulation, and multiorgan involvement. To date, there are 40 causative genes implicated in JS, all of which encode proteins of the primary cilium. Primary cilia play a crucial role in the normal development and function of many organs, including parts of the brain (cerebellum and brainstem), kidneys, and the retina. This likely explains the multiorgan involvement seen in JS. In this report, we present the first genetically confirmed case of JS in two Filipino adolescent siblings who had early onset ataxia, hepatomegaly, and global developmental delay. A cranial CT scan revealed the Molar Tooth Sign (MTS). Whole Exome Sequencing (WES), performed via buccal swab, showed biallelic pathogenic variants at NM_153704.6:c.2086C > T (NP_714915.3:p.Leu696Phe) and NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) in TMEM67, which are associated with Joubert Syndrome 6 (OMIM:610688) in a compound heterozygous state. The prevalence of NM_153704.6:c.2086C > T (NP_714915.3:p.Leu696Phe) in TMEM67 variant is very rare (< 0.001%), and the NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) has not been recorded. This case contributes valuable information to the expanding knowledge of JS and its related disorders.

Clinical and genetic spectrum of patients with IRF2BPL syndrome.

Interferon regulatory factor 2 binding protein-like (IRF2BPL) is a single-exon gene that is ubiquitously expressed in various tissues, including the brain. IRF2BPL encodes a transcription factor with two zinc-finger domains that potentially downregulate WNT signaling in the nervous system. Pathogenic IRF2BPL variants have been reported to cause developmental delay, seizures, myoclonus epilepsies, autistic spectrum disorder, and other neurodevelopmental disorders. Exome sequencing of 10 patients with developmental delay and/or epilepsy from nine families revealed nine pathogenic IRF2BPL variants, of which eight were novel: five missense, one in-frame indel, and three truncating variants. Using reported pathogenic and benign variants, we highlight here several regions of IRF2BPL that deviate in the frequency of pathogenic and benign variants. This study of detailed clinical and genetic information shows that IRF2BPL missense and in-frame indel variants are often associated with seizures and developmental delay.

Ecotoxicological impact of succinate dehydrogenase inhibitor (SDHI) fungicides on non-targeted organisms: a review.

As the global population continues to grow, the use of pesticides to increase food production is projected to escalate. Pesticides are critical in plant protection, offering a powerful defense against fungal diseases such as apple scab, leaf spot, sclerotinia rot, damping off, sheath blight, and root rot, which threaten crops like cereals, corn, cotton, soybean, sugarcane, tuberous vegetables, and ornamentals. Succinate Dehydrogenase Inhibitor (SDHI) fungicides represent a novel class essential for controlling fungal pathogens and bolstering food security. However, the impact of SDHIs on non-target organisms, including freshwater and terrestrial invertebrates, crustaceans, and oligochaetes, remains insufficiently understood. Empirical studies indicate that SDHIs can induce mortality, mitochondrial dysfunction, oxidative stress, and developmental delays in non-target organims. Additionally, the environmental persistence of these compounds raises concerns about their potential for ecological disruption. The effects of SDHIs on pollinating species and the possible transgenerational transmission of harmful effects warrant further investigation. Comprehensive transcriptomic analyses are necessary to elucidate the molecular disturbances and adverse outcome pathways triggered by SDHIs. Furthermore, there are emerging concerns about the endocrine-disrupting potential of SDHIs in aquatic organisms. For the first time, this review aims to synthesize existing knowledge on the ecotoxicological impacts of SDHIs on non-target organisms and identify critical research directions to address the ecological challenges posed by their use.

Frequency and Distribution of Parasites Detected in Children Between 2017-2022 (6-year Period).

In the study, various complaints such as gastrointestinal complaints such as diarrhea, constipation, abdominal pain, nausea and vomiting, weight loss, night urination, itching around the anus, malnutrition, malabsorption, anemia, intelligence and developmental delay were reported to University of Health Sciences Türkiye, Dr. Behçet Uz Pediatric Diseases and Surgery Training and Researhc Hospital, Microbiology Laboratory between 2017 and 2022. It was aimed to determine the frequency and distribution of intestinal parasites in patients presenting with clinical symptoms. In the study, the results of 33,249 stool and 3499 cellophane tape samples sent to the microbiology laboratory between January 2017 and September 2022 were evaluated. The stool samples were examined with saline-Lugol, modified Kinyoun acidfast and trichrome staining methods. Parasites were detected in the stool samples of 1.8% of a total of 36,748 patients. The intestinal parasite detected at the highest rate was Entamoeba histolytica (67%). In order of frequency: Enterobius vermicularis (19%), Giardia intestinalis (12%), Ascaris lumbricoides (0.6%), Hymenolepis nana (0.2%) Blastocystis spp. (0.2%) is followed by Hymenolepis diminuta (0.2%). While the rate of parasite occurrence in patients applying was found to be 19.9% in 2017, 24.6% in 2018, and 28.6% in 2019, this rate decreased to 4.3% in 2020, 16% in 2021 and 6.6% in 2022. Looking at the distribution of parasites by years, it is seen that there was a decrease in the rate of parasite occurrence with the start of the Coronavirus disease-2019 pandemic in 2020. We believe that infection control measures and strict enforcement of quarantine rules to reduce the spread of severe acute respiratory syndrome-coronavirus-2 may have significantly reduced the parasite positivity rate during the pandemic period. Data on intestinal parasites in Türkiye show regional differences, and national surveillance studies are needed, especially in children.

Novel mutations found in genes involved in global developmental delay and intellectual disability by whole-exome sequencing, homology modeling, and systems biology

Background Genes associated with global developmental delay (GDD) and intellectual disability (ID) are increasingly being identified through next-generation sequencing (NGS) technologies. This study aimed to identify novel mutations in GDD/ID phenotypes through whole-exome sequencing (WES) and additional in silico analyses. Material and methods WES was performed on 27 subjects, among whom 18 were screened for potential novel mutations. In silico analyses included protein-protein interactions (PPIs), gene-miRNA interactions (GMIs), and enrichment analyses. The identified novel variants were further modelled using I-Tasser-MTD and SWISS-MODEL, with structural superimposition performed. Results Novel mutations were detected in 18 patients, with 10 variants reported for the first time. Among these, three were classified as pathogenic (DNMT1:c.856dup, KCNQ2:c.1635_1636insT, and TMEM94:c.2598_2599insC), and six were likely pathogenic. DNMT1 and MRE11 were highlighted as key players in PPIs and GMIs. GMIs analysis emphasised the roles of hsa-miR-30a-5p and hsa-miR-185-5p. The top-scoring pathways included the neuronal system (R-HSA-112316, p = 7.73E-04) and negative regulation of the smooth muscle cell apoptotic process (p = 3.37E-06). Homology modelling and superimposition revealed a significant functional loss in the mutated DNMT1 enzyme structure. Conclusion This study identified 10 novel pathogenic/likely pathogenic variants associated with GDD/ID, supported by clinical findings and in silico analyses focused on DNMT1 mutations.

Diagnostic delay in cerebral creatine deficiency disorders: lessons learned from a cross-sectional single center study, and guanidinoacetate and creatine measurements in Switzerland between 2015 and 2023

BackgroundCerebral creatine deficiency disorders (CCDD) are rare diseases caused by defects in the enzymes L-arginine: glycine amidinotransferase (AGAT) or guanidinoacetate-N-methyltransferase (GAMT), which are involved in synthesis of creatine; or by a defect in the creatine transporter (CRTR), which is essential for uptake of creatine as important energy source into the target cells. Patients with CCDD can present with a variety of unspecific symptoms: global developmental delay, speech-language disorder, behavioral abnormalities and seizures. Early treatment initiation is essential in AGAT and GAMT deficiencies to achieve a favorable outcome. This study describes the CCDD patient cohort in a single center, and an analysis of the referrals to two Swiss laboratories in Lausanne and Zurich between 2015 and 2023 for the two marker metabolites guanidinoacetate and creatine.ResultsThe patient cohort comprised 6 patients (defects: 2 GAMT, 4 CRTR), who were initially seen by different subspecialties depending on first symptoms. There was a diagnostic and therapeutic delay between 3 and 32 months (mean 13.8). Numbers of biomarker requests showed a constant increase during the study period, with a majority of tests performed in urine, the preferred sample for CCDD detection. Almost all samples (93.3%) were sent in by large hospitals (mainly from neurology, developmental pediatrics and metabolism) and only few (5.2%) by pediatricians in private practice, although those usually see the patients first.ConclusionsThe data from this study demonstrate a relevant delay in identifying patients with these rare conditions, and a predominance of biomarker analysis requested from pediatric subspecialties that are involved in patient management often long after occurrence of symptoms. To reduce the diagnostic delay and the outcome of patients, the current practice of sample referral should be reflected and first-contact healthcare providers should be encouraged to initiate selective screening.

D-Ala2-GIP (1-30) promotes angiogenesis by facilitating endothelial cell migration via the Epac/Rap1/Cdc42 signaling pathway.

Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology.

Neurodevelopmental outcomes after infant heart surgery for congenital heart disease: a hospital-based multicentre prospective cohort study from India

BackgroundNeurodevelopmental disability is a common long-term concern following surgery for congenital heart disease (CHD). Little information is available from low-resource environments where the majority of children with CHD are born....

Effect of home environment on neuropsychiatric development in preterm infants discharged from NICU at 18 months corrected age

BackgroundThere have been numerous intervention studies focusing on the development of preterm infants, but there has been limited investigation into the home environment as a determinant of developmental outcomes in...

Maternal Fasting Plasma Glucose Level in Early Gestation and Developmental Delay in 2-year-old Children.

The association of maternal hyperglycemia with childhood developmental delay has been examined; however, only 2 studies used maternal blood glucose level as a continuous variable as an exposure. A present study aimed to investigate the influence of maternal fasting plasma glucose (mFPG) level in early gestation on developmental delay in children. This cohort study included 1541 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. mFPG level before 24 gestational weeks was obtained as a continuous and categorical variable. Developmental delay in 2-year-old children was assessed by mothers using the Ages and Stages Questionnaire (third edition). Associations between mFPG level and developmental delay in children were evaluated using multiple logistic regression analyses. The prevalence of mFPG level ≥95 mg/dL was 5.2%. At 2 years old, 15.1% of the children had developmental delays. mFPG level as a continuous variable was not associated with an increased risk of developmental delay across the 5 domains in children [adjusted odds ratio (aOR), 95% confidence interval (CI): 1.004, 0.990-1.018]. mFPG level ≤70 mg/dL was associated with developmental delay across 5 domains (aOR, 95% CI: 0.464, 0.229-0.943) in children than that with a mFPG level 71 to 94 mg/dL. No association was found between mFPG level ≤70 mg/dL and ≥95 mg/dL and developmental delay in any domains among children. mFPG level in early gestation was not associated with an increased risk of any developmental delays in 2-year-old children.

Missense variants at the p.Arg225 residue in ARHGEF40 identified in individuals with multiple congenital anomalies and developmental delay.

The ARHGEF40 gene, also known as SOLO, encodes a RhoA-targeting guanine nucleotide exchange factor (GEF) and is currently considered a candidate gene with a potential relationship to disease. Our laboratory has confirmed variants at position p.Arg225 of the ARHGEF40 protein in multiple unrelated individuals with a phenotype including dysmorphic features, congenital anomalies and neurodevelopmental abnormalities. Here, we provide genetic and phenotypic information for two individuals harboring de novo variants at p.Arg225 and sharing a highly similar phenotype. This report suggests a relationship between variants at this amino acid position and autosomal dominant disease, and further studies will be needed to characterize this disease-gene relationship and elucidate the disease mechanism.

First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome.

This study presents the first reported case of a Korean patient with Alpha-1,3-Mannosyltransferase-Congenital Disorder of Glycosylation (ALG3-CDG), characterized by a novel maternally inherited missense mutation and a previously reported paternally inherited nonsense mutation. The patient exhibited typical ALG3-CDG manifestations, including developmental delays, epilepsy, and multisystem involvement, alongside a diagnosis of Lennox-Gastaut Syndrome (LGS). Cannabidiol therapy, combined with dietary management, led to seizure freedom for over 13 months, significant EEG improvement, and enhanced developmental outcomes. This case underscores the potential of cannabidiol as a promising treatment strategy for patients with ALG3-CDG and refractory epilepsy, broadening therapeutic perspectives for this rare disorder.

De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.

Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient's death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.

Witteveen-Kolk Syndrome With Cleft Palate: A Case Report and Review of the Literature.

Witteveen-Kolk syndrome (WITKOS) is an exceptionally uncommon genetic and neurodevelopmental disorder, characterized by developmental delay, mild intellectual disability, and craniofacial dysmorphic features. Although cleft palate (CP) has rarely been reported in WITKOS, CP in this condition has not been assessed in detail. Here, we present a case of WITKOS with a CP. The patient was a 2-year-old male and he was referred to our clinic with CP and dysmorphic clinical findings. Screening for CP should be considered when a diagnosis of WITKOS is made. CP repair can be performed successfully after neurodevelopmental maturation is complete.

Prenatal phenotype of PNKP-related microcephaly, seizures, and developmental delay: A case report and literature review.

Microcephaly, epilepsy, and developmental delay (MCSZ) is a rare neurodevelopmental disorder associated with autosomal recessive inheritance of mutations in the polynucleotide kinase 3'-phosphatase (PNKP) gene. Prompt identification and management are essential, as delayed diagnosis or intervention may result in severe complications or mortality. In this case, prenatal screening in the second trimester detected fetal microcephaly with a gradual decline in head circumference, prompting the decision to terminate the pregnancy. Subsequent genetic analysis of the fetal tissue confirmed the presence of compound heterozygous mutations in the PNKP gene. The patient, a 34-year-old remarried female with no history of consanguineous marriage, underwent 2 mid-trimester termination procedures due to fetal microcephaly and sought counseling for reproductive assistance. The patient's carrier status for PNKP mutations was ascertained through whole-exome sequencing of the termination tissue and molecular genetic testing for monogenic disorders. The terminated fetus was diagnosed with MCSZ, a condition associated with compound heterozygous mutations in the PNKP gene. Fetal microcephaly was identified via mid-trimester prenatal ultrasound, leading to the termination of the pregnancy during the same trimester. Subsequent genetic analysis of the immediate family revealed compound heterozygous mutations in the PNKP gene as the underlying cause of MCSZ. Genetic counseling was provided, followed by 1 cycle of preimplantation genetic testing for monogenic. The patient carried the heterozygous c.1188 + 1G > A PNKP mutation, whereas her husband carried the heterozygous c.976G > A PNKP mutation. The fetus was found to have compound heterozygous mutations c.976G > A and c.1188 + 1G > A. After counseling, the couple underwent 1 cycle of preimplantation genetic testing for monogenic, unfortunately, no pregnancy occurred after the 2 embryos were transferred. MCSZ, a condition caused by PNKP mutations, is exceedingly rare. Women with a history of adverse pregnancy outcomes should undergo close monitoring during prenatal checkups. If fetal microcephaly is detected, it is essential to strictly follow obstetric guidelines for prenatal care, such as comprehensive cranial magnetic resonance imaging and genetic testing for confirmation. Avoidance of consanguineous marriages is advised. Early detection and timely intervention are key to preventing adverse pregnancy outcomes.

Exploratory metabolomic profiling of plasma and urine in patients with mucopolysaccharidosis type II (Hunter syndrome): A pilot study.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked lysosomal storage disorder. It results from a deficiency of the enzyme iduronate-2-sulfatase (I2S), leading to the accumulation of glycosaminoglycans (GAGs) in various tissues and organs. Clinical manifestations include skeletal abnormalities, facial coarsening, organ enlargement, and developmental delays. The main objective of this study was to identify neuronopathic MPS II-specific biomarkers for early detection, diagnosis, monitoring, and follow up of affected patients. We thus applied liquid chromatography-high-resolution mass spectrometry (LC-HRMS) based untargeted metabolomic approaches to identify these potential biomarkers which could discriminate patients with the neuronopathic form of MPS II from healthy controls. Secondary aims focused on a better understanding of how the disease may affect the metabolome of patients. Urine and plasma samples from 21 untreated neuronopathic MPS II patients characterized by severe clinical manifestations were compared to 23 age- and gender-matched healthy control samples using a Xevo G2-XS Qtof MS (Waters Corp.). A comprehensive metabolomic workflow and multivariate statistical analyses revealed metabolites consistently elevated in MPS II patients. These include acylaminosugars, dipeptides, amino acids and their derivatives, lipid structures, and various compounds indicating disruptions in metabolic pathways. Development and validation of quantitative methods will be done using tandem mass spectrometry. Furthermore, identifying biomarkers associated with the central nervous system (CNS) in MPS II patients would help detect the neuronopathic form of the disease early, and enable the evaluation of the effectiveness of novel therapeutic strategies.