Genetic testing for neurologic and developmental disorders spans the spectrum from universal newborn screening for conditions like phenylketonuria to diagnostic testing for suspected genetic conditions, to predictive genetic testing for childhood-onset conditions. Given that virtually all children in the United States undergo genetic screening in the newborn period, this article focuses on 3 actual case studies of neurologic and developmental disorders that have been included or proposed for inclusion in newborn screening programs: Duchenne muscular dystrophy (a neuromuscular disorder), Krabbe disease (a neurodegenerative disorder), and fragile X syndrome (a neurodevelopmental disorder).
Key points
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The primary justification for genetic testing and screening of children is the child’s best interest.
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To justify mandatory newborn screening for a specific condition, there must be an early intervention that is needed to prevent or reduce morbidity or mortality.
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Genetic testing methodologies are far more advanced than treatments for many neurologic and development disorders.
Introduction: a brief history of newborn screening
Virtually every infant in the United States has a few drops of blood collected within the first few days of life that is used to screen for more than 40 metabolic, endocrine, and hematologic, the vast majority of which are genetic in origin. Most infants also undergo hearing screening and pulse oximetry screening for critical congenital heart disease which may also be genetic in origin. The goal is to identify and treat conditions that present in infancy to reduce mortality and prevent morbidity.
Newborn screening (NBS) began in the 1960s when Dr Robert Guthrie developed the bacterial inhibition assay to diagnose phenylketonuria (PKU) and the filter paper on which to collect the blood samples for large-scale screening. If untreated, children with PKU experience both intellectual disability and autistic behaviors. If treatment with a low-protein diet is begun within a few weeks of birth, these individuals can have a normal life span with normal mental development.
Although PKU screening was voluntary initially, Guthrie advocated for mandatory universal screening. However, mandatory screening had its opponents. Pediatricians expressed concern that there were not enough data and that the government should not tell physicians how to practice medicine. (p209) Despite these concerns, mandatory universal PKU screening was adopted in 43 states by 1975. (p48) Screening for hypothyroidism followed shortly thereafter.
The next major breakthrough in NBS was in 1990 with the application of tandem mass spectrometry, a platform technology that allows for multiplex testing for many metabolic conditions using 1 sample. The adoption of tandem mass spectrometry in some states led to wide variability in the number of conditions included in each state’s NBS panels. In 2000, the Maternal and Child Health Bureau Health Resources Services Administration (HRSA) commissioned the American College of Medical Genetics (now the American College of Medical Genetics and Genomics [ACMG]) to outline a process of standardization of outcomes and guidelines for state NBS programs. In 2005, the ACMG/HRSA Committee proposed a “uniform panel” including 25 primary and 29 secondary conditions. In 2006, the Secretary’s Advisory Committee of Heritable Disorders of Newborns and Children endorsed the uniform panel, which was quickly adopted by all states.
The expansion had a number of critics. A major concern was that screening had expanded to include conditions that did not meet the Wilson and Jungner criteria. In 1969, Wilson and Jungner published a World Health Organization report that established 10 criteria that had to be met to justify a public health screening program. Although not designed specifically for screening newborns for rare metabolic conditions, the Wilson and Jungner criteria have become the gold standard for judging proposed NBS additions. The 10 criteria are enumerated in Box 1 . Although a number of modifications have been proposed, the basic principles remain: the condition should be treatable, the natural history should be understood, a screening test should exist that is acceptable to the population, and diagnostic testing should be accurate and accessible. If a condition does not meet all of the criteria of Wilson and Jungner, it is unclear on what grounds universal screening can be justified.
- 1.
The condition sought should be an important health problem.
- 2.
There should be an accepted treatment for patients with recognized disease.
- 3.
Facilities for diagnosis and treatment should be available.
- 4.
There should be a recognizable latent or early symptomatic stage.
- 5.
There should be a suitable test or examination.
- 6.
The test should be acceptable to the population.
- 7.
The natural history of the condition, including development from latent to declared disease, should be understood adequately.
- 8.
There should be an agreed policy on whom to treat as patients.
- 9.
The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.
- 10.
Case finding should be a continuing process and not a “once and for all” project.
Although Wilson and Jungner did not address consent, most national guidelines and consensus reports that examine the ethics of screening, both before and after the expansion, have supported seeking parental permission for all NBS on the grounds that parents must decide what is in their child’s best interest. This was most recently articulated in a joint policy statement and technical report by the American Academy of Pediatrics (AAP) and the ACMG.
In this article, we examine 3 neurologic and developmental disorders that have been considered for inclusion in the uniform panel: Duchenne muscular dystrophy (DMD), Krabbe disease, and fragile X syndrome. We consider the pros and cons of expanding NBS to include each disorder and the ethical and policy issues it raises. We will then evaluate ethical issues raised by the proposal to use genomic sequencing in NBS.
Introduction: a brief history of newborn screening
Virtually every infant in the United States has a few drops of blood collected within the first few days of life that is used to screen for more than 40 metabolic, endocrine, and hematologic, the vast majority of which are genetic in origin. Most infants also undergo hearing screening and pulse oximetry screening for critical congenital heart disease which may also be genetic in origin. The goal is to identify and treat conditions that present in infancy to reduce mortality and prevent morbidity.
Newborn screening (NBS) began in the 1960s when Dr Robert Guthrie developed the bacterial inhibition assay to diagnose phenylketonuria (PKU) and the filter paper on which to collect the blood samples for large-scale screening. If untreated, children with PKU experience both intellectual disability and autistic behaviors. If treatment with a low-protein diet is begun within a few weeks of birth, these individuals can have a normal life span with normal mental development.
Although PKU screening was voluntary initially, Guthrie advocated for mandatory universal screening. However, mandatory screening had its opponents. Pediatricians expressed concern that there were not enough data and that the government should not tell physicians how to practice medicine. (p209) Despite these concerns, mandatory universal PKU screening was adopted in 43 states by 1975. (p48) Screening for hypothyroidism followed shortly thereafter.
The next major breakthrough in NBS was in 1990 with the application of tandem mass spectrometry, a platform technology that allows for multiplex testing for many metabolic conditions using 1 sample. The adoption of tandem mass spectrometry in some states led to wide variability in the number of conditions included in each state’s NBS panels. In 2000, the Maternal and Child Health Bureau Health Resources Services Administration (HRSA) commissioned the American College of Medical Genetics (now the American College of Medical Genetics and Genomics [ACMG]) to outline a process of standardization of outcomes and guidelines for state NBS programs. In 2005, the ACMG/HRSA Committee proposed a “uniform panel” including 25 primary and 29 secondary conditions. In 2006, the Secretary’s Advisory Committee of Heritable Disorders of Newborns and Children endorsed the uniform panel, which was quickly adopted by all states.
The expansion had a number of critics. A major concern was that screening had expanded to include conditions that did not meet the Wilson and Jungner criteria. In 1969, Wilson and Jungner published a World Health Organization report that established 10 criteria that had to be met to justify a public health screening program. Although not designed specifically for screening newborns for rare metabolic conditions, the Wilson and Jungner criteria have become the gold standard for judging proposed NBS additions. The 10 criteria are enumerated in Box 1 . Although a number of modifications have been proposed, the basic principles remain: the condition should be treatable, the natural history should be understood, a screening test should exist that is acceptable to the population, and diagnostic testing should be accurate and accessible. If a condition does not meet all of the criteria of Wilson and Jungner, it is unclear on what grounds universal screening can be justified.
- 1.
The condition sought should be an important health problem.
- 2.
There should be an accepted treatment for patients with recognized disease.
- 3.
Facilities for diagnosis and treatment should be available.
- 4.
There should be a recognizable latent or early symptomatic stage.
- 5.
There should be a suitable test or examination.
- 6.
The test should be acceptable to the population.
- 7.
The natural history of the condition, including development from latent to declared disease, should be understood adequately.
- 8.
There should be an agreed policy on whom to treat as patients.
- 9.
The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.
- 10.
Case finding should be a continuing process and not a “once and for all” project.
Although Wilson and Jungner did not address consent, most national guidelines and consensus reports that examine the ethics of screening, both before and after the expansion, have supported seeking parental permission for all NBS on the grounds that parents must decide what is in their child’s best interest. This was most recently articulated in a joint policy statement and technical report by the American Academy of Pediatrics (AAP) and the ACMG.
In this article, we examine 3 neurologic and developmental disorders that have been considered for inclusion in the uniform panel: Duchenne muscular dystrophy (DMD), Krabbe disease, and fragile X syndrome. We consider the pros and cons of expanding NBS to include each disorder and the ethical and policy issues it raises. We will then evaluate ethical issues raised by the proposal to use genomic sequencing in NBS.
Duchenne muscular dystrophy
Empirical Data
DMD is an X-linked degenerative disease of skeletal muscle that affects approximately 1 in 3500 to 5000 males. The condition is characterized by progressive loss of muscle strength in boys leading to loss of ambulation and wheelchair dependency by adolescence. The 2 leading causes of death are respiratory and cardiac failure. The use of steroids in childhood prolongs ambulation.
The earliest DMD pilot screening program was in New Zealand in 1979 in which 10,000 boys were screened and 2 cases were identified. The largest number of boys have been screened in West Germany, Belgium, and Wales where the frequency is approximately 1 in 5000 boys. Most of the screening programs did not enroll girls. Although boys are much more severely affected than girls, and are affected at an earlier age, some girls do develop some musculoskeletal problems (between 2.5 and 7.8% of girls are manifesting carriers). In addition, more than one-half of female carriers have some cardiac involvement as adults, although fewer than 10% develop severe cardiomyopathy.
Early NBS programs measured creatinine kinase (CK) from the newborn blood spot in newborn males. CK can be falsely increased owing to birth trauma and so a repeat test is recommended several weeks later. Traditionally, those who still have an elevated CK would undergo biopsy. In the past decade, some NBS programs adopted genetic testing (either as first tier to reduce the number of false positives) or as an alternative to biopsy. The only active NBS program for DMD is in Belgium, which uses first tier CK testing alone.
Ethical and Policy Considerations
One way to evaluate the ethics of NBS for DMD is to evaluate whether it meets the Wilson and Jungner criteria. There is a suitable screen (CK) and accurate diagnostic testing by either genetic testing or biopsy is widely available. However, there is no treatment that is needed in infancy. Although steroids are the treatment of choice to prolong ambulation and reduce scoliosis, the initiation of glucocorticoid treatment is not recommended for a child who is still gaining motor skills, which occurs until approximately age 4 to 6 years. Because the mean age of diagnosis is approximately 5 years of age, opponents of NBS for DMD point out that these children are diagnosed early enough even without screening. Proponents argue, in contrast, that there are some preliminary data suggesting that earlier initiation of steroids may be helpful in retaining ambulation. They also argue that the earlier diagnosis avoids the diagnostic odyssey and allows for parental reproductive planning.
Avoiding the diagnostic odyssey is a true benefit for the child and family. A study published in 1982 found that the gap between first parental concern and diagnosis was about 2.5 years. More recent studies find that the gap has not changed. Symptoms also begin earlier than was originally thought. Many boys with DMD have delayed speech and delayed walking by 12 to 18 months of age. However, early intervention recommendations for developmental delays should apply regardless of the cause, and so again, it is not clear that there is a clinical need for early identification.
Does NBS produce a reproductive benefit? In Wales, the incidence of DMD dropped from a prescreening rate of 1 in 4046 boys to 1 in 5136 boys, whereas none of the families in Manitoba chose to have prenatal diagnosis. But even if NBS can reduce the number of children born with DMD, it is controversial whether this is a valid goal of NBS, because it reduces the child to his disorder and does not value the unborn child as a whole person. Although reproductive benefit may be included in a NBS risk–benefit calculation, the utility of this benefit would be greater if screening were offered in the prenatal or preconception screening period.
Even if one finds that the benefits of NBS for DMD outweigh the risks and harms, one must ask whether screening can be done outside of the newborn period. Screening later in infancy would avoid conflating those conditions that require immediate intervention to prevent early morbidity and mortality (public health emergencies) from those conditions that provide “less dramatic or immediate benefit, as well as benefits beyond those to the newborn.” (p923) Uptake will be lower because it will require a separate blood test, although this may be appropriate.
A second problem with the current design of NBS for DMD is that it only screens boys. Targeting NBS to a subpopulation ignores the equity value of universal screening programs. The main ethical reason to screen girls is to identify manifesting carriers. Identifying manifesting carriers is in the girl’s best interest because, to the extent that one is less likely to suspect DMD in girls, a screening program reduces disparities by identifying them. However, the benefits are confounded by identifying many carriers, many of whom will be asymptomatic for life. The concern here is in creating a “vulnerable child” and of creating the potential for stigma and discrimination.
Screening girls can provide (1) adult-onset cardiac risk information, (2) reproductive information to the girl’s parents (possibly before a first affected male is born), and (3) future reproductive information for the girl herself. But screening infants for adult-onset conditions is contrary to the national ethics guidelines that recommend deferring predictive genetic testing for adult-onset conditions and reproductive information until adulthood. If those are the goals of screening, screening women as young adults may be more appropriate.
Where Are We Now?
In the United States, there was a NBS pilot for DMD in the late 1980s in Western Pennsylvania. In the 2005 ACMG/HRSA report, DMD was considered and rejected for the uniform panel in part because CK was considered too nonspecific. The ability to perform CK/genetic testing as first tier resolves that concern, although it does not resolve the question of the need for early diagnosis.
Despite a number of programs over 35 years, there is currently only 1 active program. Until there is a specific treatment for boys with DMD that needs to begin before the development of symptoms, the benefit–risk ratio does not justify universal NBS; at least, it does not justify its inclusion in a mandatory universal NBS program.
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