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Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by sharing new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the third quarter of 2024 through the second quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics selected from 54 novel drugs awaiting US Food and Drug Administration approval. New cell therapies for treating cancers continue to enter the drug pipeline, while novel targeted therapies for biliary tract, gastric, pancreatic, and breast cancers, as well as 3 subcutaneous versions of already approved drugs given intravenously, are awaiting approval. Additionally, many novel drugs are being developed for treatment of rare and ultra-rare diseases such as hereditary angioedema, macular telangiectasia, congenital adrenal hyperplasia, and Barth syndrome. Two new subcutaneous drugs for hemophilia, a new oral medication for hereditary angioedema, a novel monoclonal antibody for atopic dermatitis, and the first oral penem antibiotic are also in the pipeline. Conclusion New drugs with various indications for cancers and rare diseases continue to strengthen the drug pipeline. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) are a family of rare inherited metabolic disorders. This study aimed to examine the carbohydrate-deficient transferrin (CDT) screening results of 1,328 patients with suspected CDG by using transferrin- high pressure liquid chromatography (Tf- HPLC) method and to evaluate the performance of the method as a reference diagnostic tool.Relative CDT levels (CDT concentrations expressed as percent of total transferrin) were determined in serum samples by HPLC. The method sensitivity, specificity and positive predictive value (PPV) were further calculated.Abnormal transferrin isoform profile consistent with CDG Type-I and CDG Type-II were determined in 50 cases; in 44 cases asiolo-Tf (7.63 ± 5.44 %) and disialo-Tf (36.29 ± 9.04 %), in six cases monosialo-Tf (3.95 ± 0.95 %) and trisialo-Tf (25.05 ± 4.46 %) were determined and decreased tetrasialo-Tf (49.75 ± 11.59 %) was identified in all cases. Two cases having abnormal CDT pattern were molecularly diagnosed with hereditary fructose intolerance and galactosemia and 11 cases diagnosed with CDG based on clinical and molecular analysis showed a normal pattern. The sensitivity, specificity and positive predictive values of Tf-HPLC method were 81.96 %, 99% and 96 %, respectively.Tf-HPLC is a useful, highly sensitive, cost-advantageous and reliable method for the detection and preliminary diagnosis of CDG for laboratories working with large sample series. [ABSTRACT FROM AUTHOR]

The analysis of gangliosides and glycosphingolipids is crucial for understanding cellular membrane structure and function as well as to accurately diagnose certain inborn errors of metabolism. GM2-gangliosidosis represents a rare and fatal group of lysosomal storage disorders characterized by accumulation of GM2 gangliosides in various tissues and organs. These disorders arise due to deficiency or functional impairment of the β-hexosaminidase A or B enzymes, which are responsible for degradation of GM2 ganglioside. Deficient enzyme activity primarily leads to the accumulation of GM2 gangliosides within the lysosomes of cells. Accurate and rapid diagnostic methods that detect increased levels of GM2 gangliosides in patients with GM2-gangliosidosis can play a significant role in early diagnosis and appropriate treatment of this condition. To address this need, we developed a multiplexed liquid chromatography-tandem mass spectrometry method targeting 84 species of gangliosides and other glycosphingolipids involved in ganglioside metabolism. Reproducibility, linearity, extraction efficiency, and sample stability were evaluated and proof-of-concept data obtained from analysis of serum samples from confirmed cases of GM2-gangliosidosis. This method has the potential to simultaneously monitor the biosynthesis of gangliosides and the lysosomal catabolic pathway serving as a valuable tool for screening and diagnosing an important group of lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors. Dihydroxyacetone-supplemented slices from the fed mice yielded the highest rate, further stimulated by forskolin and dibutyryl-cAMP. Moreover, using 13C isotope tracing, we assessed the contribution of glycogenolysis and gluconeogenesis to net glucose production over time. Pharmacological inhibition of the glucose 6-phosphate transporter SLC37A4 markedly reduced net glucose production and increased lactate secretion and glycogen storage, while glucose production was completely abolished in PCLS from glycogen storage disease type Ia and Ib patients. In conclusion, this study identifies PCLS as an effective ex vivo model to study hepatic glucose production and opens opportunities for its future application in IEM research and beyond. Ex vivo precision-cut liver slices allow glucose production quantification to model glycogen storage disease and inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Background/Objectives: This study aims to evaluate the efficacy and outcomes of renal replacement therapy (RRT) in pediatric patients with metabolic diseases, specifically focusing on the impact of hemodialysis (HD) and peritoneal dialysis (PD) on clinical parameters, toxin reduction, and long-term survival. Methods: This retrospective study included 10 pediatric patients (eight females and two males) treated at a pediatric nephrology department between 2020 and 2023. Patients diagnosed with metabolic disorders, including maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), and glycogen storage disease (GSD), underwent RRT. Clinical data, demographic information, and biochemical parameters were collected and analyzed. Results: Among the patients, 50% were diagnosed with MSUD, 30% with MMA, and 20% with GSD. RRT, including HD and PD, was administered to manage acute metabolic crises. HD was particularly effective in rapidly reducing toxic metabolite levels. Patients treated with HD showed significant reductions in leucine and ammonium levels, with median reductions of 94.5% and 86%, respectively. Overall, 60% of the patients demonstrated long-term survival, highlighting the critical role of RRT in managing metabolic crises. In conclusion, RRT, including HD and PD, is crucial in managing pediatric metabolic disorders by effectively reducing toxic metabolite levels and improving clinical outcomes. Conclusions: The results of this study are consistent with previous research, highlighting the critical role of RRT in the acute management of metabolic crises and supporting its adoption as a standard treatment method. [ABSTRACT FROM AUTHOR]

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. [ABSTRACT FROM AUTHOR]

The article presents a case study of congenital chloride diarrhea (CCD) that was misdiagnosed as Hirschsprung's disease, highlighting the importance of accurate diagnosis to avoid unnecessary surgery. Topics discussed include the clinical presentation and genetic factors of CCD, diagnostic challenges associated with distinguishing CCD from similar conditions, and the management strategies that can be employed to treat the disorder effectively.

Background: Secondary pseudohypoaldosteronism (S-PHA) is a rare condition resulting from renal tubular resistance to aldosterone in children with urinary tract infection (UTI) and/or nephrourological malformations. It is characterized by nonspecific symptoms but with the potential for life-threatening complications. We aim to evaluate the clinical manifestations, diagnostic approach, and therapeutic interventions in children with S-PHA, along with a review of recent publications. Methods: A retrospective observational descriptive study was conducted on S-PHA cases diagnosed over the last 15 years at a tertiary pediatric nephrology unit. The literature for the last 10 years was reviewed. Results: Twelve patients (10 males, 6 days to 6 months) were identified. Weight loss was the main reason for consultation (50%). Ninety-two percent of patients had an underlying nephrourological pathology and 62% concomitant confirmed UTI. Seven out of 12 children were admitted to the PICU. A subsequent extrapontine myelinolysis was observed in one patient as neurological sequelae. Twenty-one articles related to S-PHA have been identified on PubMed and Embase. Conclusions: S-PHA should be considered in infants under 6 months of age with UTI and/or CAKUT. Obstructive anomalies and vesicoureteral reflux can be found, affecting both unilateral and bilateral systems. Early medical and surgical interventions are crucial and require close monitoring to avoid iatrogenic complications. [ABSTRACT FROM AUTHOR]

Background: Premature loss of primary teeth (PLPT) can be a rare presentation of systemic medical conditions. Premature loss of primary teeth may present a diagnostic dilemma to paediatric dentists. Aims: To identify systemic conditions associated with PLPT and develop a clinical aid. Design: OVID Medline, Embase and Web of Science were searched up to March 2023. Citation searching of review publications occurred. Exclusion occurred for conference abstracts, absence of PLPT and absence of English‐language full text. Results: Seven hundred and ninety‐one publications were identified via databases and 476 by citation searching of review articles. Removal of 390 duplicates occurred. Following the exclusion of 466 records on abstract review, 411 publications were sought for retrieval, of which 142 met inclusion criteria. Thirty‐one systemic conditions were identified. For 19 conditions, only one publication was identified. The majority of publications, 91% (n = 129), were case reports or series. Most publications, 44% (n = 62), were related to hypophosphatasia, and 25% (n = 35) were related to Papillon–Lefèvre. Diagnostic features were synthesised, and a clinical aid was produced by an iterative consensus approach. Conclusions: A diverse range of systemic diseases are associated with PLPT. Evidence quality, however, is low, with most diseases having a low number of supporting cases. This clinical aid supports paediatric dentists in differential diagnosis and onward referral. [ABSTRACT FROM AUTHOR]

Background: Newborn screening programmes offer an opportunity to obtain dried blood spots (DBS) cards that contain a wealth of biological information that can be stored for long periods and have potential benefits for research and quality assurance. However, the storage and secondary uses of DBS cards pose numerous ethical, clinical, and social challenges. Empirical research exploring public attitudes is central to public policy planning as it can indicate whether or not there is broad public support, define public concerns, and ascertain the circumstances required to alleviate concerns and ensure support. This study aims to describe the clinical experience and attitudes towards newborn screening and investigate the perceptions and expectations of Hong Kong parents and healthcare providers regarding the retention of DBS cards and their usage for research. Methods: We conducted semi-structured in-person interviews with 20 parents and healthcare providers in Hong Kong. Thematic analysis was conducted. Results: Awareness of the significant research value of secondary uses of dried blood spot cards is low. Parents and healthcare providers support the storage and secondary uses of DBS cards with some concerns, including privacy and confidentiality breaches, the risk of discrimination or stigmatisation based on genetic information, and their inability to oversee the use of their child's biospecimen. Parents, however, prioritise their child's health over privacy concerns and support identifiable storage using pseudonymity to gain more information about their children's health. Conclusion: Child information takes precedence over potential concerns over privacy, underscoring the significance of engaging patients and the public in shaping public policy related to biobanking and healthcare research, in line with cultural and social values. [ABSTRACT FROM AUTHOR]

Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by variants in any of the following genes: BCKDHA, BCKDHB, and DBT gene. Previous reports have highlighted a variety of common causing genes and variants among different ethnic groups affected by MSUD. This study is the first to describe the molecular characteristics, potential common variants, clinical phenotypes, and treatment outcomes of 20 Thai MSUD patients before the implementation of expanded newborn screening in Thailand. Results: A cross-sectional, multicenter study was conducted, including twenty Thai MSUD patients from 1997 to 2023. Most of the patients presented with classic neonatal onset (95%). The mortality rate was 20%, while global developmental delay was observed in 40% of the patients. Variants in the BCKDHB gene were detected in 85% (17/20) of the patients, while the BCKDHA gene accounted for 15% (3/20). The study identified the 11-kb deletion involving 5'UTR, exon 1, and intron 1 in the BCKDHB gene, from a position of g.80102385 to g.80113453 (NC_000006.12), accounting for 50% of all variants (20/40 alleles) in Thai MSUD patients. All patients with the 11-kb deletion in BCKDHB presented with the classic type. The gap-PCR for this common deletion was established in the study. Conclusion: This study is the first to describe the clinical and molecular spectrum of Thai MSUD patients before the implementation of expanded NBS. The 11-kb deletion involving exon 1 in the BCKDHB emerges as the most common variant among Thai individuals with MSUD. Furthermore, the gap-PCR test for detecting the 11-kb exon 1 deletion status holds the potential for integration into stepwise molecular analysis following positive expanded newborn screening. [ABSTRACT FROM AUTHOR]

The number of quantitative systems pharmacology (QSP) submissions to the U.S. Food and Drug Administration has continued to increase over the past decade. This report summarizes the landscape of QSP submissions as of December 2023. QSP was used to inform drug development across various therapeutic areas and throughout the drug development process of small molecular drugs and biologics and has facilitated dose finding, dose ranging, and dose optimization studies. Though the majority of QSP submissions (>66%) focused on drug effectiveness, QSP was also utilized to simulate drug safety including liver toxicity, risk of cytokine release syndrome (CRS), bone density, and others. This report also includes individual contexts of use from a handful of new drug applications (NDAs) and biologics license applications where QSP modeling was used to demonstrate the utility of QSP modeling in regulatory drug development. According to the models submitted in QSP submissions, an anonymous case was utilized to illustrate how QSP informed development of a bispecific monoclonal antibody with respect to CRS risk. QSP submissions for informing pediatric drug development were summarized along with highlights of a case in inborn errors of metabolism. Furthermore, simulations of response variability with QSP were described. In summary, QSP continues to play a role in informing drug development. [ABSTRACT FROM AUTHOR]

The article discusses the importance of implementability in clinical trial planning, design, and reporting to optimize the impact of late-phase trials. It emphasizes the need for trials to be designed for implementability to improve practice, health systems, and policy. Key considerations include trial design, conduct, and reporting, as well as the involvement of end users in the process. The article also highlights the role of clinical trial networks in supporting quality consumer and community involvement and facilitating the implementation of trial outcomes. [Extracted from the article]

Objective: Multiple acyl‐coenzyme A dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation and considered an inborn error of metabolism. In recent years, we have diagnosed an increasing number of patients where, despite extensive investigation, no disease‐causing mutations have been found. We therefore investigated a cohort of consecutive patients, with the objective to detect possible non‐genetic causes. Methods: We searched the patient records and the registry of muscle biopsies, for patients with MADD, diagnosed within the past 10 years. The patient records were reviewed regarding symptoms, clinical findings, comorbidities, drugs, diagnostic investigations, and response to treatment. In addition, complementary investigations of muscle tissue were performed. Results: We identified 9 patients diagnosed with late‐onset MADD. All presented with muscle weakness and elevated levels of creatine kinase. A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood. Despite thorough genetic investigations, a probable genetic cause was found in only 2 patients. Remarkably, all 7 patients without disease‐causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved. Interpretation: Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. ANN NEUROL 2024;96:802–811 [ABSTRACT FROM AUTHOR]

Background: Classic galactosemia (CG) is an inborn error of galactose metabolism caused by mutations in the GALT gene. Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with CG due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. Methods: In this study, we performed single‐nucleus RNA sequencing (snRNA‐seq) and spatial transcriptomics on ovary tissue biopsies from prepubertal girls diagnosed with CG to investigate dynamic changes in gene expression and altered signalling pathways in granulosa cells, oocytes, and stromal cells. Results: We generated single‐nucleus and spatial transcriptomics atlas of human ovaries from prepubertal girls diagnosed with and without CG. snRNA‐seq profiling of the paediatric ovary revealed a diverse ovarian microenvironment with seven distinct major cell types. Our transcriptomic analysis revealed an increase in the expression of several endoplasmic reticulum stress and oxidative stress associated genes, which can promote apoptosis of granulosa cells in CG. PTEN/PI3K/AKT signalling, which is crucial for primordial follicle activation and survival was dysregulated as supported by upregulated PTEN transcripts and a significant reduction in phospho‐AKT levels in the granulosa cells and oocytes. We also found a marked increase in expression of phospho‐H2A.X, LC3A/B and CASP9 in the primordial follicles of CG ovaries suggesting DNA damage, autophagy, and accelerated follicular atresia. Furthermore, we noticed genes participating in extracellular matrix organisation, integrin and gap junction signalling, essential for structural support of the ovarian stroma were profoundly altered. Conclusions: Our findings provide molecular insights into the dysregulated cellular signalling pathways essential for primordial follicle growth and survival that can explain the etiology of POI in CG patients. This study has implications in the development of future therapeutic interventions to preserve ovarian function and promote female reproductive health. Highlights: Created a comprehensive single‐nucleus transcriptomic atlas and spatial landscape of paediatric ovary tissue from prepubertal girls diagnosed with classic galactosemia (CG).Our transcriptomic analysis revealed activation of genes associated with ER‐stress signalling, oxidative stress response and ATM signalling/DNA damage response as shown by significant increase in expression of p‐EIF2A, p‐H2A.X and LC3A/B in the primordial follicles of CG ovary.PTEN/PI3K/AKT signalling pathways was dysregulated evidenced by a significant reduction in phospho‐AKT expression in the primordial follicles of CG ovary, suggesting impaired follicle activation and survival. [ABSTRACT FROM AUTHOR]

Background: Inborn errors of glutathione metabolism may cause high anion gap metabolic acidosis due to pyroglutamic acid accumulation. Since 1988, cases of this acidosis have been reported in individuals without these defects. Methods: Given the poorly characterized predisposing factors, presentation, management, and prognosis of acquired pyroglutamic acidosis, we conducted a systematic review using the National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar databases. Results: A total of 131 cases were found. Most patients were females (79%), adults (92%) aged 51 years or older (66%) with pre-existing conditions (74%) such as undernutrition, alcohol-use disorder, or kidney disease, and had an ongoing infection (69%). The clinical features included diminished consciousness (60%), Kussmaul breathing (56%), and nausea or vomiting (27%). At least 92% of patients were on paracetamol therapy for >10 days at an appropriate dose, 32% on a β-lactamase-resistant penicillin, and 2.3% on vigabatrin. Besides severe anion gap acidosis, patients also presented with hypokalemia (24%) and kidney function deterioration (41%). Management involved discontinuing the offending drug (100%), bicarbonate (63%), acetylcysteine (42%), and acute kidney replacement therapy (18%). The fatality rate was 18%, which was higher without acetylcysteine (24%) compared to with it (11%). Conclusions: Acquired pyroglutamic acidosis is a rare, potentially fatal metabolic derangement, which usually occurs after paracetamol use, frequently combined with a β-lactamase-resistant penicillin or vigabatrin. This condition predominantly affects adults, especially women with factors like undernutrition, alcohol-use disorder, or kidney disease, often during infection. Increased awareness of this rare condition is necessary. [ABSTRACT FROM AUTHOR]

The article focuses on the molecular analysis of two-and-a-half-year-old twins diagnosed with odontohypophosphatasia due to a missense mutation in the alkaline phosphatase biomineralization associated (ALPL) gene. Topics discussed include the clinical presentation and diagnosis, identification of a novel heterozygous missense mutation (c.224G>A) in ALPL, and its predicted impact on tissue-nonspecific alkaline phosphatase (TNSALP) function.

Gastrointestinal (GI) sequelae, such as vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis. These complications result from disease processes (e.g., kidney disease, cystine crystal accumulation in the GI tract) and side effects of treatments (e.g., cysteamine, immunosuppressive therapy). GI involvement can negatively impact patient well-being and jeopardize disease outcomes by compromising drug absorption and patient adherence to the strict treatment regimen required to manage cystinosis. Given improved life expectancy due to advances in kidney transplantation and the transformative impact of cystine-depleting therapy, nephrologists are increasingly focused on addressing extra-renal complications and quality of life in patients with cystinosis. However, there is a lack of clinical data and guidance to inform GI-related monitoring, interventions, and referrals by nephrologists. Various publications have examined the prevalence and pathophysiology of selected GI complications in cystinosis, but none have summarized the full picture or provided guidance based on the literature and expert experience. We aim to comprehensively review GI sequelae associated with cystinosis and its treatments and to discuss approaches for monitoring and managing these complications, including the involvement of gastroenterology and other disciplines. [ABSTRACT FROM AUTHOR]

Background: Distal renal tubular acidosis (dRTA) is a condition characterized by the impaired ability to secrete hydrogen ions from the distal tubule. In pediatric patients, common clinical features of dRTA include excessive urine production (polyuria), frequent nighttime urination (nocturia), poor growth and weight gain (failure to thrive), difficulty with bowel movements (constipation), abnormal breathing, and the presence of kidney stones (nephrolithiasis). While urinary tract infections (UTIs) are frequently associated with dRTA, renal failure is uncommon and seldom reported in children. Case Presentation: A 10-year-old girl was referred for the evaluation due to a progressive loss of gross motor milestones over a period of 3 years. She also experienced an acute episode of paralysis and was found to have bilateral medullary nephrocalcinosis (right staghorn calculus) accompanied by moderate renal failure and a UTI. Her development in other areas was appropriate for her age. Importantly, there was a history suggestive of excessive urine production (polyuria), increased thirst (polydipsia), and frequent nighttime urination (nocturia). Physical examination revealed proximal myopathy, characterized by a waddling gait and a positive Gower's sign, as well as diminished reflexes and muscle tone in the lower limbs. Laboratory tests indicated the presence of sepsis (total leukocyte count – 26,660, CRP-174.29) and elevated renal parameters (serum creatinine – 4.27) along with active urinary abnormalities. Urine culture and sensitivity testing showed significant growth of Escherichia coli (>100,000 CFU). A computed tomography scan of the kidneys, ureters, and bladder revealed a staghorn calculus on the right side, as well as bilateral medullary nephrocalcinosis and swollen kidneys. The patient was diagnosed with dRTA based on several factors, including hypokalemic hyperchloremic metabolic acidosis with a normal anion gap, high urine pH, borderline hypercalciuria, presence of medullary nephrocalcinosis, and after ruling out other potential differential diagnoses. Following treatment for the UTI and sepsis, as well as standard treatment for dRTA, the child exhibited symptomatic improvement. Her creatinine levels returned to 0.8 mg/dL, and the septic markers declined to normal levels. To further investigate the cause of the initial decline in renal function in addition to the UTI, a renal biopsy was performed. Conclusion: This case report emphasizes the significance of including medullary nephrocalcinosis and renal tubular acidosis in the list of potential diagnoses for patients presenting with progressive gross motor developmental regression, acute flaccid paralysis, and proximal myopathy. Timely identification of these conditions can help avoid unnecessary and expensive investigations, while also facilitating prompt clinical recovery in affected children. Early diagnosis plays a crucial role in guiding appropriate management strategies and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases are some of the most prevalent chronic diseases that generate not only high social but also economic costs. It is becoming increasingly crucial to take into account inborn errors of immunity (IEIs, formerly known as primary immunodeficiencies (PIDs)) and secondary immunodeficiencies (SIDs) in the diagnostic and therapeutic management of cardiac patients. The number of diseases classified as IEIs is on the rise, with a current total of 485. It is essential to pay attention not only to already confirmed conditions but also to symptoms suggestive of immunodeficiencies. Objectives: The aim of this article is to present IEIs with cardiovascular symptoms that may cause or exacerbate cardiovascular disease, as well as diagnostic and therapeutic procedures. Results: It is becoming increasingly evident that immunodeficiencies can be responsible for certain cardiovascular conditions, their hastened progression, and difficulties in their control. Conclusions: Early detection of deficiencies improves not only the quality and longevity of patients, but also allows for better control of cardiovascular diseases and even prevention of their occurrence. [ABSTRACT FROM AUTHOR]

Background: Children and adolescents with Pompe disease (PD) face chronic and progressive myopathy requiring time-intensive enzyme replacement therapy (ERT). Little is known about their perspectives on the disease and its treatment. This study explored their perceptions of disease symptoms and functioning status, and more subjective feelings about the impacts on their lives as part of developing a disease-specific questionnaire. Methods: Eleven pediatric patients aged 8–18 years and 26 caregivers from six children's hospitals in Germany, Austria, and Switzerland underwent semi-structured interviews. Data were recorded, transcribed using MAXQDA software, and analyzed using qualitative content analysis. A system of meaningful categories was developed. Results: Sixteen main categories were derived across four major thematic areas: perceptions of symptoms and limitations, experiences to do with the biopsychosocial impact of PD, treatment experiences, and general emotional well-being/burden. Participants demonstrated broad heterogeneity in symptom perceptions such as muscle weakness, breathing difficulties, pain, and fatigue. Emotional appraisals of limitations were not directly proportional to their severity, and even comparatively minor impairments were often experienced as highly frustrating, particularly for social reasons. The main psychosocial topics were social exclusion vs. inclusion and experiences to do with having a disease. The main finding regarding treatment was that switching ERT from hospital to home was widely viewed as a huge relief, reducing the impact on daily life and the burden of infusions. Emotional well-being ranged from not burdened to very happy in most children and adolescents, including the most severely affected. Conclusion: This study provided qualitative insights into the perceptions and experiences of pediatric PD patients. Interestingly, biopsychosocial burden was not directly related to disease severity, and tailored psychosocial support could improve health-related quality of life. The present findings ensure the content validity of a novel questionnaire to be tested as a screening tool to identify patients in need of such support. [ABSTRACT FROM AUTHOR]

Background: Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects. Results: Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes. Conclusion: Our results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving. [ABSTRACT FROM AUTHOR]

Background: Methemoglobinemia requires early identification and treatment, but limited knowledge exists regarding the current therapeutic approach taken by clinicians as well as the outcomes that occur in children. Objectives: To determine the current prevalence of this rare disease in the pediatric population, evaluate the impact of methemoglobin and functional hemoglobin levels, and assess how this disease is approached by clinicians. We hypothesize that methemoglobinemia prevalence is low and more methylene blue use would be observed in subjects with functional hemoglobin levels less than 7 g/dL. Design: This was a retrospective observational cohort study utilizing deidentified TriNetX® electronic health record (EHR) data. Methods: Using a multicenter EHR database, we evaluated subjective characteristics, diagnostic, laboratory results, medication, and procedural codes. Results: Ninety-eight children (mean age 5.3 ± 5.3 years) from 53 healthcare organizations were included. Methemoglobinemia prevalence was 0.0015% with an overall 30-day mortality of 6.1%. Subjects with methemoglobin percentages greater than 20% had a higher frequency of methylene blue administration (70.6% versus 24.7%, P =.0005). Critical care service requirements and methylene blue administration were similar in the subjects with functional hemoglobin less than 7 g/dL and more than 7 g/dL groups. Overall, 13 (13.2%) subjects underwent glucose-6-phosphate dehydrogenase deficiency (G6PD) testing. Conclusion: In our study, we found methemoglobinemia prevalence in children is low, there is a low frequency of G6PD testing despite methylene blue hemolysis risk, and subjects appeared to be treated similarly despite a low functional hemoglobin. These findings highlight the continued critical nature of this disease and may highlight opportunities for education aimed at improving care in children diagnosed with methemoglobinemia, particularly related to G6PD testing. [ABSTRACT FROM AUTHOR]

Background: Neonatal hemochromatosis (NH) is a rare condition that is characterized by severe neonatal liver disease in association with hepatic and extrahepatic excess iron deposition (siderosis), while sparing the reticuloendothelial system. The most common cause of fetal liver injury leading to the NH phenotype (accounting for over 95% of cases) is gestational alloimmune liver disease. This condition is caused by the transfer of maternal IgG antibodies through the placenta, targeting a fetal hepatocyte antigen. Prenatal diagnosis, particularly the identification of iron overload involving both liver and thyroid, is of significant importance and can have a profound impact on patient care. To our knowledge, no case has been reported on prenatal diagnosis of iron overload involving both liver and thyroid. Case presentation: We present an exceptionally rare case of fetal hemochromatosis in a primigravida, a case that significantly contributes to our understanding of this condition. The diagnosis was made with the presence of hepatic and extrahepatic siderosis involving the thyroid using Ultrasonography (USG) and fetal Magnetic Resonance Imaging (MRI) findings. A 23-year-old primigravida was referred to our center in view of oligohydramnios, Intrauterine Growth Restriction (IUGR) and echogenic bowel at 29 weeks of gestation. USG and fetal MRI showed features of coarse liver echotexture and iron overload involving the liver and thyroid; this is the first case describing iron accumulation in the fetal thyroid gland diagnosed in utero. Conclusion: This case underscores the critical importance of performing MRI in suspected cases of fetal hemochromatosis for early diagnosis and intervention, emphasizing the potential to significantly improve patient outcomes. [ABSTRACT FROM AUTHOR]

Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular de novo biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The COASY gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in COASY have been identified in fetuses/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which Coasy was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the in vivo phenotype, ranging from very short survival (less than 2weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects. Ex vivo histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably, Coasy ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms. [ABSTRACT FROM AUTHOR]

Background: Assessing dietary phenylalanine (Phe) tolerance is crucial for managing hyperphenylalaninemia (HPA) in children. However, traditionally, adjusting the diet requires significant time from clinicians and parents. This study aims to investigate the development of a machine-learning model that predicts a range of dietary Phe intake tolerance for children with HPA over 10 years following diagnosis. Methods: In this multicenter retrospective observational study, we collected the genotypes of phenylalanine hydroxylase (PAH), metabolic profiles at screening and diagnosis, and blood Phe concentrations corresponding to dietary Phe intake from over 10 years of follow-up data for 204 children with HPA. To incorporate genetic information, allelic phenotype value (APV) was input for 2965 missense variants in the PAH gene using a predicted APV (pAPV) model. This model was trained on known pheno-genotype relationships from the BioPKU database, utilizing 31 features. Subsequently, a multiclass classification model was constructed and trained on a dataset featuring metabolic data, genetic data, and follow-up data from 3177 events. The final model was fine-tuned using tenfold validation and validated against three independent datasets. Results: The pAPV model achieved a good predictive performance with root mean squared error (RMSE) of 1.53 and 2.38 on the training and test datasets, respectively. The variants that cause amino acid changes in the region of 200–300 of PAH tend to exhibit lower pAPV. The final model achieved a sensitivity range of 0.77 to 0.91 and a specificity range of 0.8 to 1 across all validation datasets. Additional assessment metrics including positive predictive value (0.68–1), negative predictive values (0.8–0.98), F1 score (0.71–0.92), and balanced accuracy (0.8–0.92) demonstrated the robust performance of our model. Conclusions: Our model integrates metabolic and genetic information to accurately predict age-specific Phe tolerance, aiding in the precision management of patients with HPA. This study provides a potential framework that could be applied to other inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Alkaptonuria is characterized by the accumulation of homogentisic acid which causes dark coloration of urine upon standing, ochronosis, and arthritis. A 4-year old child was referred to our pediatric nephrologist with hyperoxaluria and a history of unexplained pink-to-brown discolouration of his diapers associated with a brown-staining of clothes and skin since he was six months old. He had no other symptoms and his past medical history only included minor child illnesses. His 11-month-old brother had the same dark discoloration of his diapers. Laboratory testing on a spot urine sample showed hyperoxaluria and nephrotic range proteinuria with low creatinine and normal albumin concentrations. Considered causes were hyperoxaluria, alkaptonuria, interfering substance, adulteration. The further diagnostic work-up revealed increased homogentisic acid in urine, compatible with alkaptonuria. Urinary creatinine and total protein measurements on Roche Cobas were, respectively, falsely decreased and increased in the presence of homogentisic acid. The false-low creatinine resulted in an elevated oxalate/creatinine ratio. Alkaptonuria can cause a false increase of results expressed per creatinine and should be excluded in case of an unexplained marked increase of urine total protein without a concomitant increase of albumin. [ABSTRACT FROM AUTHOR]

Acute presentation of severe motor disorders is a diagnostic and management challenge. We define severe acute motor exacerbations (SAME) as acute/subacute motor symptoms that persist for hours‐to‐days with a severity that compromise vital signs (temperature, breath, and heart rate) and bulbar function (swallowing/dysphagia). Phenomenology includes dystonia, choreoathetosis, combined movement disorders, weakness, and hemiplegic attacks. SAME can develop in diverse diseases and can be preceded by triggers or catabolic states. Recent descriptions of SAME in complex neurodevelopmental and epileptic encephalopathies have broadened appreciation of this presentation beyond inborn errors of metabolism. A high degree of clinical suspicion is required to identify appropriately targeted investigations and management. We conducted a comprehensive literature analysis of etiologies. Reported triggers are described and classified as per pathophysiological mechanism. A video of six cases displaying multiple SAME with diverse outcomes is provided. We identified 50 different conditions that manifest SAME, some associated with developmental regression. Etiologies include disorders of metabolism: energy substrate, amino acids, complex molecules, vitamins/cofactors, minerals, and neurotransmitters/synaptic vesicle cycling. Non‐metabolic neurodegenerative and genetic disorders that present with movement disorders and epilepsy can additionally manifest SAME. A limited number of triggers are grouped here, together with an approach to investigations and general management strategies. Several neurogenetic and neurometabolic disorders manifest SAME. Identifying triggers can help in certain cases narrow the differential diagnosis and guide the expeditious application of targeted therapies to minimize adverse developmental and neurological consequences. This process may inform pathogenesis and eventually improve our understanding of the mechanisms that lead to the development of SAME. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. Methods: We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019–April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. Results: In those treated 2020–2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25–86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. Discussion: Other Irish studies estimated prevalence at 11–12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. Conclusions: Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients. [ABSTRACT FROM AUTHOR]

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid and amino acid oxidation with an incidence of 1 in 200,000 live births. MADD has three clinical phenotypes: severe neonatal-onset with or without congenital anomalies, and a milder late-onset form. Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs. MADD is an autosomal recessive trait caused by biallelic mutations in the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes. Despite significant advancements in sequencing techniques, many patients remain undiagnosed, impacting their access to clinical care and genetic counseling. In this report, we achieved a definitive molecular diagnosis in a newborn by combining whole-genome sequencing (WGS) with RNA sequencing (RNA-seq). Whole-exome sequencing and next-generation gene panels fail to detect variants, possibly affecting splicing, in deep intronic regions. Here, we report a unique deep intronic mutation in intron 1 of the ETFDH gene, c.35-959A>G, in a patient with early-onset lethal MADD, resulting in pseudo-exon inclusion. The identified variant is the third mutation reported in this region, highlighting ETFDH intron 1 vulnerability. It cannot be excluded that these intronic sequence features may be more common in other genes than is currently believed. This study highlights the importance of incorporating RNA analysis into genome-wide testing to reveal the functional consequences of intronic mutations. [ABSTRACT FROM AUTHOR]

Early diagnosis of inborn errors of metabolism (IEM) is crucial to ensure early detection of conditions which are treatable. This study reports on targeted metabolomic procedures for the diagnosis of IEM of amino acids, acylcarnitines, creatine/guanidinoacetate, purines/pyrimidines and oligosaccharides, and describes its validation through external quality assessment schemes (EQA). Analysis was performed on a Waters ACQUITY UPLC H-class system coupled to a Waters Xevo triple-quadrupole (TQD) mass spectrometer, operating in both positive and negative electrospray ionization mode. Chromatographic separation was performed on a CORTECS C18 column (2.1 × 150, 1.6 µm). Data were collected by multiple reaction monitoring. The internal and EQA results were generally adequate, with a few exceptions. We calculated the relative measurement error (RME) and only a few metabolites displayed a RME higher than 30 % (asparagine and some acylcarnitine species). For oligosaccharides, semi-quantitative analysis of an educational panel clearly identified the 8 different diseases included. Overall, we have validated our analytical system through an external quality control assessment. This validation will contribute to harmonization between laboratories, thus improving identification and management of patients with IEM. [ABSTRACT FROM AUTHOR]

Background and Objective: Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that can be associated with primary immunodeficiency. The pathogenesis of PG has not yet been elucidated, although contributions from dysregulation of the immune system in patients with apparent genetic predispositions have been postulated. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review with the objective of identifying inborn errors of immunity in the presence of PG as well as their clinical characteristics of severity including number of PG lesions and anatomic areas affected, and treatment outcomes. Methods: A literature search was performed using PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science through August 24, 2023, for studies published in English using the search terms: "pyoderma gangrenosum," "inborn error of immunity," "immune defect*," and a list of genetic mutations potentially associated with PG. Results: Seventy-four cases of PG associated with inborn errors of immunity were identified. The results demonstrate an association of PG with a variety of inborn errors of immunity, including genetic mutations not classically associated with the condition. Genetic mutations such as BTK, IL1RN, ITGB2, LPIN2, MEFV, NFkB1, NLRP3, NLRP12, NOD2, PSMB8, PLCG2, PSTPIP1, RAG1, TTC37, and WDR1, as well as complement component 2/complement component 4 (C2/C4) and complement component 7 (C7) deficiencies were identified in the presence of either idiopathic or syndromic PG. Of note, mutations in genes such as PSMB8, NLRP3, and IL1RN were found to be associated with a more severe and atypical course of PG, whereas mutations in RAG1 as well as those causing a C2/C4 deficiency were associated with the mildest clinical presentations of PG. Mutations in NFkB1, ITGB2, and PSTPIP1 were associated with the most heterogeneous clinical presentations. Conclusions: Human inborn errors of immunity may be implicated in the genetic predisposition to PG and may influence the clinical presentation. Due to the rarity of these diseases, further work must be done to describe the association between inborn errors of immunity and PG. Identifying inborn errors of immunity that may contribute to the development of PG may assist in further elucidating the mechanism of PG, guiding targeted treatment, and improving clinical outcomes for these patients. [ABSTRACT FROM AUTHOR]

Introduction: Maple syrup urine disease (MSUD) is caused by the deficiency of branched‐chain keto acid dehydrogenase (BCKAD) and, it is well described that BCKAD contributed by an allograft following liver transplantation (LT) phenotypically normalizes this inborn error of metabolism (IEM). There is, however, a paucity of data especially with regards to the neurodevelopmental aspects and catch‐up growth profiles after LT in a resource‐challenged setting. We present our series of children under 6 years of age who underwent LT for MSUD particularly focusing on their amino acid homeostasis, neurodevelopmental and somatic growth profiles. Methods: Of 580 consecutive pediatric LT (PLT) performed between January 2011 and December 2022, all children who underwent LT for MSUD were included for analysis. Data accrued included peri‐LT details, pre‐ and post‐LT metabolic profile, neurodevelopmental assessment, somatic growth evaluation, and long‐term outcomes. Results: Six children underwent LT for MSUD with a median age and weight at LT of 20.5 (IQR: 8–60) months and 10.1 (IQR: 6.7–15.8) kg, respectively. One explanted liver was used as a domino graft for Arginase deficiency. Median follow‐up period was 52.5 (IQR: 27–94) months. None had vascular or biliary complications. Following LT, all children were started on an unrestricted protein diet and had normalization of BCAA levels. Post‐LT height and weight improved by 1 SD but did not achieve the normal profile. None of the children had neuro‐deterioration and have achieved new milestones. Conclusion: This is the first‐report presenting the growth aspects, amino acid and neurodevelopmental profiles of children who underwent LT for MSUD within the socio‐economic‐cultural idiosyncrasies and constraints prevalent in our part of the world. [ABSTRACT FROM AUTHOR]

Background/Objectives: Patients with life-limiting conditions (LLCs) often suffer from restlessness, spasticity, pain, and seizures. Dronabinol (DRB) may have a relieving effect; however, data on the effectiveness of DRB in children with LLCs are limited to outpatients. The aim of this study was to assess the efficacy and safety of DRB. Methods: Retrospective analysis of inpatients. Results: From 2011 to 2021, 1219 patients were admitted. Of these, 63 patients (63.5% male, age: 10.4 (SD = 6.3) years) were treated with DRB; 96.8% had a neurological disease, and 26 patients were started on DRB (group A), while 37 were admitted with existing DRB (group B). The effective doses were 0.21 (SD = 0.11) in group A and 0.48 (SD = 0.5) mg/kg/BW/day in group B (p = 0.01). Subjective response rates to DRB in both groups (good/moderate effect) were 9.5%/38.1% for spasticity and 1.6%/25.4% for restlessness. However, no reduction in seizures, restlessness, or demand medication was observed in 24 h protocols when patients started DRB in group A. Three patients experienced severe side effects (e.g., respiratory depression). Other side effects included fatigue (22.2%) and behavioral problems (14.3%). Conclusions: Subjective positive effects could not be confirmed by more objective data. Side effects can be severe. Thus, DRB should be started in a well-monitored setting and only with clear indications. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for up to 30% of antenatal congenital anomalies and is the main cause of kidney failure in children worldwide. This review focuses on practical approaches to CAKUT, particularly those with insufficient or abnormal nephron development, such as renal dysplasia, renal hypoplasia, and renal tubular dysgenesis. The review provides insights into the histological features, pathogenesis, mechanisms, etiologies, antenatal and postnatal presentation, management, and prognosis of these anomalies. Differential diagnoses are discussed as several syndromes may include CAKUT as a phenotypic component and renal dysplasia may occur in some ciliopathies, tumor predisposition syndromes, and inborn errors of metabolism. Diagnosis and genetic counseling for CAKUT are challenging, due to the extensive variability in presentation, genetic and phenotypic heterogeneity, and difficulties to assess postnatal lung and renal function on prenatal imaging. The review highlights the importance of perinatal autopsy and pathological findings in surgical specimens to establish the diagnosis and prognosis of CAKUT. The indications and the type of genetic testing are discussed. The aim is to provide essential insights into the practical approaches, diagnostic processes, and genetic considerations offering valuable guidance for pediatric and perinatal pathologists. [ABSTRACT FROM AUTHOR]

Abstract Patients with phenylketonuria (PKU) have a highly restrictive diet, which involves restriction of phenylalanine (Phe) intake and daily use of Phe‐free metabolic formula. However, little is known about the potential impact of this diet on chemical senses. The present study aimed to evaluate the olfactory and gustatory perceptions of patients with PKU. A cross‐sectional controlled study which included patients with PKU on dietary treatment and healthy controls was performed. Olfactory perception was assessed using the 12‐item Sniffin’ Sticks test, and taste perception using the Taste Strips test. Twenty‐five patients (mean age 19.3 ± 4.7 years; 13 females) and 25 controls (mean age 19.9 ± 4.9 years, p = 0.676; 13 females) were included. The mean age at treatment onset was 52.8 ± 29.7 days. The mean scores for olfactory and gustatory perceptions, and for bitter and salty flavors, were lower in patients than in controls (p = 0.039, p = 0.004, p = 0.008, and p = 0.020, respectively). Among patients, Phe levels at diagnosis correlated negatively with bitter taste (r = −0.493, p = 0.006). The lower olfaction and gustation scores found in patients may be related to understimulation caused by the highly restrictive PKU diet and the deprivation of flavors from breast milk.

Abstract Background Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by variants in any of the following genes: BCKDHA, BCKDHB, and DBT gene. Previous reports have highlighted a variety of common causing genes and variants among different ethnic groups affected by MSUD. This study is the first to describe the molecular characteristics, potential common variants, clinical phenotypes, and treatment outcomes of 20 Thai MSUD patients before the implementation of expanded newborn screening in Thailand. Results A cross-sectional, multicenter study was conducted, including twenty Thai MSUD patients from 1997 to 2023. Most of the patients presented with classic neonatal onset (95%). The mortality rate was 20%, while global developmental delay was observed in 40% of the patients. Variants in the BCKDHB gene were detected in 85% (17/20) of the patients, while the BCKDHA gene accounted for 15% (3/20). The study identified the 11-kb deletion involving 5’UTR, exon 1, and intron 1 in the BCKDHB gene, from a position of g.80102385 to g.80113453 (NC_000006.12), accounting for 50% of all variants (20/40 alleles) in Thai MSUD patients. All patients with the 11-kb deletion in BCKDHB presented with the classic type. The gap-PCR for this common deletion was established in the study. Conclusion This study is the first to describe the clinical and molecular spectrum of Thai MSUD patients before the implementation of expanded NBS. The 11-kb deletion involving exon 1 in the BCKDHB emerges as the most common variant among Thai individuals with MSUD. Furthermore, the gap-PCR test for detecting the 11-kb exon 1 deletion status holds the potential for integration into stepwise molecular analysis following positive expanded newborn screening.

Abstract Background Newborn screening programmes offer an opportunity to obtain dried blood spots (DBS) cards that contain a wealth of biological information that can be stored for long periods and have potential benefits for research and quality assurance. However, the storage and secondary uses of DBS cards pose numerous ethical, clinical, and social challenges. Empirical research exploring public attitudes is central to public policy planning as it can indicate whether or not there is broad public support, define public concerns, and ascertain the circumstances required to alleviate concerns and ensure support. This study aims to describe the clinical experience and attitudes towards newborn screening and investigate the perceptions and expectations of Hong Kong parents and healthcare providers regarding the retention of DBS cards and their usage for research. Methods We conducted semi-structured in-person interviews with 20 parents and healthcare providers in Hong Kong. Thematic analysis was conducted. Results Awareness of the significant research value of secondary uses of dried blood spot cards is low. Parents and healthcare providers support the storage and secondary uses of DBS cards with some concerns, including privacy and confidentiality breaches, the risk of discrimination or stigmatisation based on genetic information, and their inability to oversee the use of their child’s biospecimen. Parents, however, prioritise their child’s health over privacy concerns and support identifiable storage using pseudonymity to gain more information about their children's health. Conclusion Child information takes precedence over potential concerns over privacy, underscoring the significance of engaging patients and the public in shaping public policy related to biobanking and healthcare research, in line with cultural and social values.

AbstractBackground: Inborn errors of metabolism (IEM) are rare genetic disorders that usually cause the disease by blocking a metabolic pathway. Delayed diagnosis is usually due to nonspecific manifestations. In this study, we aim to evaluate the demographic and clinical characteristics of pediatric patients with IEM admitted in Nemazi hospital, a referral center in southern Iran.Methods: All 1-month- to 18-year-old patients who were admitted in the pediatric ward in Nemazi hospital, a referral center in southern Iran, with the diagnosis of IEM were enrolled. Patients with incomplete information were excluded. We collect demographic and clinical data including age, sex, parents’ consanguinity, family history of IEM, presenting symptoms, number of hospitalization, age of onset, and diagnosis of the disease. All the data were entered into SPSS ver.22 and analyzed.Results: 200 patients were enrolled in the study. 53.5% were male and 46.5% female. The most clinical symptoms were lethargy and vomiting. The most prevalent IEM were aminoacidopathies, organic acidemia, and mitochondrial disease. Consanguinity was seen in 57.5% of them, while the family history of metabolic diseases was observed in 16.5%. There was a statistically significant relationship between consanguinity and the type of the disease.Conclusion: The clinical symptoms of IEM are nonspecific and may be misdiagnosed as other diseases like septicemia. We should always keep IEM in mind to detect the disease earlier and prevent significant morbidities and mortality by appropriate timely treatment. Due to the prevalence of consanguinity marriage in Iran, we should also consider metabolic screening.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype–phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants. [ABSTRACT FROM AUTHOR]

Background: Neonatal seizures are diagnostically challenging and predominantly electrographic-only. Multichannel video continuous electroencephalography (cEEG) is the gold standard investigation, however, out-of-hours access to neurophysiology support can be limited. Automated seizure detection algorithms (SDAs) are designed to detect changes in EEG data, translated into user-friendly seizure probability trends. The aim of this study was to evaluate the diagnostic accuracy of the Persyst neonatal SDA in an intensive care setting. Methods: Single-centre retrospective service evaluation study in neonates undergoing cEEG during intensive care admission to Great Ormond Street Hospital (GOSH) between May 2019 and December 2022. Neonates with <44 weeks corrected gestational age, who had a cEEG recording duration >60 minutes, whilst inpatient in intensive care, were included in the study. One-hour cEEG clips were created for all cases (seizures detected) and controls (seizure-free) and analysed by the Persyst neonatal SDA. Expert neurophysiology reports of the cEEG recordings were used as the gold standard for diagnostic comparison. A receiver operating characteristic (ROC) curve was created using the highest seizure probability in each recording. Optimal seizure probability thresholds for sensitivity and specificity were identified. Results: Eligibility screening produced 49 cases, and 49 seizure-free controls. Seizure prevalence within those patients eligible for the study, was approximately 19% with 35% mortality. The most common case seizure aetiology was hypoxic ischaemic injury (35%) followed by inborn errors of metabolism (18%). The ROC area under the curve was 0.94 with optimal probability thresholds 0.4 and 0.6. Applying a threshold of 0.6, produced 80% sensitivity and 98% specificity. Conclusions: The Persyst neonatal SDA demonstrates high diagnostic accuracy in identifying neonatal seizures; comparable to the accuracy of the standard Persyst SDA in adult populations, other neonatal SDAs, and amplitude integrated EEG (aEEG). Overdiagnosis of seizures is a risk, particularly from cEEG recording artefact. To fully examine its clinical utility, further investigation of the Persyst neonatal SDA's accuracy is required, as well as confirming the optimal seizure probability thresholds in a larger patient cohort. [ABSTRACT FROM AUTHOR]

Abstract Background To investigate the impact of children’s inborn error of metabolism (IEMs) on the children’s and their parents’ lives from the parents’ perspective. We focused on disease-related restrictions in various issues of daily life, experienced discrimination, parental family planning, and management of metabolic emergencies. Methods We conducted a questionnaire-based survey with 108 parents of 119 children with IEM who attended a metabolic outpatient clinic. The children were categorized into 4 cohorts, based on increasing disease severity (cohort 1: IEMs with lowest severity, cohort 4: IEMs with highest severity), and compared by using Tobit regressions. Results The severity of the child’s IEM was associated with an increase in the intensity of perceived restrictions from the parents’ perspective for themselves and their children in all aspects of life: in general, in contact with friends, in the pursuit of hobbies, in childcare/school/occupation, and due to emotional stress. The highest intensity of restrictions in all cohorts was found for the parents themselves in contact with friends (compared to cohort 1: cohort 2: c. 3.556, p = 0.002; cohort 3: c. 4.159, p = 0.003; cohort 4: c. 7.224, p

Inborn errors of metabolism (IEM) are a rare and complex group of inherited disorders, typically observed in infants as autosomal recessive or, less commonly, as X-linked recessive conditions. Newborn screening (NBS) for IEMs can significantly improve prognosis and quality of life through early diagnosis and intervention, marking a significant public health achievement. NBS programs vary by country, but generally include tests for a range of metabolic errors, endocrine disorders, primary immunodeficiency disorders, congenital deafness, congenital heart defects, and cystic fibrosis. Integrating mass spectrometry (MS/MS), genetic sequencing, and emerging technologies such as next-generation sequencing into NBS programs represents a substantial advancement in the field of healthcare. These technologies enable early detection, intervention, and the possibility of personalized treatments through gene therapies. Such advancements are poised to shape the future of NBS, potentially enhancing healthcare outcomes for newborns on a global scale. Neonatal screening is the most well-known and widely implemented proactive and preventative pediatric public health initiative worldwide. It encompasses a comprehensive education system, screening, diagnostic confirmation, management, follow-up, and counseling. This article reviews recent advances in newborn metabolic screening, drawing on the results of various clinical trials and pilot studies.

Abstract Background The etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare. Case Presentation We describe a 7-month-old male patient presenting with fatigue and edema. His initial laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria. Further examinations reveals hemolysis in peripheral blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported a diagnosis of nephrotic syndrome. The patient’s condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement. Discussion/Conclusion This case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again.

Abstract Objectives Although recent discoveries regarding the biomarkers of newborn screening (NBS) programs by tandem mass spectrometry (MS/MS) highlight the critical need to establish reference intervals (RIs) specifically for preterm infants, no such RIs has been formally published yet. This study addressed the gap by offering a comprehensive set of reference intervals (RIs) for preterm neonates, and illustrating the dynamic changes of each biomarker with age. Design and methods The NBS data of 199,693 preterm newborns (

Background: To investigate the impact of children's inborn error of metabolism (IEMs) on the children's and their parents' lives from the parents' perspective. We focused on disease-related restrictions in various issues of daily life, experienced discrimination, parental family planning, and management of metabolic emergencies. Methods: We conducted a questionnaire-based survey with 108 parents of 119 children with IEM who attended a metabolic outpatient clinic. The children were categorized into 4 cohorts, based on increasing disease severity (cohort 1: IEMs with lowest severity, cohort 4: IEMs with highest severity), and compared by using Tobit regressions. Results: The severity of the child's IEM was associated with an increase in the intensity of perceived restrictions from the parents' perspective for themselves and their children in all aspects of life: in general, in contact with friends, in the pursuit of hobbies, in childcare/school/occupation, and due to emotional stress. The highest intensity of restrictions in all cohorts was found for the parents themselves in contact with friends (compared to cohort 1: cohort 2: c. 3.556, p = 0.002; cohort 3: c. 4.159, p = 0.003; cohort 4: c. 7.224, p < 0.001). Parents of 8% of children reported that their children were discriminated against because of IEM, with the highest proportion of affected children (43%) in cohort 4. Parental family planning decisions were influenced in 34% of parents, with fear of recurrence being a predominant aspect. Of the parents of children diagnosed with IEMs associated with metabolic emergencies, 68% stated that they felt well or very well prepared for the occurrence of a metabolic emergency, and 100% of parents were able to name the necessary action steps from memory. Nevertheless, 58% stated that they experienced an occurring emergency as rather or very stressful. Conclusions: From the parents' perspective, the intensity of restrictions increased with the severity of the child's IEM. The study shows the high impact of IEM on parents of children with IEM and the daily challenges they face. These findings emphasize the importance of comprehensive support for parents of children with IEM. [ABSTRACT FROM AUTHOR]

Epilepsy can be caused by a variety of causes, such as inborn errors of metabolism, organic acid disorders are the most significant type of metabolic disorders that cause seizures. The clinical manifestations of these diseases are generally nonspecific, and the types of seizures are different. Screening for multisystem clinical symptoms and identifying the underlying etiology are crucial for early treatment of epileptic seizures. This article provides a comprehensive summary of the pathogenesis, clinical features, diagnosis and treatment of epilepsy associated with organic acid metabolism disorders. Furthermore, relevant literature has also been reviewed to assist clinicians in the diagnosis of cases characterized by the coexistence of multisystemic symptoms and epileptic manifestations. [ABSTRACT FROM AUTHOR]

Background: Generally, it is not well known that Lowe's syndrome may coexist with hyperammonemia and hipocarnitynemia. The importance of hyperammonemia in the diagnosis of kidney diseases is not completely understood. Case presentation: We present the history of a 13-year-old boy, admitted to the hospital due to proteinuria. In the past, the boy was diagnosed with binocular cataracts in infancy. Then he went through neurological diagnostic tests which diagnosed muscular hypotonia and psychomotor retardation but no inherited errors of metabolism were found. Proteinuria has been observed since the age of 2. Ultrasound imaging at the age of 5 showed the presence of a shading deposit in the kidney. At the age of 13, the boy was referred to the Pediatric Nephrology Ward. The laboratory tests revealed: a reduction of glomerular filtration rate, metabolic acidosis, proteinuria, hypercalciuria, increased activity of AST (SGOT), CK, LDH, hyperammonemia, and decreased concentration of total carnitine in blood serum. Based on the clinical presentation, Lowe's syndrome was diagnosed. The genetic testing revealed an OCRL gene hemizygous mutation. Conclusion: Lowe's syndrome is an example of a disease in which clinical symptoms—although occurring early and in high intensity—may not raise the suspicion of tubulopathy for a long time if they are not analyzed in a complex manner. There is a necessity to educate healthcare practitioners from other fields about the extrarenal symptoms of genetically determined tubulopathies. l-carnitine deficiency may be a symptom of proximal tubulopathy, including Lowe's syndrome. l-carnitine deficiency leads to disturbances in the efficiency of the urea cycle, which results in hyperammonemia. Hyperammonemia is not only a symptom of inborn errors of metabolism and liver failure, but it may also lead to the diagnosis of tubulopathy. Since carnitine supplementation could have the desired beneficial effect on the patient's general condition, it is postulated to conduct further studies on larger groups of patients with Lowe's syndrome. [ABSTRACT FROM AUTHOR]

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3–4% and 0.5–1% (5/1–10/1 ratio), with medium-chain triglyceride supplementation at 10–25% of total energy (total MCT+LCT ratio = 20–35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation. [ABSTRACT FROM AUTHOR]

Background: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. Results: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. Conclusion: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases. [ABSTRACT FROM AUTHOR]