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OBJECTIVE: In individuals with urea cycle disorders (UCDs) and neonatal disease onset, extracorporeal detoxification by continuous kidney replacement therapy is considered the therapeutic method of choice in addition to metabolic emergency treatment to resolve hyperammonemic decompensation. However, the indications for the initiation of dialysis are heterogeneously implemented transnationally, thereby hampering our understanding of (optimal) short-term health outcomes. METHODS: We performed a retrospective comparative analysis evaluating the therapeutic effects of initial dialysis on survival as well as neurocognitive outcome parameters in individuals with UCDs in comparison to a severity-adjusted non-dialyzed control cohort. Overall, 108 individuals with a severe phenotype of male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) were investigated by stratification based on a recently established and validated genotype-specific disease prediction model. RESULTS: Mortality is associated with the height of initial peak plasma ammonium concentration, but appears to be independent from treatment with initial dialysis in mOTC-D. However, improved survival after initial dialysis was observed in CTLN1, while there was a trend towards improved survival in ASA. In survivors, annual frequency of (subsequent) metabolic decompensations did not differ between the dialyzed and non-dialyzed cohorts. Moreover, treatment with initial dialysis was not associated with improved neurocognitive outcomes. INTERPRETATION: The present severity-adjusted comparative analysis reveals that general practice of initial dialysis is neither associated with improved survival in individuals with mOTC-D nor does it differ with regard to the neurocognitive outcome for the investigated UCD subtypes. However, initial dialysis might potentially prove beneficial for survival in CTLN1 and ASA. CLINICAL TRIAL REGISTRATION: The UCDC database is recorded at the US National Library of Medicine (https://clinicaltrials.gov).

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Diagnosing Congenital Disorders of Glycosylation (CDG) is challenging due to clinical heterogeneity and the limited sensitivity of the classic serum transferrin isoelectric focusing (IEF) or capillary zone electrophoresis test. This study investigates the potential of using the glycoprotein carnosinase 1 (CN1) activity as a diagnostic marker for CDG patients. CN1 activity was measured photometrically in serum from 81 genetically confirmed CDG patients and healthy individuals. While the IEF transferrin method detected 77 patients, four remained undetected. In healthy individuals, serum CN1 activity ranged from 0.1 to 6.4 µmol/ml/h depending on age, with mean CN1 activities up to four-fold higher than in CDG patients. CDG patients´ CN1 activities never exceeded 2,04 µmol/ml/h. Using the 25th percentile to differentiate between groups, the test performance varied by age. For children over 10 years old, the sensitivity and specificity were 96 % and 83 %, respectively. For those under 10, sensitivity and specificity dropped to 71 % and to 64 %. However, CN1 activity successfully identified three of four patients with normal IEF patterns. Although mean CN1 activity in CDG patients is significantly lower than in healthy controls, the test's reliability for classic CDG diagnosis is limited, as the diagnosis is usually made at a young age. Nevertheless, it is a simple, cost-effective assay that can complement classic tests, especially in settings with limited access to complex methods or for patients with normal transferrin patterns but suspicious for CDG.

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BACKGROUND: Assessment of myelination is a core issue in paediatric neuroimaging and can be challenging, particularly in settings without dedicated paediatric neuroradiologists. Deep learning models have recently been shown to be able to estimate myelination age in children with normal MRI, but currently lack validation for patients with myelination delay and implementation including pre-processing suitable for local imaging is not trivial. Standardized myelination scores, which have been successfully used as biomarkers for myelination in hypomyelinating diseases, rely on visual, semiquantitative scoring of myelination on routine clinical MRI and may offer an easy-to-use alternative for assessment of myelination. METHODS: Myelination was scored in 13 anatomic sites (items) on conventional T2w and T1w images in controls (n = 253, 0-2 years). Items for the score were selected based on inter-rater variability, practicability of scoring, and importance for correctly identifying validation scans. RESULTS: The resulting myelination score consisting of 7 T2- and 5 T1-items delineated myelination from term-equivalent to advanced, incomplete myelination which 50 % and 99 % of controls had reached by 19.1 and 32.7 months, respectively. It correctly identified 20/20 new control MRIs and 40/43 with myelination delay, missing one patient with borderline myelination delay at 8.6 months and 2 patients with incomplete T2-myelination of subcortical temporopolar white matter at 28 and 34 months. CONCLUSIONS: The proposed myelination score provides an easy to use, standardized, and versatile tool to delineate myelination normally occurring during the first 1.5 years of life.

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Newborn screening (NBS) is one of the most effective measures of secondary prevention. While the benefit of NBS on the clinical long-term outcomes of children with inherited metabolic diseases (IMD) has been demonstrated, the potential burden of families living with an early diagnosed and treated child with an IMD has not been thoroughly investigated. The aim of this longitudinal questionnaire-based study on 369 families living with a child with an IMD was to investigate the psychosocial and financial burden following a true-positive NBS. The reported psychosocial burden differed between children and their parents, and was associated with the child's age, diagnosis, and treatment. At younger ages, parent-reported burden was higher for the parents than for the individual child, while it increased for children and decreased for parents as the child grew older. Furthermore, psychosocial burden increased if the child required a strict dietary treatment and was at risk of metabolic decompensation. Regardless of diagnosis and treatment, the developmental delay of their child independently increased the parental psychosocial burden. Financial burden was reported by 24% of all families, and was higher in low-income families and in families whose children required dietary treatment. In conclusion, a substantial psychosocial and financial burden was revealed for children and their families after true-positive NBS. Since this burden is likely to have a negative impact on the long-term individual health benefits of NBS, this study underlines the importance of regularly assessing the psychosocial and financial needs of these families.

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OBJECTIVE: Maple syrup urine disease (MSUD), a life-threatening metabolic disorder, is included in newborn screening (NBS) programs worldwide. The study aims to evaluate the impact of NBS on the long-term outcome of MSUD patients. METHODS: We performed a prospective, national, multicenter, observational study. RESULTS: In the studied NBS cohort (N = 33; 22 classic MSUD [cMSUD], 11 variant MSUD [vMSUD]; median age at last visit 10.4 years), 32 (97%) patients survived, 58% of them had normal cognitive functions (median IQ 87). Initial peak leucine increased linearly with age in cMSUD (median: 1712 µmol/L), but not in vMSUD. Global IQ correlated inversely with the initial peak leucine concentration (P = .04; ß = -0.0081) and the frequency of decompensations (P = .02; ß = -9.133). A cluster analysis identified 2 subgroups differing in their long-term metabolic control (median leucine concentration: 162 vs 278 µmol/L; P < .001). In cMSUD, lower leucine concentrations were associated with a higher IQ (95.5 vs 80; P = .008). Liver transplantation (median age 5.8 years) was not associated with better cognitive outcome. NBS is highly sensitive for cMSUD, but vMSUD might be missed (N = 2 missed by NBS). CONCLUSIONS: NBS and the early start of treatment improve survival and long-term outcome in individuals with cMSUD. Disease severity is an important modifier of outcome; however, the time to NBS report and the quality of long-term metabolic control had an independent impact on cognitive outcome, highlighting the importance of an early diagnosis and the quality of treatment.

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BACKGROUND: Vitamin B12 deficiency (VitB12D) might cause neuro-developmental impairment in the first year of life. Newborn screening (NBS) for VitB12D was shown to be technically feasible and early treated infants developed favorably. This study aims to evaluate the impact of NBS in prevention of symptomatic infantile VitB12D. METHODS: In a nationwide surveillance study in cooperation with the German Pediatric Surveillance Unit, incident cases with VitB12D (<12 months of age) were prospectively collected from 2021 to 2022. RESULTS: In total, 61 cases of VitB12D reported to German Pediatric Surveillance Unit were analyzed, either identified by NBS (N = 31) or diagnosed after the onset of suggestive symptoms (non-NBS; N = 30). Ninety percent of the infants identified by NBS were still asymptomatic, whereas the non-NBS cohort presented at median 4 month of age with muscular hypotonia (68%), anemia (58%), developmental delay (44%), microcephalia (30%), and seizures (12%). Noteworthy, symptomatically diagnosed VitB12D in the first year of life was reported 4 times more frequently in infants who did not receive NBS for neonatal VitB12D (14 in 584 800) compared with those screened for VitB12D as newborns (4 in 688 200; Fisher's Exact Test, odds ratio 4.12 [95% confidence interval: 1.29-17.18], P = .008). The estimated overall cumulative incidence was 1:9600 newborns per year for neonatal VitB12D and 1:17 500 for symptomatic infantile VitB12D. CONCLUSIONS: NBS for neonatal VitB12D may lead to a fourfold risk reduction of developing symptomatic VitB12D in the first year of life compared with infants without NBS.

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Phenylketonuria (PKU) is a genetic disorder caused by variations in the phenylalanine hydroxylase (PAH) gene. Among the 3369 reported PAH variants, 33.7% are missense alterations. Unfortunately, 30% of these missense variants are classified as variants of unknown significance (VUS), posing challenges for genetic risk assessment. In our study, we focused on analyzing 836 missense PAH variants following the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines specified by ClinGen PAH Variant Curation Expert Panel (VCEP) criteria. We utilized and compared variant annotator tools like Franklin and Varsome, conducted 3D structural analysis of PAH, and examined active and regulatory site hotspots. In addition, we assessed potential splicing effect of apparent missense variants. By evaluating phenotype data from 22962 PKU patients, our aim was to reassess the pathogenicity of missense variants. Our comprehensive approach successfully reclassified 309 VUSs out of 836 missense variants as likely pathogenic or pathogenic (37%), upgraded 370 likely pathogenic variants to pathogenic, and reclassified one previously considered likely benign variant as likely pathogenic. Phenotypic information was available for 636 missense variants, with 441 undergoing 3D structural analysis and active site hotspot identification for 180 variants. After our analysis, only 6% of missense variants were classified as VUSs, and three of them (c.23A>C/p.Asn8Thr, c.59_60delinsCC/p.Gln20Pro, and c.278A >T/p.Asn93Ile) may be influenced by abnormal splicing. Moreover, a pathogenic variant (c.168G>T/p.Glu56Asp) was identified to have a risk exceeding 98% for modifications of the consensus splice site, with high scores indicating a donor loss of 0.94. The integration of ACMG/AMP guidelines with in silico structural analysis and phenotypic data significantly reduced the number of missense VUSs, providing a strong basis for genetic counseling and emphasizing the importance of metabolic phenotype information in variant curation. This study also sheds light on the current landscape of PAH variants.

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Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene-disease lists from gNBS studies, evaluating gene-disease count, composition, group proportions, and ClinGen curations of individual disorders. Despite shared selection criteria, we observe substantial variation in total gene count (median 480, range 237-889) and disease group composition. An intersection was identified for 53 genes, primarily inherited metabolic diseases (83%, 44/53). Each study investigated a subset of exclusive gene-disease pairs, and the total number of exclusive gene-disease pairs was positively correlated with the total number of genes included per study. While most pairs receive "Definitive" or "Strong" ClinGen classifications, some are labeled as "Refuted" (n = 5) or "Disputed" (n = 28), particularly in genetic cardiac diseases. Importantly, 17%-48% of genes lack ClinGen curation. This study underscores the current absence of consensus recommendations for selection criteria for target diseases for gNBS resulting in diversity in proposed gene-disease pairs, their coupling with gene variations and the use of ClinGen curation. Our findings provide crucial insights into the selection of target diseases and accompanying gene variations for future gNBS program, emphasizing the necessity for ongoing collaboration and discussion about criteria harmonization for panel selection to ensure the screening's objectivity, integrity, and broad acceptance.

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The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine ß-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-ß-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.

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The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

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OBJECTIVE: Liver transplantation (LTx) is an intervention when medical management is not sufficiently preventing individuals with urea cycle disorders (UCDs) from the occurrence of hyperammonemic events. Supplementation with L-citrulline/arginine is regularly performed prior to LTx to support ureagenesis and is often continued after the intervention. However, systematic studies assessing the impact of long-term L-citrulline/arginine supplementation in individuals who have undergone LTx is lacking to date. METHODS: Using longitudinal data collected systematically, a comparative analysis was carried out by studying the effects of long-term L-citrulline/arginine supplementation vs. no supplementation on health-related outcome parameters (i.e., anthropometric, neurological, and cognitive outcomes) in individuals with UCDs who have undergone LTx. Altogether, 52 individuals with male ornithine transcarbamylase deficiency, citrullinemia type 1 and argininosuccinic aciduria and a pre-transplant "severe" disease course who have undergone LTx were investigated by using recently established and validated genotype-specific in vitro enzyme activities. RESULTS: Long-term supplementation of individuals with L-citrulline/arginine who have undergone LTx (n = 16) does neither appear to alter anthropometric nor neurocognitive endpoints when compared to their severity-adjusted counterparts that were not supplemented (n = 36) after LTx with mean observation periods between four to five years. Moreover, supplementation with L-citrulline/arginine was not associated with an increase of disease-specific plasma arithmetic mean values for the respective amino acids when compared to the non-supplemented control cohort. CONCLUSION: Although supplementation with L-citrulline/arginine is often continued after LTx, this pilot study does neither identify altered long-term anthropometric or neurocognitive health-related outcomes nor does it find an adequate biochemical response as reflected by the unaltered plasma arithmetic mean values for L-citrulline or L-arginine. Further prospective analyses in larger samples and even longer observation periods will provide more insight into the usefulness of long-term supplementation with L-citrulline/arginine for individuals with UCDs who have undergone LTx.

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Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

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Newborn screening (NBS) for cystic fibrosis (CF) based on pancreatitis-associated protein (PAP) has been performed for several years. While some influencing factors are known, there is currently a lack of information on the influence of seasonal temperature on PAP determination or on the course of PAP blood concentration in infants during the first year of life. Using data from two PAP studies at the Heidelberg NBS centre and storage experiments, we compared PAP determinations in summer and winter and determined the direct influence of temperature. In addition, PAP concentrations measured in CF-NBS, between days 21-35 and 36-365, were compared. Over a 7-year period, we found no significant differences between PAP concentrations determined in summer or winter. We also found no differences in PAP determination after 8 days of storage at 4 °C, room temperature or 37 °C. When stored for up to 3 months, PAP samples remained stable at 4 °C, but not at room temperature (p = 0.007). After birth, PAP in neonatal blood showed a significant increasing trend up to the 96th hour of life (p < 0.0001). During the first year of life, blood PAP concentrations continued to increase in both CF- (36-72 h vs. 36-365 d p < 0.0001) and non-CF infants (36-72 h vs. 36-365 d p < 0.0001). Seasonal effects in central Europe appear to have a limited impact on PAP determination. The impact of the increase in blood PAP during the critical period for CF-NBS and beyond on the applicability and performance of PAP-based CF-NBS algorithms needs to be re-discussed.

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OBJECTIVE: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. METHODS: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. RESULTS: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. INTERPRETATION: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.

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Long-chain fatty acid oxidation disorders (lcFAODs) are associated with a high disease burden due to both the risk of metabolic decompensation as well as chronic, partly irreversible complications in some. Little research has been performed on the impact of these disorders on the daily life of parents and caregivers. We performed a web-based questionnaire study among parents/caregivers of patients affected with lcFAODs. The questionnaire focused on challenges at different ages of the child, on disease management issues, schooling, family and social life as well as the parental job situation, and their overall attitude toward the disease and the future life of their child. Data were collected from parents/caregivers of 63 patients (87 respondents, 63% mothers, 36% fathers) with lcFAODs (median age of patients 8.0 years, range 0-25 years, long-chain 3-hydrocyacyl-CoA dehydrogenase deficiency 40%, mitochondrial trifunctional protein deficiency 14%, very long-chain acyl-CoA dehydrogenase deficiency 41%, carnitine palmitoyltransferase 2 deficiency 5%). The overall disease burden of parents was considered highest during infancy and decreased with increasing age of their child. More than one third of parents were afraid that their child's disease might have an impact on his/her career choice and adult life. Negative effects of the child's disease on the job situation and career development were more commonly reported by mothers compared to fathers. Although the majority of parents considered their child's metabolic disorder a severe disease, most parents had a positive attitude toward their child's disease and seemed to cope well with their situation.

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BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

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PURPOSE: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. METHODS: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into "severe" and "attenuated" categories based on the genotype-specific and validated in vitro enzyme activity. RESULTS: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. CONCLUSION: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx-as currently performed-was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.

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The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long-term follow-up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease-immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long-term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries.

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Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B12 deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study "NGS2025" from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B12 deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B12 deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B12, vitamin B6 respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.

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There is a clinical need for early detection of chronic kidney disease (CKD) in patients with organic acidurias. We measured kidney markers in a longitudinal study over 5 years in 40 patients with methylmalonic aciduria (Mut0 ), propionic aciduria (PA), cobalamin A (CblA), and cobalamin C (CblC) deficiencies. Neutrophil gelatinase-associated lipocalin (NGAL), calprotectin (CLP), kidney injury molecule-1 (KIM-1), dickkopf-3 (DKK-3), albumin and beta-2-microglobulin (B2MG) in urine, as well as cystatin C (CysC) in serum were quantified. In Mut0 patients, mean concentrations of B2MG, KIM-1, and DKK-3 were elevated compared with healthy controls, all markers indicative of proximal tubule damage. In PA patients, mean B2MG, albumin, and CLP were elevated, indicating signs of proximal tubule and glomerulus damage and inflammation. In CblC patients, mean B2MG, NGAL, and CLP were increased, and considered as markers for proximal and distal tubule damage and inflammation. B2MG, was elevated in all three diseases, and correlated with DKK-3 in Mut0 /CblA and with eGFR(CysC) and KIM-1 in PA patients, respectively. None of the markers were elevated in CblA patients. Significant deterioration of kidney function, as determined by steady increase in CysC concentrations was noted in seven patients within the observation period. None of the investigated biomarker profiles showed a clear increase or added value for early detection. In conclusion, we identified disease-specific biomarker profiles for inflammation, tubular, and proximal damage in the urine of Mut0 , PA, and CblC patients. Whether these biomarkers can be used for early detection of CKD requires further investigation, as significant kidney function deterioration was observed in only a few patients.

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