Nutritional status of adults with phenylketonuria on pegvaliase: A 15-month prospective study.

Background: Pegvaliase has allowed many adults with phenylketonuria (PKU) to achieve acceptable blood Phe control while eating an unrestricted diet. However, little is known about potential differences in nutritional status and eating behaviors after transitioning from a phenylalanine (Phe)-restricted to an unrestricted diet. Here we assessed change in nutritional status in adults with early-treated PKU who were consuming a Phe-restricted diet (intact protein ≤0.8 g/kg/day) prior to starting pegvaliase. Methods: A 15-month, prospective, longitudinal study to assess change in anthropometrics, dietary intake, laboratory indices of nutritional status, bone mineral density (BMD), body composition, measured resting energy expenditure (REE), and eating behaviors between baseline and Month 15. Results: Eleven adults (n = 7 female) aged 19.5-52.9 years completed the study. Six participants had a substantial blood Phe reduction (responders) and five participants had a modest blood Phe reduction (partial responders) by Month 15. Intact protein intake increased by an average of 49.4 g/day and 26.7 g/day in responders and partial responders, respectively. Plasma concentrations of most vitamins, minerals, and essential fatty acids assessed were normal, though micronutrient intakes decreased as participants decreased or discontinued PKU medical food(s). Responders had a more variable change in body mass index (BMI) and lean mass index (LMI) compared to partial responders, though there were no clear trends in BMD or body composition changes. Total protein intake was positively correlated with LMI. Responders, but not partial responders, self-reported increased in enjoyment of food and decreased food neophobia, uncontrolled eating, and emotional eating. Discussion: Participants transitioning to an unrestricted diet while on pegvaliase maintained adequate nutritional status overall with no clinically significant changes in cardiovascular or glycemic markers. Responders reported improvements in eating behaviors, including reduced food neophobia, uncontrolled eating, and emotional eating, and increased enjoyment of food. There were no consistent trends in BMD, body composition, or BMI changes. A larger sample size and longer follow-up period are needed to further assess potential changes.

Reinstitution of pegvaliase therapy during lactation.

Pegvaliase, an injectable form of phenylalanine ammonia lyase, is an enzyme substitution therapy for adults with phenylketonuria (PKU). Experience with pegvaliase during lactation is scarce. Limited evidence suggests that pegvaliase does not pass into breast milk. The case presented here describes the pregnancy and lactation experience of a woman with PKU who was treated with pegvaliase prior to pregnancy, discontinued pegvaliase and was treated with a phenylalanine-restricted diet in preparation for and during pregnancy, and then reinstituted pegvaliase two weeks after giving birth and throughout lactation. No pegvaliase activity was detected in pumped breast milk samples prior to reinstituting pegvaliase, and at doses of 80, 110 and 140 mg/week during lactation. The phenylalanine content of breast milk samples collected during pegvaliase therapy were not significantly different than controls, and the infant has grown and developed normally, indicating that pegvaliase therapy during lactation is safe.

Pegvaliase dosing in adults with PKU: Requisite dose for efficacy decreases over time.

Novel pharmaceutical therapies such as pegvaliase, phenylalanine ammonia lyase (PAL), have enhanced disease control for many individuals with phenylketonuria (PKU). We present a retrospective chart review to assess pegvaliase doses over time in individuals followed at the Boston Children's Hospital PAL Clinic, including those who started pegvaliase in a clinical trial ("trial patients") and those who started after drug came to market ("post-market patients"). Trial patients were on pegvaliase an average of 4.8 years longer, and their mean current pegvaliase dose was 126 ± 92 compared to 223 ± 147 mg/week for post-market patients (p = 0.0155), suggesting that the pegvaliase dose for target efficacy may decrease over time in adults with PKU. In post-market patients, we demonstrated a significant, inverse correlation with dose change and number of weeks from response (r = -0.46, p = 0.046). The entire cohort showed significant variability in terms of time to achieve a therapeutic response, response dose, and current dose. Our data suggest that patients tolerate a reduction in pegvaliase dose over time while maintaining efficacy. This is a clinically meaningful finding as it indicates that patients may reduce number of weekly injections over time on pegvaliase.

Nutrition status of adults with phenylketonuria treated with pegvaliase.

BACKGROUND: Pegvaliase is an enzyme substitution therapy that reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU), and often allows normalization of protein intake (≥0.8 g protein/kg). Here we examine the nutrition status of adults with PKU consuming a normal protein intake without medical food after being treated with pegvaliase for ≥1 year. METHODS: A cross-sectional study evaluating nutritional intake (3-day food record and food frequency questionnaire), anthropometrics, laboratory indices of protein, micronutrient, and essential fatty acid (EFA) status, and questionnaires evaluating food neophobia and Epicurean eating pleasure. RESULTS: Participants (n = 18, 61% female) started pegvaliase 4.9 ± 2.1 years prior to enrollment and were aged 38.2 ± 8.8 years with a mean BMI of 29.2 ± 4.1 kg/m2. Participants consumed a mean of 73.2 ± 17.6 g protein/d (1.0 ± 0.3 g/kg/d). Eleven participants had low blood Phe (<30 µmol/L) with adequate protein intake and normal indices of protein status. Micronutrient and EFA concentrations were normal except for mildly low vitamin D (<30 ng/mL, n = 12). Intakes of sodium, saturated fat, and added sugars exceeded recommendations for healthy adults, though mean diet quality was comparable to a US adult reference population. Lower food neophobia scores correlated with an increased aesthetic appreciation of food. However, 53% of participants self-reported having moderate (n = 6) to high (n = 3) food neophobia. DISCUSSION: Participants treated with pegvaliase consumed an unrestricted diet with adequate dietary protein and, overall, had normal protein, micronutrient, and fatty acid status. Despite low blood Phe, protein nutriture was not compromised. While nutritional deficiencies were not identified, diet quality was suboptimal and some participants reported food neophobia. Nutrition education remains an important component of care as patients adapt to a normal diet.

First 1.5 years of pegvaliase clinic: Experiences and outcomes.

We present Boston Children's Hospital's clinic model for pegvaliase therapy in adults with phenylketonuria (PKU) and clinical outcomes in 46 patients over the first 1.5 years of commercial therapy. Approximately 70% (18/26) of patients starting pegvaliase achieved blood phenylalanine (Phe) <360 µmol/L, with an average of a 68 ± 24% decrease in blood Phe from baseline. All patients experienced at least minor side effects, but in most, management of the side effects allowed for treatment to continue.

Clinical and biochemical outcomes of patients with medium-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency is a fatty acid oxidation disorder that can have variable clinical severity. There is still limited information on its clinical presentation and longitudinal history by genotype, and effectiveness of newborn screening (NBS). METHODS: Retrospective data were collected from 90 patients (44 female, 46 male) to compare biochemical data with clinical outcomes. The frequency of adverse events (number of hypoglycemia-related ER visits and admissions) was assessed by genotype (homozygosity or not for the common pathogenic variant, p.Lys329Glu, in the ACADM gene), and method of diagnosis (NBS vs. clinical). RESULTS: MCAD deficiency in Utah was more frequent compared to the United States average (1: 9266 versus 1:17,759 newborns). With age, C8-carnitine did not change significantly whereas C2-carnitine decreased (p < .001), possibly reflecting reduced carnitine supplementation typically seen with age. Children with MCAD deficiency had normal growth. p.Lys329Glu homozygotes had higher NBS C8-carnitine (23.4 ± 19.6 vs. 6.6 ± 3.0 µmol/L) and lifetime plasma C8-carnitine levels (6.2 ± 5 vs. 3.6 ± 1.9 µmol/L) compared to patients with at least one other pathogenic variant (p < .001 for both) and higher transaminases compared to compound heterozygotes (ALT 41.9 ± 6.2 vs. 31.5 ± 3.7 U/L, AST 63.9 ± 5.8 vs. 45.7 ± 1.8 U/L, p < .05 for both). On average, p.Lys329Glu homozygotes had more hypoglycemic events than compound heterozygotes (1.44 versus 0.49 events/patient) as did patients diagnosed clinically compared to those diagnosed by NBS (2.15 versus 0.62 events/patient), though these differences were not statistically significant. Neonatal death was observed before results of newborn screening were available in one patient homozygous for the common p.Lys329Glu pathogenic variant, but severe neonatal complications (hypoglycemia, cardiac arrhythmia) were also seen in patients with other mutations. No irreversible complications were observed after diagnosis in any patient with MCAD deficiency. DISCUSSION: Homozygosity for the common ACADM p.Lys329Glu pathogenic variant was associated with increased levels of C8-carnitine and transaminases. Newborn screening provides the opportunity to reduce morbidity and post-neonatal mortality in all patients with MCAD deficiency, regardless of genotype.

Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation included in the recommended uniform newborn screening (NBS) panel in the USA. It can have variable clinical severity and there is limited information on the natural history of this condition, clinical presentation according to genotype and effectiveness of newborn screening. METHODS: Retrospective data (growth parameters, morbidity, biochemical and genetic testing results) were collected from patients with VLCAD deficiency, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate continuous variables. RESULTS: VLCAD deficiency (screened by measuring elevated levels of C14:1-carnitine in blood spots) was more frequent in Utah than the national average (1:27,617 versus 1:63,481) in the first ten years of screening. Twenty-six patients had a confirmed diagnosis of VLCAD deficiency using DNA testing or functional studies. The c.848T>C (p.V283A) variant in the ACADVL gene was the most frequent in our population. Novel variants (c.623-21A>G (IVS7-21A>G); c.1052C>T (p.T351I); c.1183-7A>G (IVS11-7A>G); c.1281G>C (p.W427C); c.1923G>C (p.L641F); c.1924G>A (p.V642M)) were identified in this study, with their pathogenicity remaining unclear in most cases. C14:1-carnitine levels decreased with age and significantly correlated with CK levels as index of muscle involvement. There were no cases of HELLP syndrome nor liver disease during pregnancies in the mothers of VLCAD patients. None of our patients developed cardiac involvement after birth and all patients had normal growth parameters while on treatment. Clinical manifestations were related to concomitant infections and altered biochemical parameters. DISCUSSION: VLCAD deficiency can be identified by neonatal screening. Most patients compliant with therapy normalized biochemical parameters and had no major clinical manifestations. Complications were completely prevented with a relatively low number of pre-emptive ER visits or hospital admissions. It remains unclear whether neonatal screening is now identifying less severely affected patient or if complications will arise as subjects become older. Observation beyond puberty is necessary to fully understand the impact of VLCAD deficiency on morbidity in patients with VLCAD deficiency.

Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria.

PURPOSE: Phenylketonuria (PKU) is a rare metabolic disorder that requires life-long management to reduce phenylalanine (Phe) concentrations within the recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can metabolize Phe) as a new therapy necessitates the provision of guidance for its use. METHODS: A Steering Committee comprising 17 health-care professionals with experience in using pegvaliase through the clinical development program drafted guidance statements during a series of face-to-face meetings. A modified Delphi methodology was used to demonstrate consensus among a wider group of health-care professionals with experience in using pegvaliase. RESULTS: Guidance statements were developed for four categories: (1) treatment goals and considerations prior to initiating therapy, (2) dosing considerations, (3) considerations for dietary management, and (4) best approaches to optimize medical management. A total of 34 guidance statements were included in the modified Delphi voting and consensus was reached on all after two rounds of voting. CONCLUSION: Here we describe evidence- and consensus-based recommendations for the use of pegvaliase in adults with PKU. The manuscript was evaluated against the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and is intended for use by health-care professionals who will prescribe pegvaliase and those who will treat patients receiving pegvaliase.

Biochemical changes and clinical outcomes in 34 patients with classic galactosemia.

Impaired activity of galactose-1-phosphate uridyltransferase (GALT) causes galactosemia, an autosomal recessive disorder of galactose metabolism. Early initiation of a galactose-restricted diet can prevent or resolve neonatal complications. Despite therapy, patients often experience long-term complications including speech impairment, learning disabilities, and premature ovarian insufficiency in females. This study evaluates clinical outcomes in 34 galactosemia patients with markedly reduced GALT activity and compares outcomes between patients with different levels of mean galactose-1-phosphate in red blood cells (GAL1P) using logistic regression: group 1 (n = 13) GAL1P ≤1.7 mg/dL vs. group 2 (n = 21) GAL1P ≥ 2 mg/dL. Acute symptoms at birth were comparable between groups (p = 0.30) with approximately 50% of patients presenting with jaundice, liver failure, and failure-to-thrive. However, group 2 patients had significantly higher prevalence of negative long-term outcomes compared to group 1 patients (p = 0.01). Only one of 11 patients >3 yo in group 1 developed neurological and severe behavioral problems of unclear etiology. In contrast, 17 of 20 patients >3 yo in group 2 presented with one or more long-term complications associated with galactosemia. The majority of females ≥15 yo in this group also had impaired ovarian function with markedly reduced levels of anti-Müllerian hormone. These findings suggest that galactosemia patients with higher GAL1P levels are more likely to have negative long-term outcome. Therefore, evaluation of GAL1P levels on a galactose-restricted diet might be helpful in providing a prognosis for galactosemia patients with rare or novel genotypes whose clinical presentations are not well known.

Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency.

Deficiency of the mitochondrial trifunctional protein (TFP) and long-chain 3-Hydroxy Acyl-CoA dehydrogenase (LCHAD) impairs long-chain fatty acid oxidation and presents with hypoglycemia, cardiac, liver, eye, and muscle involvement. Without treatment, both conditions can be life-threatening. These diseases are identified by newborn screening (NBS), but the impact of early treatment on long-term clinical outcome is unknown. Moreover, there is lack of consensus on treatment, particularly on the use of carnitine supplementation. Here, we report clinical and biochemical data in five patients with TFP/LCHAD deficiency, three of whom were diagnosed by newborn screening. All patients had signs and symptoms related to their metabolic disorder, including hypoglycemia, elevated creatine kinase (CK), and rhabdomyolysis, and experienced episodes of metabolic decompensation triggered by illness. Treatment was started shortly after diagnosis in all patients and consisted of a diet low in long-chain fats supplemented with medium chain triglycerides (MCT), essential fatty acids, and low-dose carnitine (25 mg/kg/day). Patients had growth restriction early in life that resolved after 2 years of age. All patients but the youngest (2 years old) developed pigmentary retinopathy. Long-chain hydroxylated acylcarnitines did not change significantly with age, but increased during acute illnesses. Free carnitine levels were maintained within the normal range and did not correlate with long-chain hydroxylated acylcarnitines. These results show that patients with LCHAD deficiency can have normal growth and development with appropriate treatment. Low-dose carnitine supplements prevented carnitine deficiency and did not result in increased long-chain hydroxylated acylcarnitines or any specific toxicity.

Effect of dietary lysine restriction and arginine supplementation in two patients with pyridoxine-dependent epilepsy.

Pyridoxine-Dependent Epilepsy (PDE) is a recessive disorder caused by deficiency of α-aminoadipic semialdehyde dehydrogenase in the catabolic pathway of lysine. It is characterized by intractable seizures controlled by the administration of pharmacological doses of vitamin B6. Despite seizure control with pyridoxine, intellectual disability and developmental delays are still observed in some patients with PDE, likely due to the accumulation of toxic intermediates in the lysine catabolic pathway: alpha-aminoadipic semialdehyde (AASA), delta-1-piperideine-6-carboxylate (P6C), and pipecolic acid. Here we evaluate biochemical and clinical parameters in two PDE patients treated with a lysine-restricted diet and arginine supplementation (100-150mg/kg), aimed at reducing the levels of PDE biomarkers. Lysine restriction resulted in decreased accumulation of PDE biomarkers and improved development. Plasma lysine but not plasma arginine, directly correlated with plasma levels of AASA-P6C (p<0.001, r(2)=0.640) and pipecolic acid (p<0.01, r(2)=0.484). In addition, plasma threonine strongly correlated with the levels of AASA-P6C (p<0.0001, r(2)=0.732) and pipecolic acid (p<0.005, r(2)=0.527), suggesting extreme sensitivity of threonine catabolism to pyridoxine availability. Our results further support the use of dietary therapies in combination with pyridoxine for the treatment of PDE.

Phone-based motivational interviewing to increase self-efficacy in individuals with phenylketonuria.

OBJECTIVE: To measure change in patient activation and self-efficacy in individuals with phenylketonuria (PKU) before and after a 6-month phone-based motivational interviewing (MI) intervention and determine the feasibility of implementing dietary counseling for PKU using an MI approach. METHODS: Participants (n = 31) included preadolescents (7-12 years), adolescents (13-17 years), and adults (18-35 years) with early-treated PKU. Participants completed online questionnaires assessing self-reported stage of change (SOC), patient activation, and self-efficacy for PKU self-management behaviors. The intervention included monthly phone-based dietary counseling using MI during which participants set monthly goals. RESULTS: Patient activation and self-efficacy were significantly different by age group (both p < 0.01) with higher scores in older participants. Self-efficacy significantly increased from baseline to month 6 among adolescents and adults (7.4 ± 1.9 and 8.6 ± 1.3, respectively, p = 0.002). Preadolescents did not have a significant change in self-efficacy (p = 0.79). There was no increase in patient activation for preadolescents or adolescents/adults (p = 0.19 and p = 0.24, respectively). Indicators of learning problems were not significantly associated with self-efficacy (p = 0.33) or patient activation (p = 0.83). CONCLUSION: These results demonstrate the feasibility of implementing phone-based dietary counseling for PKU using MI. This study also supports further investigation of MI as an intervention approach to improving self-efficacy and self-management behaviors in adolescents and adults with PKU.

Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency.

BACKGROUND: Guanidinoacetate methyltransferase (GAMT) deficiency causes cerebral creatine deficiency. Patients can have autistic behavior, seizures, intellectual disability, and severe speech delay. The goal of therapy is to increase creatine while reducing potentially neurotoxic guanidinoacetate concentrations. Here we evaluate how different therapies affect plasma guanidinoacetate levels in patients with GAMT deficiency. METHODS: Retrospective analysis of data from five new patients with GAMT deficiency (four with delays and seizures, one diagnosed at birth). RESULTS: The four symptomatic patients had decreased brain creatine by magnetic resonance spectroscopy and three also had abnormal globi pallidi by MRI. GAMT sequencing identified four previously reported mutations and one novel missense mutation (c.233T>A/p.V78E). Treatment with creatine (250-1000 mg/kg/day), ornithine (100-800 mg/kg/day), and sodium benzoate (50-135 mg/kg/day) supplements along with dietary protein restriction (0.8-1.5 g/kg/day) improved seizures and development with all patients becoming verbal. The patient treated at birth remains developmentally normal. Reduction in glycine and increase in ornithine levels significantly decreased plasma guanidinoacetate, with glycine levels being the best predictor of guanidinoacetate levels. In contrast, arginine levels were not significantly correlated with plasma guanidinoacetate. CONCLUSIONS: Our results show that supplements of creatine, sodium benzoate (to reduce glycine) and ornithine reduce guanidinoacetate levels in patients with GAMT deficiency (dietary therapy was not evaluated in our study). Normal development with early therapy renders GAMT deficiency an ideal candidate for inclusion in newborn screening panels.

Glutaric acidemia type 1: outcomes before and after expanded newborn screening.

Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism. Patients may present with brain atrophy, macrocephaly, and acute dystonia secondary to striatal degeneration typically triggered by an infection, fever, and/or dehydration. This disorder is identified on expanded newborn screening by increased glutarylcarnitine. We evaluated the outcome of 19 patients with GA-1. Ten patients were diagnosed by newborn screening and 9 were diagnosed clinically. DNA testing in 12 patients identified 15 different mutations in the glutaryl-CoA dehydrogenase gene. Plasma glutarylcarnitine and urinary 3-hydroxyglutaric acid were elevated in all patients. However, only 10 of 17 patients who underwent urine organic acid analysis were high excretors of glutaric acid. Levels of glutarylcarnitine in plasma correlated with the urinary excretion of glutaric and 3-hydroxyglutaric acid, but not with clinical outcome. Plasma lysine was also significantly correlated with urinary glutaric acid, but not with urinary 3-hydroxyglutaric acid. Brain magnetic resonance imaging in all patients showed wide Sylvian fissures before treatment, which normalized by 4 years of age in treated patients. The occurrence of three adverse outcomes (oral motor function, ambulatory capability, and dystonic movements) was on average reduced by 75% (relative risk 0.25 to 0.28) in patients identified by newborn screening compared to patients diagnosed before newborn screening (Fisher's exact test; p=0.0055 for oral motor function and ambulatory capability; p=0.023 for dystonic movements). Newborn screening is effective in the prevention of complications in patients with GA-1 when coupled with treatment strategies.

Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria.

Patients with treated phenylketonuria (PKU) can have subtle deficits in intellect, academic skills, and executive functioning. This study evaluates the relationship between intellectual outcome and concentration/variation in blood phenylalanine (Phe) during specific developmental periods (0-6 years, 7-12 years, >12 years) in our patients with PKU. Verbal comprehension, perceptual reasoning, and processing speed were used as measures of intelligence. Data were collected from 55 patients receiving treatment at the University of Utah Metabolic Clinic. Yearly median Phe levels increased and mean number of blood Phe samples decreased as patients aged. Yearly median blood Phe from 0-6 and 7-12 years were inversely associated with perceptual reasoning abilities using linear regression. Additionally, increased blood Phe concentration negatively impacted specific areas of verbal comprehension abilities for those 0-6 years of age (p = 0.001). Variation of Phe levels around the mean (assessed as standard deviation) in each patient was associated with diagnostic (highest pretreatment) Phe levels and yearly median Phe levels (p < 0.001 for both), but did not significantly impact intelligence in our group of patients. Frequent blood Phe monitoring from 7-12 years significantly reduced the probability of yearly median Phe exceeding 360 µM (p = 0.005). Our data show that compliance with treatment in patients with PKU affects both the concentration and variation of blood Phe levels, and may have a greater impact on verbal comprehension and perceptual reasoning skills during the first 12 years of life when compared the influence beyond 12 years.

Warfarin knowledge in patients with atrial fibrillation: implications for safety, efficacy, and education strategies.

BACKGROUND: Multiple factors influence warfarin metabolism and can significantly affect the risk of adverse events. The extent to which patients understand the modifiable factors that impact on warfarin safety and efficacy is unclear. METHODS: A 52-item questionnaire related to knowledge of warfarin was administered to patients with atrial fibrillation in a face-to-face interview with a dietitian. Results were compiled based on five categories: general warfarin knowledge, compliance, drug interactions, herbal or vitamin interactions, and diet. RESULTS: 100 patients were surveyed. Stroke risk factors included hypertension (57%), heart failure (36%), age >75 years (33%), diabetes (22%), and prior stroke/transient ischemic attack (29%). The majority were either high-school (49%) or college graduates (27%). Ten (10%) had a stroke while on warfarin, 11 (11%) had a blood transfusion, and 26 (26%) had at least one fall. The percentages correct for questionnaire items in the five categories were as follows: general knowledge (62%), compliance (71%), drug interactions (17%), herbal or vitamin interactions (7%), and diet (23%). Neither education level nor duration of therapy correlated with warfarin knowledge. Patients at highest risk of stroke had very low knowledge scores in general. DISCUSSION: Patients on warfarin have a poor general understanding of the medication, particularly those at highest risk of stroke.