Newborn Screening Articles- March/April 2008
J Pediatr Psychol. 2008 Mar 30 [Epub ahead of print]
Supporting Family Adaptation to Presymptomatic and "Untreatable" Conditions
in an Era of Expanded Newborn Screening.
Bailey DB Jr, Armstrong FD, Kemper AR, Skinner D, Warren SF.
RTI International, Miller School of Medicine and Holtz Children's Hospital at
Jackson Memorial Medical Center, Program on Pediatric Health Services
Research, Duke University, FPG Child Development Institute, University of
North Carolina at Chapel Hill, and Schiefelbush Institute for Lifespan Studies,
University of Kansas.
OBJECTIVE: As technology advances, newborn screening will be possible for
conditions not screened today. With an expansion of screening, strategies will be
needed to support family adaptation to unexpected and possibly uncertain genetic
information provided shortly after birth. METHOD: Although candidate
conditions for expanded newborn screening will typically be associated with
increased morbidity or mortality, for most there is no proven medical treatment
that must be implemented quickly. Many will have clinical features that gradually
emerge and for which the severity of impact is not predictable. Parents will seek
guidance on information, support, and treatment possibilities. This article
summarizes issues evoked by expanded newborn screening and suggests
strategies for supporting families of identified children. RESULTS: We propose
four components necessary to support family adaptation to pre-symptomatic and
"untreatable" conditions in an era of expanded newborn screening: (1) accurate
and understandable information; (2) formal and informal support; (3) active
surveillance; and (4) general and targeted interventions. We argue that no
condition is "untreatable" and that a well-designed program of prevention and
support has the potential to maximize benefit and minimize harm.
CONCLUSIONS: Pediatric psychologists can play important roles in an era of
expanded newborn screening by helping families understand genetic information,
make informed decisions about genetic testing, and cope with the potential
psychosocial consequences of genetic information.
J Paediatr Child Health. 2008 Apr;44(4):232-3; author reply 233.
Community-wide screening for cystic fibrosis carriers could replace newborn
screening for the diagnosis of cystic fibrosis.
Wilcken B.
Clin Chem. 2008 Apr;54(4):627-9.
Enhancing newborn screening for tyrosinemia type I.
Pass KA, Morrissey M.
J Public Health Policy. 2008;29(1):121-42.
Newborn blood spot screening in four countries: stakeholder involvement.
Potter BK, Avard D, Wilson BJ.
1Department of Epidemiology and Community Medicine, University of Ottawa,
Canada.
While newborn blood spot screening has historically been viewed as a public
health success, the potential harms and benefits are more finely balanced for new
conditions being considered for program expansion. We highlight complex issues
that must be addressed in policy decisions, which in turn requires a consideration
of many stakeholder perspectives. Using national policy documents from the
United Kingdom, the United States, Australia, and Canada, we describe the
participation of stakeholder organizations in the newborn screening policy
process, how such organizations have incorporated stakeholder views into their
own policy writing, and their recommendations for inclusiveness. Stakeholder
participation in newborn screening decision-making is widely acknowledged as
important, and many methods have been endorsed - consultation as well as direct
or indirect input into policy development. Differences across organizations and
jurisdictions raise questions about the most effective approaches for facilitating
inclusiveness, suggesting a need for formal evaluative research. Journal of Public
Health Policy (2008) 29, 121-142. doi:10.1057/palgrave.jphp.3200161
Soc Sci Med. 2008 Mar 19 [Epub ahead of print]
The expansion of abnormality and the biomedical norm: Neonatal screening,
prenatal diagnosis and cystic fibrosis in France.
Vailly J.
Inserm, Institut de Recherche Interdisciplinaire sur les enjeux Sociaux (Iris),
CNRS, EHESS, Université Paris 13, 74 rue Marcel Cachin, F-93017 Bobigny,
France.
Developments in biomedicine have remodelled the time-honoured questions of
how to define the normal and the connection between the normal and the norm.
This article deals with the expansion of the idea of abnormality through a study of
the practices involved in neonatal screening for cystic fibrosis in France. It is
based on observations made at meetings between paediatricians and geneticists
involved in the screening programme, and a seven-month study in a tertiary care
centre for cystic fibrosis. On one hand, the study highlights the technical
limitations of screening, which have the effect of expanding biological
abnormality. On the other, it deals with the rationales and associated practices
used by health care professionals for paediatric monitoring that are behind the
expansion of clinical abnormality. Lastly, the consequences of those practices are
analysed at the point where neonatal screening and prenatal diagnosis meet,
showing how the biomedical norm, with respect to foetuses, is altered. The
political and moral space in which this development has occurred is discussed.
Arch Dis Child. 2008 Apr;93(4):357-8
Long-term health outcomes of neonatal screening for cystic fibrosis.
Festini F, Taccetti G, Galici V, Campana S, Mergni G, Repetto T.
J Inherit Metab Dis. 2008 Feb 22 [Epub ahead of print]
The consequences of extended newborn screening programmes: Do we know who
needs treatment?
Wilcken B.
Biochemical Genetics and Newborn Screening, The Children’s Hospital at
Westmead, Hawkesbury Road, Westmead, NSW, 2145, Australia,
bridgetw@chw.edu.au.
The development of an evidence base for newborn screening is especially difficult
because of the rarity of disorders now detectable. One consequence of expanded
newborn screening is that physicians are being called upon to manage
asymptomatic babies with persistent biochemical disturbances that indicate likely
enzyme deficiencies. Some of these may be very mild. There is not always
agreement as to who should be treated. Particular problems are seen with
disorders that were previously thought very rare but are now found frequently by
newborn screening. Some of these disorders appear benign or nearly so, and in the
present state of knowledge should clearly not be included in routine newborn
screening panels.
Eur J Pediatr. 2008 May;167(5):569-73. Epub 2007 Jul 28.
Outcome of three cases of untreated maternal glutaric aciduria type I.
Garcia P, Martins E, Diogo L, Rocha H, Marcão A, Gaspar E, Almeida M, Vaz C,
Soares I, Barbot C, Vilarinho L.
Hospital Pediátrico de Coimbra, Av. Bissaya Barreto, 3000, Coimbra, Portugal.
We report, for the first time, the outcome of three children born to two women
with untreated glutaric aciduria type I (GA I). Isolated hypocarnitinemia in
neonatal screening in one baby allowed the identification of the disease in his
mother, who was undiagnosed so far and had had a previous daughter. The other
baby was born to an already diagnosed mother who was not treated; newborn
screening in the child reflected the metabolic state of the mother. Biochemical
abnormalities returned to normal within one week. At the age of 4 months,
neuroimaging showed Sylvian enlargement in both infants and bilateral temporal
arachnoid cysts in one. Physical and neurological developments were normal for
the three patients at ages 2 and 5 years. We conclude that long-term follow up will
determine the true impact of GA I in such children.
Clin Chem. 2008 Apr;54(4):657-64. Epub 2008 Feb 15.
Combined newborn screening for succinylacetone, amino acids, and
acylcarnitines in dried blood spots.
Turgeon C, Magera MJ, Allard P, Tortorelli S, Gavrilov D, Oglesbee D, Raymond
K, Rinaldo P, Matern D.
Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester,
MN.
BACKGROUND: Tyrosinemia type I (TYR 1) is a disorder causing early death if
left untreated. Newborn screening (NBS) for this condition is problematic because
determination of the diagnostic marker, succinylacetone (SUAC), requires a
separate first-tier or only partially effective second-tier analysis based on tyrosine
concentration. To overcome these problems, we developed a new assay that
simultaneously determines acylcarnitines (AC), amino acids (AA), and SUAC in
dried blood spots (DBS) by flow injection tandem mass spectrometry (MS/MS).
METHODS: We extracted 3/16-inch DBS punches with 300 muL methanol
containing AA and AC stable isotope-labeled internal standards. This extract was
derivatized with butanol-HCl. In parallel, we extracted SUAC from the residual
filter paper with 100 muL of a 15 mmol/L hydrazine solution containing the
internal standard (13)C(5)-SUAC. We combined the derivatized aliquots in
acetonitrile for MS/MS analysis of AC and AA with additional SRM experiments
for SUAC (m/z 155-137) and (13)C(5)-SUAC (m/z 160-142). Analysis time was
1.2 min. RESULTS: SUAC was increased in retrospectively analyzed NBS
samples of 11 TYR 1 patients (length of storage, 52 months to 1 week; SUAC
range, 13-81 mumol/L), with Tyr concentrations ranging from 65 to 293 mumol/L
in the original NBS analysis. The mean concentration of SUAC in 13 521 control
DBS was 1.25 mumol/L. CONCLUSION: The inclusion of SUAC analysis into
routine analysis of AC and AA allows for rapid and cost-effective screening for
TYR 1 with no tangible risk of false-negative results.
Eur J Pediatr. 2008 Apr;167(4):479-481. Epub 2007 May 22.
False negative 17-hydroxyprogesterone screening in children with classical
congenital adrenal hyperplasia.
Schreiner F, Brack C, Salzgeber K, Vorhoff W, Woelfle J, Gohlke B.
Pediatric Endocrinology Division, Children’s Hospital, University of Bonn,
Adenauerallee 119, 53113, Bonn, Germany, felix.schreiner@ukb.uni-bonn.de.
We report 5 out of 214 children with classical congenital adrenal hyperplasia
(CAH) that was not detected by neonatal 17-Hydroxyprogesterone screening.
Therefore, diagnosis was only based on a suspect clinical picture and subsequent
re-evaluation. In addition to 3 patients suffering from the simple virilizing form of
CAH and not reported so far, the remaining 2 children whose CAH was missed by
the screening suffered from the severe salt-wasting form. This report underlines
the importance of a careful clinical investigation of newborns to detect signs of
genital virilization. The differential diagnosis of classical CAH should be kept in
mind even if neonatal screening is reported to be normal.
Genet Test. 2008 Spring;12(1):25-35.
CFTR Mutations in Turkish and North African Cystic Fibrosis Patients in Europe:
Implications for Screening.
Lakeman P, Gille JJ, Dankert-Roelse JE, Heijerman HG, Munck A, Iron A,
Grasemann H, Schuster A, Cornel MC, Ten Kate LP.
Department of Clinical Genetics, VU University Medical Center, Amsterdam,
The Netherlands., Department of EMGO Institute, VU University Medical
Center, Amsterdam, The Netherlands.
Aims: To obtain more insight into the variability of the CFTR mutations found in
immigrant cystic fibrosis (CF) patients who are living in Europe now, and to
estimate the test sensitivity of different frequently used methods of DNA analysis
to detect CF carriers or patients among these Turkish or North African
immigrants. Methods: A survey among 373 European CF centers asking which
CFTR mutations had been found in Turkish and North African CF patients.
Results: 31 and 26 different mutations were reported in Turkish and North
African patients, identifying 64.2% (113/176) and 87.4% (118/135) alleles,
respectively (p < 0.001). The mean sensitivity (detection rate) of three most
common CFTR mutation panels to detect these mutations differed between
Turkish and North African people, 44.9% (79/176) versus 69.6% (94/135) (p <
0.001), and can be increased to 57.4% (101/176) and 79.3% (107/135) (p <
0.001), respectively, by expanding these panels with 13 mutations which have
been found on two or more alleles. Conclusion: 35.8% and 12.6%, respectively,
of CF alleles in Turkish and North African patients living in Europe now had not
been identified. Among these populations, the test sensitivity of common CFTR
mutation panels is insufficient for use in screening programs in Europe, even after
expansion with frequent Turkish and North African mutations. This raises
questions about whether and how to implement CF carrier and neonatal screening
in a multiethnic society.
Mol Genet Metab. 2008 Apr;93(4):363-70. Epub 2007 Dec 21.
A Delphi-based consensus clinical practice protocol for the diagnosis and
management of 3-methylcrotonyl CoA carboxylase deficiency.
Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B,
Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, Goodman SI, Harding C,
Kahler S, Kronn D, Longo N.
Department of Pediatrics, University of Rochester School of Medicine and
Dentistry, 601 Elmwood Avenue, Box 777, Rochester, NY 14642, USA.
Georgianne_Arnold@URMC.Rochester.edu
3-MCC deficiency is among the most common inborn errors of metabolism
identified on expanded newborn screening (1:36,000 births). However, evidencebased guidelines for diagnosis and management of this disorder are lacking. Using
the traditional Delphi method, a panel of 15 experts in inborn errors of
metabolism was convened to develop consensus-based clinical practice guidelines
for the diagnosis and management of 3-MCC screen-positive infants and their
mothers. The Oxford Centre for Evidence-based Medicine system was used to
grade the literature review and create recommendations graded from A (evidence
level of randomized clinical trials) to D (expert opinion). Panelists reviewed the
initial evaluation of the screen-positive infant-mother dyad, diagnostic guidelines,
and management of diagnosed patients. Grade D consensus recommendations
were made in each of these three areas. The panel did not reach consensus on all
issues. This consensus protocol is intended to assist clinicians in the diagnosis and
management of screen-positive newborns for 3-MCC deficiency and to encourage
the development of evidence-based guidelines.
Pathology. 2008 Apr;40(2):104-15.
Newborn screening.
Wilcken B, Wiley V.
NSW Newborn Screening Programme, The Children's Hospital at Westmead and
the University of Sydney, Sydney, Australia.
The aim of newborn screening is to detect newborns with serious, treatable
disorders so as to facilitate appropriate interventions to avoid or ameliorate
adverse outcomes. Mass biochemical testing of newborn babies was pioneered in
the 1960s with the introduction of screening for phenylketonuria, a rare inborn
error of metabolism, tested by using a dried blood spot sample. The next disorder
introduced into screening programs was congenital hypothyroidism and a few
more much rarer disorders were gradually included. Two recent advances have
greatly changed the pace: modification of tandem mass spectrometry and DNA
extraction and analysis from newborn screening dried blood spot. These two
technologies make the future possibilities of newborn screening seem almost
unlimited. Newborn screening tests are usually carried out on a dried blood spot
sample, for which there are special analytical considerations. Dried blood spot
calibrators and controls, prepared on the same lot number of filter paper, are
needed. Methods have a co-efficient of variation of about 10% due to the
increased variability of a dried filter paper sample compared with other
biochemical samples. The haematocrit is an additional variable not able to be
measured. Also of importance is obtaining a balance between the sensitivity and
specificity of each assay. Fixing cut-off points for action needs consideration of
what is an acceptable percentage of the population to recall for further testing.
Few assays are 100% discriminatory. Programs in Australasia currently screen for
at least 30 disorders. Detection of these requires not only the assay of a primary
marker but often determination of a ratio of that marker with another, or possibly
an alternative assay, for example a DNA mutation. The most important disorders
screened for are described briefly: phenylketonuria, primary congenital
hypothyroidism, cystic fibrosis, the galactosaemias, medium-chain acyl-CoA
dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency and
congenital adrenal hyperplasia, together with several other disorders detectable by
tandem mass spectrometry. Newborn screening deals with rare disorders and
benefit cannot be shown easily without very large pilot studies. There have been
randomized controlled trials of screening for cystic fibrosis, and now several
studies are beginning to establish the benefit of tandem mass spectrometry
screening for disorders of fatty acid and amino acid metabolism. Two things will
influence the new directions for newborn screening: the development of effective
treatments for hitherto untreatable disorders, and advancing technology, enabling
new testing strategies to be developed. There are novel treatments on the horizon
for many discrete disorders. Susceptibility testing has recently been considered
for newborn screening application, but is more controversial. Newborn screening
has entered a new and exciting phase, with an explosion of new treatments, new
technologies, and, possibly in the future, new preventive strategies.
J Clin Invest. 2008 Mar 3;118(3):839-841.
Gene modifiers in cystic fibrosis.
Accurso FJ, Sontag MK.
Department of Pediatrics, Mike McMorris Cystic Fibrosis Care and Research
Center, Children’s Hospital, and Department of Preventive Medicine and
Biometrics, University of Colorado, Aurora, Colorado, USA.
Studies of modifier genes in cystic fibrosis (CF) have often been performed in
small or narrowly defined populations, leading to conflicting results. In this issue
of the JCI, Dorfman et al. demonstrate in a large, population-based study that two
previously studied modifier genes, coding for mannose-binding lectin 2 and TGFbeta1, influence pulmonary outcome in pediatric CF patients (see the related
article beginning on page 1040). They further show gene-gene interaction
between the two, underscoring the complexity of CF lung disease. Their findings
provide further impetus to study these molecules and associated signaling
pathways in CF. In addition, these findings argue strongly for collecting
genotypes of known modifiers prospectively in CF clinical trials as well as in
longitudinal studies of infants identified through newborn screening, where the
full impact of such modifiers can be defined more precisely.
Arch Pediatr Adolesc Med. 2008 Mar;162(3):205-11.
Results of newborn screening for hearing loss: effects on the family in the first 2
years of life.
Vohr BR, Jodoin-Krauzyk J, Tucker R, Johnson MJ, Topol D, Ahlgren M.
Department of Pediatrics, Women and Infants Hospital, 101 Dudley St,
Providence, RI 02905, USA. Betty_Vohr@brown.edu
OBJECTIVE: To determine whether there was increased stress and impact on the
family for mothers of infants whose screening results and subsequent diagnostic
findings indicated hearing loss (HL) and mothers of infants with a positive
screening result who subsequently pass the rescreening (false-positive group),
compared with mothers of infants who pass the initial screening (control group),
when their children were aged 6 to 10, 12 to 16, and 18 to 24 months. DESIGN:
Matched cohort analytic study. SETTING: Home visits. Patients/
PARTICIPANTS: Mothers of 33 infants with confirmed HL, 42 infants with a
false-positive screening result, and 70 infants in the control group.
INTERVENTIONS: Screening for HL. OUTCOME MEASURES: Scores on the
Parenting Stress Index and the Impact on Family-Adapted Version G. RESULTS:
Mothers of infants in the false-positive group did not report increased stress or
impact. Mothers of infants with HL reported greater financial impact, total
impact, and caretaker burden compared with mothers of infants in the control
group. In multivariate analysis of the total cohort, the presence of HL was
associated with increased total impact on the family; a neonatal intensive care unit
stay was associated with increased stress and total impact on the family; and older
maternal age and greater family resources were associated with decreased stress
and total impact on the family. CONCLUSIONS: Although a false-positive result
or a pass of the screening for HL was not associated with increased stress or
impact, identification of HL was independently associated with greater total
impact on the family when the child was 18 to 24 months of age.
Arch Pediatr Adolesc Med. 2008 Mar;162(3):199-204.
Comment in:
Arch Pediatr Adolesc Med. 2008 Mar;162(3):280-1.
Liver Transpl. 2008 Mar;14(3):270-1.
Assessment of parental understanding by pediatric residents during counseling
after newborn genetic screening.
Farrell MH, Kuruvilla P.
Center for Patient Care and Outcomes Research, Medical College of Wisconsin,
8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. mfarrell@mcw.edu
OBJECTIVE: To investigate pediatric residents' efforts to assess understanding in
discussions about positive newborn screening test results. Newborn screening
saves lives, but confusion about false-positive and carrier results often leads to
psychosocial problems. DESIGN: Explicit-criteria abstraction of transcripts of
encounters with standardized parents of a fictitious infant found to carry cystic
fibrosis or sickle cell hemoglobinopathy. SETTING: Simulated doctor-patient
encounter. PARTICIPANTS: Pediatric residents participating in an educational
workshop on how to inform parents about positive newborn screening test results.
MAIN OUTCOME MEASURES: Abstraction used an explicit-criteria data
dictionary with definitions for 5 different ways to assess understanding. A
"partial" designation was used for leading syntax or no pause for response.
RESULTS: Interabstractor reliability over 59 transcripts (2 per resident) was
kappa = 0.93. Only 26 of 59 transcripts (44.1%) met definite criteria for at least 1
assessment of understanding. Most assessments were the less effective closeended (37.3% of transcripts) and "OK?" question types (32.2% of transcripts).
Only 3 transcripts met definite criteria for an open-ended assessment and no
transcripts included a request for a teach-back, the type thought to be most
effective. Four transcripts (6.8%) included an advance request for questions. With
partial-criteria assessments included, an additional 31 transcripts (52%) were
identified. CONCLUSIONS: The small number of assessments of understanding
and the high fraction of less effective assessments do not bode well for parental
understanding, especially for parents with limited health literacy. Training
programs should address assessments of understanding, but quality improvement
activities using these types of assessment methods may also be needed.
Br J Gen Pract. 2008 Mar;58(548):161-8.
Parents' experiences of universal screening for haemoglobin disorders:
implications for practice in a new genetics era.
Locock L, Kai J.
Department of Primary Care, University of Oxford, Oxford.
BACKGROUND: England is the only country in the world that currently has
universal population screening for haemoglobin disorders through linked
antenatal and newborn screening. Little is known about the acceptability of such
screening. AIM: To explore parents' experiences of, and attitudes towards, new
universal genetic screening for haemoglobin disorders. DESIGN OF STUDY:
Narrative interview study. SETTING: Primary and community care settings
across England. METHOD: Narrative interviews were undertaken with a
maximum variation sample of 39 people who had experienced gene-carrier
identification through antenatal and newborn screening for sickle cell,
thalassaemia, and other haemoglobin variants within the previous 2 years.
RESULTS: Most parents were unaware screening had occurred or had given it
little consideration and so were surprised or shocked by results. However, they
were glad to learn of their carrier status, reproductive genetic risk, or their
newborn's carrier status. Participants emphasized that antenatal screening should
happen as early as possible. Many would rather have known their carrier status
before pregnancy or before entering a relationship. Although most were satisfied
with the information they received, significant misunderstandings remained.
There were culturally diverse attitudes towards prenatal diagnosis and
termination. These procedures were acceptable to some parents with strong
religious beliefs, including Christians and Muslims. CONCLUSION: Parents
support screening for haemoglobin disorders but need to be better informed and
better prepared for results and what they mean. Sensitivity to patient diversity in
attitudes and choices is also required. Universal screening for genetic
reproductive risk will increasingly involve generalists, particularly in primary
care, presenting opportunities for screening before or earlier in pregnancy, which
is likely to be welcomed by patients.
Clin Chem. 2008 Mar;54(3):602-5.
EDTA in dried blood spots leads to false results in neonatal endocrinologic
screening.
Holtkamp U, Klein J, Sander J, Peter M, Janzen N, Steuerwald U, Blankenstein
O.
Screening-Labor Hannover, Hannover, Germany.
BACKGROUND: Blood samples for neonatal screening for inborn errors of
metabolism are collected and shipped on standardized filter paper cards.
Occasionally these samples are contaminated with EDTA, which is often used for
anticoagulation. EDTA may interfere with newborn screening tests based on
lanthanide fluorescence and thus lead to false-negative or false-positive results.
METHODS: We used tandem mass spectrometry (MS/MS) to detect EDTA in
dried blood spots by use of an extra experiment that was integrated into the
standard MS/MS neonatal screening and did not require an additional sample
spot, nor extra time or work. We analyzed the influence of different blood
sampling procedures on lanthanide fluorescence tests for thyroid-stimulating
hormone (TSH) and 17-hydroxyprogesterone (17-OHP). RESULTS: EDTA was
increased in 138 of 190 000 newborn screening samples, 27 of which caused
false- positive results in the immunoassay for 17-OHP. No false-negative TSH
results were found. False-positive results in the 17-OHP test occurred when
EDTA concentrations were >2.0 g/L; the TSH test, however, produced false
negatives only when EDTA concentrations were >3.0 g/L. Using EDTAcontaining devices the procedure of blood collection significantly influenced the
concentration of the anticoagulant. CONCLUSION: Addition of EDTA
quantification into standard MS/MS tests is a simple and useful method to avoid
false-positive or false-negative neonatal screening results in lanthanide
fluorescence-based tests.
Clin Chem. 2008 Mar;54(3):542-9. Epub 2008 Jan 4.
Second-Tier Test for Quantification of Alloisoleucine and Branched-Chain
Amino Acids in Dried Blood Spots to Improve Newborn Screening for Maple
Syrup Urine Disease (MSUD).
Oglesbee D, Sanders KA, Lacey JM, Magera MJ, Casetta B, Strauss KA,
Tortorelli S, Rinaldo P, Matern D.
Departments of Laboratory Medicine and Pathology, Medical Genetics, Pediatric
and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN.
BACKGROUND: Newborn screening for maple syrup urine disease (MSUD)
relies on finding increased concentrations of the branched-chain amino acids
(BCAAs) leucine, isoleucine, and valine by tandem mass spectrometry (MS/MS).
d-Alloisoleucine (allo-Ile) is the only pathognomonic marker of MSUD, but it
cannot be identified by existing screening methods because it is not differentiated
from isobaric amino acids. Furthermore, newborns receiving total parenteral
nutrition often have increased concentrations of BCAAs. To improve the
specificity of newborn screening for MSUD and to reduce the number of dietrelated false-positive results, we developed a LC-MS/MS method for quantifying
allo-Ile. METHODS: Allo-Ile and other BCAAs were extracted from a 3/16-inch
dried blood spot punch with methanol/H(2)O, dried under nitrogen, and
reconstituted into mobile phase. Quantitative LC-MS/MS analysis of allo-Ile, its
isomers, and isotopically labeled internal standards was achieved within 15 min.
To determine a reference interval for BCAAs including allo-Ile, we analyzed 541
dried blood spots. We also measured allo-Ile in blinded samples from 16 MSUD
patients and 21 controls and compared results to an HPLC method. RESULTS:
Intra- and interassay imprecision (mean CVs) for allo-Ile, leucine, isoleucine, and
valine ranged from 1.8% to 7.4%, and recovery ranged from 91% to 129%. All 16
MSUD patients were correctly identified. CONCLUSIONS: The LC-MS/MS
method can reliably measure allo-Ile in dried blood spots for the diagnosis of
MSUD. Applied to newborn screening as a second-tier test, it will reduce falsepositive results, which produce family anxiety and increase follow-up costs. The
assay also appears suitable for use in monitoring treatment of MSUD patients.
Hum Gene Ther. 2008 Mar;19(3):213-6.
Candidate disorders for gene therapy: newborn screening facilitates ascertainment
of presymptomatic individuals.
Pindolia KR, Wolf B.
J Paediatr Child Health. 2008 Mar;44(3):87-91.
Post-natal hearing loss in universal neonatal hearing screening communities:
current limitations and future directions.
Hutt N, Rhodes C.
SWISH, Sydney Children's Hospital, Randwick, New South Wales, Australia.
Universal hearing screening has dramatically improved outcomes for babies born
with detectable hearing abnormalities; yet there are some infants who develop
significant hearing problems after passing a neonatal screen. There is much
conjecture as to the number and the characteristics of infants with post-natal
hearing losses; yet evidence suggests that many children may be affected, and that
a large proportion have no discoverable cause. Currently, screening programmes
use lists of risk factors to enroll babies into surveillance programmes. This
practice is problematic because audiological follow-ups are expensive and underutilized, and parental disclosure is often inaccurate. The large databases from
universal neonatal programmes could inform the development of effective,
evidence-based practice and policy for the detection and intervention of children
who develop post-natal hearing losses.
Pediatrics. 2008 Mar;121(3):e693-704.
Ethical, legal, and social concerns about expanded newborn screening: fragile X
syndrome as a prototype for emerging issues.
Bailey DB Jr, Skinner D, Davis AM, Whitmarsh I, Powell C.
RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709-2194,
USA. dbailey@rti.org
Technology will make it possible to screen for fragile X syndrome and other
conditions that do not meet current guidelines for routine newborn screening. This
possibility evokes at least 8 broad ethical, legal, and social concerns: (1) early
identification of fragile X syndrome, an "untreatable" condition, could lead to
heightened anxiety about parenting, oversensitivity to development, alterations in
parenting, or disrupted bonding; (2) because fragile X syndrome screening should
be voluntary, informed consent could overwhelm parents with information,
significantly burden hospitals, and reduce participation in the core screening
program; (3) screening will identify some children who are or appear to be
phenotypically normal; (4) screening might identify children with other
conditions not originally targeted for screening; (5) screening could overwhelm an
already limited capacity for genetic counseling and comprehensive care; (6)
screening for fragile X syndrome, especially if carrier status is disclosed,
increases the likelihood of negative self-concept, societal stigmatization, and
insurance or employment discrimination; (7) screening will suggest risk in
extended family members, raising ethical and legal issues (because they never
consented to screening) and creating a communication burden for parents or
expanding the scope of physician responsibility; and (8) screening for fragile X
syndrome could heighten discrepancies in how men and women experience
genetic risk or decide about testing. To address these concerns we recommend a
national newborn screening research network; the development of models for
informed decision-making; materials and approaches for helping families
understand genetic information and communicating it to others; a national forum
to address carrier testing and the disclosure of secondary or incidental findings;
and public engagement of scientists, policy makers, ethicists, practitioners, and
other citizens to discuss the desired aims of newborn screening and the
characteristics of a system needed to achieve those aims.
Prenat Diagn. 2008 Mar;28(3):197-202.
Prenatal diagnosis of cystic fibrosis: the 18-year experience of Brittany (western
France).
Scotet V, Duguépéroux I, Audrézet MP, Blayau M, Boisseau P, Journel H, Parent
P, Férec C.
Inserm, U613, Brest, F-29200, France.
OBJECTIVE: This study reports 18 years of experience in prenatal diagnosis
(PD) of cystic fibrosis (CF) in a region where CF is frequent and the uptake of PD
is common (Brittany, western France). METHOD: All PDs made over the period
1989-2006 in women living in Brittany were collected. RESULTS: We recorded
268 PDs made in 1 in 4 risk couples, plus 22 PDs directly made following the
sonographic finding of echogenic bowel. Most of the 268 PDs were done in
couples already having CF child(ren) (n = 195, 72.8%). Close to one-fifth
followed cascade screening (n = 49, 18.3%), which identified 26 new 1 in 4 risk
couples among the relatives of CF patients or of carriers identified through
newborn screening (NBS). The remaining PDs were mainly made in couples
whose 1 in 4 risk was evidenced following the diagnosis of echogenic bowel in a
previous pregnancy (n = 22, 8.2%). Although patients' life expectancy has
considerably improved, in our population the great majority of couples chose
pregnancy termination when PD indicated that the foetus had CF (95.9%).
CONCLUSION: This study describes the distribution of PDs according to the
context in which the 1 in 4 risk was discovered and highlights the real decisions
of couples as regards pregnancy termination after a positive PD. Copyright (c)
2008 John Wiley & Sons, Ltd.
N Engl J Med. 2008 Feb 28;358(9):973-4.
Newborn screening showing decreasing incidence of cystic fibrosis.
Hale JE, Parad RB, Comeau AM.
Mol Genet Metab. 2008 Feb 25 [Epub ahead of print]
Maternal glutaric acidemia, type I identified by newborn screening.
Crombez EA, Cederbaum SD, Spector E, Chan E, Salazar D, Neidich J, Goodman
S.
Department of Pediatrics, University of California, Los Angeles, CA, USA.
We report two women with glutaric acidemia type I in whom the diagnosis was
unsuspected until a low carnitine level was found in their newborn children. Both
mothers had low carnitine in plasma. In the first, organic acid analysis was only
done after fibroblast studies revealed normal carnitine uptake. Having learned
from the first family, organic acid analysis was done immediately in the mother of
family 2. In both, the plasma acylcarnitine profile was normal but both excreted
the metabolites typical of their disorder. One of the women was a compound
heterozygote for distinct mutations in the glutaric acid dehydrogenase gene,
whereas the second was either homozygous or hemizygous for a mutation in Exon
6 of the gene.
J Am Acad Audiol. 2007 Oct;18(9):725-38.
New clicklike stimuli for hearing testing.
Cebulla M, Stürzebecher E, Elberling C, Müller J.
ENT Clinic, Faculty of Medicine, Julius-Maximilians-University Würzburg,
Germany. mario.cebulla@mail.uni-wuerzburg.de
The click stimulus generally used for newborn hearing screening generates a
traveling wave along the basilar membrane, which excites each of the frequency
bands in the cochlea, one after another. Due to the lack in synchronization of the
excitations, the summated response amplitude is low. A repetitive click-like
stimulus can be set up in the frequency domain by adding a high number of
cosines, the frequency intervals of which comply with the desired stimulus
repetition rate. Straight-forward compensation of the cochlear traveling wave
delay is possible with a stimulus of this type. As a result, better synchronization of
the neural excitation can be obtained so that higher response amplitudes can be
expected. The additional introduction of a frequency offset enables the use of a qsample test for response detection. The results of investigations carried out on a
large group of normal-hearing test subjects have confirmed the enhanced
efficiency of this stimulus design. The new stimuli lead to significantly higher
response SNRs and thus higher detection rates and shorter detection times. Using
band-limited stimuli designed in the same manner, a "frequency-specific" hearing
screening seems to be possible.
B-ENT. 2007;3(4):185-90.
Organisation of a universal newborn hearing screening programme in Flanders.
Van Kerschaver E, Boudewyns AN, Stappaerts L, Wuyts FL, Van de Heyning
PH.
Kind en Gezin, Brussels, Belgium.
OBJECTIVE: Since 1998 an integrated universal newborn hearing screening
programme (UNHSP) based on automated auditory brainstem response (AABR)
has been implemented in Flanders. The protocol of the UNHSP is based on
guidelines defined by the American Academy of Paediatrics (AAP). The aim of
this paper is to report on the screening protocol and to assess its feasibility.
METHODOLOGY: Descriptive study based upon an analysis of the screening
results in the neonatal non-NICU population of Flanders between 1999 and 2004.
The UNHSP, organized by Kind en Gezin (K&G), uses a 2-stage protocol:
children with a refer at the first screening test are retested, and those with a refer
at the retest are referred to a certified centre. Screening and referral centres
communicate their data to a central database at K&G. RESULTS: From the
beginning of 1999 until the end of 2004 a screening was offered to 97.91% of all
eligible babies in Flanders; 91.5% of these babies were screened by K&G using
the Algo Portable Newborn Screener. Three-quarters of the referred babies had a
confirmed hearing loss. In 57.6% of these babies, hearing loss was bilateral. Some
babies had a temporary hearing problem. The false positive rate after two tests
was 0.53 per thousand. All ascertained babies started early intervention, most of
them before the age of 4 months. CONCLUSIONS: K&G has succeeded in
organizing a new, well-structured community-based UNHSP according to the
guidelines of the AAP on Neonatal Hearing Screening.
Int J Pediatr Otorhinolaryngol. 2008 May;72(5):599-608. Epub 2008 Mar 4.
Impact of early hearing screening and treatment on language development and
education level: Evaluation of 6 years of universal newborn hearing screening
(ALGO((R))) in Flanders, Belgium.
Verhaert N, Willems M, Van Kerschaver E, Desloovere C.
Department of Otorhinolaryngology, Head and Neck Surgery, University
Hospitals Leuven, Belgium.
OBJECTIVES: Early intervention in hearing-impaired children may improve
language outcomes and subsequent school and occupational performance. The
objective of this study was to retrospectively analyze over 6 years the educational
outcome and language development of a first cohort of children, detected by the
Flemish universal newborn hearing screening (UNHS) program based on
automated auditory brainstem response (AABR), with the oldest children being in
primary school. METHODS: We studied 229 hearing-impaired children from
1998 till 2003. The following variables were considered: the age during the
school year 2005-2006, the degree of hearing loss, additional impairments
including presence of intellectual disability, school placement and early
intervention. RESULTS: Analysis showed that 85.4% of the children with
moderate, severe or profound hearing loss and no additional disability, older than
5.5 years, reach mainstream education. Further detailed description was provided
for the outcomes of children with uni- and bilateral cochlear implants. Overall
results stress that 46% of all children with a cochlear implant obtain mainstream
education. Of all cochlear implant (CI) children above 5.5 years, without
additional handicaps, 78.9% of children attend primary mainstream school. Data
on language development show that up to 45% of the children with unilateral
cochlear implant and no additional disabilities had normal to slight delay on
language development. These data are fulfilling the goals stated by the JCIH and
the American Academy of Pediatrics (AAP) in 2000. The role and impact of
additional handicaps is discussed. The importance of early hearing loss
identification and hearing therapy for appropriate language development is
highlighted. Finally our preliminary results on children with bilateral cochlear
implants without additional handicaps present an improved language development
in comparison to unilateral CI-children. CONCLUSION: A vast majority of the
children detected by the UNHS program, with moderate, severe or profound
hearing loss and no additional disability, older than 5.5 years, reach mainstream
education. Additional disabilities have a major influence.
Ann Clin Biochem. 2008 Jan;45(Pt 1):11-7.
Newborn bloodspot screening in the UK--past, present and future.
Downing M, Pollitt R.
Clinical Chemistry and Newborn Screening, The Children's Hospital, Western
Bank, Sheffield, UK. melanie.downing@sch.nhs.uk
Screening newborn babies for inherited metabolic disease began in the UK in the
late 1950s with the 'nappy test' for phenylketonuria. In 1969 the Department of
Health recommended changing to bloodspot screening using the techniques
developed in the USA by Robert Guthrie and his associates. Bloodspot screening
for various other disorders (galactosaemia, maple syrup urine disease,
homocystinuria, cystic fibrosis and others) was introduced on a patchy local basis
but, until 2000, the only additional disorder officially recommended was
congenital hypothyroidism. Screening for haemoglobinopathies received official
support in 2000 and for cystic fibrosis in 2001 though implementation was slow,
particularly for the latter. Both these screens have raised difficult issues relating to
genetic privacy and the detection of carrier status in children. During the last
decade screening has become increasingly subject to central control. Though a
more consistent and systematic approach was clearly needed, this has
undoubtedly slowed the rate of innovation. In particular the UK has lagged behind
many other European countries in the application of tandem mass spectrometry
(MS-MS) though, following a major pilot study, screening for medium-chain
acyl-CoA dehydrogenase deficiency is now in the process of introduction.
Attempts to codify clinical and laboratory procedures have also proved
controversial, highlighting marked differences in practice in various parts of the
country and the difficulty of rationalizing these within a practicable and
scientifically justified framework. Notwithstanding this, there are many positive
developments and newborn screening remains a stimulating and rewarding field
in which to work.