Maternal Phenylketonuria Research Articles

Clinical case of microcephaly against the background of maternal phenylketonuria

Clinical case of microcephaly against the background of maternal phenylketonuria

Characteristics and outcomes of pregnancies among women with phenylketonuria from the NBS Connect registry

Women with phenylketonuria (PKU) should maintain blood phenylalanine (phe) concentration within the recommended range before and during pregnancy to prevent maternal PKU syndrome (MPKUS) in their offspring. Women who gave birth to children with MPKUS symptoms were more likely to report elevated phe concentration before pregnancy, and barriers to accessing components of their dietary management during pregnancy, including blood phe testing, medical food, modified low-protein foods, and healthcare visits with PKU specialists.

Benefits of a prolonged-release amino acid mixture in four pregnant women with phenylketonuria.

Background: Maternal phenylketonuria (mPKU) is a pathologic condition occurring in the fetus of a mother with PKU that is caused by prolonged elevated intrauterine blood phenylalanine (Phe) levels, which can lead to congenital abnormalities and mental retardation of newborns. Management of PKU during pregnancy can be challenging as protein substitutes may exacerbate nausea, vomiting, and gastrointestinal symptoms. Aim: To report the successful management of four PKU pregnant women. Methods: The patients were administered with prolonged-release amino acid supplementation and were recommended to follow a strict diet. Blood Phe concentration, adherence to diet, and occurrence of adverse events were monitored. Results: All patients achieved safe levels of blood Phe concentration (120-360 µmol/L) since preconception and during pregnancy (mean Phe concentration values of 143.34 ± 137.59, 226.48 ± 194.57, 186.68 ± 133.67, and 187.47 ± 42.59 µmol/L). During the first trimester of pregnancy, all patients manifested gastrointestinal symptoms such as nausea, gastrointestinal reflux, and abdominal bloating, which were managed by either changing protein substitute or extending the time window between different meals and amino acid mixtures administration. The four women continued their pregnancies without experiencing further complications and delivered neonates with normal growth parameters and no malformations. Conclusion: Findings of this case series suggest that the intake of a prolonged-release amino acid mixture in granules is well tolerated by pregnant PKU patients, eventually leading to good metabolic control and fetal growth within normal ranges.

A phenylalanine-free recombinant nutritional protein for the dietary management of phenylketonuria.

Phenylketonuria (PKU) is a congenital metabolic disorder that causes the systemic elevation of phenylalanine (Phe), which is neurotoxic and teratogenic. PKU is currently incurable, and management involves lifelong adherence to an unpalatable protein-restricted diet based on Phe-free amino acid mixtures. Seeking a palatable dietary alternative, we identified a Bacillus subtilis protein (GSP16O) with a well-balanced but low-Phe amino acid profile. We optimized the sequence and expressed a modified Phe-free version (GSP105) in Pseudomonas fluorescens, achieving yields of 20 g/L. The purified GSP105 protein has a neutral taste and smell, is highly soluble, and remains stable up to 80°C. Homozygous enu2 mice, a model of human PKU, were fed with diets containing either GSP105 or normal protein. The GSP105 diet led to normalization of blood Phe levels and brain monoamine neurotransmitter metabolites, and prevented maternal PKU. The GSP105 diet thus provides an alternative and efficacious dietary management strategy for PKU.

Phenylketonuria and the brain

Classic phenylketonuria (PKU) is caused by defective activity of phenylalanine hydroxylase (PAH), the enzyme that coverts phenylalanine (Phe) to tyrosine. Toxic accumulation of phenylalanine and its metabolites, left untreated, affects brain development and function depending on the timing of exposure to elevated levels. The specific mechanisms of Phe-induced brain damage are not completely understood, but they correlate to phenylalanine levels and on the stage of brain growth. During fetal life, high levels of phenylalanine such as those seen in maternal PKU can result in microcephaly, neuronal loss and corpus callosum hypoplasia. Elevated phenylalanine levels during the first few years of life can cause acquired microcephaly, severe cognitive impairment and epilepsy, likely due to the impairment of synaptogenesis. During late childhood, elevated phenylalanine can cause alterations in neurological functioning, leading to ADHD, speech delay and mild IQ reduction. In adolescents and adults, executive function and mood are affected, with some of the abnormalities reversed by better control of phenylalanine levels. Altered brain myelination can be present at this stage. In this article, we review the current knowledge about the consequences of high phenylalanine levels in PKU patients and animal models through different stages of brain development and its effect on cognitive, behavioural and neuropsychological function.

Maternal-fetal outcomes of pregnancies in women treated at an inborn errors of metabolism unit

IntroductionIntermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-fetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. MethodsRetrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50 (P25–P75). Results24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother’s disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31 + 5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. ConclusionsPregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and fetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.

Resultados materno-fetales de las gestaciones de mujeres atendidas en una unidad de errores innatos del metabolismo

IntroductionIntermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-foetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. MethodsRetrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50(P25-P75). Results24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother's disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31 + 5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. ConclusionsPregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and foetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.

Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria.

To prevent maternal phenylketonuria (PKU) syndrome low phenylalanine concentrations (target range, 120-360 μmol/L) during pregnancy are recommended for women with PKU. We evaluated the feasibility and effectiveness of current recommendations and identified factors influencing maternal metabolic control and children's outcome. Retrospective study of first successfully completed pregnancies of 85 women with PKU from 12 German centers using historical data and interviews with the women. Children's outcome was evaluated by standardized IQ tests and parental rating of child behavior. Seventy-four percent (63/85) of women started treatment before conception, 64% (54/85) reached the phenylalanine target range before conception. Pregnancy planning resulted in earlier achievement of the phenylalanine target (18 weeks before conception planned vs. 11 weeks of gestation unplanned, p < 0.001) and lower plasma phenylalanine concentrations during pregnancy, particularly in the first trimester (0-7 weeks of gestation: 247 μmol/L planned vs. 467 μmol/L unplanned, p < 0.0001; 8-12 weeks of gestation: 235 μmol/L planned vs. 414 μmol/L unplanned, p < 0.001). Preconceptual dietary training increased the success rate of achieving the phenylalanine target before conception compared to women without training (19 weeks before conception vs. 9 weeks of gestation, p < 0.001). The majority (93%) of children had normal IQ (mean 103, median age 7.3 years); however, IQ decreased with increasing phenylalanine concentration during pregnancy. Good metabolic control during pregnancy is the prerequisite to prevent maternal PKU syndrome in the offspring. This can be achieved by timely provision of detailed information, preconceptual dietary training, and careful planning of pregnancy.

Тетрада фалло: современные данные. Обзор литературы

Tetralogy of Fallot (TоF) is a congenital heart disease that includes ventricular septal defect (VSD), right ventricular outflow tract obstruction, aortic root dextraposition, and right ventricular hypertrophy. TоF occurs in 3 out of 10,000 live births and accounts for 7–10% of all congenital heart defects. The etiology of TоF is multifactorial and may include untreated maternal diabetes, phenylketonuria, and retinoic acid intake. Associated chromosomal abnormalities include trisomies 21, 18, and 13, but recent studies indicate a much higher association with microdeletion of chromosome 22. The familial risk of TоF is 3%. The article presents the results of scientific publications about ToF. In particular, modern and topical issues of genetic predisposition, morphology, diagnosis, indications for surgical treatment, including radical and staged, are considered.

Neurotoxicity of phenylalanine on human iPSC-derived cerebral organoids.

Phenylketonuria (PKU) is a common genetic metabolic disorder that causes phenylalanine accumulation in the blood. The most serious symptoms are related to the brain, as intellectual disability, seizure, and microcephaly are commonly found in poorly treated PKU patients and the babies of maternal PKU. However, the mechanism of hyperphenylalaninemia on human neurodevelopment is still unclear. Here we utilized human induced pluripotent stem cell (iPSC)-derived cerebral organoids to investigate the neurotoxicity of hyperphenylalaninemia. Cerebral organoids at days 40 or 100 were treated with different concentrations of phenylalanine for 5 days. After phenylalanine treatments, the cerebral organoids displayed alterations in organoid size, induction of apoptosis, and depletion of neural progenitor cells. However, phenylalanine did not have an impact on neurons and glia, including astrocytes, immature oligodendrocytes, and mature oligodendrocytes. Remarkably, a reduction in the thickness of the cortical rosettes and a decrease in myelination at the intermediate zone were inspected with the elevated phenylalanine concentrations. RNA-seq of phenylalanine-treated organoids revealed that gene sets related to apoptosis, p53 signaling pathway, and TNF signaling pathway via NF-kB were enriched in upregulated genes, while those related to cell cycle and amino acid metabolism were enriched in downregulated genes. In addition, there were several microcephaly disease genes, such as ASPM, LMNB1, and CENPE, ranked at the top of the downregulated genes. These findings indicate that phenylalanine exposure may contribute to microcephaly, abnormal cortical expansion, and myelination lesions in the developing human brain.

The Impact of the Quality of Nutrition and Lifestyle in the Reproductive Years of Women with PKU on the Long-Term Health of Their Children.

A woman’s nutritional status before and during pregnancy can affect the health of her progeny. Phenylketonuria (PKU), a rare disorder causing high blood and brain phenylalanine (Phe) concentrations, is associated with neurocognitive disability. Lifelong treatment is mainly dietetic with a Phe-restricted diet, supplemented with a low-Phe protein substitute. Treatment adherence commonly decreases in adolescence, with some adults ceasing dietary treatment. In maternal PKU, elevated blood Phe is harmful to the fetus so a strict Phe-restricted diet must be re-established preconception, and this is particularly difficult to achieve. A woman’s reproductive years introduces an opportunity to adopt healthier behaviours to prepare for successful pregnancies and positive health outcomes for both themselves and their children. Several factors can influence the health status of women with PKU. Political, socioeconomic, and individual food and lifestyle choices affect diet quality, metabolic control, and epigenetics, which then pre-condition the overall maternal health and long-term health of the child. Here, we reflect on a comprehensive approach to treatment and introduce practical recommendations to optimize the wellbeing of women with PKU and the resultant health of their children.

Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document.

There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.

Preventing maternal phenylketonuria (PKU) syndrome: important factors to achieve good metabolic control throughout pregnancy

BackgroundInsufficient metabolic control during pregnancy of mothers with phenylketonuria (PKU) leads to maternal PKU syndrome, a severe embryo-/fetopathy. Since maintaining or reintroducing the strict phenylalanine (Phe) limited diet in adults with PKU is challenging, we evaluated the most important dietary and psychosocial factors to gain and sustain good metabolic control in phenylketonuric women throughout pregnancy by a questionnaire survey with 38 questions concerning therapy feasibility. Among them, the key questions covered 5 essential items of PKU care as follows: General information about maternal PKU, PKU training, diet implementation, individual metabolic care, personal support. In addition, all participating PKU mothers were asked to estimate the quality of their personal metabolic control of the concluded pregnancies. 54 PKU mothers with 81 pregnancies were approached at 12 metabolic centers in Germany and Austria were included. According to metabolic control, pregnancies of PKU women were divided in two groups: group “ideal” (not more than 5% of all blood Phe concentrations during pregnancy > 360 µmol/l; n = 23) and group “suboptimal” (all others; n = 51).ResultsThe demand for support was equally distributed among groups, concerning both amount and content. Personal support by the direct social environment (partner, family and friends) (“suboptimal” 71% vs “ideal” 78%) as well as individual metabolic care by the specialized metabolic center (both groups around 60%) were rated as most important factors. The groups differed significantly with respect to the estimation of the quality of their metabolic situation (p < 0.001). Group “ideal” presented a 100% realistic self-assessment. In contrast, group “suboptimal” overestimated their metabolic control in 53% of the pregnancies. Offspring of group “suboptimal” showed clinical signs of maternal PKU-syndrome in 27%.ConclusionThe development of training programs by specialized metabolic centers for females with PKU in child bearing age is crucial, especially since those mothers at risk of giving birth to a child with maternal PKU syndrome are not aware of their suboptimal metabolic control. Such programs should provide specific awareness training for the own metabolic situation and should include partners and families.

Guide for diagnosis and treatment of hyperphenylalaninemia.

Sapropterin hydrochloride, a natural coenzyme (6R-tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin-responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin-responsive hyperphenylalaninemia. It is recommended that tetrahydrobiopterin-responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels. If tetrahydrobiopterin-responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required.

The first study of successful pregnancies in Chinese patients with Phenylketonuria

BackgroundSince the inception of newborn screening programs in China in the 1990s, pregnancy among patients with inherited, metabolic disorders has become more common. This study explores the management and outcomes of planned, full-term pregnancies in patients with phenylketonuria (PKU).MethodMarried patients with PKU from 2012 to 2017 were enrolled to receive prenatal counseling and regular health assessments. Study-related assessments included the timing of Phe-restricted diets, maternal weight gain, gestational age, pregnancy complications, and blood Phe concentrations (both pre-conception and during pregnancy), obstetrical data, and offspring outcomes(e.g. anthropomorphic measurements and developmental quotients [DQs]).ResultsA total of six offspring were successfully delivered. The mean ± SD (range) age of the mother at delivery was 26.3 ± 4.7 (range: 21.1–32.5) years. The mean duration of Phe control before pregnancy was 5.5 ± 1.3(range: 3.1–6.5) months. During pregnancy, the proportion of blood Phe concentrations within the clinically-recommended target range (120–360 μmol/L) ranged from 63.2–83.5%. Low birth weight (< 2500 g) offspring occurred in two women who experienced suboptimal metabolic control. In addition, offspring DQ was related to the proportion of blood Phe levels per trimester that were within the recommended range (r = 0.886, p = 0.016).ConclusionThis is the first report of women in China with PKU who successfully gave birth to clinically healthy babies. Infant outcomes were related to maternal blood Phe management prior to and during pregnancy. In maternal PKU patients with poor compliance to dietary treatment, sapropterin dihydrochloride (6R-BH4) may be an option to improve the management of blood Phe levels.

Maternal PKU: Defining phenylalanine tolerance and its variation during pregnancy, according to genetic background

Background and aimsPhenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity. Methods and ResultsA total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype.Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations. ConclusionsSeveral factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.

Evaluation of PKU Sphere in Maternal PKU

Evaluation of PKU Sphere in Maternal PKU

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Phenylketonuria (PKU) due to recessively inherited phenylalanine hydroxylase (PAH) deficiency results in hyperphenylalaninemia, which is toxic to the central nervous system. Restriction of dietary phenylalanine intake remains the standard of PKU care and prevents the major neurologic manifestations of the disease, yet shortcomings of dietary therapy remain, including poor adherence to a difficult and unpalatable diet, an increased incidence of neuropsychiatric illness, and imperfect neurocognitive outcomes. Gene therapy for PKU is a promising novel approach to promote lifelong neurological protection while allowing unrestricted dietary phenylalanine intake. In this study, liver-tropic recombinant AAV2/8 vectors were used to deliver CRISPR/Cas9 machinery and facilitate correction of the Pahenu2 allele by homologous recombination. Additionally, a non-homologous end joining (NHEJ) inhibitor, vanillin, was co-administered with the viral drug to promote homology-directed repair (HDR) with the AAV-provided repair template. This combinatorial drug administration allowed for lifelong, permanent correction of the Pahenu2 allele in a portion of treated hepatocytes of mice with PKU, yielding partial restoration of liver PAH activity, substantial reduction of blood phenylalanine, and prevention of maternal PKU effects during breeding. This work reveals that CRISPR/Cas9 gene editing is a promising tool for permanent PKU gene editing.

AIUM Practice Parameter for the Performance of Fetal Echocardiography.

AIUM Practice Parameter for the Performance of Fetal Echocardiography.

Inborn errors of metabolism leading to neuronal migration defects.

The development and organisation of the human brain start in the embryonic stage and is a highly complex orchestrated process. It depends on series of cellular mechanisms that are precisely regulated by multiple proteins, signalling pathways and non-protein-coding genes. A crucial process during cerebral cortex development is the migration of nascent neuronal cells to their appropriate positions and their associated differentiation into layer-specific neurons. Neuronal migration defects (NMD) comprise a heterogeneous group of neurodevelopmental disorders including monogenetic disorders and residual syndromes due to damaging factors during prenatal development like infections, maternal diabetes mellitus or phenylketonuria, trauma, and drug use. Multifactorial causes are also possible. Classification into lissencephaly, polymicrogyria, schizencephaly, and neuronal heterotopia is based on the visible morphologic cortex anomalies. Characteristic clinical features of NMDs are severe psychomotor developmental delay, severe intellectual disability, intractable epilepsy, and dysmorphisms. Neurometabolic disorders only form a small subgroup within the large group of NMDs. The prototypes are peroxisomal biogenesis disorders, peroxisomal ß-oxidation defects and congenital disorders of O-glycosylation. The rapid evolution of biotechnology has resulted in an ongoing identification of metabolic and non-metabolic disease genes for NMDs. Nevertheless, we are far away from understanding the specific role of cortical genes and metabolites on spatial and temporal regulation of human cortex development and associated malformations. This limited understanding of the pathogenesis hinders the attempt for therapeutic approaches. In this article, we provide an overview of the most important cortical malformations and potential underlying neurometabolic disorders.