Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

L-serine treatment in patients with GRIN-related encephalopathy: A phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52-weeks. Primary endpoints included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months treatment. Secondary outcomes included seizure frequency and intensity reduction and electroencephalography improvement. Assessments were performed 3 months and 1 day before starting treatment and 1-3-6-12 months after the beginning of the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Clinical phenotype showed: 91% intellectual disability (61% severe), 83% behavioral problems, 78% movement disorders and 58% with epilepsy. Based on Vineland Adaptive Behavior Composite standard score, nine children were classified as mildly impaired level group (cut-off > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in Daily Living Skills domain (P = 0,035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. Growth Score Values cognitive subdomain on the Bayley-III showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068) regardless of severity. L-serine normalized EEG pattern in five children, and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve the adaptive, motor function and quality of life, with a better response to the treatment in mild phenotypes.

New description of an MRPS2 homozygous patient: Further features to help expend the phenotype.

Mutated mito-ribosomal protein S2 (MRPS2) was already described in only three subjects, two with sensorineural hearing impairment, mild developmental delay, hypoglycemia, lactic acidemia and combined oxidative phosphorylation system deficiency and another, recently, presenting with a less severe phenotype. In order to expand the phenotype, we describe a new MRPS2 homozygous subject who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features.

Comparative Metabolomics in Single Ventricle Patients after Fontan Palliation: A Strong Case for a Targeted Metabolic Therapy.

Most studies on single ventricle (SV) circulation take a physiological or anatomical approach. Although there is a tight coupling between cardiac contractility and metabolism, the metabolic perspective on this patient population is very recent. Early findings point to major metabolic disturbances, with both impaired glucose and fatty acid oxidation in the cardiomyocytes. Additionally, Fontan patients have systemic metabolic derangements such as abnormal glucose metabolism and hypocholesterolemia. Our literature review compares the metabolism of patients with a SV circulation after Fontan palliation with that of patients with a healthy biventricular (BV) heart, or different subtypes of a failing BV heart, by Pubmed review of the literature on cardiac metabolism, Fontan failure, heart failure (HF), ketosis, metabolism published in English from 1939 to 2023. Early evidence demonstrates that SV circulation is not only a hemodynamic burden requiring staged palliation, but also a metabolic issue with alterations similar to what is known for HF in a BV circulation. Alterations of fatty acid and glucose oxidation were found, resulting in metabolic instability and impaired energy production. As reported for patients with BV HF, stimulating ketone oxidation may be an effective treatment strategy for HF in these patients. Few but promising clinical trials have been conducted thus far to evaluate therapeutic ketosis with HF using a variety of instruments, including ketogenic diet, ketone esters, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. An initial trial on a small cohort demonstrated favorable outcomes for Fontan patients treated with SGLT2 inhibitors. Therapeutic ketosis is worth considering in the treatment of Fontan patients, as ketones positively affect not only the myocardial energy metabolism, but also the global Fontan physiopathology. Induced ketosis seems promising as a concerted therapeutic strategy.

Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.

Impact of the SARS-CoV-2 pandemic on the health of individuals with intoxication-type metabolic diseases-Data from the E-IMD consortium.

The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%-50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed.

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision.

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Altered gut microbiome diversity and function in patients with propionic acidemia.

Propionic acidemia (PA) is an inherited metabolic disorder of propionate metabolism, where the gut microbiota may play a role in pathophysiology and therefore, represent a relevant therapeutic target. Little is known about the gut microbiota composition and activity in patients with PA. Although clinical practice varies between metabolic treatment centers, management of PA requires combined dietary and pharmaceutical treatments, both known to affect the gut microbiota. This study aimed to characterize the gut microbiota and its metabolites in fecal samples of patients with PA compared with healthy controls from the same household. Eight patients (aged 3-14y) and 8 controls (4-31y) were recruited from Center 1 (UK) and 7 patients (11-33y) and 6 controls (15-54y) from Center 2 (Austria). Stool samples were collected 4 times over 3 months, alongside data on dietary intakes and medication usage. Several microbial taxa differed between patients with PA and controls, particularly for Center 1, e.g., Proteobacteria levels were increased, whereas butyrate-producing genera, such as Roseburia and Faecalibacterium, were decreased. Most measured microbial metabolites were lower in patients with PA, and butyrate was particularly depleted in patients from Center 1. Furthermore, microbiota profile of these patients showed the lowest compositional and functional diversity, and lowest stability over 3 months. As the first study to map the gut microbiota of patients with PA, this work represents an important step forward for developing new therapeutic strategies to further improve PA clinical status. New dietary strategies should consider microbial propionate production as well as butyrate production and microbiota stability.

ost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism.

Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17ß-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC-MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here.

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.

The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Caregiver burden, and parents' perception of disease severity determine health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism.

Background: Living with a non-acute (phenylketonuria) or acute (e.g. urea cycle disorders, organic acidurias) intoxication-type inborn error of metabolism (IT-IEM) can have a substantial impact on health-related quality of life (HrQoL) of paediatric patients and their families. Parents take primary responsibility for treatment monitoring and experience worry and fear about their child's health status. Quantitative evidence on parental psychological factors which may influence the HrQoL of patients with IT-IEM are sparse to non-existent. Methods: In this multicenter survey study 50 parents of IT-IEM patients (ages 5-19) assessed the severity of their child's disease, reported on caregiver burden, and proxy-rated their child's HrQoL. Additionally, 35 patient self-reports on HrQoL were obtained (n = 16 female patients, n = 19 male patients). Multiple linear regressions were conducted to examine the predictive power of child age, sex, medical diagnosis type (acute / non-acute), parental perceived disease severity and caregiver burden on patients' HrQoL. Mediation analyses were used to investigate the relation of caregiver burden and parental ratings of disease severity with patients' HrQoL. Results: Significant regression models for self-reported [F(5,34) = 10.752, p < .001, R 2 adj.. = 0.59] and parent proxy reported HrQoL [F(5,49) = 20.513, p < .001, R 2 adj.. = 0.67] emerged. High caregiver burden and perceived disease severity predicted significantly lower patient self- and proxy-reported HrQoL while type of diagnosis (acute versus non-acute) did not. Female sex predicted significantly lower self-reported HrQoL. High caregiver burden was the mediating factor between high perceived severity of the child's disease and lower proxy- by parent rated HrQoL. Conclusion: Detecting elevated burden of care and providing support for parents seems crucial to prevent adverse consequences for their children's HrQoL. Intervention studies are needed, to assess which support programs are most efficient.

Workload and job satisfaction among Austrian pediatricians: gender and generational aspects.

BACKGROUND: The aim of this study was to evaluate different factors that may contribute to workload and job satisfaction among Austrian pediatricians. METHODS: We conducted an online survey with 16 questions and performed statistical analyses. RESULTS: Of 375 participating pediatricians, 61% were female, 39% male, 61% clinicians, 21% panel doctors and 12% private doctors. Overall, job satisfaction was moderate (6 ± 2.4 on a positive scale of 0-10). Higher working hours (p = 0.014) and higher patient numbers (p = 0.000) were significantly associated with lower job satisfaction. Lowest satisfaction was described for administrative or other nonmedical work. Lack of time for patient consultation was also correlated with poor satisfaction. Pediatricians older than 65 years reported the highest job satisfaction whereas pediatricians between 55 and 65 years and younger than 36 years showed the lowest scores. Although male pediatricians worked significantly more often more than 40 h per week than females (75% vs. 53%, p = 0.000), female pediatricians were less satisfied about the proportion of administrative (p = 0.015) and other nonmedical work (p = 0.014). CONCLUSION: New working models considering less workload, particularly less nonmedical work and intensified collaboration between pediatric clinicians and practitioners are needed to allow more available time per patient, to increase job satisfaction and thus to raise attractivity for pediatric primary care.

Changes in the Cerebrospinal Fluid and Plasma Lipidome in Patients with Rett Syndrome.

Rett syndrome (RTT) is defined as a rare disease caused by mutations of the methyl-CpG binding protein 2 (MECP2). It is one of the most common causes of genetic mental retardation in girls, characterized by normal early psychomotor development, followed by severe neurologic regression. Hitherto, RTT lacks a specific biomarker, but altered lipid homeostasis has been found in RTT model mice as well as in RTT patients. We performed LC-MS/MS lipidomics analysis to investigate the cerebrospinal fluid (CSF) and plasma composition of patients with RTT for biochemical variations compared to healthy controls. In all seven RTT patients, we found decreased CSF cholesterol levels compared to age-matched controls (n = 13), whereas plasma cholesterol levels were within the normal range in all 13 RTT patients compared to 18 controls. Levels of phospholipid (PL) and sphingomyelin (SM) species were decreased in CSF of RTT patients, whereas the lipidomics profile of plasma samples was unaltered in RTT patients compared to healthy controls. This study shows that the CSF lipidomics profile is altered in RTT, which is the basis for future (functional) studies to validate selected lipid species as CSF biomarkers for RTT.

Immunological Memory and Affinity Maturation After Vaccination in Patients With Propionic Acidemia.

Earlier studies have recommended routine childhood immunization in patients with propionic acidemia (PA); however, the literature presents insufficient data on the response to vaccines, notably specific IgG concentrations and avidity maturation, after measles, mumps, rubella (MMR), and diphtheria/tetanus (DiphtTe) vaccinations in this population. In patients with PA, cellular and humoral changes of the immune system (e.g. a decreased CD4+ T cell count, with a reversal of CD4/CD8 T cell ratio, a deficient gamma-globulin fraction, and in one case a decreased lymphocyte blastogenesis) have been reported. Former reports also detected pancytopenias accompanying febrile infections in PA patients. In the current study, we analyzed vaccine-specific IgG concentrations and avidity maturation after MMR and DiphtTe vaccinations in 10 patients with PA. Compared to gender and age matched controls, all 10 had protective IgG concentrations for at least one tested antigen, and in 6 out of 10 patients high relative avidity indices for measles and rubella were detected. In summary, the present study revealed a sufficient immune response and outcome, indicating an acceptable humoral memory in patients with PA after booster vaccinations.

Nitisinone treatment during two pregnancies and breastfeeding in a woman with tyrosinemia type 1 - a case report.

OBJECTIVES: Tyrosinaemia type 1, an inherited disorder of tyrosine metabolism, is usually treated with a tyrosine-defined diet and since 2000 with nitisinone. So far, data about effects of nitisone during pregnancy and breastfeeding are rare. This is the first report of two pregnancies in a patient with tyrosinaemia type 1 while under treatment with nitisinone. CASE PRESENTATION: We here present a 20-year-old female patient with tyrisonemia type 1 receiving treatment with nitisinone and a tyrosine-defined diet since she was diagnosed with tyrosinaemia type 1 at the age of 18 months. During two pregnancies blood concentrations of tyrosine, succinylacetone and nitisinone were measured regularly. Neither infant has tyrosinaemia type 1 and both showed an initial increase in concentrations of tyrosine, succinylacetone and nitisinone. All three metabolites dropped within two weeks after birth. Both were exclusively breastfed for about two weeks. Both children show age-appropriate physical and mental development. CONCLUSIONS: Nitisinone therapy during pregnancy and the short breastfeeding period did not result in adverse events in our patient or her children. Regular assessments of tyrosine, succinylacetone and nitisinone should be made during pregnancy and the breastfeeding period in both the mother and the infant. For better understanding, in principle, all cases of pregnancy and breastfeeding with tyrosinemia type 1 should be assessed and followed to further evaluate the implications of tyrosinaemia type 1 and its treatment during pregnancy. Additionally, even though experience with breastfeeding is limited, medication with nitisinone is safe and there is no reason to consider breastfeeding unsafe or to not recommend it.

The Manchester Triage System in a Pediatric Emergency Department of an Austrian University Hospital: A Retrospective Analysis of Urgency Levels.

OBJECTIVES: The Manchester Triage System (MTS) has entered widespread international use in emergency departments (EDs). This retrospective study analyzes urgency of patient visits (PV) at the ED of the Clinic for Pediatrics at the Medical University of Innsbruck. METHODS: We collected demographic and outcome information, including PV urgency levels (UL) according to the MTS, for 3 years (2015-2018), separating PV during regular office hours (ROH; 8:00 am to 5:00 pm) from PV during afternoon and night hours (5:00 pm to 8:00 am), and PV on weekdays from PV on weekends and bank holidays (WE). RESULTS: A total of 56,088 PV were registered with a UL. Most (68.4%) PV were classified as nonurgent. During ROH, more PV per hour (PV/h) were recorded than during afternoon and night hours (3.0 PV/h vs 1.6 PV/h), with a higher proportion of less urgent cases during ROH. On WE, the amount of PV/h was higher than on weekdays (3.6 PV/h vs 2.8 PV/h), with a higher proportion of nonurgent cases (74.6% vs 68.6%). Likelihoods of inpatient admission and hospital stay lengths increased in step with UL. CONCLUSIONS: The MTS proved useful for delineating UL distributions. The MTS analyses may be of value in managing EDs. Prompted by the results of our study, a general practice pediatric care unit was established to support the ED during WE.

100 years of inherited metabolic disorders in Austria-A national registry of minimal birth prevalence, diagnosis, and clinical outcome of inborn errors of metabolism in Austria between 1921 and 2021.

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties.

Amino Acid and Phospholipid Metabolism as an Indicator of Inflammation and Subtle Cardiomyopathy in Patients with Marfan Syndrome.

Patients with Marfan syndrome (MFS) have an increased risk of aortic aneurysm formation, dissection and development of a subtle cardiomyopathy. We analyzed amino acid and lipid metabolic pathways in MFS patients, seeking biomarker patterns as potential monitoring tools of cardiovascular risk with deterioration of myocardial function. We assessed myocardial function in 24 adult MFS patients and compared traditional laboratory values and mass spectrometry-based amino acid, phospholipid and acylcarnitine metabolomes in patients with those in healthy controls. Analytes for which values differed between patients and controls were subjected to regression analysis. A high proportion of patients had signs of impaired diastolic function and elevated serum levels of NT-proBNP. Patients had lower serum levels of taurine, histidine and PCaeC42:3 than controls. The evidence of diastolic dysfunction, aortic root dimensions and history of aortic root surgery correlated with NT-proBNP and taurine levels. Alterations in serum levels of metabolism derived analytes link MFS pathophysiology with inflammation, oxidative stress and incipient cardiomyopathy.