Outcomes in 14 live births resulting from Pegvaliase-treated pregnancies in PKU-affected females.

BACKGROUND: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were responsive to pegvaliase and chose to remain on pegvaliase throughout their pregnancy. METHODS: Fourteen pregnancies (one triplet pregnancy) and their offspring were identified at eight PKU treatment centers and medical records from pregnancy and birth were submitted for this study. Institutional Review Board approval was obtained. Responses to a dataset were provided to a single center and analyzed. RESULTS: Six females and eight males were born without congenital anomalies and all offspring had normal growth parameters. While mothers had preexisting comorbidities, no additional comorbidities were reported in the offspring. Four of eleven infants (excluding triplet pregnancies) were delivered preterm (36%), a higher rate than the general population (12%). A single first trimester (eight weeks) miscarriage in a 40y was not counted in this cohort of 14 live born infants. CONCLUSION: This retrospective study suggests that pegvaliase is effective at maintaining safe maternal blood Phe levels during pregnancy without deleterious effects on mother or child. A tendency toward premature birth (4/11; 36%) is higher than expected.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

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.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Real-world treatment, dosing, and discontinuation patterns among patients treated with pegvaliase for phenylketonuria: Evidence from dispensing data.

Background: Phenylketonuria (PKU) is an inborn metabolic error characterized by a deficiency of the enzyme required for the metabolism of phenylalanine, an essential amino acid found in most protein-containing foods. Pegvaliase (Palynziq®) is an enzyme substitution therapy approved for adults with PKU who have inadequate blood phenylalanine control (≥600 µmol/L) on existing management. Objective: To characterize the treatment, discontinuation, and dosing patterns in patients treated with pegvaliase in real-world practice settings in the United States following commercial availability in 2018. Study design: Retrospective cohort study using BioMarin's proprietary drug dispense database associated with the pegvaliase REMS program. Methods: Sample construction identified all patients who properly initiated pegvaliase in real world settings ('full cohort') and a subset of patients ('extended follow-up cohort') with ≥12 months between first dispense of maximum dose and last pegvaliase dispense. Key outcomes were quantified across patients in both cohorts: maximum daily dose; time to maximum daily dose; maximum daily syringes; and dose escalation over time. The overall dose at discontinuation and time to discontinuation were calculated. Patients who subsequently reinitiated therapy were identified. For the extended follow-up cohort, 12-month changes in dose and syringes and dispensing gaps during the 12 months after maximum dose were quantified across all patients and were further stratified by maximum dose. Results: Overall, 1596 patients associated with 33,814 dispenses were reflected in the pegvaliase dispense dataset during the study period from July 9, 2018, through December 31, 2021; 1280 patients associated with 25,973 dispenses met inclusion criteria for the full cohort, with 19.9 dispenses each on average. Of these patients, 483 patients associated with 15,149 dispenses also met the extended follow-up criteria, with an average of 31.4 dispenses.Average treatment duration in the full cohort was 82.2 weeks, including 50.8 weeks after maximum daily dose was achieved. The average maximum daily dose was 30 mg with an average time to maximum dose of 31.8 weeks: 43.0% of patients had a maximum dose of 20 mg, 31.3% a maximum dose of 40 mg, and 12.0% a maximum dose of 60 mg. At data cut-off, 289 patients (22.6%) had discontinued; within this group, 126 patients (43.6%) discontinued within the first 6 months after reaching maximum dose.The overall average treatment duration for patients in the extended follow up cohort at data cut off was 131.2 weeks, including 98.6 weeks after maximum dose was achieved. The average maximum daily dose across the cohort was 32.9 mg: 42.4% of patients had a maximum dose of 20 mg, 41.0% a maximum dose of 40 mg, and 11.2% a maximum dose of 60 mg. At 12 months after achieving maximum dose, 35% of patients had down-dosed, with a 46.8% decrease (on average) from their maximum dose. Conclusions: Real-world use of pegvaliase reflects longer titration periods than in the dosing schedule based on trial experience. Over time, a substantial number of patients are able to reduce their daily dose by titrating down from their maximum dose, a finding of great interest to clinicians and patients alike.

Comparison of willingness and preference for genetic counseling via telemedicine: before vs. during the COVID-19 pandemic.

The COVID-19 pandemic required genetic counseling services, like most outpatient healthcare, to rapidly adopt a telemedicine model. Understanding the trends in patients' preferences for telemedicine relative to in-person service delivery both before and after the advent of the COVID-19 pandemic may aid in navigating how best to integrate telemedicine in a post-COVID-19 era. Our study explored how respondents' willingness to use, and preference for, telemedicine differed from before to after the onset of the COVID-19 pandemic. Respondents included patients, or their parent/guardian, seen in a general medical genetics clinic in 2018, prior to the COVID-19 pandemic, and in 2021, during the COVID-19 pandemic. Respondents were surveyed regarding their willingness to use telemedicine, preference for telemedicine relative to in-person care, and the influence of various factors. Among 69 pre-COVID-19 and 40 current-COVID-19 respondents, there was no shift in willingness to use, or preference for, telemedicine across these time periods. About half of respondents (50.6%) preferred telemedicine visits for the future. Of the 49.4% who preferred in-person visits, 79.1% were still willing to have visits via telemedicine. Predictors of these preferences included comfort with technology and prioritization of convenience of location. This study suggests that a hybrid care model, utilizing telemedicine and in-person service delivery, may be most appropriate to meet the needs of the diverse patients served. Concern for COVID-19 was not found to predict willingness or preference, suggesting that our findings may be generalizable in post-pandemic contexts.

Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics.

OBJECTIVE: To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers. METHODS: Sixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings. RESULTS: Fifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important. CONCLUSION: This case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice.

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.

Perceived barriers to paternal expanded carrier screening following a positive maternal result: To screen or not to screen.

Expanded carrier screening identifies individuals who are at risk of having a child with an autosomal recessive condition. The most accurate risk assessment requires that both mother and father undergo carrier screening to determine whether they are carriers of the same autosomal recessive condition. A couple identified as carriers of the same condition has a 25% chance of having a child with that condition. However, the father does not always opt for carrier screening following a positive result in the mother. This study aimed to identify barriers that prevent the father from carrier screening after a positive finding in the mother. A total of 58 women participated in this study. All participants had undergone expanded carrier screening prior to the study and had met with a genetic counselor for a pre-test, informed consent session. Of the 58 women, 34 had partners who did not undergo screening and 24 had partners who did. Participants completed a survey to determine the barriers that prevented the father of the baby's participation. We report that the mother's insurance type, whether the father has insurance, relationship status, and knowledge of the carrier screen showed statistically significant differences between women whose partners underwent screening and those that did not. In summary, our finding suggests that increasing insurance coverage of paternal screening and improving the patient's knowledge of the expanded screen would encourage paternal screening.

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.

The progression of Wiedemann-Steiner syndrome in adulthood and two novel variants in the KMT2A gene.

Wiedemann-Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long-term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann-Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann-Steiner syndrome is important for families of affected individuals.

Compound heterozygous mutations in desmoplakin associated with skin fragility, follicular hyperkeratosis, alopecia, and nail dystrophy.

Desmoplakin mutations are associated with a wide variety of phenotypes affecting the skin, nails, hair, and heart. A 21-month-old boy was born with multiple erosions resembling epidermolysis bullosa, complete alopecia, nail dystrophy, palmoplantar keratoderma, and areas of follicular hyperkeratosis. He was found to have two heterozygous mutations in the desmoplakin gene: c.478 C>T in exon 4 (p.Arg160X) and c.3630T>A in exon 23 (Tyr1210X). This case expands the clinical spectrum associated with desmoplakin mutations and highlights a mutation in exon 23 that has not been previously reported in the literature.

Novel phenotype of 5p13.3-q11.2 duplication resulting from supernumerary marker chromosome 5: implications for management and genetic counseling.

BACKGROUND: Supernumerary marker chromosomes derived from chromosome 5 (SMC5) and 5p13 duplication syndrome are rare disorders, and phenotypic descriptions of patients are necessary to better define genotype-phenotype correlations for accurate, comprehensive genetic counseling. The purpose of this study is to highlight the unique findings of a patient with a 5p13.3-q11.2 duplication arising from a SMC5 and compare and contrast the phenotype with cases in the literature. CASE PRESENTATION: We report on an adult male with a 22 Mb duplication of chromosome 5p13.3-q11.2 resulting from a small SMC5. The patient has a history of prenatal polyhydramnios, dysmorphic features, respiratory issues, talipes equinovarus, hypotonia, developmental delay, and autistic features. The patient also has novel features of aortic dilation, pectus excavatum, kyphoscoliosis, and skin striae, suggestive of a connective tissue disorder. Despite these features he did not meet clinical diagnostic criteria for a well-characterized connective tissue disorder. Additional molecular genetic testing for syndromic and non-syndromic aortic aneurysms was negative. CONCLUSIONS: Many of the patient's features are consistent with individuals reported with 5p13 duplication syndrome and similar cases of SMC5, including polyhydramnios, macrocephaly, dolichocephaly, pre-auricular pits, arachnodactyly, respiratory problems, and developmental delays. It is unclear if the patient's unique features of aortic dilation, pectus excavatum, kyphoscoliosis, and skin striae could be novel features of the SMC5 given its rarity and the few well-phenotyped adults in the literature. This report reviews the literature and provides additional phenotypic information to define the genotype-phenotype correlation of SMC5 and 5p13 duplication syndrome.

Cancer Genetic Counselors' Current Practices and Attitudes Related to the Use of Tumor Profiling.

Tumor profiling (TP) is primarily used to identify driver mutations within a tumor for treatment purposes, but it may also identify germline mutations. Current involvement of cancer genetic counselors (GCs) in the TP process is not clear. Members of the National Society of Genetic Counselors Cancer Special Interest Group were invited to participate in a confidential, web-based survey to characterize current practices and attitudes related to the use of TP. Of 105 useable responses, 86.7% of GCs reported their institutions were using TP, although only 6.7% did this routinely. Although 63.7% reported personal involvement in the process, largely with result interpretation and follow-up germline testing, 69.7% reported seeing fewer than 5 patients for this reason and 97.9% desired further education on this topic. Work and regional setting were not predictors of involvement with TP; however, GCs in the academic setting were less aware of who obtains consent (p = 0.001). GCs reported they were not often utilized as a resource regarding TP. Overall, GCs believed TP is beneficial in identifying hereditary cancer syndromes, although most reported finding a germline mutation in <10% of cases. This study provides a snapshot of current GC involvement with TP, and documents the desire by GCs for additional education on tumor profiling.

A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation.

We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome.

An infant with large fontanelles, aplasia cutis congenita, tessier facial cleft, polydactyly inversus, and toe syndactyly: a previously undescribed syndrome?

We report on a 5-month-old female with large and widely spaced anterior and posterior fontanelles, aplasia cutis congenita, Tessier 3 oblique facial cleft, polydactyly, and syndactyly of toes. The polydactyly is unusual as an accessory finger is attached to the left fifth finger with mirrored, end-to-end fusion. We are naming this anomaly "polydactyly inversus." The infant appears to have a previously unreported syndrome of unknown cause.