Strategies to engage lost to follow-up patients with phenylketonuria in the United States: Best practice recommendations.

BACKGROUND: Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by mutations in the gene encoding phenylalanine hydroxylase, an enzyme that converts phenylalanine to tyrosine. Untreated, PKU is characterized by a range of neuropsychological and neurocognitive impairments. Due to ubiquitous newborn genetic screening programs, treatment for PKU can be commenced shortly after birth and can prevent many of the severe manifestations of the disease. However, lifelong management is critical for patients with PKU as high levels of phenylalanine are neurotoxic. As for all chronic diseases, long-term management can be challenging and most adult patients with PKU become lost to follow-up (LTFU). A survey of PKU clinics across the United States and a multidisciplinary Expert Meeting were conducted to develop best practices to engage LTFU patients with PKU. RESULTS: We defined LTFU patients with PKU as "patients with no contact with the clinic for at least 2 consecutive years." Combining the results from our survey and our discussion at the Expert Meeting, we have prepared six best practice recommendations to engage LTFU patients with PKU: 1) Ensure patients are aware of the current treatment guidelines for PKU; 2) Communicate to patients any new treatment and diet options as they become available for PKU; 3) Consider the neuropsychological and neurocognitive aspects of PKU; 4) Prioritize motivated LTFU patients; 5) Explore new approaches of outreach to LTFU patients; and 6) Formalize approaches to track and/or identify PKU patients. CONCLUSION: We strongly advocate the importance of engaging LTFU patients with PKU and encourage implementation of our best practice recommendations. Although it takes time and effort to engage LTFU patients, we believe that clinics are capable of supporting this significant patient group.

Strategies for Successful Long-Term Engagement of Adults With Phenylalanine Hydroxylase Deficiency Returning to the Clinic

Abstract Nearly half of all patients diagnosed with phenylalanine hydroxylase (PAH) deficiency, also known as phenylketonuria, are lost to follow-up (LTFU); most are adults who stopped attending clinic after the age of 18 years. To understand why adult patients with PAH deficiency disengage from their clinic, a focus group of 8 adults with PAH deficiency who had been LTFU for 2 or more years was held in March 2016. Ten clinicians observed the focus group and discussed strategies for successfully reengaging adult patients and encouraging lifelong management of PAH deficiency. Four strategies were proposed: (1) create a safe, supportive environment, (2) acknowledge patients as partners in their care, (3) develop individualized management plans, and (4) provide patients with additional resources. These strategies provide a framework to motivate change in clinical practice to meet the unique needs of adults with PAH deficiency.

Altered DNA methylation in PAH deficient phenylketonuria.

While phenylalanine (PHE) is the toxic insult in phenylketonuria (PKU), mechanisms underlying PHE toxicity remain ill-defined. Altered DNA methylation in response to toxic exposures is well-recognized. DNA methylation patterns were assessed in blood and brain from PKU patients to determine if PHE toxicity impacts methylation. Methylome assessment, utilizing methylated DNA immunoprecipitation and paired-end sequencing, was performed in DNA obtained from brain tissue of classical PKU patients, leukocytes from poorly controlled PKU patients, leukocytes from well controlled PKU patients, and appropriate control tissues. In PKU brain tissue, expression analysis determined the impact of methylation on gene function. Differential methylation was observed in brain tissue of PKU patients and expression studies identified downstream impact on gene expression. Altered patterns of methylation were observed in leukocytes of well controlled and poorly controlled patients with more extensive methylation in patients with high PHE exposure. Differential methylation of noncoding RNA genes was extensive in patients with high PHE exposure but minimal in well controlled patients. Methylome repatterning leading to altered gene expression was present in brain tissue of PKU patients, suggesting a role in neuropathology. Aberrant methylation is observed in leukocytes of PKU patients and is influenced by PHE exposure. DNA methylation may provide a biomarker relating to historic PHE exposure.