Burden of phenylketonuria in Latin American patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. If untreated, the complications of PKU lead to significant neucognitive and neuropsychiatric impairments, placing a burden on both the individual's quality of life and on the healthcare system. We conducted a systematic literature review to characterize the impact of PKU on affected individuals and on healthcare resources in Latin American (LATAM) countries. METHODS: Searches of the global medical literature as well as regional and local medical literature up to September 2021. Observational studies on patients with PKU from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias. RESULTS: 79 unique studies (47 cross-sectional studies, 18 case series, 12 case reports, and two cohort studies) with a total of 4090 patients were eligible. Of these studies, 20 had data available evaluating early-diagnosed PKU patients for meta-analysis of burden outcomes. Intellectual disability in the pooled studies was 18% [95% Confidence Interval (CI) 0.04-0.38; I2 = 83.7%, p = 0.0133; two studies; n = 114]. Motor delay was 15% [95% CI 0.04-0.30; I2 = 74.5%, p = 0.0083; four studies; n = 132]. Speech deficit was 35% [95% CI 0.08-0.68; I2 = 93.9%, p < 0.0001; five studies; n = 162]. CONCLUSIONS: There is currently evidence of high clinical burden in PKU patients in LATAM countries. Recognition that there are many unmet neuropsychological needs and socioeconomic challenges faced in the LATAM countries is the first step in planning cost-effective interventions.

Adherence to clinic recommendations among patients with phenylketonuria in the United States.

OBJECTIVE: Assess current management practices of phenylketonuria (PKU) clinics across the United States (US) based on the key treatment metrics of blood phenylalanine (Phe) concentrations and blood Phe testing frequency, as well as patient adherence to their clinic's management practice recommendations. METHODS: An online survey was conducted with medical professionals from PKU clinics across the US from July to September 2015. Forty-four clinics participated in the survey and account for approximately half of PKU patients currently followed in clinics in the US (Berry et al., 2013). RESULTS: The majority of PKU clinics recommended target blood Phe concentrations to be between 120 and 360µM for all patients; the upper threshold was relaxed by some clinics for adult patients (from 360 to 600µM) and tightened for patients who are pregnant/planning to become pregnant (to 240µM). Patient adherence to these recommendations (percentage of patients with blood Phe below the upper recommended threshold) was age-dependent, decreasing from 88% in the 0-4years age group to 33% in adults 30+ years. Patient adherence to recommendations for blood testing frequency followed a similar trend. Higher staffing intensity (specialists per 100 PKU patients) was associated with better patient adherence to clinics' blood Phe concentrations recommendations. CONCLUSION: Clinic recommendations of target blood Phe concentrations in the US are now stricter compared to prior years, and largely reflect recent guidelines by the American College of Medical Genetics and Genomics (Vockley et al., 2014). Adherence to recommended Phe concentrations remains suboptimal, especially in older patients. However, despite remaining above the guidelines, actual blood Phe concentrations in adolescents and adults are lower than those reported in the past (Walter et al., 2002; Freehauf et al., 2013). Continued education and support for PKU patients by healthcare professionals, including adequate clinic staffing, are needed to improve adherence. Future research is needed to understand how to improve adherence to reduce the number of patients lost to follow-up, as the findings of this and similar surveys do not address how to keep patients in clinic.

Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence.

BACKGROUND: The National Institute of Health (NIH) published a Consensus Statement on the screening and management of Phenylketonuria (PKU) in 2000. The panel involved in the development of this consensus statement acknowledged the lack of data regarding the potential for more subtle suboptimal outcomes and the need for further research into treatment options. In subsequent years, the approval of new treatment options for PKU and outcome data for patients treated from the newborn period by dietary therapy alone have become available. We hypothesized that a review of the PKU literature since 2000 would provide further evidence related to neurocognitive, psychosocial, and physical outcomes that could serve as a basis for reassessment of the 2000 NIH Consensus Statement. METHODS: A systematic review of literature residing in PubMed, Scopus and PsychInfo was performed in order to assess the outcome data over the last decade in diet-alone early-treated PKU patients to assess the need for new recommendations and validity of older recommendations in light of new evidence. RESULTS: The majority of publications (140/150) that contained primary outcome data presented at least one suboptimal outcome compared to control groups or standardized norms/reference values in at least one of the following areas: neurocognitive/psychosocial (N=60; 58 reporting suboptimal outcomes); quality of life (N=6; 4 reporting suboptimal outcomes); brain pathology (N=32; 30 reporting suboptimal outcomes); growth/nutrition (N=34; 29 reporting suboptimal outcomes); bone pathology (N=9; 9 reporting suboptimal outcomes); and/or maternal PKU (N=19; 19 reporting suboptimal outcomes). CONCLUSIONS: Despite the remarkable success of public health programs that have instituted newborn screening and early introduction of dietary therapy for PKU, there is a growing body of evidence that suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology and maternal PKU outcomes are suboptimal. The time may be right for revisiting the 2000 NIH Consensus Statement in order to address a number of important issues related to PKU management, including treatment advancements for metabolic control in PKU, blood Phe variability, neurocognitive and psychological assessments, routine screening measures for nutritional biomarkers, and bone pathology.

Prenatal diagnosis of holocarboxylase synthetase deficiency by assay of the enzyme in chorionic villus material followed by prenatal treatment.

Deficiency of holocarboxylase synthetase leads to multiple carboxylase deficiency, which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase, prenatal diagnosis was performed by assay of the enzyme in chorionic villus material. The Km for biotin was 220.8 nmol/l, which was 33 times the control value of 6.6 nmol/l. Biotinyl AMP synthesis was undetectable in cultured chorionic villus material. Prenatal treatment of the mother was begun with 10 mg a day of biotin and continued through pregnancy. There was no accumulation of the characteristic metabolites in the urine at birth and prior to oral treatment of the newborn. Holocarboxylase synthetase activity was undetectable in lymphocytes and in fibroblasts of the newborn. Furthermore, the activities of all three carboxylases in fibroblasts of the infant were deficient. The newborn was clinically well and maintained on biotin treatment after birth at 20 mg per day. Carboxylase activities in lymphocytes were normal or slightly lower than the normal range.

Isovaleric acidemia: response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy.

OBJECTIVE: To assess the effectiveness of glycine and carnitine therapy on isovaleryl conjugate excretion in isovaleric acidemia (IVA). STUDY DESIGN: Urinary isovalerylglycine (IVG) and isovalerylcarnitine (IVC) were measured from 12-hour urine specimens collected overnight from an 8-year-old patient with IVA (who had no residual activity of isovaleryl-CoA dehydrogenase in fibroblasts) before and during 3-week courses of supplementation with glycine alone (250 mg/kg per day), L-carnitine alone (100 mg/kg per day) therapy, and both of these agents combined, with a 2 gm leucine challenge performed at the end of each treatment period. RESULTS: Isovalerylglycine was the predominant metabolite excreted throughout the study, and its mean value doubled with glycine treatment. Isovalerylcarnitine excretion was minimal without carnitine supplementation. L-Carnitine therapy was associated with a 50% decline in excretion of IVG without a fully compensatory increase in IVC. The readdition of glycine to the carnitine regimen resulted in an increase in IVG excretion. Leucine challenge resulted in a 2.7- and 2.4-fold increase of IVG and IVC excretion, respectively, during L-carnitine therapy but not during glycine supplementation, and a 3.5- and 4-fold increase in excretion of both metabolites during glycine plus L-carnitine therapy. Total conjugate excretion was highest after a leucine load during combined glycine and L-carnitine therapy. CONCLUSIONS: Combined glycine and L-carnitine therapy maximally increases isovaleryl conjugate excretion during metabolic stress but not under stable conditions.

Prenatal counseling in heterozygotes for ornithine transcarbamylase deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) often leads to fatal neonatal hyperammonemia in affected males (hemizygotes). In prenatal management of subsequent pregnancies, families carrying female fetuses are often reassured of the low risk of clinically overt disease. We suggest that such reassurance may be misleading. While OTCD heterozygotes may show no symptoms or only mild protein intolerance, the clinical course in a fraction of children can include manifestations similar to those in affected males. We present three cases of symptomatic and previously undiagnosed OTCD heterozygotes to illustrate the potential severity of this condition. Significant improvement in function and growth followed diagnosis and treatment; however, two of the three children remain significantly developmentally delayed. While a quantitative risk estimate cannot be derived from these data, the cases are indicative of an adverse outcome in manifesting heterozygotes. Accordingly, OTCD carrier families should be counseled regarding the possibility of significant hyperammonemia, neurologic deficit, and the need for pharmacologic and dietary intervention in their heterozygote daughters.

Compliance with childhood cholesterol screening among members of a prepaid health plan.

OBJECTIVE: To assess compliance with cholesterol screening and intervention by children who were members of a prepaid health plan in which there was no financial barrier to intervention. RESEARCH DESIGN: Children with family histories of hypercholesterolemia, coronary heart disease, and stroke were advised to have a random cholesterol test. Those with total cholesterol levels of 4.80 mmol/L (185 mg/dL) or higher were asked to return for a fasting blood test; of this group, compliant subjects with low-density lipoprotein values of 3.25 mmol/L (125 mg/dL) or higher were offered a nutrition program. SETTING: Kaiser Permanente Medical Center, Oakland, Calif. SUBJECTS AND PARTICIPANTS: The parents of 1160 children aged 2 to 18 years who had routine pediatric appointments at Kaiser Permanente Medical Center were asked to complete screening forms on family history. SELECTION PROCEDURES: Children with family histories of hypercholesterolemia, coronary heart disease, and stroke were advised to have a random cholesterol test. Subjects with total cholesterol levels of 4.80 mmol/L or higher were asked to return for a fasting test, and subjects with low-density lipoprotein levels of 3.25 mmol/L or higher were offered a nutrition program. INTERVENTIONS: Telephone call, letter, low-cholesterol diet, and nutrition program. MAIN OUTCOME MEASURES: Of the 1,160 subjects contacted, 529 (46%) had positive family histories. Of these subjects, random blood cholesterol levels were determined for 369 (70%); 160 (30%) did not comply. Ninety-three subjects had total cholesterol levels of 4.80 mmol/L or higher; of these, 35 (38%) did not comply with follow-up testing. Of the 58 compliant subjects, 25 (43%) had low-density lipoprotein values of 3.25 mmol/L or higher and were offered either a 3-week or a 6-week nutrition program. Only nine subjects (36%) enrolled; 16 (64%) did not comply. CONCLUSIONS: Parents do not comply well with a childhood cholesterol screening program that involves two blood tests and moderately intensive educational intervention. Compliance is an important component of cholesterol screening and intervention.