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Newborn screening (NBS) for inherited metabolic diseases (IMDs) substantially shortens a patient's journey. It enables the early start of metabolic treatment which might prevent potentially lethal neonatal disease manifestations, while promoting favorable development and long-term clinical outcomes. This study aims to assess growth in screened individuals with IMDs under different dietary regimes. Anthropometric data (3585 prospective measures) of 350 screened individuals with IMDs born between 1999 and 2018 and participating in a German prospective multicenter observational study were evaluated. Overall, birth measures were within the reference ranges, suggesting unaffected prenatal growth, except for phenylketonuria (weight) and glutaric aciduria Type 1 (head circumference). After birth, longitudinal analysis of anthropometric measures revealed a loss of height standard deviation score (SDS; -0.5 SDS; p 0.0001), head circumference SDS (-0.2 SDS; p = 0.0028), but not for weight SDS (0.1 SDS; p = 0.5097) until the age of 18 years, while BMI SDS increased (0.4 SDS; p 0.0001). The significant interaction with age and diet groups was pronounced for the linear growth in individuals receiving diets being low in protein, long-chain triglycerides, and galactose (p 0.001). Identification by NBS and subsequent early (dietary) treatment cannot completely protect against alterations in growths. Disease-specific (e.g., metabolic impairments, neurotoxins) and dietary-specific (e.g., diets reduced in protein) factors may have an amplified impact on longitudinal growth. Therefore, alongside other important follow-ups, the continuous observation of the anthropometric development of screened individuals with IMDs needs special attention to early identify and support individuals at risk.

Background Previous studies suggest that PAP-based CF protocols are suitable for newborn screening (NBS) for cystic fibrosis (CF) when newborns designated as CFSPID should not be detected. However, there are still discussions about the performance of IRT/PAP algorithms. We present the final results of a pilot study evaluating a IRT/PAP protocol with an IRT-dependent safety net (SN) conducted from 2008 to 2016 in southwestern Germany on nearly 500,000 newborns. Methods To achieve reliable data, all newborns were screened using both the PAP-based and a DNA-based CFNBS algorithm. PAP quantification and genetic analysis of the four most common CFTR mutations in Germany were performed in all newborns with IRT≥99.0 percentile. NBS was rated positive if either PAP was ≥1.6 µg/l and/or at least one CFTR mutation was detected. In addition, an IRT-dependent SN resulted in positive rating for both protocols if IRT was ≥99.9 percentile. To evaluate the IRT/PAP protocol, its performance was compared to that of the IRT/DNA protocol. Results The IRT/PAP protocol with IRT-based SN used in the study achieved a sensitivity of 94%, if false-negative detected neonates with meconium ileus and those designated as CFSPID were excluded from analysis. CF/CFSPID ratio was 92. However, PPV of the IRT/PAP+SN protocol was with 10.3% very low. Conclusions PAP-based CFNBS protocols can be used, if less detection of CFSPID is desired. The IRT/PAP protocol with IRT-dependent SN evaluated here achieved adequate sensitivity but should probably be used in combination with a third-tier test to also achieve an acceptable PPV.

Newborn screening (NBS) is a public health measure to identify children with treatable disorders within the first days of life allowing presymptomatic treatment. It is the most successful measure of secondary medical prevention and part of public health programs in many countries worldwide. Application of second-tier strategies in NBS allows for increased specificity and consecutively a higher positive predictive value. Second-tier strategies can include analysis of specific biomarkers for a target disorder or may be based on molecular genetic analyses. Improving the quality of NBS, for example by second-tier strategies, is of utmost importance to maintain the high acceptance of NBS by families – especially as an increasing number of target disorders is being consecutively included into NBS programs.

Cystic fibrosis (CF) was added to the German newborn bloodspot screening (NBS) panel in 2016. This study assesses parental perceptions of CF-NBS and confirmatory testing.Prospective questionnaire-based survey administered to parents of children with positive CF-NBS over 40 months after initiation of CF-NBS in Southwest Germany. Parental perceptions were compared to results from Bavaria and Switzerland.Questionnaires with 29 standardized questions were sent to 343 families with children born between October 2016 and January 2020. A total of 178 (51.9%) replied. Although required by law, only a minority were informed about CF-NBS by a physician. The information provided about NBS was sufficient for 78% of parents. Regarding the information about positive CF-NBS, 52.9% were satisfied but the majority expressed negative emotions (89.5%). While most of these were resolved after confirmatory diagnostics, 17% of parents of children with false-positive CF-NBS and 66.7% of children confirmed with CF remained anxious. Waiting time for sweat testing was3 days in 56.1%, considerably longer than in more centralized screening systems. Parents who waited for a maximum of 3 days were significantly more satisfied. 70.7% of parents were satisfied with the information given during confirmatory diagnostics and 91.4% were satisfied with participating in CF-NBS.CF-NBS stands in high regard with parents. Smooth organization, timely initiation of confirmatory testing, and professional communication are most important to limit parental anxiety. A more centralized system of confirmatory diagnostics appears advantageous in several regards as it reduces time from positive NBS to final diagnosis and increases parental satisfaction.

Vitamin B12 deficiency, mostly of maternal origin in newborns, is a well-treatable condition but can cause severe neurologic sequelae in infants. Early detection of vitamin B12 deficiency allows the pre-symptomatic treatment of affected children. This evaluation assesses the characteristics of maternal vitamin B12 deficiency detected by newborn screening. In a prospective single-center study, a systematic screening strategy for vitamin B12 deficiency using a combination of two second-tier strategies was applied. In addition to confirmatory diagnostics in children, the systematic work-up of vitamin B12 status was also performed for their mothers. Maternal characteristics were assessed including ethnic origin, diet, and vitamin supplementation during pregnancy. For affected mothers, a work-up by internal medicine was recommended. In total, 121 mother–infant couples were analyzed. 66% of mothers adhered to a balanced diet including meat. The cause of maternal vitamin B12 deficiency was unknown in 56% of cases, followed by dietary causes in 32%, and organic causes in 8%. All mothers following a vegan diet and most mothers with a vegetarian diet took vitamin preparations during pregnancy, whereas only 55.8% of mothers with a balanced diet took folic acid or other vitamins. Maternal vitamin B12, folic acid, and homocysteine levels were significantly correlated with the child’s folic acid levels, and with homocysteine, methylmalonic, and methylcitric acid levels in first and second NBS dried blood spots. Most children had normal blood counts and showed normocytosis. Although 36.7% of mothers showed anemia, only one presented with macrocytosis. Adherence to vitamin supplementation in pregnancy is low despite the recommendation for supplementation of folic acid. Ideally, the evaluation of mothers for vitamin B12 levels and appropriate therapy should be initiated in early pregnancy. In infants detected through newborn screening, the multidisciplinary assessment and therapy of both children and mothers should be performed.

Objective To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B12 deficiency identified by newborn screening (NBS). Study design Prospective multicenter observational study on health outcomes of 31 infants with vitamin B12 deficiency identified by NBS. Neurodevelopment was assessed by the Denver Developmental Screening Test. Results In 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin B12 deficiency was 26 in 100 000 newborns, with high seasonal variations (lowest in summer: 8 in 100 000). Infants participating in the outcome study (N = 31) were supplemented with vitamin B12 for a median (range) of 5.9 (1.1-16.2) months. All achieved age-appropriate test results in Denver Developmental Screening Test at age 15 (11-23) months and did not present with symptoms characteristic for vitamin B12 deficiency. Most (81%, n = 25) mothers of affected newborns had a hitherto undiagnosed (functional) vitamin B12 deficiency, and, subsequently, received specific therapy. Conclusions Neonatal vitamin B12 deficiency can be screened by NBS, preventing the manifestation of irreversible neurologic symptoms and the recurrence of vitamin B12 deficiency in future pregnancies through adequate treatment of affected newborns and their mothers. The high frequency of mothers with migrant background having a newborn with vitamin B12 deficiency highlights the need for improved prenatal care.

Vitamin B

Determination of methylmalonic acid (MMA) from dried blood spots (DBS) is commonly performed in clinical diagnostics and newborn screening for propionic acidemia (PA) and methylmalonic acidemia. Isobaric compounds of MMA having the same mass can affect diagnostic reliability and quantitative results, which represents a previously unrecognized pitfall in clinical assays for MMA. We set out to identify interfering substances of MMA in DBS, serum and urine samples from confirmed patients with PA and methylmalonic acidemia.Techniques included quadrupole time-of-flight high-resolution mass spectrometry (QTOF HR-MS), nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography (LC) and tandem mass spectrometry (MS/MS).The five isobaric metabolites detected in DBS, serum and urine from PA and methylmalonic acidemia patients were confirmed as 2-methyl-3-hydroxybutyrate, 3-hydroxyisovalerate, 2-hydroxyisovalerate, 3-hydroxyvalerate and succinate using a series of experiments. An additional unknown substance with low abundance remained unidentified.The presented results facilitate the diagnostic and quantitative reliability of the MMA determination in clinical assays. Isobaric species should be investigated in assays for MMA to eliminate possible interference in a wide range of conditions including PA, methylmalonic acidemia, a vitamin B

Newborn screening for cystic fibrosis (CF-NBS) was introduced in Germany in 2016. Currently, systematic follow-up of positive CF-NBS results is not implemented or reimbursed in the NBS program. We investigated results of confirmatory testing over 24 months after implementation of CF-NBS for a large German NBS center before and after introduction of an active tracking system and performed a cost calculation for tracking. Results are compared with the federal state of Bavaria, where a centralized tracking system has been in place for many years. At the NBS center, 244 of 281,907 children had a positive CF-NBS result requiring diagnostic confirmation. Before implementation of a telephone tracking system, only 43% of confirmatory results were returned despite repeated written requests. The consecutive strategy including telephone tracking led to an increase of resolved cases to 84%. However, the centralized tracking system in Bavaria, assigning children with positive CF-NBS directly to a responsible CF-center, resolved 99% of cases. The calculated additional cost for a tracking system in Germany including telephone tracking is 1.20€ per newborn screened.Conclusion: The implementation of a tracking system achieves a distinct improvement in CF-NBS with justifiable costs. The effect can be limited by absence of centralized organization of confirmatory testing. What is Known:• Newborn screening for cystic fibrosis (CF-NBS) has been performed for many years in several countries worldwide• While many studies have focused on different CF-NBS strategies, the organization of confirmatory testing and process quality concerning returned information to the NBS center has so far received less attention. What is New:• The implementation of an active tracking system achieves a distinct improvement of clarified cases after positive CF-NBS with justifiable costs.• The effect of a tracking system can be limited by the absence of a centralized organization of confirmatory testing.

Summary Vitamin B12 deficiency, mostly of maternal origin in newborns, is a well treatable condition but can cause severe neurologic sequelae. In women of childbearing age and pregnant women worldwide vitamin B12 deficiency has been reported with frequencies of 10%–50%. Children with vitamin B12 deficiency are asymptomatic at birth but may develop severe multisystemic symptoms, including irreversible developmental impairment in the second half-year of life. Early detection of vitamin B12 deficiency allows for presymptomatic treatment. This article provides an overview over the function of vitamin B12 and discusses causes and frequency of vitamin B12 deficiency in newborns, infants, and women of childbearing age. It describes novel successful approaches to newborn screening (NBS) for vitamin B12 deficiency and results of a pilot study which performed systematic NBS for vitamin B12 deficiency using so-called second-tier strategies by measuring homocysteine and methylmalonic acid in dried blood spots. Recommendations for diagnostics in mothers of children with vitamin B12 deficiency are described as well as results of systematic work-up in mothers and treatment and follow-up of children with vitamin B12 deficiency detected by NBS. Treatment options of vitamin B12 deficiency are presented including a newly developed standardized supplementation scheme with exclusively oral vitamin B12 supplementation. Recommendations for preventive approaches to vitamin B12 deficiency for children and mothers are stated. Many children worldwide could benefit from systematic inclusion of vitamin B12 deficiency into NBS panels. In addition, preventive approaches to maternal vitamin B12 deficiency should be implemented systematically during maternal care.

BackgroundDuring the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients ResultsAll 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘sapropterin extension’ group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘sapropterin continuous’ group (95% CI 28.9, 48.6;p p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters.ConclusionsLong-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at 4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment.Trial registrationClinicalTrials.gov, NCT01376908. Registered 17 June 2011,https://clinicaltrials.gov/ct2/show/NCT01376908.

ObjectiveTo evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.MethodsIn this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients.ResultsNineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 (p= 0.003), total tau (p< 0.001), and phosphorylated tau (p= 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r= 0.64,p= 0.003), neuropsychiatric symptoms (r= 0.73,p< 001), motor evoked potential latency (r= 0.48,p= 0.030), and parietal lobe atrophy.ConclusionsOur study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.

To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin BProspective multicenter observational study on health outcomes of 31 infants with vitamin BIn 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin BNeonatal vitamin B

Zusammenfassung Hintergrund Ein Vitamin‑B12-Mangel ist bei Neugeborenen meist bedingt durch einen mütterlichen Vitamin‑B12-Mangel. Beim Kind führt ein schwerer, unerkannter Vitamin‑B12-Mangel zu irreversiblen neurologischen Schädigungen und einer dauerhaften Entwicklungsstörung, die meist erst im zweiten Lebenshalbjahr klinisch erkannt wird. Eine Früherkennung durch das Neugeborenenscreening wird derzeit in Pilotprojekten evaluiert. Fragestellung Der vorliegende Beitrag gibt einen Überblick über mögliche Ursachen eines Vitamin‑B12-Mangels und präsentiert erfolgreiche Ansätze zur Früherkennung durch das Neugeborenenscreening sowie Empfehlungen zur Diagnostik bei Mutter und Kind. Für die Behandlung des Vitamin‑B12-Mangels im Neugeborenen- und Säuglingsalter wird bislang häufig zunächst eine intramuskuläre Applikation von Vitamin B12 verwendet. Als Alternative wird von den Autoren ein ausschließlich orales Supplementationsschema mit Vitamin B12 vorgestellt. Ergebnisse Im Rahmen des Pilotprojektes „Neugeborenenscreening 2020“ am Screeningzentrum Heidelberg wurde für die Behandlung von Kindern mit Vitamin‑B12-Mangel nach Detektion über das Neugeborenenscreening ein standardisiertes ausschließlich orales Supplementationsschema mit Vitamin B12 entwickelt und erfolgreich angewendet. Dieses besteht in der Verabreichung von Vitamin B12 0,5 mg/Tag p.o. über 3 Tage in Form eines Flüssigpräparates, gefolgt von 0,1 mg/Tag p.o. Über die erste Woche erfolgt zusätzlich die Gabe von 0,4 mg Folsäure pro Tag p.o. Nach Normalisierung aller Parameter des Vitamin‑B12-Haushaltes (einschließlich der funktionellen Marker Homozystein und Methylmalonsäure) erfolgt während der Stillzeit eine Vitamin‑B12-Supplementation in Erhaltungsdosis von 5 µg/Tag p.o. bis zur sicheren Einführung fleischhaltiger Beikost bzw. von Vitamin‑B12-haltiger Nahrung. Schlussfolgerung Das hier dargestellte rein orale Behandlungsschema für den Vitamin‑B12-Mangel stellt eine effektive, kostengünstige, schmerzlose und damit besonders kinderfreundliche Behandlung dar.

Vitamin B

BACKGROUND: Although extended newborn screening (NBS) programs have been introduced more than 20 years ago, their impact on the long-term clinical outcome of individuals with inherited metabolic diseases (IMDs) is still rarely investigated. METHODS: We studied the clinical outcomes of individuals with IMDs identified by NBS between 1999 and 2016 in a prospective multicenter observational study. RESULTS: In total, 306 screened individuals with IMDs (115 with phenylketonuria and 191 with other IMDs with a lifelong risk for metabolic decompensation) were followed for a median time of 6.2 years. Although the risk for metabolic decompensation was disease-specific and NBS could not prevent decompensations in every individual at risk (n = 49), the majority did not develop permanent disease-specific signs (75.9%), showed normal development (95.6%) and normal cognitive outcome (87.7%; mean IQ: 100.4), and mostly attended regular kindergarten (95.2%) and primary school (95.2%). This demonstrates that not only individuals with phenylketonuria, serving as a benchmark, but also those with lifelong risk for metabolic decompensation had a favorable long-term outcome. High NBS process quality is the prerequisite of this favorable outcome. This is supported by 28 individuals presenting with first symptoms at a median age of 3.5 days before NBS results were available, by the absence of neonatal decompensations after the report of NBS results, and by the challenge of keeping relevant process parameters at a constantly high level. CONCLUSIONS: NBS for IMDs, although not completely preventing clinical presentations in all individuals, can be considered a highly successful program of secondary prevention.

ObjectiveTo expand the genetic spectrum of hereditary spastic paraparesis by a treatable condition and to evaluate the therapeutic effects of biotin supplementation in an adult patient with biotinidase deficiency (BD).MethodsWe performed exome sequencing (ES) in a patient with the clinical diagnosis of complex hereditary spastic paraparesis. The patient was examined neurologically, including functional rating scales. We performed ophthalmologic examinations and metabolic testing.ResultsA 41-year-old patient presented with slowly progressive lower limb spasticity combined with optic atrophy. He was clinically diagnosed with complex hereditary spastic paraparesis. The initial panel diagnostics did not reveal the disease-causing variant; therefore, ES was performed. ES revealed biallelic pathogenic variants in the BTD gene leading to the genetic diagnosis of BD. BD is an autosomal recessive metabolic disorder causing a broad spectrum of neurologic symptoms, optic atrophy, and dermatologic abnormalities. When treatment is initiated in time, symptoms can be prevented or reversed by biotin supplementation. After diagnosis in our patient, biotin supplementation was started. One year after the onset of therapy, symptoms remained stable with slight improvement of sensory deficits.ConclusionsThese findings expand the genetic spectrum of the clinical diagnosis of complex hereditary spastic paraparesis by a treatable disease. Today, most children with BD should have been identified via newborn screening to start biotin supplementation before the onset of symptoms. However, adult patients and those born in countries without newborn screening programs for BD are at risk of being missed. Therapeutic success depends on early diagnosis and presymptomatic treatment.

Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidelberg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4% of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 1 3-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. Within 13 months, the study “Newborn Screening 2020” identified additional 12 children with treatable conditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.

In Deutschland begann das Neugeborenenscreening auf Phenylketonurie in einzelnen Regionen 1964, bundesweit 1969. In den folgenden Jahrzehnten folgte eine Erweiterung des Screenings um weitere Zielkrankheiten. Erfassung der Patienten, die bislang in Deutschland durch das Neugeborenenscreening auf angeborene Stoffwechsel- und Hormonstorungen identifiziert wurden. Auf Grundlage fruherer Publikationen, deutschlandweiter Erhebungen zum Neugeborenenscreening und eigener Daten aus dem Screeninglabor Heidelberg wird dargestellt, wie viele Patienten bislang in Deutschland vom Neugeborenenscreening profitieren konnten. Fur einzelne Jahrgange ohne systematische Daten erfolgt eine Abschatzung aufgrund von Geburtenzahl, fur die Vorjahre erhobenen Krankheitspravalenzen und Teilnahmeraten am Screening. In Deutschland wurden in den letzten 50 Jahren im Neugeborenenscreening mehr als 34 Mio. Kinder untersucht. Bei mehr als 11.000 Kindern, unter Berucksichtigung von Schatzungen sogar mehr als 14.000 Kindern, wurde hierdurch die fruhe Diagnose einer angeborenen Stoffwechsel- oder Hormonstorung ermoglicht. Dies erlaubte eine praventive Behandlung, die betroffene Kinder vor schwerer Behinderung oder Tod bewahrt. Die Zahl der Patienten, die vom Screening bislang profitiert haben, liegt vermutlich noch hoher, da in Pilotstudien Patienten mit weiteren Zielkrankheiten identifiziert wurden. Neue Untersuchungsmethoden und Projekte zur Erkennung weiterer Zielkrankheiten werden dazu beitragen, dass in Zukunft noch mehr Kinder vom Neugeborenenscreening profitieren. Ein flachendeckendes „tracking“ und die Transition der Patienten in eine spezialisierte Versorgung in der Erwachsenenmedizin stellen aktuell entscheidende Herausforderungen dar.

Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-s-synthase deficiency). Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar. A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine, methionine-phenylalanine-ratio and propionylcarnitine as second-tiers. Proposed cut-offs were also retrospectively evaluated in newborn screening samples of 12 patients with remethylation disorders and vitamin B12 deficiency from Qatar and Germany. Over a 12 months period, the proposed strategy led to a decrease in the recall rate in homocysteine screening for Qatar from 1.09% to 0.68%, while allowing for additional systematic inclusion of remethylation disorders and vitamin B12 deficiency into the screening panel for Qatar. In the evaluated period the applied strategy would have detected all patients with classical homocystinuria identified by the previous strategy and in addition 5 children with maternal nutritional vitamin B12 deficiency and one patient with an isolated remethylation disorder. Additional retrospective evaluation of newborn screening samples of 12 patients from Germany and Qatar with remethlyation disorders or vitamin B12 deficiency showed that all of these patients would have been detected by the cut-offs used in the proposed new strategy. In addition, an adapted strategy for Germany using methionine, methionine-phenylalanine-ratio and propionylcarnitine as first-tier, and homocysteine as a second-tier test was also positively evaluated retrospectively. The proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B12 deficiency in the screening panel, while lowering the recall rate. An adapted second-tier strategy is presented for screening in Germany and will be prospectively evaluated over the next years in a pilot project named “Newborn Screening 2020”.

To evaluate a systematic newborn screening (NBS) strategy for vitamin BIn a prospective single-center NBS study, a systematic screening strategy for vitamin BIn a cohort of 176 702 children screened over 27 months, 33 children were detected by NBS in whom (maternal) vitamin BVitamin B

Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study. Plasma and cerebrospinal fluid (CSF) Phe, 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP), 3,4-dihydroxy-l-phenylalanine (l-DOPA) and homovanillic acid (HVA) were analyzed. Voxel-based morphometry statistical nonparametric mapping was used to test the age-corrected correlation between gray matter atrophy and CSF biogenic amines levels. 5-HIAA and 5-HTP were significantly reduced in PKU patients compared to controls. Significant negative correlations were found between CSF 5-HIAA, HVA, and 5-HTP and Phe levels. A decrease in 5-HIAA and 5-HTP concentrations correlated with precuneus and frontal atrophy, respectively. Lower HVA levels correlated with occipital atrophy. Biogenic amines deficits correlate with specific brain atrophy patterns in adult PKU patients, in line with serotonin and dopamine projections. These findings may support a more rigorous Phe control in adult PKU to prevent neurotransmitter depletion and accelerated brain damage due to aging.

Background Patients with phenylketonuria have been reported to be deficient in long-chain polyunsaturated fatty acids (LCPUFAs). It has been postulated that good compliance with the dietary regimen negatively influences LCPUFA status. Methods In 36 patients with phenylketonuria and 18 age-matched healthy control subjects LCPUFA-levels in plasma phospholipids and cholesteryl esters, erythrocyte phosphatidylcholine and phosphatidylethanolamine were evaluated. Results Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels did not differ significantly between patients and control subjects in plasma and erythrocyte fractions. There was a significant negative correlation between SDS (standard deviation) scores of DHA-levels in erythrocyte parameters from the respective age-matched control group and patients’ concurrent and long-term phenylalanine levels for erythrocyte phosphatidylethanolamine and erythrocyte phosphatidylcholine. Patients with lower (higher) phenylalanine levels had positive (negative) DHA-SDS. Conclusion In contrast to previous reports we did not find lower LCPUFA-levels in patients with phenylketonuria compared to age-matched healthy control subjects. Good dietary control was associated with better LCPUFA status.

Hydroxyprolinemia is an inborn error of amino acid degradation that is considered a non-disease. Known for more than 50 years, its genetic cause and prevalence have remained unclear. In MS/MS newborn screening, the mass spectrum of hydroxyproline cannot be differentiated from isoleucine and leucine causing false positive newborn screening test results for maple syrup urine disease (MSUD). We studied two siblings with hydroxyprolinemia via exome sequencing and confirmed the candidate gene in five further individuals with hydroxyprolinemia, who were all characterized biochemically and clinically. The prevalence was calculated based on the number of individuals with hydroxyprolinemia detected via MS/MS newborn screening at our centre from 2003 to 2014. In six cases, we identified homozygous or compound heterozygous mutations in PRODH2 as the underlying genetic cause of hydroxyprolinemia. One individual was heterozygous for a deletion in PRODH2 and had an intermittent biochemical phenotype with partial normalization of hydroxyproline concentrations. In one further individual with persistent hydroxyprolinemia no mutation in PRODH2 was found, raising the possibility of another defect of hydroxyproline degradation yet to be identified as the underlying cause of hydroxyprolinemia. Plasma hydroxyproline concentrations were clearly elevated in all individuals with biallelic mutations in PRODH2. All studied individuals remained asymptomatic, giving further evidence that hydroxyprolinemia is a benign condition. The estimated prevalence of hydroxyprolinemia in Germany is about one in 47,300 newborns. Our results establish mutations in PRODH2 as a cause of human hydroxyprolinemia via impaired dehydrogenation of hydroxyproline to delta1-pyroline-3-hydroxy-5-carboxylic acid, and we suggest PRODH2 be renamed HYPDH. Hydroxyprolinemia is an autosomal-recessively inherited benign condition. It is a frequent cause of false positive screening results for MSUD, the prevalence being about 2.5 times higher than that of MSUD.

Objective To evaluate a systematic newborn screening (NBS) strategy for vitamin B12 deficiency. Study design In a prospective single-center NBS study, a systematic screening strategy for vitamin B12 deficiency was developed and evaluated. Tandem-mass spectrometry screening was complemented by 2 second-tier strategies, measuring methylmalonic/3-OH-propionic/methylcitric acid, and homocysteine from dried blood spots. Results In a cohort of 176 702 children screened over 27 months, 33 children were detected by NBS in whom (maternal) vitamin B12 deficiency was confirmed. Homocysteine was the most sensitive marker for vitamin B12 deficiency, but only combination with a second-tier strategy evaluating methylmalonic acid allowed for detection of all 33 children. Mothers were of various ethnic origins, and 89% adhered to a balanced diet. Treatment in children was performed predominantly by oral vitamin B12 supplementation (84%), and all children remained without clinical symptoms at short-term follow-up. Conclusions Vitamin B12 deficiency is a treatable condition but can cause severe neurologic sequelae in infants if untreated. The proposed screening strategy is feasible and effective to identify moderate and severe cases of vitamin B12 deficiency. With an incidence of 1:5355 newborns, vitamin B12 deficiency is more frequent than inborn errors of metabolism included in NBS panels. Treatment of vitamin B12 deficiency is easy, and additional benefits can be achieved for previously undiagnosed affected mothers. This supports inclusion of vitamin B12 deficiency into NBS but also stresses the need for increased awareness of vitamin B12 deficiency in caregivers of pregnant women.

Background Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. Methods To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. Results In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. Conclusions Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients. Electronic supplementary material The online version of this article (10.1186/s13023-018-0890-7) contains supplementary material, which is available to authorized users.

PURPOSE Prospective evaluation of family history (FH) of glaucoma and FH of optic disc drusen (ODD) in patients with sonographically confirmed ODD. PATIENTS AND METHODS A total of 87 patients with ODD interviewed all their first-degree and second-degree relatives using a detailed questionnaire on whether an ophthalmologist had diagnosed or excluded glaucoma or ocular hypertension (OH). Using a second questionnaire, 62 of these patients also provided information about ODD in their FH. Control groups for FH of glaucoma consisted of 2170 patients with glaucoma or OH evaluated with the same methods and identical questions for FH of glaucoma in a previous study, and of 176 healthy individuals without glaucoma or ODD who were interviewed on family history of glaucoma. RESULTS Glaucoma in FH was significantly more frequent in patients with ODD with an incidence of 20.7% compared with healthy controls with an incidence of 2.8%, and half as frequent as in glaucoma patients with an incidence of 40%. ODD in FH were found in 9.7% of patients with ODD. CONCLUSIONS As there is a high frequency of family history of glaucoma in patients with ODD, evaluation of FH of ODD and FH of glaucoma is essential in patients with ODD. Glaucoma in FH of ODD patients requires intraocular pressure monitoring and whenever deemed beneficial timely initiation of intraocular pressure-lowering therapy.

Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel.Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin BOver a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4% of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 1 3-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin BWithin 13 months, the study "Newborn Screening 2020" identified additional 12 children with treatable conditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B

Background: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children, SCOPUS: ar.j, info:eu-repo/semantics/published

Background In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses—the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. Methods Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. Results Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. Conclusion This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease.

To compare stage of visual field loss (VFL) and age at diagnosis between patients with different types of glaucoma with regard to glaucoma screening and driving ability. In a cross-sectional study of 1988 consecutive patients with different types of glaucoma VFL at diagnosis and age at diagnosis were assessed. Patients with binocular advanced or severe VFL were classified unable, patients with no VFL in one eye and VFL I–V (Aulhorn classification) in the other eye able, all other constellations questionably able to drive. There were significant differences in age at diagnosis between different glaucomas and between patients with different stages of VFL at diagnosis. Age-related assessment of VFL at diagnosis in normal tension glaucoma (NTG) compared to primary open-angle glaucoma (POAG) showed that NTG is not a disease of the elderly but a disease with late diagnosis at severe VFL. In POAG a solely age-related glaucoma screening, e.g. from the age of 50 years, does not sufficiently lead to diagnosis at an early stage of the disease. In POAG solely based on binocular VFL 11.5% of patients were judged unable, 29.2% questionably able to drive, in NTG 19.6%/43.1%, pigmentary glaucoma 16%/22%, pseudoexfoliation glaucoma 9.1%/16.7%, and in primary angle-closure glaucoma 14.6%/30%. Depending on type of glaucoma more than 50% of patients require counselling regarding safe driving as part of clinical care. A disease-specific, age-related perimetric examination considering additional risk factors like family history of glaucoma is essential for early detection of glaucoma and road safety.

Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-ß-synthase deficiency). Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar.A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine, methionine-phenylalanine-ratio and propionylcarnitine as second-tiers. Proposed cut-offs were also retrospectively evaluated in newborn screening samples of 12 patients with remethylation disorders and vitamin BOver a 12 months period, the proposed strategy led to a decrease in the recall rate in homocysteine screening for Qatar from 1.09% to 0.68%, while allowing for additional systematic inclusion of remethylation disorders and vitamin BThe proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B

Purpose To evaluate frequency of migraine, vasospasm (VS), family history (FH) of migraine, and family history of glaucoma (FHG) in different types of glaucoma in relation to age and stage of visual field loss (VFL) at diagnosis. Methods A total of 2170 patients with glaucoma or ocular hypertension (OH) were interviewed by using standardized questions concerning FHG, age at diagnosis, and potential risk factors, including migraine and VS. Of 2027 patients providing information on migraine, 1244 had primary open-angle glaucoma (POAG), 140 normal tension glaucoma (NTG), 49 pigmentary glaucoma, 64 pseudoexfoliation glaucoma (PEX), 138 OH, and 218 primary angle closure glaucoma (PACG). Results Of all patients, 13.7% reported migraine, 19.0% VS, 30.8% FH of migraine, and 40.3% FHG. Patients with FHG had a significantly higher frequency of migraine than patients without FHG (15.7% vs. 12.3%, P = 0.02). Migraine was significantly more frequent in NTG (21.4%) than POAG (13.1%; P = 0.01), PEX (7.8%; P = 0.02), and PACG (10.1%; P = 0.004). Compared to patients with POAG, patients with NTG had a 63.5% higher age-corrected probability for migraine (P = 0.007). There was no evidence for migraine or VS being prognostic factors regarding the extent of VFL at diagnosis. Migraine and VS were significantly more frequent in females. Conclusions The higher frequency of migraine and VS in females could contribute to the female preponderance in NTG. Our findings suggest an association of NTG and migraine and a common, possibly polygenetic, vascular etiology of these two diseases both with familial predisposition.