to determine whether adults are accessing treatment for their pku , an estimated number of 
 adults with pku was calculated for comparison with the number of adults with pku who are 
 actively followed by metabolic clinics . data on number of births and those diagnosed by 
 nbs programs with hyperphenylalaninemia ( 120 mol / l ) are available from the national newborn screening and 
 genetics resource center . an analysis of the national newborn screening and genetics 
 resource center records from 1996 to 2005 was performed to derive a combined composite 
 incidence rate for hyperphenylalaninemia and classic pku . because classifications vary by 
 clinic , incidence rates for hyperphenylalaninemia and classic pku were combined and will 
 be referred to as  pku  throughout . the number of patients with pku born each 
 year from 1996 to 2005 was tabulated , and the sum of these figures provided a cumulative 
 incidence rate to be used as a model for estimating the number of patients diagnosed with 
 pku in the united states . the results obtained using the cumulative incidence model were 
 then compared against those reported in the literature . the incidence rate of pku calculated from the national newborn screening and genetics 
 resource center records for the decade 19962005 was applied to the annual number of 
 births in the united states , as recorded in the national vital statistics system of the 
 centers for disease control and prevention through 2010 . patients born before the 
 initiation of nbs in 1965 in the united states were not included in the analysis . the 
 calculated prevalence was then applied to the us census current population survey from the 
 calendar year 2010 to estimate the number of individuals with pku by age cohort . biomarin pharmaceutical has developed and maintained a database of 137 metabolic clinics 
 known to be following patients with pku throughout the united states . during routine and 
 ongoing visits , biomarin collected the number of patients actively followed by each 
 metabolic clinic in the database . for this analysis , collected data were distributed by 
 age groups of 04 years , 512 years , 1318 years , 1924 years , 
 2545 years and 46 years . data not distributed by patient age in the database 
 were analyzed and allocated into age groups using the aggregate percentages reported by 
 clinics that provided data distributed by age . the number of pku patients estimated from 
 us birth data was compared with the number of patients with pku reported by metabolic 
 clinics as being treated in order to estimate the number of individuals with pku who are 
 not followed by a metabolic program . finally , online searches of government and private websites were performed to identify 
 insurance coverage of medical formula and special low - protein foods by state and to assess 
 the impact of insurance coverage on adult patients continuing to seek treatment . authors 
 also offered input from their experience regarding factors reported by patients and their 
 families as well as issues encountered in the clinic . table 1 includes tabulation of the annual number of 
 patients with pku and the calculated incidence of pku for the 10-year period 
 19962005 . the results of the incidence model are consistent with reported 
 prevalence of pku , which vary from 1:11,400 live births in the united states to 1:15,000 . therefore , an average incidence of 1:12,707 was applied to annual 
 births reported to the national vital statistics system of the centers for disease control 
 and prevention , resulting in an estimate of 14,988 individuals with pku diagnosed from 
 1965 to 2010 . comparing this analysis with clinic reports , > 50% of all individuals with 
 pku the percentage increases with age , 
 ranging from 19% of individuals in the 04 years group to > 70% of individuals in 
 the 1945 years group ( table 2 ) . data collected for state - based insurance coverage and access to care for adults with pku 
 reveal that eight states ( 15.4% ) have coverage for medical formula only , whereas 18 
 ( 34.6% ) have no coverage for treatment for adult patients , yielding a total of 50% of 
 states that provide either no coverage of medical formula and modified special low - protein 
 products or only partial coverage of these front - line medical food therapies required for 
 the treatment of adults with pku ( table 3 ) the 
 experience of the authors reinforces the difficulties patients experience accessing 
 insurance as well other factors , which are further supported by reports in the literature 
 ( figure 1 ) . given that there are more than 30 metabolic and genetic disorders now diagnosed by nbs 
 programs , we must consider the experience with pku as an important model to establish the 
 context for long - term treatment from universal nbs programs . data collected through 
 government statistics and industry suggest that an estimated 71% of adults with pku 
 between the ages of 19 and 45 years who were diagnosed by nbs are not actively treated by 
 a metabolic clinic ( table 2 ) . although these data are 
 consistent with those reported in the literature , there is the possibility of a sampling error in the number of adults 
 reported as being seen in clinic because data were collected by interview with clinic 
 personnel conducted by representatives of biomarin , the pharmaceutical company that 
 markets sapropterin . there is also the potential that some adult patients are being 
 treated by physicians not associated with metabolic clinics and therefore not included in 
 this total . moreover , the estimate that 19% of 0- to 4-year - old children with pku are not 
 followed by a clinic suggests that some of these patients may have a variant form of 
 hyperphenylalanemia that is not considered to require therapy and , as such , a similar 
 percentage of adults may also not need diet therapy . regardless , this is a sobering 
 statistic that emphasizes the need to address barriers to access to medical care in an 
 effort to prevent similar issues from arising with other chronic diseases identified 
 through nbs and to improve the outcomes for a greater majority of individuals with 
 pku . despite an increase in health and neuropsychiatric issues affecting adults with poor 
 metabolic control , these concerns are rarely lethal , and those with pku typically have a 
 normal life span regardless of treatment status . therefore , disparity between prevalence 
 of pku based on health statistics and the number of adults reported by metabolic clinics 
 is not primarily due to morbidity in the patient population . this disparity may , in part , be due to the dramatic changes in 
 treatment recommendations and clinical guidelines over time . previous recommendations for 
 early discontinuation of treatment likely resulted in the loss to follow - up of many adults 
 with pku . because many metabolic clinics report that they do not see adult 
 patients ( table 
 2 ) and some clinics associated with children 's hospitals are not 
 allowed to see adults , the vast majority of adults with pku are not being followed by a 
 metabolic clinic and encounter difficulties locating clinics able to accept new adult 
 patients with pku . helped a veteran find a clinic when he was unable to 
 be treated at children 's hospital of los angeles because his metabolic physician was 
 not permitted to treat adult patients . in addition to the inability to access a metabolic clinic , results of the current study 
 clearly identify a lack of or limited insurance coverage for required medical food therapy 
 as a significant and primary barrier for the treatment of adults with pku ( table 3 ) . only 50% of the states 
 in the united states provide coverage of both required medical food and modified special 
 low - protein food products , and almost 35% do not provide any coverage for these therapies 
 for adults with pku . even for those states that do 
 have mandated coverage , barriers to access to medical formula and low - protein special 
 foods may exist for the patient from employer self - insured plans , which do not have to 
 comply with state - imposed mandates . we do not know whether a causal relationship exists 
 between third - party health insurance coverage and access to clinics ; however , the 
 contribution of this factor is supported by the literature , as well as by our own experience . in far too many states without mandates , private health insurance may cover prescribed 
 pharmaceutical treatments such as sapropterin but not the cost of medical formula and 
 special low - protein foods that are also required to maintain phe levels within the 
 recommended treatment range , even with sapropterin administration . for those without 
 coverage , the expense associated with medical foods and special low - protein 
 foods or 
 insurance copayments may be prohibitive for many patients . for those with coverage , the 
 deductible is often too high to be met by the patient . author k.m . reports one patient who 
 benefits from sapropterin treatment and has a small monthly copayment for this medication 
 through his pharmacy benefit . however , as he can not afford the deductible for the medical 
 food products required to keep blood phe levels within treatment range , he has access to 
 neither medically necessary treatment for his pku despite the small monthly copayment for 
 sapropterin . ironically , as medicaid covers the cost of medical foods in all states ( table 3 ) , those individuals with the greatest neurocognitive 
 impairments who are unemployed or underemployed may be better able financially to access 
 treatment compared with employed individuals without the benefits of adequate insurance 
 for the coverage of medical foods . however , individuals with neurocognitive impairments 
 may not be aware of the details of medicaid coverage or may be unable to independently 
 complete the paperwork required to receive coverage from medicaid . for those in group 
 homes , care providers assist in completing forms and securing assistance from regional 
 centers . those who are not referred to social workers must rely on their clinic to assist 
 with paperwork . the time required to complete paperwork , including not only completion of 
 applications but also accessing required documents and supplementary materials , is often 
 prohibitive , and there can be significant lapses for some patients before obtaining 
 treatment for their pku . this may be the case even for those who are pregnant , when high 
 phe levels may result in maternal pku syndrome for the fetus . a variety of other factors have also been identified as affecting adult patients ' 
 ability to access appropriate treatment for pku ( figure 
 1 ) . psychiatric and executive 
 function impairments such as attention and processing - speed deficits , behavioral and emotional problems , psychiatric disorders , and cognitive 
 deficits may have an overall negative effect on the individual 's 
 quality of life . if an adult is not followed by a metabolic clinic , he or she may not know 
 that diet treatment is now recommended for life or that new treatment options are 
 available that may make adherence more attainable . the resulting neurocognitive deficits 
 may contribute to unemployment or underemployment , with the subsequent socioeconomic 
 barriers to treatment and difficulty navigating the insurance system to secure access to 
 treatment . even for those adults who 
 continue treatment , there remains a higher risk than the general population for 
 neurocognitive and psychological deficits associated with elevated and/or fluctuating phe 
 levels . the less severe neurocognitive issues may still result in patients having difficulties 
 with daily living , such as scheduling and keeping medical appointments . moreover , because the majority of metabolic clinics have limited 
 access to mental health - care professionals and encounter difficulties obtaining 
 authorization for psychological evaluations , adult patients with neurocognitive and 
 psychological impairment may have limited access to health - care professionals suitably 
 prepared to treat them . familial , social , and health - care provider support systems are important to assist individuals with pursuing treatment for 
 pku . distance to the metabolic clinic , lack of 
 transportation , and inability to get time off work have also been cited as reasons for not 
 accessing treatment . these barriers are not isolated to the american health - care 
 system or unique to pku . similar barriers have 
 been identified in other chronic diseases lacking episodes of acute illness requiring 
 immediate medical attention , such as diabetes , asthma , and other inborn errors of 
 metabolism . since the nih guidelines in 2000 recommended treatment for life , transitional care has become an important aspect of managing 
 individuals with pku and an important concern for many metabolic clinics . some metabolic clinics have initiated adult - focused clinics to 
 transition patients from pediatric to adult care . however , patient response to transition 
 varies ; some patients report feeling uncomfortable at pediatric clinics , whereas others 
 are uncomfortable transitioning from clinics where they have been followed since 
 childhood . educating caregivers as well as individuals with 
 pku can help prepare them for transition 
 to adult care , an important focus for successful lifelong management of pku . although early treatment of pku after nbs has been appropriately hailed a success story , 
 it should also be considered a cautionary tale of the success of nbs coupled with the 
 resulting issues of lifelong chronic disease management . while there is a near - universal 
 diagnosis of pku in the united states , the goal of access to culturally sensitive , 
 age - appropriate treatment programs remains elusive . the majority of adults with pku are 
 not accessing treatment despite the 2000 nih recommendation of lifelong diet treatment and 
 the growing evidence of the positive results of resuming treatment for those adults who 
 have not been maintaining metabolic control . significant barriers to treatment access are societal , institutional , and multifaceted , 
 starting with the structure of the health - care delivery system and attitudes toward adults 
 with neurocognitive and other disabilities , and ending with logistical , socioeconomic , and 
 insurance coverage issues . although we can not with certainty say what has happened to the 
 significant number of pku patients identified through nbs who are not being followed by a 
 metabolic clinic and are not in contact with patient support organizations , we can say 
 with confidence that outcomes are likely to be significantly poorer for those who are not 
 treated and followed regularly by a metabolic clinic . updated treatment recommendations must advise metabolic clinics on how to be prepared for 
 the schism between the treatment needs of adult patients who have been treated early and 
 continuously , and those treated before the  treatment for life  paradigm was 
 implemented . we must also continue to advocate for access to appropriate mental 
 health - care and clinic support for all adult patients with pku , and not just those who 
 have maintained ongoing contact with pediatric clinics . however , as shown by data from 
 this study , insurance coverage issues persist for many patients , meaning that adults with 
 pku may go for extended periods of time without access to medical and special low - protein 
 food products . even for those adults with insurance , one - third of states in the united 
 states ( 34.6% ) may still not have mandated insurance coverage for treatment of adults , and 
 15.4% of the states may continue to cover only medical formula and not the cost of special 
 low - protein foods ( table 3 ) . as the nih , genetic metabolic dietitians international , and the american college of 
 medical genetics and genomics prepare these updated treatment recommendations for pku , we 
 need to develop the means to implement the recommendations for all patients , not just a 
 few . as a society , it is unethical and ineffective to diagnose a condition and then 
 systematically deny treatment in a variety of ways . we need to improve long - term 
 engagement with chronic - care patients identified through universal nbs programs to ensure 
 optimal lifetime outcomes , and not just celebrate the amelioration of the most severe 
 manifestations of disease . the national pku alliance has received funding from abbott nutrition , applied nutrition , 
 biomarin pharmaceutical , cambrooke foods , mead johnson , nutricia , pku perspectives , solace 
 nutrition , and vitaflo . mitzie 
 grant has received funding from biomarin pharmaceutical for consultant services and 
 clinical research .
fifty years after the implementation of universal newborn screening programs for 
 phenylketonuria , the first disease identified through newborn screening and considered a 
 success story of newborn screening , a cohort of adults with phenylketonuria treated from 
 birth provides valuable information about effects of long - term treatment for inborn errors 
 of metabolism in general , and phenylketonuria specifically . for phenylketonuria , 
 newborn 
 screening allows early implementation of the phenylalanine - restricted diet , eliminating 
 the severe neurocognitive and neuromotor impairment associated with untreated 
 phenylketonuria . 
 however , executive function impairments and psychiatric problems are 
 frequently reported even for those treated early and continuously with the 
 phenylalanine - restricted diet alone . moreover , a large percentage of adults with 
 phenylketonuria are reported as lost to follow - up by metabolic clinics . while a group of 
 experts identified by the national institutes of health convenes to update treatment 
 guidelines for phenylketonuria , we explore individual patient , social , and economic 
 factors preventing > 70% of adult phenylketonuria patients in the united states from 
 accessing treatment . 
 as more conditions are identified through newborn screening , factors 
 affecting access to treatment grow in importance , and we must continue to be vigilant in 
 assessing and addressing factors that affect patient treatment outcomes and not just 
 celebrate amelioration of the most severe manifestations of disease.genet med 2013:15(8):591599