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Abstract Background Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Main body In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. Conclusion This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Background: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe. Methods: A cross sectional questionnaire (survey monkey®) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis. Results: Weaning started at 17–26 weeks in 85% (n = 81/95) of centres, >26 weeks in 12% (n = 11/95) and 26 weeks. First solids were mainly low Phe vegetables (59%, n = 56/95) and fruit (34%, n = 32/95).A Phe exchange system to allocate dietary Phe was used by 52% (n = 49/95) of centres predominantly from Northern and Southern Europe and 48% (n = 46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods.A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% (n = 39/95) of centres at infant age 26–36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% (n = 35/95) at infant age > 1y mainly from Southern Europe. 53% (n = 50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form. Conclusions: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development. Keywords: Weaning, Infant, Phenylketonuria, Phenylalanine, Phe-free infant formula

Background: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. Methods: We sent a cross sectional, survey monkey® questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Results: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, ≥26 weeks in 12% and

Abstract Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Pyruvate dehydrogenase complex (PDHc) defect is a well-known cause of mitochondrial disorders (MD) with at least six responsible genes (PDHA1, PDHB, DLAT, DLD, PDHX, PDP1). The aim of this work was to assess the diagnostic value of biochemical methods in recognition of PDHc defect in Polish patients with suspicion of MD. In the first step, Western blot of the E1α subunit was performed on 86 archive muscle bioptates with suspicion of MD. In the second step, Sanger PDHA1 sequencing was performed in 21 cases with low E1α expression. In the third step, 7 patients with negative results of PDHA1 sequencing were subjected to whole-exome sequencing (WES). This protocol revealed 4 patients with PDHA1 and one with DLD mutations. Four additional probands were diagnosed outside the protocol (WES or Sanger sequencing). The molecular characterization of PDHc defect was conducted in a total of 9 probands: 5 according to and 4 off the protocol. Additionally, two affected relatives were recognized by a family study. Altogether we identified seven different PDHA1 changes, including two novel variants [c.464T > C (p.Met155Thr) and c.856_859dupACTT (p.Arg288Leufs*10)] and one DLD variant. The lactate response to glucose load in the PDHA1 subset was compared to a subset of non PDHc-related MD. Opposite responses were observed, with an increase of 23% and decrease of 27%, respectively. The results show that determining lactate response to glucose load and muscle E1α expression may contribute to distinguishing PDHc-related and other MD, however, WES is becoming the method of choice for MD diagnostics.

An amendment to this paper has been published and can be accessed via the original article.

In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1-57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.

Background: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only eight documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1., Objective: To provide a comprehensive overview of the clinical and immunological findings of patients with B-cell deficiency attributed to variants in IGLL1., Methods: NBS programs reporting using kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts and no alternative diagnosis were included., Results: The study included 13 patients identified through NBS, two clinically diagnosed patients, and two asymptomatic siblings. All had severely reduced CD19+ B-cells (< 0.1×10 9 /L) on first evaluation, yet subsequent follow-ups indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with immunoglobulin G substitution. Two patients successfully discontinued substitution without developing susceptibility to infections and maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100´000, almost double of X-linked agammaglobulinemia., Conclusion: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far., (Copyright © 2024. Published by Elsevier Inc.)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320, ORPHA:98920) is a rare autosomal recessive congenital motor neuron disease. It is caused by variants in the IGHMBP2 gene. Clinically, it presents with respiratory failure due to diaphragmatic paralysis, progressive muscle weakness starting in the distal parts of the limbs, dysphagia, and damage to sensory and autonomic nerves. Unlike spinal muscular atrophy (SMA), SMARD1 has a distinct genetic etiology and is not detected in the population newborn screening programs. Most children with SMARD1 do not survive beyond the first year of life due to progressive respiratory failure. Artificial ventilation can prolong survival, but no specific treatment is available. Therapy focuses on mechanical ventilation and improving the patient's quality of life. Research into gene therapy is ongoing. We report three female patients with SMARD1, including twins from a triplet pregnancy. In twin sisters (patient no. 1 and patient no. 2), two heterozygous variants in the IGHMBP2 gene were identified: c.595G>C/p.Ala199Pro and c.1615&#95;1623del/p.Ser539&#95;Tyr541del. In patient no. 3, a variant c.1478C>T/p.Thr493Ile and a variant c.439C>T/p.Arg147* in the IGHMBP2 gene were detected. Our findings underscore the variability of clinical presentations, even among patients sharing the same pathogenic variants in the IGHMBP2 gene, and emphasize the importance of early genetic diagnosis in patients presenting with respiratory failure, with or without associated diaphragmatic muscle paralysis.

Background: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe., Methods: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications., Results: A total of 1323 patients (age range:1-57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU ( n = 625, 48%), followed by mild PKU ( n = 357, 27%) and hyperphenylalaninemia (HPA) ( n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2-5 years: 84%; 6-12 years: 73%; 13-18 years: 85%; 19-30 years: 64%; 31-40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher ( p < 0.001) in patients with HPA (290 ± 325 μmol/L; 96 ± 24%) and mild PKU (365 ± 224 μmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 μmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels ( p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6-12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13-18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31-40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin ( n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 μmol/L; percentage within target 84 ± 39% vs. 406 ± 334 μmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control ( p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 μmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 μmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 μmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 μmol/L, (70 ± 58%)., Conclusions: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Phenylketonuria (PKU) is a genetic disorder that follows an autosomal recessive inheritance pattern. Dietary treatment is the cornerstone of therapy and is based on natural protein restriction, Phe-free L-amino acid supplements (protein substitutes) and low protein foods. The aim of this project was to collect information about the clinical management of patients with PKU, focusing on understudied or unresolved issues such as blood phenylalanine (Phe) fluctuations and clinical symptoms, particularly gastro intestinal (GI) discomfort and sleep problems. The survey consisted of 10 open-ended and 12 multiple-choice questions that collected information about size of the PKU population in each center, the center's clinical practices and the outcomes observed by the center concerning adherence, clinical and biochemical abnormalities and clinical symptoms (GI and sleep). The questionnaire was sent to 72 experts from metabolic centers in 11 European countries. Thirty-three centers answered. The results of this survey provide information about the clinical practice in different age groups, concentrating on dietary tolerance, treatment adherence, and metabolic control. All the centers prescribed a Phe-restricted diet, with Phe-free/low Phe protein substitutes and low protein foods. Daily doses given of protein substitutes varied from 1 to 5, with adherence to the prescribed amounts decreasing with increasing age. Respondents identified that improvement in the flavor, taste, volume and smell of protein substitutes may improve adherence. Finally, the survey showed that clinical symptoms, such as GI discomfort and sleep problems occur in patients with PKU but are not systematically evaluated. Twenty-four-hour Phe fluctuations were not routinely assessed. The results highlight a strong heterogeneity of approach to management despite international PKU guidelines. More clinical attention should be given to gastrointestinal and sleep problems in PKU., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue. It presents with a wide spectrum of skeletal and extraskeletal features, and ranges in severity from mild to perinatal lethal. The disease is characterized by a heterogeneous genetic background, where approximately 85%-90% of cases have dominantly inherited heterozygous pathogenic variants located in the COL1A1 and COL1A2 genes. This paper presents the results of the first nationwide study, performed on a large cohort of 197 Polish OI patients. Variants were identified using a next-generation sequencing (NGS) custom gene panel and multiplex ligation probe amplification (MLPA) assay. The following OI types were observed: 1 (42%), 2 (3%), 3 (35%), and 4 (20%). Collagen type I pathogenic variants were reported in 108 families. Alterations were observed in α1 and α2 in 70% and 30% of cases, respectively. The presented paper reports 97 distinct causative variants and expands the OI database with 38 novel pathogenic changes. It also enabled the identification of the first glycine-to-tryptophan substitution in the COL1A1 gene and brought new insights into the clinical severity associated with variants localized in "lethal regions". Our results contribute to a better understanding of the clinical and genetic aspects of OI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sałacińska, Pinkier, Rutkowska, Chlebna-Sokół, Jakubowska-Pietkiewicz, Michałus, Kępczyński, Salachna, Wieczorek-Cichecka, Piotrowicz, Chilarska, Jamsheer, Matusik, Wilk, Petriczko, Giżewska, Stecewicz, Walczak, Rybak-Krzyszkowska, Lewiński and Gach.)

The two aims of this study were (i) to describe and expand the phenotypic spectrum of PIGT deficiency in affected individuals harboring the c.1582G>A; p.Val528Met or the c.1580A > G; p.Asn527Ser variant in either homozygous or compound heterozygous state, and (ii) to identify potential genotype-phenotype correlations and any differences in disease severity among individuals with and without the PIGT variants. The existing literature was searched to identify individuals with and without the two variants. A detailed phenotypic assessment was performed of 25 individuals (both novel and previously published) with the two PIGT variants. We compared severity of disease between individuals with and without these PIGT variants. Twenty-four individuals carried the PIGT variant Val528Met in either homozygous or compound heterozygous state, and one individual displayed the Asn527Ser variant in a compound heterozygous state. Disease severity in the individual with the Asn527Ser variant was compatible with that in the individuals harboring the Val528Met variant. While individuals without the Asn527Ser or Val528Met variant had focal epilepsy, profound developmental delay (DD), and risk of premature death, those with either of the two variants had moderate to severe DD and later onset of epilepsy with both focal and generalized seizures. Individuals homozygous for the Val528Met variant generally became seizure-free on monotherapy with antiepileptic drugs, compared to other PIGT individuals who were pharmaco-resistant. Two patients were diagnosed with myoclonic-atonic seizures, and a single patient was diagnosed with eyelid myoclonia. Our comprehensive analysis of this large cohort of previously published and novel individuals with PIGT variants broadens the phenotypical spectrum and shows that both Asn527Ser and Val528Met are associated with a milder phenotype and less severe outcome. Our data show that PIGT is a new candidate gene for myoclonic atonic epilepsy. Our genotype-phenotype correlation will be useful for future genetic counseling. Natural history studies of this mild spectrum of PIGT- related disorder may shed light on hitherto unknown aspects of this rare disorder., Competing Interests: ABe was employed by the company GeneDx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the author MG., (Copyright © 2021 Bayat, Pendziwiat, Obersztyn, Goldenberg, Zacher, Döring, Syrbe, Begtrup, Borovikov, Sharkov, Karasińska, Giżewska, Mitchell, Morava, Møller and Rubboli.)

Background: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH 4 ), although there is no consensus on the definition of BH 4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH 4 responsiveness being used around the world., Methods: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other)., Results: We analysed 166 responses. Long-term BH 4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH 4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently., Conclusion: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH 4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH 4 treatment., Competing Interests: Declaration of Competing Interest RAFE has received financial support from Biomarin for attending symposia. AMJvW has received a research grant form Nutricia, honoraria from Biomarin as speaker, and travel grants from Nutricia and Vitaflo. AMB has received a speakers fee from Nutricia and has been a member of advisory boards for Biomarin. MG received honoraria and was a consultant for: Nutricia International/Danone, Merck-Serono, Mead Johnson, BioMarin and Vitaflo. JCR has been a member of the European Nutritionist Expert Panel [Biomarin], the Advisory Board for Applied Pharma Research and Nutricia, and received honoraria as a speaker from APR, Merck Serono, Biomarin, Nutricia, Vitaflo, Cambrooke, PIAM and Lifediet. FJvS is a member of scientific advisory boards for PKU and aminoacid defects that are supported by Agios, Applied Pharma Research, Arla Food Int, BioMarin, Eurocept, Homology, Lucane, Nestle-Codexis Alliance, Nutricia, orphan Europe, Rivium Medical BV, Vivet, has received research grants from Alexion, BioMarin, Beatrix Research Fund, Codexis, ESPKU, NPKUA, NPKUV, Nutricia, Sobi, Tyrosinemia Foundation, Vitaflo, ZONMW, and has received honoraria as a consultant and speaker from Applied Pharma Research, Biomarin, MendeliKABS, Nutricia, Pluvia, SoBi, and Vitaflo. AM is an advisory board member for ELEMENT, Danone-Nutricia, Arla, and Applied Pharma Research, and has received research funding and honoraria from Applied Pharma Research, Nutricia, and Vitaflo International. All other authors reported no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000-100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-B low NK+ SCID, one case of atypical T low B low NK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe., (Copyright © 2020 Giżewska, Durda, Winter, Ostrowska, Ołtarzewski, Klein, Blankenstein, Romanowska, Krzywińska-Zdeb, Patalan, Bartkowiak, Szczerba, Seiberling, Birkenfeld, Nauck, von Bernuth, Meisel, Bernatowska, Walczak and Pac.)

An amendment to this paper has been published and can be accessed via the original article.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine., Main Body: In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment., Conclusion: This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Cysts of the septum pellucidum (CSP) are usually asymptomatic; however, in some cases they can begin expanding and cause neurological deterioration. The mechanism leading to the formation of an expanding cyst of the septum pellucidum (ECSP) is not known. Based on observations made during endoscopic treatment of ECSP we analyzed intraoperative findings in respect to cyst formation mechanism and treatment prognosis. A group of 31 patients was studied. Only cases with bulging cyst walls occupying the frontal horns observed on imaging studies were included. The main symptom was a severe, intermittent headache. In three cases short term memory deficits were diagnosed. In one case papilloedema was observed. All patients underwent endoscopic fenestration of the ECSP. There were no cases of cyst reocclusion during a follow-up period of 1-14 years (mean 6.2 years). In 30 cases headaches resolved completely and in one case its intensity was significantly smaller. There was one case of postoperative hemiparesis. In all but two cases the thin, translucent region in the anterior part of the cyst floor was found. In the region small fissures and in three cases choroid plexus were observed. Endoscopic fenestration is the efficient treatment for ECSP. ECSP is formed on the basis of not completely closed, developmental communication of the cyst with other fluid spaces. The communication is opened by transient elevation of intraventricular pressure, and acts as a valve leading to fluid accumulation among the walls of the previously asymptomatic cavum septum pellucidum.

Background: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe., Methods: A cross sectional questionnaire (survey monkey®) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis., Results: Weaning started at 17-26 weeks in 85% ( n  = 81/95) of centres, >26 weeks in 12% ( n  = 11/95) and < 17 weeks in 3% ( n  = 3/95). Infant's showing an interest in solid foods, and their age, were important determinant factors influencing weaning commencement. 51% ( n  = 48/95) of centres introduced Phe containing foods at 17-26 weeks and 48% ( n  = 46/95) at >26 weeks. First solids were mainly low Phe vegetables (59%, n  = 56/95) and fruit (34%, n  = 32/95).A Phe exchange system to allocate dietary Phe was used by 52% ( n  = 49/95) of centres predominantly from Northern and Southern Europe and 48% (n = 46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods.A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% ( n  = 39/95) of centres at infant age 26-36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% ( n  = 35/95) at infant age > 1y mainly from Southern Europe. 53% ( n  = 50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form., Conclusions: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development.

Introduction: Inborn errors of tetrahydrobiopterin (BH 4 ) biosynthesis or recycling are a group of very rare neurometabolic diseases. Following growing awareness and improved availability of drug treatment the number of patients with BH 4 disorders reaching adulthood is constantly increasing. Pregnancy care of patients with these disorders is therefore a new challenge for clinicians., Methods: This retrospective study summarises for the first time clinical and biochemical monitoring data of 16 pregnancies in seven women with different disorders of BH 4 metabolism and evaluates treatment regimens before and during pregnancy in relation to the obstetrical outcome and paediatric follow-up., Results: Worsening of pre-existing neurological symptoms or occurrence of new symptoms during pregnancy was not observed in most of the cases. Treatment regimens remained mostly unchanged. Pregnancies were not complicated by disease-specific features. Organ abnormalities, miscarriage, prematurity, IUGR and chromosomal changes were occasionally reported, without showing any association with the standard drug treatment for BH 4 deficiencies., Conclusion: Although our data on 16 pregnancies in seven patients did not present any association of standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or paediatric outcome, an intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH 4 deficiency is essential since available data on pregnancies in patients with BH 4 deficiencies is limited.

Background: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe., Methods: We sent a cross sectional, survey monkey® questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions., Results: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres ( n  = 35/95), whereas 44% ( n  = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, ≥26 weeks in 12% and < 17 weeks in 3%., Discussion: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development.

Rationale: Existing research into the effects of teat application has mainly focused on its negative and positive influence on the development of the oral cavity. Our work demonstrates that apart from changing the setting of the articulatory organs, the teat can also affect the quality of breathing, eating and sleeping., Patients Concerns: We described the cases of 2 children: a 19-month-old girl and a 2.5-month-old boy, who had breathing disorders due to withdrawal of the tongue and impaired food intake., Intervention: The babies were bottled fed with a special teat for cleft lip patients to observe the influence of the teat on the setting of the articulatory organs and breathing., Diagnosis: We suspected that the specific construction of the teat-the wide outer part and the short internal part-would affect children's reflexes and articulatory organs so as to force the frontal position of the tongue, which was meant to facilitate breathing and eating., Outcomes: It was found that feeding with the cleft lip teat stimulates the gyro-linguistic muscle, which results in the proper position of the tongue and consequently better breathing and improved quality of sleep., Lessons: A specialist bottle teat designed for babies with cleft lips can constitute an effective tool in the therapy of nonspecific respiratory disorders resulting from improper position of the tongue and other articulatory organs.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 μmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 μmol/L and 600 μmol/L, and lifelong treatment is recommended if the concentration is more than 600 μmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 μmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 μmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 μmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pyruvate dehydrogenase complex (PDHc) defect is a well-known cause of mitochondrial disorders (MD) with at least six responsible genes (PDHA1, PDHB, DLAT, DLD, PDHX, PDP1). The aim of this work was to assess the diagnostic value of biochemical methods in recognition of PDHc defect in Polish patients with suspicion of MD. In the first step, Western blot of the E1α subunit was performed on 86 archive muscle bioptates with suspicion of MD. In the second step, Sanger PDHA1 sequencing was performed in 21 cases with low E1α expression. In the third step, 7 patients with negative results of PDHA1 sequencing were subjected to whole-exome sequencing (WES). This protocol revealed 4 patients with PDHA1 and one with DLD mutations. Four additional probands were diagnosed outside the protocol (WES or Sanger sequencing). The molecular characterization of PDHc defect was conducted in a total of 9 probands: 5 according to and 4 off the protocol. Additionally, two affected relatives were recognized by a family study. Altogether we identified seven different PDHA1 changes, including two novel variants [c.464T > C (p.Met155Thr) and c.856&#95;859dupACTT (p.Arg288Leufs*10)] and one DLD variant. The lactate response to glucose load in the PDHA1 subset was compared to a subset of non PDHc-related MD. Opposite responses were observed, with an increase of 23% and decrease of 27%, respectively. The results show that determining lactate response to glucose load and muscle E1α expression may contribute to distinguishing PDHc-related and other MD, however, WES is becoming the method of choice for MD diagnostics.

To avoid potentially severe outcomes, phenylketonuria (PKU) must be detected as soon as possible after birth and managed with life-long treatment. A questionnaire-based survey was performed to document diagnosis and management practices for PKU in a region of Southern and Eastern Europe. Prevalence and management data were obtained from 37/59 (63 %) centres within 19/22 (86%) contacted countries (N = 8600 patients). The main results' analysis was based on completed questionnaires obtained from 31 centres (53%) within 15 countries (68%). A median of 10 % of patients per centre had been diagnosed after the newborn period. Metabolic dieticians and specialised adult PKU clinics were lacking in 36 and 84% of centres, respectively. In 26% of centres, treatment initiation was delayed until >15 days of life. Blood phenylalanine (Phe) thresholds to start treatment and upper Phe targets were inconsistent across centres. Ten percent of centres reported monitoring Phe every 2 weeks for pregnant women with PKU, which is insufficient to minimise risk of neonatal sequalae. Sapropterin dihydrochloride treatment was available in 48% of centres, with 24-h responsiveness tests most common (36%). Only one centre among the five countries lacking newborn screening provided a completed questionnaire., Conclusion: Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches for PKU in Southern and Eastern Europe., What Is Known: PKU must be detected early and optimally managed throughout life to avoid poor outcomes, yet newborn screening is not universal and diagnostic and management practices for PKU are known to vary widely between different centres and countries. Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches., What Is New: PKU management practices are documented in 19 South and Eastern European countries indicating a heterogeneous situation across the region. Key areas for improvement identified in surveyed centres include a need for comprehensive screening in all countries, increased number of metabolic dietitians and specialised adult PKU clinics, delayed time to treatment initiation, appropriate Phe thresholds, Phe targets and monitoring frequencies, and universal access to currently available treatment options.

We present a case of a child with MELAS syndrome (mitochondrial encephalo-myopathy with lactic acidosis and stroke-like episodes), discussing clinical manifestation, ocular findings and diagnostic challenges. Predominant ocular symptom was a transient complete visual loss, while the predominant ocular sign was a visual field defect. The diagnosia was based on clinical manifestation, laboratory tests, brain scans and genetic testing which confirmed the pathognomonic mutation in the MTTL1 gene encoding the mitochondrial tRNA for leucine 3243> G. Ocular examination demonstrated decreased visual acuity (with bilateral best corrected visual acuity of .1). Periodical, transient visual loss and visual field defects were clinically predominant. Specialist investigations were carried out, which demonstrated homonymous hemianopia (kinetic perimetry), bilateral partial optic nerve atrophy (RetCam). Funduscopy and electrophysiology mfERG study did not confirm features of retinitis pigmentosa. The brain scans revealed numerous small cortical ischemic lesions within the frontal, parietal and temporal lobes, post-stroke focal areas within the occipital lobes and diffuse calcifications of the basal ganglia. During several years of follow-up, visual field defects showed progressive concentric narrowing. The patient received a long-term treatment with arginine, coenzyme Q and vitamin D, both oral and intravenous, but no beneficial effect for the improvement of ophthalmic condition was observed. As it is the case in severe MELAS syndrome, the course of disease was fatal and the patientdied at the age of 14.

Introduction: The few published case reports of co-existent disease with phenylketonuria (PKU) are mainly genetic and familial conditions from consanguineous marriages. The clinical and demographic features of 30 subjects with PKU and co-existent conditions were described in this multi-centre, retrospective cohort study., Methods: Diagnostic age of PKU and co-existent condition, treatment regimen, and impact of co-existent condition on blood phenylalanine (Phe) control and PKU management were reported., Results: 30 patients (11 males and 19 females), with PKU and a co-existent condition, current median age of 14 years (range 0.4 to 40 years) from 13 treatment centres from Europe and Turkey were described. There were 21 co-existent conditions with PKU; 9 were autoimmune; 6 gastrointestinal, 3 chromosomal abnormalities, and 3 inherited conditions. There were only 5 cases of parental consanguinity. Some patients required conflicting diet therapy (n=5), nutritional support (n=7) and 5 children had feeding problems. There was delayed diagnosis of co-existent conditions (n=3); delayed treatment of PKU (n=1) and amenorrhea associated with Grave's disease that masked a PKU pregnancy for 12 weeks. Co-existent conditions adversely affected blood Phe control in 47% (n=14) of patients. Some co-existent conditions increased the complexity of disease management and increased management burden for patients and caregivers., Conclusions: Occurrence of co-existent disease is not uncommon in patients with PKU and so investigation for co-existent disorders when the clinical history is not completely consistent with PKU is essential. Integrating care of a second condition with PKU management is challenging., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: There appears little consensus concerning protein requirements in phenylketonuria (PKU)., Methods: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics., Results: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day)., Conclusions: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Fluctuations in blood phenylalanine concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). This review evaluates the studies on phenylalanine fluctuations, factors affecting fluctuations, and if stabilizing phenylalanine concentrations affects outcomes, particularly neurocognitive outcome. Electronic literature searches of Embase and PubMed were performed for English-language publications, and the bibliographies of identified publications were also searched. In patients with PKU, phenylalanine concentrations are highest in the morning. Factors that can affect phenylalanine fluctuations include age, diet, timing and dosing of protein substitute and energy intake, dietary adherence, phenylalanine hydroxylase genotype, changes in dietary phenylalanine intake and protein metabolism, illness, and growth rate. Even distribution of phenylalanine-free protein substitute intake throughout 24h may reduce blood phenylalanine fluctuations. Patients responsive to and treated with 6R-tetrahydrobiopterin seem to have less fluctuation in their blood phenylalanine concentrations than controls. An increase in blood phenylalanine concentration may result in increased brain and cerebrospinal fluid phenylalanine concentrations within hours. Although some evidence suggests that stabilization of blood phenylalanine concentrations may have benefits in patients with PKU, more studies are needed to distinguish the effects of blood phenylalanine fluctuations from those of poor metabolic control., (© 2013.)

Unlabelled: Klippel-Trenaunay syndrome (KTS) is a rare, congenital vascular anomaly, defined as a triad including a port-wine stain, underlying bone and soft tissue hypertrophy and varicose veins and/or venous malformations., Aim: Our aim is to present the case of a 13-year-old girl with a delayed proper diagnosis of incomplete expression of KTS presenting with a port-wine stain of her left lower extremity associated with hypertrophy of the affected limb (upon the moment of diagnosis no varicose veins were observed). The patient did not experience any pain in the affected limb, nor was she diagnosed with neuropathy - both of above mentioned symptoms are often a significant issue. To ensure proper diagnosis, the patient underwent a broad spectrum of diagnostic tests, including physical examination with anthropometric measuring, biochemical tests, as well as radiological examinations including CT scan, Doppler vein ultrasound and bone X-ray. Based on physical examination and test results we were able to establish the diagnosis of incomplete expression of Klippel-Trenaunay syndrome., Summary: The authors aim to emphasise the very rare incidence of KTS, as well as the low level of awareness of the described disease, which resulted in the significantly delayed final diagnosis in the presented case. Establishing the diagnosis of KTS before the onset of severe vascular complications, regular check-ups in the Outpatient Clinic of Haemangioma Care and compression dressing may help avoid/diminish the severity and significantly delay the development of venous failure of the affected limb.

Introduction: Doses of glucocorticoids used when treating congenital adrenal hyperplasia (CAH) are larger than physiological secretion of hydrocortisone in healthy people. Optimal dosage should provide metabolic control and should not cause complications of steroid therapy., Aim of the Study: 1. Evaluation of the influence of CAH treatment on bone mineralisation established with densitometry. 2. Evaluation of steroid profiles usage, in estimation of bone mineralisation disorders risk in patients with CAH., Material and Methods: A total number of 28 patients with CAH, aged 2.7-27 years and receiving treatment with glucocorticoids was examined. Therapeutic coefficient and steroidal coefficient which relate to doses of hydrocortisone used were established using urine steroid profiling, which was effectuated by gas chromatography/mass spectrometry (GC/MS). Additionally dual energy x-ray absorptiometry (DXA) of the lumbar spine (L1-L4) was conducted, where bone mineral density (BMD) was established in g/cm(2), and interpreted as Z-score., Results: BMD presented in Z-score, evaluated in correlation to bone age was significantly lower (p <0.01) than BMD presented in Z-score in correlation to chronological age. It was proved that greater hormonal treatment efficacy (lower steroidal coefficient or greater therapeutic coefficient) correlates with greater bone mineralisation deficits in relation to chronological age., Conclusions: 1. Greater efficiency of hormonal treatment links with larger bone mineralisation deficits in relation to CAH patients' chronological age. 2. Evaluation of steroid profiles, as one of the estimation methods for metabolic control of the disease, described by steroidal coefficient and therapeutic coefficient, allows for practical application of the above mentioned in prediction of bone mineralisation risk in patients with CAH.

In recent years our understanding of the follow up policies for PKU has increased substantially. In particular, we now understand the importance of maintaining control of blood phenylalanine (phe) concentrations life-long to achieve the best long-term neuropsychological outcomes. The concordance with the follow up strategy remains a key challenge for the future, especially with respect to adolescents and young adults. The recent therapies could ease the burden of the dietary phe restriction for PKU patients and their families. The time may be right for revisiting the guidelines for follow up of PKU in order to address a number of important issues related to PKU management: promotion of breastfeeding to complementary feeding up to 2 years of age for prevention of early growth retardation and later overweight development, treatment advancements for metabolic control, blood phe and tyr variability, routine screening measures for nutritional biomarkers, neurocognitive and psychological assessments, bone pathology, understanding the challenges of compliance and transitioning into adulthood as an individual with PKU and addressing unmet needs in this population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

No reports are available about the course of pregnancies in women with tetrahydrobiopterin (BH(4)) deficiencies or the effects of treatment with BH(4), L-dopa/carbidopa and 5-hydroxytryptophan (5-OHTrp) on fetal development. We present for the first time the case of a mother with late-diagnosed mild form of 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, the course of her two subsequent pregnancies and clinical evaluation with follow-up of two offspring. In both pregnancies neurotransmitter precursors, as well as BH(4) dosages were increased proportionally to the mother's weight gain. To prevent maternal phenylketonuria (MPKU) syndrome, special attention was paid to increasing BH(4) dosages. Both pregnancies were complicated by threatened premature labour, by the mother's nicotinism and additionally, in the first pregnancy, by gestational diabetes mellitus and vaginitis. The first child was born in the 31st week of pregnancy with the symptoms of moderate intrauterine growth retardation (IUGR) and brain malformation in the form of right sided closed-lip schizencephaly with absence of septum pellucidum. Although the girl demonstrates mild left-sided hemiparesis, her psychological development at the age of 8 years is above average. The second child was born in the 37th week of pregnancy without brain anomalies and at the age of 5 years his psychomotor development is appropriate for the age. As the cause of brain malformations resulting in physical impairment in the first child is unknown, more data are essential to verify conclusions about the influence of the mother's BH(4) deficiency and the safety of her treatment for fetal development.