Treatment Outcomes for Maple Syrup Urine Disease Detected by Newborn Screening.

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.

Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias.

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.

A Needs-Based Analysis of Teaching on Vaccinations and COVID-19 in German Medical Schools.

The COVID-19 pandemic highlights the need for improving public confidence in vaccines. Academic gaps and redundancies on vaccinations must be identified to revise the medical curriculum for up-to-date training of medical students. This cross-sectional survey assessed the status of vaccine-related teaching in general and specific to COVID-19 in medical schools across Germany. A total of 4313 medical students completed a questionnaire comprising items on national learning goals and perceived needs for teaching on vaccinations. Mixed methods were used to analyse data quantitatively for relative frequencies (%) and correlations between teaching items and semesters (Spearman's rho), and qualitatively (content analysis). Our findings showed that 38.92% of the students were dissatisfied with teaching on vaccine-preventable diseases, but the perceived satisfaction increased in later semesters (r = 0.46, p < 0.001). Moreover, 75.84% and 68.15% of the students were dissatisfied with teaching related to vaccine scepticism and vaccine-related communication strategies, respectively. Furthermore, 63.79% reported dissatisfaction with teaching on COVID-19 disease and 72.93% with teaching on COVID-19 vaccines. A total of 79.12% stated they educated others on COVID-19 and its vaccines and 75.14% felt responsible to do so. A majority of the medical students were dissatisfied with teaching on dealing with vaccine scepticism, communication strategies and COVID-19 vaccines. We recommend practice-oriented vaccine education, especially for teaching communication skills to medical students.

How longitudinal observational studies can guide screening strategy for rare diseases.

Newborn screening (NBS) is an important secondary prevention program, aiming to shift the paradigm of medicine to the pre-clinical stage of a disease. Starting more than 50 years ago, technical advances, such as tandem mass spectrometry (MS/MS), paved the way to a continuous extension of NBS programs. However, formal evidence of the long-term clinical benefits in large cohorts and cost-effectiveness of extended NBS programs is still scarce. Although published studies confirmed important benefits of NBS programs, it also unraveled a significant number of limitations. These include an incompletely understood natural history and phenotypic diversity of some screened diseases, unreliable early and precise prediction of individual disease severity, uncertainty about case definition, risk stratification, and indication to treat, resulting in a diagnostic and treatment dilemma in individuals with ambiguous screening and confirmatory test results. Interoperable patient registries are multi-purpose tools that could help to close the current knowledge gaps and to inform further optimization of NBS strategy. Standing at the edge of introducing high throughput genetic technologies to NBS programs with the opportunity to massively extend NBS programs and with the risk of aggravating current limitations of NBS programs, it seems overdue to include mandatory long-term follow-up of NBS cohorts into the list of screening principles and to build an international collaborative framework that enables data collection and exchange in a protected environment, integrating the perspectives of patients, families, and the society.

Impact of interventional and non-interventional variables on anthropometric long-term development in glutaric aciduria type 1: A national prospective multi-centre study.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl-CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long-term outcome. This national prospective, observational, multi-centre study included 79 patients identified by NBS and investigated effects of interventional and non-interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non-adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS -1.07; P = .023) and body length (mean SDS -1.34; P = -.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS -0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS -0.68; P = .016). In GA1, recommended long-term treatment is effective and allows for normal anthropometric long-term development up to adolescence, with gender- and excreter type-specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis.

PURPOSE: Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome. METHODS: Systematic literature search for articles published from 2000 to 2019 was performed using the PRISMA protocol. Studies reporting on more than one individual identified by NBS were included. We investigated effects of interventional and noninterventional variables on neurological outcome. RESULTS: Fifteen publications reporting on 647 GA1 patients were included. In the NBS group (n = 261 patients), 195 patients remained asymptomatic (74.7%), while 66 patients (25.3%) developed a MD. Compared with the NBS group, a much higher proportion of patients (349/386; 90.4%; p < 0.0001) diagnosed after the manifestation of neurologic symptoms had a MD and an abnormal motor development (285/349; 81.7%; p < 0.0001). For NBS patients, deviations from the recommended diet increased the risk of insidious onset MD, while delayed start of emergency treatment increased the risk of acute onset MD. CONCLUSIONS: This meta-analysis demonstrates that NBS programs for GA1 have an overall positive effect on the neurological outcome of affected individuals but their success critically depends on the quality of therapy.

Newborn screening: A disease-changing intervention for glutaric aciduria type 1.

OBJECTIVE: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. METHODS: This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children. RESULTS: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study. INTERPRETATION: NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.