Policy issues for expanding newborn screening programs: the cystic fibrosis newborn screening experience in the United States

OBJECTIVE: To describe the screening approaches and implementation strategies for cystic fibrosis newborn screening in the 12 programs that were offered in 11 states in 2002. STUDY DESIGN: Telephone interviews conducted in the spring of 2003 with program representatives in the 11 states. Screening approaches were defined in four overlapping categories: state mandated screening, state-wide offering, hospital based screening, and screening with informed consent. RESULTS: Screening was state mandated in seven states but was routinely offered to most infants in nine states. The primary care provider or hospital determined if screening was done in three states (four programs). Informed consent was explicitly documented in two states. In five programs, immunoreactive trypsinogen exclusively was used to identify at-risk infants. In seven programs, a second tier DNA test was also used, but these programs each had distinct strategies. In only two programs where DNA testing was performed and normal sweat tests indicated carrier status, were results routinely provided to parents "in person" at a CF center. CONCLUSION: The diversity of approaches for screening approaches and strategies has advantages for future policy decisions, provided that data about the clinical and psychosocial impact of screening from these programs are collected and disseminated. As additional states determine that the resources are available, programs can be designed with a more favorable benefit/risk balance as a result of the successes and challenges faced by other states.     

Human LAT1 single nucleotide polymorphism N230K does not alter phenylalanine transport

The deleterious effects on the brain of phenylketonuria are caused by the saturation of the blood-brain barrier large neutral amino acid transporter type 1 (LAT1) by high plasma phenylalanine concentrations. There is only one known single nucleotide polymorphism (SNP) of the open reading frame of human LAT1, N230K. Site-directed mutagenesis of the wild type human LAT1 cDNA replicated the N230K SNP, and the corresponding cloned RNA encoding either the wild type or N230K human LAT1 were injected into frog oocytes. The kinetics of phenylalanine transport via either form of the human LAT1 was not significantly different. Similarly, there was no difference in the kinetics of phenylalanine transport via the wild type rabbit LAT1 or the corresponding K226N mutant of rabbit LAT1. These studies demonstrate that the only known SNP in the open reading frame of human LAT1 has no effect on the kinetics of large neutral amino acid transport via this carrier.     

Optimal management of phenylketonuria: a centralized expert team is more successful than a decentralized model of care

OBJECTIVE: To compare phenylketonuria (PKU) management by a centralized, expert team in the Province of Nova Scotia (NS) with the decentralized approach in New Brunswick (NB). STUDY DESIGN: Retrospective chart review documented frequency of outpatient visits, phenylalanine (Phe) concentration, and medical formula use. Structured telephone interviews with the 8 regional NB dietitians (NB-D) documented their knowledge and support in PKU management. Patients with PKU (n=108; age, birth to 42 years) reside in NB (n=69) and NS (n=39). More were lost to contact in NB than in NS (9/69 vs 1/39) and more were completely off diet in NB than in NS (24/60 vs 1/38, P=.05). All 15 children <2 years old followed by a PKU team in either NS or Saint John, NB had optimal Phe levels. Children 2 to 12 years of age in NS had better Phe control and more medical visits than in NB (P <.01). Older patients had more episodes of elevated Phe levels (P=.01). Formula was dispensed in appropriate yearly amounts to 52% in NB and >95% in NS. Mental handicap or borderline intelligence was common in both NB (44%) and NS (42%). All NB-D wished additional specialized medical, nursing, or social work assistance. CONCLUSIONS: PKU management appears to be more effective with an expert, coordinated team approach.     

A role for overdominant selection in phenylketonuria? Evidence from molecular data

To date, the reason is unknown for the high prevalence of phenylalanine hydroxylase (PAH) mutations causing phenylketonuria (PKU) in extant European populations. However, molecular genetic data generated over the last decade suggest that the concomitant excess of (unaffected) PKU carriers is at least in part the result of overdominant selection ("heterozygous advantage"). Such selection would have acted upon several different mutations in different historical populations. The exact nature of the underlying selective mechanism is unknown; its elucidation requires further investigation.     

Effects of maternal hyperphenylalaninemia on fetal brain development: A morphological study

We examined the effects of maternal hyperphenylalaninemia on body and brain growth, and the biochemical maturation of the fetal and neonatal rat brain. Elevated concentrations of plasma phenylalanine were induced in pregnant rats under two experimental conditions from the 14th through the 21st days of gestation. In the first treatment, pregnant rats were injected subcutaneously with alpha-methylphenylalanine (to inhibit maternal liver phenylalanine hydroxylase) at a dosage of 30 mg/100 g body weight plus phenylalanine supplementation (to increase maternal and fetal plasma phenylalanine) at a dosage of 60 mg/100 g body weight two times daily. In the second treatment, pregnant dams were injected with phenylalanine only at a dosage of 65 mg/100 g body weight three times daily. Treatment with alpha-methylphenylalanine/phenylalanine (mPhe/Phe) resulted in a 76% inhibition in the activity of maternal phenylalanine hydroxylase and a 25-fold increase in the mean daily concentration of phenylalanine in the maternal and fetal plasma. Phenylalanine treatment alone resulted in a 15-fold increase in plasma phenylalanine in the maternal and fetal animals. Significant reductions in body and brain weights in the fetal and neonatal rats were found in both treatment groups. Biochemical determinations indicated that the total DNA, RNA, and protein contents of the cerebra were reduced, with the reductions being greater in the mPhe/Phe- than the phenylalanine-treated rats. However, the retardation in body and brain growth of both treatment groups did not appear to be permanent because substantial recovery was noted in the rats after postnatal day 7. These results suggest that exposure of the fetus to high plasma concentrations of phenylalanine caused a delay in the biochemical maturation of the fetal rat brain.     

Maternal phenylketonuria: comparison of two treated full term pregnancies

This case report documents the fetal outcome of two full term pregnancies in a patient with phenylketonuria (PKU). She was treated with a low phenylalanine diet preceeding and during both pregnancies. During her first full term pregnancy she was not able to maintain the rigid diet, and this pregnancy resulted in the delivery of a growth-retarded, microcephalic boy. In her second pregnancy the patient maintained the diet until her delivery at full term. Maternal blood phenylalanine levels remained with two exceptions below 600 mol/l throughout pregnancy and an infant of normal weight and head circumference was born.Abbreviations PKU phenylketonuria - BPD biparietal diameter     

Emotional outcome of adolescents and young adults with early and continuously treated phenylketonuria.

OBJECTIVE: To assess the emotional functioning of adolescents and young adults with early and consistently treated phenylketonuria (PKU). METHODS: Twenty PKU-affected participants, ages 14-25, were compared with age-matched chronically ill (n = 17) and peer (n = 16) controls on a structured clinical interview, the Minnesota Multiphasic Personality Inventory, and the Tennessee Self-Concept Scale-2. Affected participants and nonparticipants were assessed using a multidomain assessment of functioning interview. RESULTS: There were no significant differences between groups for observable psychiatric disorders or emotional and functional symptoms. No significant differences were found in self-concept. Although there were no differences between groups for IQ or treatment variables, PKU-affected participants were more likely than nonparticipants to have sought help for psychological concerns. CONCLUSIONS: Results suggest that early-treated PKU-affected adolescents and young adults do not show a higher risk for psychological disturbance than appropriate controls.     

How does physician gender influence primary care quality? evidence from a standardised patient audit study in China

Background

Studies in high-income countries have found that female physicians exhibit better performance than their male counterparts. However, it is largely unclear whether these findings are influenced by case and patient mix bias. We aimed to objectively assess differences in clinical practice and treatment between female and male primary care providers in rural China.

Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan

Tetrahydrobiopterin (BH₄) deficiency is a rare, congenital and lethal condition resulting in phenylalanine build-up that can lead to mental retardation and developmental defects, unless properly treated. About 1 million newborn infants in Japan undergo neonatal PKU screening every year, of which about 1 in 2 million are diagnosed with the condition. In this post-marketing surveillance study, 19 patients with BH₄ deficiency in whom BH₄ supplementation with sapropterin dihydrochloride (Biopten®) (hereafter referred to as ‘BH₄ therapy’) was initiated before the age of 4 years, were followed up for ?28 years. Patients who screened positive for BH₄ deficiency were treated with supplemental BH₄ plus L-dopa and 5-hydroxytryptophan. Data on the patients’ clinical courses were collected once yearly at 10 medical centers in Japan. Seventeen patients were diagnosed with 6-pyruvoyl tetrahydropterin synthase deficiency and two with dihydropteridine reductase deficiency at an average age of 3.6 months; the mean age at end of follow-up was 14.6 years. Average duration of BH₄ therapy (mean dose, 5 mg/kg per day) was 13.2 years. Serum phenylalanine was reduced from more than 10 mg/dL at the start of drug administration to less than 2 mg/dL at end of follow-up. No abnormalities in height or weight were observed in any patients, except for one female patient with familial obesity. No unwarranted side effects were reported throughout the long-term course of treatment, even during pregnancy. BH₄ therapy can effectively maintain serum phenylalanine levels within the normal range in patients with BH₄ deficiency, and demonstrated excellent long-term safety, with no side effects.     

Localized brain proton NMR spectroscopy in young adult phenylketonuria patients

Localized proton magnetic resonance spectroscopy with short echo time (TE = 20 ms) was used to investigate biochemical changes in the cerebral white matter of 20 young adult patients (median 19 years) with phenylketonuria (PKU). Results were compared with those of a group of 12 age-matched healthy volunteers (median 25 years). Concentrations of Nacetyl-aspartate (NAA) and choline (Cho) relative to creatine (Cr) were unchanged. However, concentrations of inositol (Ins) relative to creatine were found to be significantly lower (P < 0.001) in the PKU patients (0.30 ± 0.09 versus 0.57 ± 0.17). Individual inositol concentrations did not correlate with age, diet, serum phenylalanine (Phe) levels or extent of pathological regions in the T,-weighted images. The lack of correlation with individual data suggests that the decreased inositol concentration could be related to a metabolic deficiency during fetal development. No signal from the phenyl ring protons of phenylalanine was detected in the PKU patients (phenylalanine serum concentration ? 1.27 mM), which suggests that concentration of phenylalanine may be lower in brain than in serum.