Evaluating the Influence of Social Determinants of Health on Blood Phenylalanine Levels in Phenylketonuria Patients.

Phenylketonuria (PKU) is a genetic metabolic disorder that causes the accumulation of phenylalanine (Phe) in tissues, leading to intellectual disability, seizures, and socioemotional challenges. The role of social determinants of health (SDOH) in PKU management has not been formally studied, and this investigation evaluates the association between in-home and in-office factors on blood Phe levels in PKU patients. We conducted a retrospective chart review on over 200 patients attending the well-resourced PKU Clinic at Lurie Children's Hospital of Chicago. Data included patients' average Phe level, various demographic information, and CDC/ATSDR social vulnerability index (SVI) score. The analysis revealed no significant association between social vulnerability status and average Phe level. However, a significant correlation was found between sapropterin dihydrochloride use and average Phe level. Age interacted separately with sex assigned at birth, pegvaliase use, total Phe samples submitted, and the presence of genetic testing to significantly influence the average Phe level. This study highlights the multifactorial influences on PKU management and underscores the importance of social resources, such as clinic social workers and state-provided formula, in modulating the effects of SDOH on PKU control. Further research in different healthcare settings is needed to understand the social determinants affecting PKU patients comprehensively, which will strengthen advocacy efforts for this population.

Management of a urea cycle disorder in the setting of socioeconomic and language barriers.

Argininosuccinic aciduria (ASA) is a disorder that results from a deficiency in the urea cycle enzyme argininosuccinate lyase. Variable manifestations of this hereditary disorder are associated with hyperammonemia and can include lethargy, somnolence, and respiratory alkalosis in neonates, and vomiting, headaches, and neurocognitive deficiencies later in life. Management of ASA includes rapid measures to address hyperammonemia and long-term steps to maintain metabolic stability. Management paradigms should also consider social determinants of health, which are non-medical factors that influence health outcomes. Here, we describe the case of a male pediatric patient with ASA whose treatment has included considerations for his family's refugee status, language barriers, cultural adjustments, limited income, and transportation challenges.

Pegvaliase dose escalation to 80 mg daily may lead to efficacy in patients who do not exhibit an optimal response at lower doses.

In 2018, pegvaliase was approved as the first enzyme substitution treatment for phenylketonuria (PKU) and is now the second medication available for PKU patients since the approval of sapropterin dihydrochloride in 2007. Historically, dietary management has been the mainstay of treatment for PKU. While sapropterin response rate is limited to approximately 50% of PKU patients, pegvaliase has the potential to reduce phenylalanine levels in all PKU patients (Vockley et al., 2014; Longo et al., 2019 [1,3]). Current FDA labeling for pegvaliase includes a dose maximum of 60 mg daily (Longo et al., 2019; BioMarin Pharmaceutical Inc., 2020 [3,4]). We report a case series of four phenylalanine hydroxylase (PAH) deficient patients, previously treated with dietary management only, who initiated treatment with pegvaliase and were titrated to 80 mg daily dosing. The safety profile in these four cases did not differ from lower maintenance dosing (Longo et al., 2019 [3]). Subsequent decreases in Phe levels were observed on 80 mg maintenance dosing, allowing for individualized dietary liberalization in three out of four patients. We conclude that pegvaliase dosing must be personalized to achieve therapeutic goals and that some patients may require higher doses than those included on the product label.

Variable disease manifestations and metabolic management within a single family affected by ornithine transcarbamylase deficiency.

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency.