Low bone mineral density (BMD) in individuals with phenylketonuria (PKU) due to phenylalanine hydroxylase (PAH) deficiency has been variably reported in the medical literature, but the clinical significance of this observation has been uncertain. We measured BMD in a cross-sectional cohort of 117 individuals with PAH deficiency between 6.2 and 56.8 years age who participate in the PHEFREE Consortium Longitudinal Natural History Study. 49% of children under age 18 years and 26% of adults were consuming a phenylalanine (Phe)-restricted diet, supplemented with low Phe or Phe-free medical foods and treated with sapropterin dihydrochloride. 22% of adults and 32% of children were not responsive to sapropterin and were treated with dietary Phe restriction and supplementary medical foods alone. 20 adults (37%) reported receiving enzyme replacement therapy with pegvaliase. Phenotype predictions from the genotypes of the participants in these three treatment groups were predominantly classical PKU. Participants with mild PKU or mild hyperphenylalaninemia (HPA) phenotypes treatable with sapropterin alone without the need for medical foods made up 9% of adults and 14% of children in the study cohort. Mean (± SD) blood phenylalanine (Phe) concentrations over the year prior to bone densitometry studies measured 449 ± 336 μM in the entire study cohort. Mean BMD z-scores for both adults and children in all body regions were negative with the difference between study participants and the comparator non-PKU population reaching statistical significance (p < 0.05). At least one z-score was <-2 in 15% of children and 10% of adults with PKU (2.3% expected). These differences were apparent in some children already at 6 years age, the earliest time point measured. Mean BMD was more negative in individuals with history of fracture than in those without, but this difference did not reach statistical significance. Multivariate analysis revealed a positive correlation between BMD and body mass index (BMI) in children, with minor contributions from age and natural protein intake. There was no correlation between BMD and blood Phe concentration measured in the year prior to BMD measurement. The pathophysiologic mechanism causing and the clinical significance of these differences remain uncertain, but concern persists that low BMD in this relatively well-treated cohort could portend frank osteopenia and increased fracture risk as these individuals reach advanced age. Whether novel therapeutics, that both correct hyperphenylalaninemia and allow increased dietary intact protein intake, will impact bone mineralization is yet unknown. Longitudinal monitoring of BMD throughout the lifespan is warranted.

Classic homocystinuria (HCU) is caused by a deficiency in cystathionine beta-synthase, leading to excessive accumulation of homocysteine and methionine in plasma and tissues. Clinical manifestations typically involve the eyes, skeleton, central nervous system, and vasculature. Thromboembolic events, such as stroke and deep vein thrombosis, are well-recognized complications. Here, we report four patients with poorly controlled HCU who developed acute pancreatitis (AP) with varying outcomes, along with 11 additional cases identified through a literature review. This study highlights AP as a potential complication in poorly controlled HCU, expanding the clinical spectrum of the disease and offering guidance on surveillance and appropriate acute management.

PURPOSE:Because the standard-of-care treatment for classical homocystinuria (HCU) often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy. METHODS:Participants with HCU aged 12 to 65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into 6 increasing dose cohorts (each n ≈ 4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to posttreatment (geometric mean of weeks 6-12). RESULTS:Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; 1 serious [acute urticaria]). At the 2 highest doses, substantial tHcy reductions were observed after treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW), and all participants maintained tHcy < 100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy < 15 μM (normal) and methionine < 14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy. CONCLUSION:Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.

Over fifty years have passed since the last large scale longitudinal study of individuals with PAH deficiency in the U.S. Since then, there have been significant changes in terms of treatment recommendations as well as treatment options. The Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium was recently established to collect a more up-to-date and extensive longitudinal natural history in individuals with phenylketonuria across the lifespan. In the present paper, we describe the structure and methods of the PHEFREE longitudinal study protocol and report cross-sectional data from an initial sample of 73 individuals (5 months to 54 years of age) with PAH deficiency who have enrolled. Looking forward, the study holds the promise for advancing the field on several fronts including the validation of novel neurocognitive tools for assessment in individuals with PKU as well as evaluation of the long-term effects of changes in metabolic control (e.g., effects of Phe-lowering therapies) on outcome.

We look to the past as prologue for guidance in predicting and circumventing potential psychosocial–ethical challenges, including those that may influence the attachment process for some parents. We consider the evolution of bioethics and developmental psychology as they intersect with newborn screening while exploring potential implications of positive findings, be they false positives, true positives, or secondary as well as incidental findings. We reflect on navigating the complex landscape that may be significantly impacted by variable phenotypes, the age of onset, and uncertain prognoses, mindful of the diagnostic odyssey continuum. We explore select facets of ethical and psychological challenges encountered with positive newborn screening findings by highlighting enduring debates to improve the policy process in public health and medicine. We believe substantive empirical research is needed, including long-term follow-up, routine prenatal assessment of tolerance for uncertainties, and especially innovative methodologies to better evaluate potential psychological distress that may be present in some at-risk individuals during the perinatal period preceding and following reports of positive findings. Mitigation strategies building on lessons learned from NBS and clinical follow-up should be implemented and studied. We conclude by pondering why we remain far afield from providing these services. Research directed towards understanding the implications of positive NBS findings will further reduce the burdens on families and care providers alike and should lead to improved communication.

Newborn screening (NBS) began a revolution in the management of biochemical genetic diseases, greatly increasing the number of patients for whom dietary therapy would be beneficial in preventing complications in phenylketonuria as well as in a few similar disorders. The advent of next generation sequencing and expansion of NBS have markedly increased the number of biochemical genetic diseases as well as the number of patients identified each year. With the avalanche of new and proposed therapies, a second wave of options for the treatment of biochemical genetic disorders has emerged. These therapies range from simple substrate reduction to enzyme replacement, and now ex vivo gene therapy with autologous cell transplantation. In some instances, it may be optimal to introduce nucleic acid therapy during the prenatal period to avoid fetopathy. However, as with any new therapy, complications may occur. It is important for physicians and other caregivers, along with ethicists, to determine what new therapies might be beneficial to the patient, and which therapies have to be avoided for those individuals who have less severe problems and for which standard treatments are available. The purpose of this review is to discuss the "Standard" treatment plans that have been in place for many years and to identify the newest and upcoming therapies, to assist the physician and other healthcare workers in making the right decisions regarding the initiation of both the "Standard" and new therapies. We have utilized several diseases to illustrate the applications of these different modalities and discussed for which disorders they may be suitable. The future is bright, but optimal care of the patient, including and especially the newborn infant, requires a deep knowledge of the disease process and careful consideration of the necessary treatment plan, not just based on the different genetic defects but also with regards to different variants within a gene itself.

BACKGROUND Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored. OBJECTIVE AND RATIONALE The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage. SEARCH METHODS In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed. OUTCOMES A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level. WIDER IMPLICATIONS Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathways might serve as markers of disease progression and efficiency of new treatment options.