Longitudinal Natural History of Pediatric Subjects Affected with Mucopolysaccharidosis IIIB.

OBJECTIVE: To characterize the longitudinal natural history of disease progression in pediatric subjects affected with mucopolysaccharidosis (MPS) IIIB. STUDY DESIGN: Sixty-five children with a confirmed diagnosis of MPS IIIB were enrolled into 1 of 2 natural history studies and followed for up to 4 years. Cognitive and adaptive behavior functions were analyzed in all subjects, and volumetric magnetic resonance imaging analysis of liver, spleen, and brain, as well as levels of heparan sulfate (HS) and heparan sulfate nonreducing ends (HS-NRE), were measured in a subset of subjects. RESULTS: The majority of subjects with MPS IIIB achieved an apex on both cognition and adaptive behavior age equivalent scales between age 3 and 6 years. Development quotients for both cognition and adaptive behavior follow a linear trajectory by which subjects reach a nadir with a score <25 for an age equivalent of 24 months by age 8 years on average and by 13.5 years at the latest. All tested subjects (n = 22) had HS and HS-NRE levels above the normal range in cerebrospinal fluid and plasma, along with signs of hepatomegaly. Subjects lost an average of 26 mL of brain volume (-2.7%) over 48 weeks, owing entirely to a loss of cortical gray matter (32 mL; -6.5%). CONCLUSIONS: MPS IIIB exists along a continuum based on cognitive decline and cortical gray matter atrophy. Although a few individuals with MPS IIIB have an attenuated phenotype, the majority follow predicted trajectories for both cognition and adaptive behavior. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02493998, NCT03227042, and NCT02754076.

Postauthorization safety study of betaine anhydrous.

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 µmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Gene Therapy for Neuronopathic Mucopolysaccharidoses: State of the Art.

The need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed.

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

Newborn screening for homocystinurias: Recent recommendations versus current practice.

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

Potential protective role of endogenous glutamate-oxaloacetate transaminase against glutamate excitotoxicity in fetal hypoxic-ischaemic asphyxia.

AIM: Fetal blood contains higher concentrations of glutamate-oxaloacetate transaminase (GOT; a blood enzyme able to metabolize glutamate) than maternal blood. The aim of this study was to determine the relationship between GOT and glutamate levels in arterial blood samples from umbilical cord in control newborn infants and newborn infants with hypoxic-ischaemic insult and/or symptoms of hypoxia-ischemia after delivery. METHOD: A total of 46 newborn infants (28 females, 18 males) were prospectively included in the study. Twenty-three infants (18 females, five males) were included as control participants and 23 (10 females, 13 males) were included as newborn infants at risk of adverse neurological outcome (defined as umbilical blood with pH <7.1). RESULTS: Analysis of glutamate concentration and GOT activity in umbilical blood samples showed that newborn infants with pH <7.1 had higher levels of glutamate (142.4 µmol/L [SD 61.4] vs 62.8 µmol/L [SD 25.5]; p<0.001) and GOT (83.1 U/L [SD 60.9] vs 34.9 U/L [SD 18.2]; p<0.001) compared to newborn infants without fetal distress. Analysis of Apgar scores and blood pH values (markers of perinatal distress) showed that conditions of severe distress were associated with higher glutamate and GOT levels. INTERPRETATION: During fetal development, the ability of GOT to metabolize glutamate suggests that this enzyme can act as an endogenous protective mechanism in the control of glutamate homeostasis.

Dimethylarginines as biomarkers for the kidney transplant management in methylmalonic aciduria.

Methylmalonic aciduria (MMA) is an inborn error of metabolism associated with many complications despite treatment. Chronic renal failure is the most common problem, and patients may eventually require kidney transplant. Therefore, it is worth investigating whether living donor kidney transplant offers a better option than deceased kidney donors; and the value of novel vascular risk biomarkers in the assessment of transplanted MMA patients. We report a case of a 26-year-old man with MMA, who progressed to end-stage renal disease and received kidney transplant from a heterozygous next-of-kin living donor at 20 years of age. Although post-transplant urinary levels of methylmalonic acid decreased, this reduction was lower than previously reported for deceased donors. No episodes of metabolic decompensation were observed after transplantation. During his clinical progress, vascular complications appeared; and finally, pancreatitis was the cause of death. After kidney transplant, we evaluated novel vascular risk factors, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which were used as early biomarkers of progression and metabolic management for this transplanted patient. This case report illustrates the disadvantage of transplantation with an allograft from a heterozygous living donor, and the utility of vascular risk biomarkers in renal transplant assessment.

Sanfilippo syndrome: Overall review.

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. It is characterized by progressive cognitive decline and severe hyperactivity, with relatively mild somatic features. This review focuses on clinical features, diagnosis, treatment, and follow-up of MPS III, and provides information about supplementary tests and differential diagnosis. Given that few reviews of MPS III have been published, several studies were compiled to establish diagnostic recommendations. Quantitative urinary glycosaminoglycan analysis is strongly recommended, and measurement of disaccharides, heparin cofactor II-thrombin complex and gangliosides is also used. Enzyme activity of the different enzymes in blood serum, leukocytes or fibroblasts, and mutational analysis for SGSH, NAGLU, HGSNAT or GNS genes are required to confirm diagnosis and differentiate four subtypes of MPS III. Although there is no global consensus for treatment, enzyme replacement therapy and gene therapy can provide appropriate results. In this regard, recent publications on treatment and follow-up are discussed.

Pain and heart rate variability in neonates receiving dexmedetomidine.

INTRODUCTION: Neonates in a NICU experience pain. Based on the cardiovascular and nociceptive systems link, a Newborn Infant Parasympathetic Evaluation (NIPE) monitor was designed to assess pain. The use of α2-agonists as analgesic-sedative drugs has increased in neonates. Given their effect on the autonomic system, we hypothesized that their use may alter NIPE's measurement capacity. METHODS: Data were prospectively collected. The included patients were evaluated using combined pain assessment systems. RESULTS: Sixteen newborns requiring sedoanalgesia underwent a total of 84 pain assessments. A good correlation was found between the NIPE-index and the COMFORT-neo and the crSO2 (cerebral regional oxygen saturation). No correlation was found in premature infants. By sedation group, the correlation remained in those receiving α2-agonist. CONCLUSION: NIPE is a reliable tool for pain assessment. Further studies in premature infants are needed. The use of α2-agonist does not alter the measuring capacity of NIPE. The correlation between NIPE-index and crSO2 was also demonstrated.

Health care-associated infections in neonatology.

Health care-associated infections are common in neonatology, but there is no consensus on their definitions. This makes it difficult to compare their incidence or assess the effectiveness of prevention bundles. This is why we think it is very important to achieve a consensus on the definitions and diagnostic criteria for one of the most frequent causes of morbidity in hospitalised neonates. This document aims to standardise the definitions for the most frequent health care-associated infections, such as catheter-associated bloodstream infection, ventilator-associated pneumonia and surgical wound infection, as well as the approach to their diagnosis and treatment.

Age- and Sex-Dynamic Fluctuations and Reference Intervals for Alkaline Phosphatase Among the Spanish Population.

CONTEXT.­: Interpretation of alkaline phosphatase (ALP) activity is essential for the diagnosis of certain diseases. ALP changes during life and may vary between different populations. OBJECTIVE.­: To establish reference intervals (RIs) and percentile charts for ALP activity in the Spanish population through a multicentric observational study and to compare the RIs to those defined in other countries. DESIGN.­: A total of 662 350 ALP measurements from individuals ages 0 to 99 years from 9 Spanish tertiary care centers collected between 2020 and 2022 were analyzed. This study is the largest published in the literature to date. RESULTS.­: Continuous percentile charts for ALP according to sex and age were established which can be used as RIs. Higher levels are reached during the first weeks of life. In puberty, a differential evolution is observed in both sexes, reaching a peak at 10 to 13 years of age in boys and remaining stable in girls at this age. Significant differences were also observed in adults, higher in men between ages 20 and 49 years and between ages 50 and 79 years in women, as reported in some countries. CONCLUSIONS.­: ALP activity follows an age- and sex-dependent fluctuation with geographic differences. It is important to have appropriate reference values for each population in order to allow for a correct diagnostic interpretation and early diagnosis of diseases related to ALP abnormalities.

Supplementation for Performance and Health in Patients with Phenylketonuria: An Exercise-Based Approach to Improving Dietary Adherence.

Supplementation is crucial for improving performance and health in phenylketonuria (PKU) patients, who face dietary challenges. Proteins are vital for athletes, supporting muscle growth, minimizing catabolism, and aiding muscle repair and glycogen replenishment post-exercise. However, PKU individuals must limit phenylalanine (Phe) intake, requiring supplementation with Phe-free amino acids or glycomacropeptides. Tailored to meet nutritional needs, these substitutes lack Phe but fulfill protein requirements. Due to limited supplement availability, athletes with PKU may need higher protein intake. Various factors affect tolerated Phe levels, including supplement quantity and age. Adhering to supplement regimens optimizes performance and addresses PKU challenges. Strategically-timed protein substitutes can safely enhance muscle synthesis and sports performance. Individualized intake is essential for optimal outcomes, recognizing proteins' multifaceted role. Here, we explore protein substitute supplementation in PKU patients within the context of physical activity, considering limited evidence.

Postnatal exposure to organic pollutants in maternal milk in north-western Spain.

Evaluation of postnatal exposure to organic pollutants is especially important for suckling infants during breastfeeding, a crucial perinatal growth period when organs and hormonal systems develop. We determined levels of 60 pollutants, including organochlorine pesticides (OCPs), organophosphorus pesticides (OPPs), pyrethroids (PYRs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and polybrominated diphenyl ethers (PBDEs), in 81 breast milk samples from breastfeeding mothers from Santiago de Compostela (north-western Spain). For most detected organic pollutants, levels were correlated with the season of milk sampling, maternal age at delivery, and place of residence. Dietary consumption habits (eggs, molluscs, and vegetable oils) were also correlated with OCP, OPP, PCB, PBDE and PYR levels. We also assessed the risk to infant health of exposure to organic pollutants in breast milk. PAHs, OCPs, OPPs, and PYRs accounted for almost 95% of the targeted organic pollutants in the samples analysed.

Breastfeeding and Inborn Errors of Amino Acid and Protein Metabolism: A Spreadsheet to Calculate Optimal Intake of Human Milk and Disease-Specific Formulas.

Human milk (HM) offers important nutritional benefits. However, except for phenylketonuria (PKU), there are little data on optimal levels of consumption of HM and a special formula free of disease-related amino acids (SF-AA) in infants with inborn errors of metabolism of amino acids and proteins (IEM-AA-P). We designed a spreadsheet to calculate the amounts of SF-AA and HM required to cover amino acid, protein, and energy needs in patients with the nine main IEM-AA-P in infants aged under 6 months. Upon entering the infant's weight and the essential amino acid or intact protein requirements for the specific IEM, the spreadsheet calculates the corresponding required volume of HM based on the amino acid concentration in HM. Next, the theoretical daily fluid intake (typical range, 120-200 mL/kg/day) is entered, and the estimated daily fluid intake is calculated. The required daily volume of SF-AA is calculated as the difference between the total fluid intake value and the calculated volume of HM. The spreadsheet allows for the introduction of a range of requirements based on the patient's metabolic status, and includes the option to calculate the required volume of expressed HM, which may be necessary in certain conditions such as MMA/PA and UCD. In cases in which breastfeeding on demand is feasible, the spreadsheet determines the daily amount of SF-AA divided over 6-8 feeds, assuming that SF-AA is administered first, followed by HM as needed. Intake data calculated by the spreadsheet should be evaluated in conjunction with data from clinical and nutritional analyses, which provide a comprehensive understanding of the patient's nutritional status and help guide individualized dietary management for the specific IEM.

Non-invasive biomonitoring of infant exposure to environmental organic pollutants in north-western Spain based on hair analysis. Identification of potential sources.

Recent years have seen growing interest in hair sample analysis to detect organic pollutants (OPs). This biological matrix can be analysed non-invasively for biomonitoring of OPs over a wide exposure window. Obtaining hair sample amounts that meet the needs of the analytical methodology required for the determination of the POs of interest can be challenging, especially in infants. As a result, studies assessing organic pollutants in infant hair have been very scarce. We quantified levels of about 60 OPs, including persistent organic pollutants (POPs), in 110 hair samples from a patient cohort (60 mothers and 50 infants) from Santiago de Compostela (north-western Spain). For each participant we examined relationship between OP levels and corresponding epidemiological parameters using correlations, principal component analysis (PCA), hierarchical cluster analysis, and Multivariate analysis of variance (MANOVA). For many OPs we observed significant correlations with place of residence, parity, and maternal age, as well as pet ownership. Evaluation of dietary habits showed significant associations between levels some OPs and the consumption of fish, molluscs, and cereal. There were significant associations between chlorpyrifos and deltamethrin levels and infant birth characteristics such as birthweight and head circumference. Relations between OP levels in the hair of mothers and their infants were also examined, revealing common sources of exposure for dioxin-like polychlorinated biphenyls (DLPCBs), non-dioxin-like polychlorinated biphenyls (NDLPCBs), polybrominated diphenyl ethers (PBDEs), and polycyclic aromatic hydrocarbons (PAHs). Levels of fluoranthene (F), pyrene (P), endrin, and some PBDEs in maternal hair were significantly correlated with those in infant hair. Our findings identified common sources of exposure to OPs of distinct chemical classes.

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B.

BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

Perinatal palliative care.

Perinatal Palliative Care is a model of care designed to prevent and treat the physical, spiritual, emotional, and social needs of fetuses and newborn infants with life-threatening or life-limiting conditions. The care extends to the infant's family. It is delivered by an interdisciplinary team to improve the quality of life from the time of diagnosis (possibly in utero) into death and bereavement (days, months or years later). To guarantee the access of this vulnerable population to high quality palliative care, structured programs and protocols need to be further developed in tertiary hospitals that treat highly complex obstetric and neonatal pathologies. Basic training is required for all the professionals involved.