Health status and comorbidities of adult patients with late-diagnosed phenylketonuria (PKU) born before the newborn screening in France - A nationwide study of health insurance claims data.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism. When diagnosed late, it causes developmental delay or severe irreversible intellectual disability. This study aimed at evaluating the health status and healthcare consumption of late-diagnosed PKU patients in France. METHODS: This retrospective observational study used health insurance claims data from the French SNDS (Système National des Données de Santé) database, which contains data from over 66 million French inhabitants. Patients with PKU were identified between 2006 and 2018 by ICD-10 diagnosis codes E70.0 / E70.1 documented as a chronic condition (affection de longue durée - ALD) or in the inpatient setting. Patients with PKU were matched to controls by age, sex, and region. Patients with late-diagnosed PKU were defined as patients born before the nationwide implementation of newborn screening in France in 1972. Outcomes were analyzed for the year 2018. RESULTS: In total, 3549 patients with PKU were identified in the database on January 1st, 2018. Of those, 3469 patients could be matched to 17,170 controls without PKU. Of these, 2175 patients were at least 16 years old of whom 647 patients were categorized as late-diagnosed. The late-diagnosed PKU patients suffered significantly more often from hypertension (60.9% vs. 50.4%, p < 0.0001), hypercholesterolemia (41.7% vs. 26.9%, p < 0.0001), diabetes (24.4% vs. 14.1%, p < 0.0001), depression (20.6% vs. 13.8%, p < 0.0001), ischemic heart disease (16.1% vs. 6.6%, p < 0.0001), obesity (7.9% vs. 2.5%, inpatient diagnoses only, p < 0.0001), and chronic kidney disease (5.2% vs. 1.3%, inpatient diagnoses only, p < 0.0001) compared with their non-PKU controls. Consequently, significantly more patients with late-diagnosed PKU received medication to treat comorbidities associated with the nervous (82.6% vs 77.0%; p = 0.0021) and cardiovascular system (69.5% vs 58.0%; p < 0.0001). Overall, only 3.4% of patients with late-diagnosed PKU received dietary amino-acid supplements and 0.7% received sapropterin. CONCLUSION: The results indicate that PKU is associated with a significantly higher risk of comorbidities along with increased pharmaceutical prescriptions in patients with late-diagnosed PKU, compared with non-PKU controls. The increased risk of comorbidities was more pronounced than in patients with early-diagnosed PKU, as shown in previous research, but these patients are older than those with early-diagnosed PKU. Only few late-diagnosed patients were treated specifically for PKU. Patients with late-diagnosed PKU should be referred to specialized centers to prevent and manage comordities and introduce PKU-specific treatment when it is possible.

Adults with early diagnosis of phenylketonuria have higher resting energy expenditure than adults with late diagnosis.

INTRODUCTION: To date, there is a gap regarding resting energy expenditure (REE) in adults with phenylketonuria (PKU), whether PKU type and time of diagnosis interfere with REE, and whether the available predictive equations are valid in this population. OBJECTIVE: To compare the REE of adult subjects with PKU with healthy subjects and secondarily, examine the REE of adults with PKU according to type and time of diagnosis, and check the agreement of commonly used predictive equations of REE. METHODS: Concordance study with adults with PKU and a comparison group (CG) with healthy adults. Anthropometric and body composition assessments and REE assessment by indirect calorimetry (IC) were performed. The results obtained by IC were compared with predictive equations. RESULTS: Sixty-nine adults were evaluated (PKU: 36; CG: 33). The REE of adults with mild and classic PKU is similar (p>.05) and similar to CG (p>.05). The REE of individuals with early diagnosis is higher (p < .05) than the REE of individuals with late diagnosis. The REE obtained by IC differed (p < .05) from all estimated REE. CONCLUSION: Late diagnosis of PKU showed lower REE compared to individuals with early diagnosis. The REE of adults with PKU does not differ in relation to the type of PKU, nor does it differ from the CG. Predictive equations overestimate REE.

Health status and comorbidities of adult patients with phenylketonuria (PKU) in France with a focus on early-diagnosed patients - A nationwide study of health insurance claims data.

BACKGROUND: This study aimed at evaluating the health status and healthcare consumption of ≥16-year-old patients with phenylketonuria (PKU), with a focus on early-diagnosed patients. METHODS: This retrospective observational study used health insurance claims data from the French SNDS (Système National des Données de Santé) database. Patients with PKU were identified between 2006 and 2018 by ICD-10 diagnosis codes E70.0 (classic PKU) or E70.1 (other causes of hyperphenylalaninemia). They were matched to controls by age, sex, and region. Patients with early-diagnosed PKU were defined as patients born after implementation of nationwide newborn screening in France in 1972. Outcomes were analyzed for the year 2018. RESULTS: Overall, 3549 patients with PKU were identified on January 1st, 2018. Of those, 3469 patients could be matched to 17,170 controls without PKU. Of these patients, 2175 were at least 16 years old and suffered significantly more than controls from specific comorbidities of interest - osteoporosis (28.7% vs 19.8%, p < 0.0001), hypertension (20.9% vs 17.0%, p < 0.0001), hypercholesterolemia (12.8% vs 8.3%, p < 0.0001), diabetes (7.8% vs 4.7%, p < 0.0001), obesity (4.2% vs 1.3%, p < 0.0001), ischemic heart diseases (4.8% vs 2.0%, p < 0.0001), and depression (10.3% vs 8.2%, p = 0.0011). Prescriptions for many medications were also more frequent in patients with PKU than controls. Among ≥16-year-old patients, 1528 were categorized as early-diagnosed. Osteoporosis (0.3% vs 0.01%, p = 0.0035), chronic renal failure (0.6% vs 0.1%, p = 0.0020), hypertension (4.0% vs 2.7%, p = 0.0063), and obesity (2.5% vs 0.8%, p < 0.0001) were significantly more prevalent in early-diagnosed adult patients compared with matched controls. In total, 28.6% of ≥16-year-old patients with PKU and 40.4% of early-diagnosed patients with PKU received dietary amino-acid supplements. Sapropterin was prescribed to 5.0% and 7.0% patients, respectively. CONCLUSION: The results indicate that PKU is associated with a significantly higher comorbidity risk along with increased pharmaceutical prescriptions in adulthood. The comorbidity burden is less distinct in early-diagnosed patients but still present. Few patients are treated specifically for PKU in adulthood. Healthcare of patients with PKU should include prevention and management of comorbidities and especially target PKU-specific treatment adherence and consistent care in specialized medical centers in adulthood.

Neuropsychological and quality of life outcomes in PKU patients: expert recommendations of assessment tools in Brazil.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by deficient activity of phenylalanine hydroxylase. In Brazil, the National Neonatal Screening Program enables early treatment of patients with PKU, which prevents them from developing severe neurological damage and mental disabilities. However, between 20 and 30% of early-treated patients with PKU present focal cognitive deficits, including deficits in working memory, processing speed, and psychiatric symptoms such as anxiety, depression, and attention deficit hyperactivity disorder (ADHD). Therefore, age-specific neuropsychiatric and cognitive tests are important components of PKU patient care. To date, there are no officially approved guidelines or recommendations of tools in Portuguese validated for use in Brazil that could be applied to assess these parameters in patients with PKU. OBJECTIVE: To recommend tools validated for use in Brazil that can be used in daily clinical practice to assess quality of life and neuropsychological outcomes in patients with PKU. METHODS: Six Brazilian experts discussed about eligible tools based on their clinical experience, the feasibility of their use in clinical routines, and their availability in public health services. Before the meeting, an independent review of the literature was conducted to identify the currently validated tools in Brazil, using the MEDLINE and SciELO databases. RESULTS: The experts recommended nine tools to assess quality of life (Peds-QL, SF-36 or WHOQOL-bref), executive function (BRIEF or Bayley-III), IQ (SONR 2½-7[a] or WASI) and ADHD (MTA-SNAP-IV and ASRS). CONCLUSION: These instruments may be easily incorporated into clinical practice and improve the quality of multidisciplinary care of patients with PKU.

ANTECEDENTES: A fenilcetonúria (PKU) é um erro inato do metabolismo causado pela atividade deficiente da fenilalanina hidroxilase. No Brasil, o Programa Nacional de Triagem Neonatal permite o tratamento precoce de pacientes com PKU, o que os impede de desenvolver danos neurológicos e deficiências intelectuais graves. No entanto, já foi descrito que de 20 a 30% dos pacientes tratados precocemente com PKU apresentam déficits cognitivos focais, incluindo déficits na memória de trabalho, velocidade de processamento e sintomas psiquiátricos como ansiedade, depressão e Transtorno de Déficit de Atenção e Hiperatividade (TDAH). Neste sentido, testes neuropsiquiátricos e cognitivos são componentes importantes no cuidado destes pacientes. Atualmente, não existe um compêndio científico ou recomendações de ferramentas validadas em português para avaliar a saúde mental em pacientes brasileiros com PKU. OBJETIVO: Recomendar ferramentas validadas localmente para avaliar a qualidade de vida e aspectos neuropsicológicos de pacientes com PKU. MéTODOS: Seis especialistas brasileiros discutiram as ferramentas mais apropriadas com base em suas experiências clínicas, a viabilidade de realizar as avaliações na rotina clínica, e o acesso às ferramentas na saúde pública. Antes da reunião, foi realizada uma revisão independente da literatura para identificar as ferramentas validadas no Brasil, utilizando as bases de dados MEDLINE e Scielo. RESULTADOS: Os especialistas recomendaram nove ferramentas para avaliar a qualidade de vida (Peds-QL, SF-36 ou WHOQOL-bref), função executiva (BRIEF ou Bayley-III), QI (SONR 2½-7[a] ou WASI) e TDAH (MTA-SNAP-IV e ASRS). CONCLUSãO: Estes instrumentos podem ser facilmente incorporados na prática clínica e melhorar a qualidade dos cuidados multidisciplinares dos pacientes com PKU.

Cost-Effectiveness of Newborn Screening for Phenylketonuria and Congenital Hypothyroidism.

OBJECTIVE: To evaluate the long-term costs and health effects of the Swedish newborn screening program for classic phenylketonuria (PKU) alone and in combination with congenital hypothyroidism compared with no screening. STUDY DESIGN: A decision-analytic model was developed to estimate and compare the long-term (80 years) costs and health effects of newborn screening for PKU and congenital hypothyroidism. Data were obtained from the literature and translated to Swedish conditions. A societal perspective was taken, including costs falling on health care providers, municipal care and services, as well as production loss due to morbidity. RESULTS: Screening 100 000 newborns for PKU resulted in 73 gained quality-adjusted life-years (QALYs) compared with no screening. When adding congenital hypothyroidism, the number of gained QALYs was 232 compared with PKU alone, adding up to a total of 305 QALYs gained. Corresponding cost estimates were $80.8, $70.3, and $10.05 million USD for no screening, PKU screening, and PKU plus congenital hypothyroidism screening, respectively, indicating that screening for PKU plus congenital hypothyroidism was more effective and less costly compared with the other strategies. The majority of cost savings with PKU plus congenital hypothyroidism screening was due to reductions in productivity losses and municipal care and services costs. CONCLUSION: The Swedish newborn screening program for PKU and congenital hypothyroidism saves substantial costs for society while generating additional QALYs, emphasizing the importance of public investments in early diagnosis and treatment.

Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria.

Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU.

Assessment of parents´ knowledge regarding phenylketonuria and its affecting factors: a cross-sectional study.

Introduction: the management of phenylketonuria (PKU) is complex. Practical skills and knowledge of individuals taking care of PKU patients are important for treatment compliance. This study investigated parents´ knowledge about PKU and its affecting factors. The study group consisted of 62 parents of PKU patients. Methods: data were collected using a ready-made questionnaire on sociodemographic characteristics, PKU and dietary treatment. Total knowledge score (KS) was calculated by giving 5 points for each correct answer. Results: the study included 34 mothers and 28 fathers; 90.3% of patients were diagnosed during the newborn screening program, 6.5% between ages 1 and 2, and 3.2% at age 6 or after. Among all, 38.7% presented to their follow-up appointments with their mothers, 61.3% with both their parents and none with their father alone. Mothers answered all questions more accurately than fathers. Mothers´ and fathers´ mean KSs were 73.97 ± 12.72 and 53.04 ± 22.25, respectively. The highest KS was obtained among parents whose children were 13 years of age or older. Conclusion: the presence of another family member, parents´ education level, working status and professional qualifications, previous training on PKU and family´s economic status were the affecting factors. Creating a PKU dietary plan requires knowledge and diligence. Patients and their parents should be periodically informed about the disease and dietary treatment in order to increase their level of knowledge.

Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey.

Many countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS.

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective.

Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60-80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.

Multiple SNPs Detection Based on Lateral Flow Assay for Phenylketonuria Diagnostic.

Single nucleotide polymorphisms (SNPs) are closely related to genetic diseases, but current SNP detection methods, such as DNA microarrays that include tedious procedures and expensive, sophisticated instruments, are unable to perform rapid SNPs detection in clinical practice, especially for those multiple SNPs related to genetic diseases. In this study, we report a sensitive, low cost, and easy-to-use point-of-care testing (POCT) system formed by combining amplification refractory mutation system (ARMS) polymerase chain reaction with gold magnetic nanoparticles (GMNPs) and lateral flow assay (LFA) noted as the ARMS-LFA system, which allow us to use a uniform condition for multiple SNPs detection simultaneously. The genotyping results can be explained by a magnetic reader automatically or through visual interpretation according to the captured GMNPs probes on the test and control lines of the LFA device. The high sensitivity (the detection limit of 0.04 pg/µL with plasmid) and specificity of this testing system were found through genotyping seven pathogenic SNPs in phenylalanine hydroxylase gene ( PAH, the etiological factor of phenylketonuria). This system can also be applied in DNA quantification with a linear range from 0.02 to 2 pg/µL of plasmid. Furthermore, this ARMS-LFA system was applied to clinical trials for screening the seven pathogenic SNPs in PAH of 23 families including 69 individuals. The concordance rate of the genotyping results detected by the ARMS-LFA system was up to 97.8% compared with the DNA sequencing results. This method is a very promising POCT in the detection of multiple SNPs caused by genetic diseases.

An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand.

BACKGROUND: Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. METHOD: A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. RESULTS: The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. CONCLUSION: At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem.

Trascendencia del Test del Piecito en la unidad de salud de la familia (USF) de Capitán Meza Km. 16 durante los meses de enero a junio del 2015 / Transcendence of the Piecito Test in the family health unit (USF) of Captain Meza Km. 16 during the months of january to june 2015

El test del piecito es un estudio que debe hacerse a todo recién nacido y sirve para diagnosticar enfermedades que pueden producir retardo mental. La detección temprana de los bebés afectados es muy importante para el éxito en la prevención de la enfermedad. Debe hacerse a todo recién nacido de manera obligatoria hasta los 30 días después del alumbramiento. En Paraguay la frecuencia de del Hipotiroidismo congénito es de alrededor 1 por cada 3.000 nacidos. El objetivo del presente trabajo es analizar la trascendencia que tuvo la realización del Test del piecito en la Unidad de Salud de la Familia (USF) de Capitán Meza Km. 16 durante los meses de Enero a Junio del 2015. Se realizó un estudio descriptivo, analítico, trasversal, retrospectivo, con metodología cuali-cuantitativa. Se revisaron en total 22 historias clínicas de niños a los que se les realizó el tamizaje neonatal. Los meses de Abril y Mayo fueron los que más Test del Piecito realizaron durante el periodo de estudio con un 22,73 % cada uno. Durante el periodo de estudio, el 100 % de los niños examinados tuvieron resultados negativos al Test del piecito. El sexo de los recién nacidos y sus lugares de procedencia no determinan la realización o no de los exámenes. Si bien el hecho de vivir en zonas alejadas pudiera significar un contratiempo en la accesibilidad al sistema de salud. Desde la toma de la muestra hasta la entrega de los resultados transcurren aproximadamente dos meses. Si los padres no se acercan a retirar los resultados estos se les llevan a su casa durante las visitas domiciliarias que se realizan como parte del trabajo de la atención primaria que desarrolla la USF de Capitán Meza Km. 16

The "Test del piecito" is a test that should be done every newborn and used to diagnose diseases that can cause mental retardation. Early detection of affected babies is very important for success in preventing disease. Everything must be done compulsorily newborn up to 30 days after delivery. In Paraguay the frequency of congenital hypothyroidism is about 1 per 3,000 births. The aim of this paper is to analyze the importance that had the realization of "Test del piecito" in Unit Family Health (USF) Capitan Meza Km. 16 during the months of January to June 2015. A descriptive study was conducted, analytical, transversal, and retrospective, with qualitative and quantitative methodology. Medical records of 22 children who underwent neonatal screening were reviewed in total. The months of April and May were the most "Test del piecito" performed during the study period with 22.73% each. During the study period, 100% of the children surveyed had negative results to "Test del piecito". The sex of newborns and their places of origin do not determine how or whether the exams. While the fact of living in remote areas could mean a setback in accessibility to health care. From sampling to delivery of results takes approximately two months. If parents do not come close to removing these results are taken home during home visits carried out as part of the work of primary care developed by the USF Capitan Meza Km. 16

Newborn screening in southeastern Europe.

The aim of our study was to assess the current state of newborn screening (NBS) in the region of southeastern Europe, as an example of a developing region, focusing also on future plans. Responses were obtained from 11 countries. Phenylketonuria screening was not introduced in four of 11 countries, while congenital hypothyroidism screening was not introduced in three of them; extended NBS programs were non-existent. The primary challenges were identified. Implementation of NBS to developing countries worldwide should be considered as a priority.

Two faces of patient advocacy: the current controversy in newborn screening.

Newborn screening programmes began in the 1960s, have traditionally been conducted without parental permission and have grown dramatically in the last decade. Whether these programmes serve patients' best interests has recently become a point of controversy. Privacy advocates, concerned that newborn screening infringes upon individual liberties, are demanding fundamental changes to these programmes. These include parental permission and limiting the research on the blood samples obtained, an agenda at odds with the viewpoints of newborn screening advocates. This essay presents the history of newborn screening in the USA, with attention to factors that have contributed to concerns about these programmes. The essay suggests that the rapid increase in the number of disorders screened for and the addition of research without either public knowledge or informed consent were critical to the development of resistance to mandatory newborn screening and research. Future newborn screening initiatives should include public education and comment to ensure continued support.

[Assessment of the life quality in children with phenylketonuria].

BACKGROUND: Phenylketonuria (PKU) - the most common inherited disorder of amino acid metabolism, identified in Russia by neonatal screening. The results of dietary treatment demonstrate a positive effect. However, the quality of PKU patients life remains unknown. OBJECTIVE: The aim of the study was to assess the quality of PKU children life in comparison with their healthy peers, also depending on the treatment onset and the patient's age. METHODS: The study involved 64 pairs - PKU child and one of his parents. It was used the common questionnaire survey Pediatric Quality of Life Inventory (PedsQLtm4. 0, Varni et al., USA, 2001) and the program SPSS v. 14.0 (US) for statistical processing of the results. RESULTS: The statistically significant (p <0.001) differences between PKU patients and healthy children in the physical, emotional, social and role functioning were found. The most pronounced differences were observed in the social (70 points vs 90 respectively) and role (57.5 vs 80 respectively) functioning. Maximum significant correlation (p <0.001) was installed between the social functioning of PKU patients and timing of the dietary treatment. Also the statistically significant interaction (p <0.05) was found between the role functioning, patient's age and treatment onset. The assessment points of social and role functioning were higher (p <0.05) in the PKU patients subgroup with early treatment initiation. CONCLUSION: These results confirmed the need of early diagnostics of PKU and initiation of dietary treatment, as well as the organization of timely psychological support for parents of sick children.

[Use of computerized neuropsychological tests and of nuclear magnetic resonance spectroscopy in clinical assessment of adult patients with phenylketonuria]. / Zastosowanie komputerowych testów neuropsychologicznych oraz spektroskopii magnetycznego rezonansu jadrowego w klinicznej ocenie doroslych pacjentów z fenyloketonuria.

Phenylketonuria is the most common inborn error of metabolism. Adult patients often discontinue dietary treatment and can subsequently develop serious brain dysfunction. Some of them, however, do not present any symptoms, despite long-term exposition to high blood phenylalanine concentration. As the extent of brain toxicity of hyperphenylalaninemia is not clear in adults, new diagnostic methods are needed to assess brain effects of hyperphenylalaninemia. The aim of the study was to evaluate the usefulness of magnetic resonance spectroscopy and of computerized neuropsychological tests for measurement of brain phenylalanine concentration and for early detection of hyperphenylalaninemia-related brain dysfunction. Assessment of sustained attention, working memory and inhibitive control was performed in a group of 50 adults with phenylketonuria by means of computerized CANTAB system. Additionally, in 40 patients, measurement of brain phenylalanine signal was done by means of magnetic resonance spectroscopy. The results were correlated with plasma phenylalanine concentrations. Worsening of neuropsychological efficiency as well as increase of brain phenylalanine concentration correlated with high levels of plasma phenylalanine. Interestingly, in two cases, despite high plasma phenylalanine concentration, low brain phenylalanine concentration was observed accompanied by good results of neuropsychological tests. This finding suggests presence of mechanisms limiting brain toxicity of hyperphenylalaninemia in some patients. It should be stressed, however, that such situation can be expected rarely, and is probably restricted to cases with moderate hyperphenylalaninemia. Combination of computerized neu- ropsychological tests and of magnetic resonance spectroscopy is a useful diagnostic method which could allow for careful individualization of dietary recommendations in selected patients with phenylketonuria.

Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany.

BACKGROUND: National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome. METHODS: In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated. RESULTS: Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two. CONCLUSIONS: Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.