Relationship satisfaction in adults with phenylketonuria is positively associated with following recommended treatment, having a partner involved in management, and maintaining good health.

RATIONALE: Phenylketonuria (PKU) is a metabolic condition that requires treatment for life. There is increasing evidence that chronic illnesses put strain on relationships and marriages. However, no studies have examined the unique factors that metabolic conditions have on affected individuals and their relationship satisfaction. We surveyed a population of adult patients with PKU and assessed how management, treatment, and lifestyle factors impact their relationship satisfaction. PURPOSE: The purpose of our study was to explore whether factors such as involvement of partner in PKU management, impact of challenges unique to PKU (e.g., diet, family planning, mood disturbances), and PKU treatment types were associated with the degree of relationship satisfaction. METHOD: We surveyed adult patients with PKU (n = 82) who were either currently in or had previously been in a long-term relationship. We developed a 78-question survey that included unique questions regarding lifestyle, treatment, and management of their PKU in addition to a validated Relationship Assessment Score. Questions included single choice, multiple choice, and 3 open-ended questions. RESULTS: We found that higher relationship satisfaction was associated with increased partner involvement, increased health, and adherence to recommended PKU treatments. Participants utilizing both diet and pharmaceutical treatment had the highest relationship satisfaction. Finally, participants who reported that their PKU did not contribute to the ending of a previous relationship reported higher relationship satisfaction scores. CONCLUSION: This study suggests that involvement of partners in the management and treatment of a chronic illness and adherence to recommended treatments can significantly improve relationship satisfaction.

Dicarboxylic acylcarnitine biomarkers in peroxisome biogenesis disorders.

The peroxisome is an essential eukaryotic organelle with diverse metabolic functions. Inherited peroxisomal disorders are associated with a wide spectrum of clinical outcomes and are broadly divided into two classes, those impacting peroxisome biogenesis (PBD) and those impacting specific peroxisomal factors. Prior studies have indicated a role for acylcarnitine testing in the diagnosis of some peroxisomal diseases through the detection of long chain dicarboxylic acylcarnitine abnormalities (C16-DC and C18-DC). However, there remains limited independent corroboration of these initial findings and acylcarnitine testing for peroxisomal diseases has not been widely adopted in clinical laboratories. To explore the utility of acylcarnitine testing in the diagnosis of peroxisomal disorders we applied a LC-MS/MS acylcarnitine method to study a heterogenous clinical sample set (n = 598) that included residual plasma specimens from nineteen patients with PBD caused by PEX1 or PEX6 deficiency, ranging in severity from lethal neonatal onset to mild late onset forms. Multiple dicarboxylic acylcarnitines were significantly elevated in PBD patients including medium to long chain (C8-DC to C18-DC) species as well as previously undescribed elevations of malonylcarnitine (C3-DC) and very long chain dicarboxylic acylcarnitines (C20-DC and C22-DC). The best performing plasma acylcarnitine biomarkers, C20-DC and C22-DC, were detected at elevated levels in 100% and 68% of PBD patients but were rarely elevated in patients that did not have a PBD. We extended our analysis to residual newborn screening blood spot cards and were able to detect dicarboxylic acylcarnitine abnormalities in a newborn with a PBD caused by PEX6 deficiency. Similar to prior studies, we failed to detect substantial dicarboxylic acylcarnitine abnormalities in blood spot cards from patients with x-linked adrenoleukodystrophy (x-ald) indicating that these biomarkers may have utility in quickly narrowing the differential diagnosis in patients with a positive newborn screen for x-ald. Overall, our study identifies widespread dicarboxylic acylcarnitine abnormalities in patients with PBD and highlights key acylcarnitine biomarkers for the detection of this class of inherited metabolic disease.

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder.

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.

Palynziq clinic: One year and 43 patients later.

Pegvaliase-pqpz (Palynziq) is an enzyme substitution therapy FDA approved May 2018 to treat phenylketonuria in adults with blood phenylalanine levels greater than 600 µmol/L (10 mg/dL). Pegvaliase is administered via subcutaneous injection and carries a high risk of side effects including anaphylaxis. A consensus statement on its use recommends careful education and monitoring of patients. We established a dedicated Palynziq Clinic in October 2018 with detailed protocols to minimize these risks. In the first year, we evaluated 43 patients, initiated Palynziq in 37 and transitioned two trial patients to commercial drug. 13/37 patients (35.1%) have sustained blood phenylalanine levels <360 µmol/L (6 mg/dL) without adjunct sapropterin dihydrochloride treatment or medical food. The timing and dosage needed to achieve a response did not correlate with patient weight, starting phenylalanine level, starting diet, or co-treatment with sapropterin dihydrochloride. Some patients had consistently low phenylalanine levels <30 µmol/L (0.5 mg/dL) and required doses as low as 20 mg weekly. Anaphylactic episodes were reported by 21.6% (8/37 patients) versus 10% seen in the clinical trial. Rates of other side effects were similar to or less than those in the trial. Adverse reactions commonly occurred shortly after dosage increases. We provide a model for safely introducing and managing pegvaliase in adult patients with PKU.

Genetic Testing and Counseling in Metabolic Liver Disease: An Interactive Lecture for Medical Students.

Introduction: Medical students have limited opportunities to learn about current genetic testing. This session provided exposure to different types of testing and the complex issues that physicians may encounter when counseling patients on proper testing and interpreting results. Methods: We designed a 1-hour interactive lecture for second-year medical students. We presented an overview of the topic, then applied the concepts to specific disorders and cases. Students were asked to answer questions regarding cases using an audience response system, and we used their responses as the basis for our in-class discussion. This session has been held twice, with 25 students attending in 2018 and 31 students in 2019. The session was also recorded so that additional students not in attendance could watch, and was available to 151 students in 2018 and 333 students in 2019. Results: Students answered questions via audience response system. There was a range of 47%-100% of students giving the correct answers in 2018, and 55%-93% in 2019. Exam questions covering genetic counseling issues were answered correctly by 66% and 77% of students in 2018, and 70% and 68% of students in 2019. Discussion: This session provided an opportunity for medical students to be exposed to some of the complex ethical and psychosocial issues that may arise with genetic testing for liver disease and to consider how to navigate them. Using an audience response system during the lecture made the session more interactive and allowed the teacher to correct errors and teach based on the responses.

Survival of a Male Infant with a Familial Xp11.4 Deletion Causing Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase (OTC) deficiency is well known to cause severe neonatal hyperammonemia in males with absent enzyme activity. In families with large deletions of the X chromosome involving OTC and other contiguous genes, male infants appear to have an even more severe course. Notably, there are no published reports of these males surviving to liver transplant, even in cases where the diagnosis was known or suspected at birth. We describe two male newborns and their mother who all have a 1.5-Mb deletion of Xp11.4 encompassing the genes TSPAN7, OTC, and part of RPGR. The first child succumbed to his illness on his fourth day of life. His younger brother was diagnosed prenatally, and with early aggressive treatment, he survived the neonatal period. He suffered multiple life-threatening complications but stabilized and received a liver transplant at 7 months of age. This report demonstrates both the possibility of survival and the complications in caring for these patients.