Summer 2011 Newborn Screening Articles

Summer 2011 Newborn Screening Articles

1.Br J Haematol. 2011 Oct;155(1):

Mortality and causes of death in children with sickle cell disease in the Netherlands, before the introduction of neonatal screening.

van der Plas EM, van den Tweel XW, Geskus RB, Heijboer H, Biemond BJ, Peters M, Fijnvandraat K.

Abstract

This study analyzed the mortality and causes of death in sickle cell disease patients in the Netherlands, to provide a baseline for monitoring the effect of the recently introduced neonatal screening programme and to indicate areas of improvement in the care for these patients. All children (<18 years) diagnosed with sickle cell disease in a tertiary hospital from 1985 to 2007 were included. Vital status was determined up to March 2008. A total of 298 children were included: 189 (63%) patients had HbSS, 17 (6%) HbSβ(0) thalassaemia, 72 (24%) HbSC and 20 (7%) HbSβ(+) thalassaemia. Twelve patients (4%) died during a total follow-up of 3896 patient years. All known deaths were sickle cell disease-related. Meningitis/sepsis (n = 4; 33%), stroke (n = 3; 25%) and death during a visit to the country of origin (n = 3; 25%) were the most common causes of death. The overall mortality rate was 0·27 deaths/100 patient years [95% confidence interval (CI): 0·15-0·43]. The estimated survival at the age of 18 years was 97·3% (95% CI: 95-99%). This report confirms that the burden of mortality in sickle cell disease is increasingly shifting to adults. It is recommended that compliance to antibiotic prophylaxis, thorough counselling and support for patients travelling abroad and specialized peri-operative care should receive continuous attention.

2. Int J Lab Hematol. 2011 Oct;33(5):540-4.

An assessment of three noncommercial DNA extraction methods from dried blood spots for beta-thalassaemia mutation identification.

Karthipan SN, George E, Jameela S, Lim WF, Teh LK, Lee TY, Chin VK, Lai MI.

Abstract

Introduction: Dried blood spots (DBS) are currently the recommended sample collection method for newborn screening programmes in America. Early diagnosis of beta-thalassaemia screening is essential as it provides an added advantage especially in sickle cell disease. Beta-thalassaemia frequency is high in many poor countries, and the cost of using commercial DNA extraction kits can be prohibitive. Our study assessed three methods that use minimal reagents and materials to extract DNA from DBS for beta-thalassaemia identification. Methods: The methods assessed in this study were Tris-EDTA (TE) buffer-based method by Bereczky etal. (American Journal of Tropical Medicine and Hygiene 72, 2005, 249), NaCL/NaOH/Sodium dodecyl sulphate (SDS) method by Huang etal. (Human Genetics 84, 1990, 129) and NaOH method by Zhou etal. (Analytical Biochemistry 354, 2006, 159). Extracted DNA was amplified for three common beta-thalassaemia mutations in Malaysia. Results: Amplicons derived from TE buffer-based method were very faint and almost nonexistent while the NaCl/NaOH/SDS method did not produce any visible amplicons. The extraction using NaOH method produced visible bands that were comparable to the standard method using extraction kit. Conclusion: The NaOH method is a simple method that uses minimal equipment and reagents that make it labour- and cost-effective. This method could be adopted by poorer countries to extract DNA for beta-thalassaemia mutation characterization.

3. Int J Pediatr Otorhinolaryngol. 2011 Oct;75(10):1225-9. Epub 2011 Jul 28.

Performance of two hearing screening protocols in NICU in Shanghai.

Xu ZM, Cheng WX, Yang XL.

Abstract

OBJECTIVE:

To study the sensitivity and specificity of targeted neonatal hearing screening for the single-session distortion product otoacoustic emissions (DPOAE) technique and the combined DPOAE/automated auditory brain-stem response (AABR) technique.

METHODS:

3000 high-risk newborns were studied at Children's Hospital of Fudan University. They were required to take two different screening procedures separately. The first procedure consisted of DPOAE alone and the second consisted of DPOAE combined with the AABR. Based upon the etiology in high-risk babies, they were divided into four groups. In group I there were 670 very-low-birth-weight (VLBW) newborns (1340 ears), and in group II there were 890 preterm babies (1780 ears). 850 babies (1700 ears) suffered from hyperbilirubinemia in group III, whereas 790 babies (1580 ears) with asphyxia were in group IV. The babies in groups II, III, and IV came from the neonatal intensive-care unit (NICU) of our hospital. The study protocols consisted of the DPOAE alone and DPOAE combined with AABR hearing screening at an age of less than 1 month, and a diagnostic stage at the age of 2 months.

RESULTS:

With single-session DPOAE screening, the referral rate (8% of the NICU babies), the false-positive rate (4.96%) and the false-negative rate (0.8%) were higher. The different etiologies in NICU babies had significantly different referral rates (F-test, p<0.01). A 4.46% referral rate of hyperbilirubinemi babies was much lower. The combined DPOAE/AABR screening technique revealed a referral rate of 5.03%, a false-positive rate of 2% and a false-negative rate of 0.06%. The false-positive rate was well below the suggested 3% of the American Academy of Pediatric. Comparisons of the referral rate, false-positive rate and false-negative rate of two hearing screening protocols (DPOAE alone and combined DPOAE/AABR) revealed significant differences (t-test, p<0.05, p<0.01, p<0.01). 91 infants (3.03% of the NICU babies) who failed the combined DPOAE/AABR screening were confirmed on hearing impairment. Of 22 babies who passed DPOAE screening but failed the AABR screening had a severe to profound hearing loss based on classic ABR. These patients (24% of the NICU babies with hearing losses) with hyperbilirubinemia and asphyxia problems at newborn stage were diagnosed as auditory neuropathy based on evaluations of DPOAE screening passed, abnormal ABR and absent middle-ear muscle reflexes (MMR).

CONCLUSION:

Our study demonstrates the use of a combination of DPOAE and AABR testing ensures high sensitivity and acceptable specificity, and predict the AN profile in NICU babies. Our efforts identified 22 NICU babies with auditory neuropathy who hopefully will benefit from early remediation of their hearing deficit

4. Int J Pediatr Otorhinolaryngol. 2011 Oct;75(10):1225-9. Epub 2011 Jul 28.

Performance of two hearing screening protocols in NICU in Shanghai.

Xu ZM, Cheng WX, Yang XL.

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

5. Curr Allergy Asthma Rep. 2011 Sep 8. [Epub ahead of print]

Should Newborns be Screened for Immunodeficiency? Lessons Learned from Infants with Recurrent Otitis Media.

Yilmaz-Demirdag Y.

Abstract

Recurrent otitis media in children is considered one of the warning signs of primary immunodeficiencies (PIDs), particularly antibody deficiencies. Infants who have the most serious and potentially lethal form of PID, severe combined immunodeficiency (SCID), sometimes present with recurrent otitis media. Most of the time, because of the severity of the immune defect, they develop more serious and systemic infections. SCID is distinct among the PIDs and considered a pediatric emergency. Diagnosing SCID during the newborn period is crucial because survival completely depends on early diagnosis and treatment. Mortality declines significantly if immune reconstitution is established before 3.5months of age, particularly before severe infections have occurred. However, most patients are diagnosed after they have suffered chronic or recurrent infections and developed permanent sequelae. Without institution of population-based newborn screening, most infants will miss the opportunity to live a healthy life.

6. Growth Horm IGF Res. 2011 Sep 6. [Epub ahead of print]

Analysis of the GH content within archived dried blood spots of newborn screening cards from children diagnosed with growth hormone deficiency after the neonatal period.

Binder G, Hettmann S, Weber K, Kohlmüller D, Schweizer R.

Abstract

OBJECTIVE:

It is unknown whether GH secretion of children with growth hormone deficiency (GHD) is already diminished at birth. We aimed to determine the GH content within archived dried blood spots of newborn screening cards from children diagnosed with GHD at childhood.

DESIGN:

At our hospital, all children with the diagnosis of GHD and an actual age <10years were identified. For 16 patients (mean age, 7.4years; range, 1.0-9.7), screening cards were available. The archived dried blood from the first 48 to 96h of life was eluated in buffer of a highly sensitive hGH-ELISA to measure the GH content. Reference values were calculated based on 600 anonymous newborn screening cards of different ages.

RESULTS:

Median GH content within the archived dried blood spots of the reference had declined by 30% during the first year and by further 35% during the next 8.5years of storage. After correction for time of storage, four out of the 16 archived dried blood spots of the GHD children contained low amounts of GH (≤5th percentile). Diminished GH secretion at birth was absent in isolated GHD, but associated with multiple pituitary hormone deficiency (MPHD) (P=0.0013), ectopic neurohypophysis (P=0.0013), lower GH test peak values (P=0.02) and higher weight at diagnosis (P=0.015).

CONCLUSIONS:

Children with isolated GHD have normal GH secretory capacity during the first week of life while the majority of children with MPHD and pituitary malformation were GH deficient immediately after birth.

7. Med J Aust. 2011 Sep 5;195(5):260-262.

Is it time to commence newborn screening for congenital adrenal hyperplasia in Australia?

Wu JY, Sudeep, Cowley DM, Harris M, McGown IN, Cotterill AM.

Abstract

21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia, with an incidence of 1: 14000live births and equal prevalence among males and females. Newborns with the most severe "salt-wasting" form of 21-OHD are susceptible to salt-wasting crises in the first few weeks of life. This is associated with morbidity and mortality. 21-OHD newborn screening (NBS) is currently performed in many countries. Despite several prominent medical societies recommending 21-OHD NBS, no state in Australia currently screens for this condition. We report a case that illustrates the need to reconsider including 21-OHD in NBS. 21-OHD NBS can be reliable, sensitive and effective in reducing morbidity and mortality.

8. Am J Med Genet A. 2011 Sep;155(9):x-xi.

A majority of parents accept newborn screening for fragile X.

[No authors listed]

9. Ann Clin Biochem. 2011 Sep;48(Pt 5):468-70. Epub 2011 Jul 20.

An improved ultra performance liquid chromatography-tandem mass spectrometry method for the determination of alloisoleucine and branched chain amino acids in dried blood samples.

Alodaib A, Carpenter K, Wiley V, Sim K, Christodoulou J, Wilcken B.

Abstract

BACKGROUND:

Branched chain amino acid (BCAA) analysis is needed for the diagnosis and management of patients with maple syrup urine disease (MSUD). We report an improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of BCAAs and Allo-Ile in dried blood spot (DBS) samples.

METHODS:

BCAAs were extracted from a 3 mm blood spot into methanol/water containing stable isotope internal standards. Eluents were dried and reconstituted in the mobile phase. Gradient elution was performed on an Acquity™ BEH C(18) (100 × 2.1 mm, 1.7 μm) column. BCAAs were detected and quantified in the multiple reaction monitoring mode in a five-minute analysis.

RESULTS:

The assay was calibrated to give best possible alignment with plasma results. Retrospective analysis of newborn DBSs from six classic MSUD patients showed elevated alloisoleucine (Allo-Ile) in all cases. Two of four patients with mild disease had normal values; the other two had significant elevations in Allo-Ile.

CONCLUSIONS:

Analysis of BCAA in DBS by UPLC-MS/MS is a useful second tier newborn screening test to identify classical MSUD and for monitoring of remote patients.

10. Clin Chem. 2011 Sep;57(9):1286-94. Epub 2011 Jul 19.

Simplified newborn screening protocol for lysosomal storage disorders.

Metz TF, Mechtler TP, Orsini JJ, Martin M, Shushan B, Herman JL, Ratschmann R, Item CB, Streubel B, Herkner KR, Kasper DC.

Abstract

BACKGROUND:

Interest in lysosomal storage disorders, a collection of more than 40 inherited metabolic disorders, has increased because of new therapy options such as enzyme replacement, stem cell transplantation, and substrate reduction therapy. We developed a high-throughput protocol that simplifies analytical challenges such as complex sample preparation and potential interference from excess residual substrate associated with previously reported assays.

METHODS:

After overnight incubation (16-20 h) of dried blood spots with a cassette of substrates and deuterated internal standards, we used a TLX-2 system to quantify 6 lysosomal enzyme activities for Fabry, Gaucher, Niemann-Pick A/B, Pompe, Krabbe, and mucopolysaccharidosis I disease. This multiplexed, multidimensional ultra-HPLC-tandem mass spectrometry assay included Cyclone P Turbo Flow and Hypersil Gold C8 columns. The method did not require offline sample preparation such as liquid-liquid and solid-phase extraction, or hazardous reagents such as ethyl acetate.

RESULTS:

Obviating the offline sample preparation steps led to substantial savings in analytical time (approximately 70%) and reagent costs (approximately 50%). In a pilot study, lysosomal enzyme activities of 8586 newborns were measured, including 51 positive controls, and the results demonstrated 100% diagnostic sensitivity and high specificity. The results for Krabbe disease were validated with parallel measurements by the New York State Screening Laboratory.

CONCLUSIONS:

Turboflow online sample cleanup and the use of an additional analytical column enabled the implementation of lysosomal storage disorder testing in a nationwide screening program while keeping the total analysis time to <2 min per sample.

11. Mol Genet Metab. 2011 Sep-Oct;104(1-2):144-8. Epub 2011 Jul 23.

The use of dried blood spot samples in the diagnosis of lysosomal storage disorders - Current status and perspectives.

Reuser AJ, Verheijen FW, Bali D, van Diggelen OP, Germain DP, Hwu WL, Lukacs Z, Mühl A, Olivova P, Piraud M, Wuyts B, Zhang K, Keutzer J.

Abstract

Dried blood spot (DBS) methods are currently available for identification of a range of lysosomal storage disorders (LSDs). These disorders are generally characterized by a deficiency of activity of a lysosomal enzyme and by a broad spectrum of phenotypes. Diagnosis of LSD patients is often delayed, which is of particular concern as therapeutic outcomes (e.g. enzyme replacement therapy) are generally more favorable in early disease stages. Experts in the field of LSDs diagnostics and screening programs convened and reviewed experiences with the use of DBS methods, and discuss the diagnostic challenges, possible applications and quality programs in this paper. Given the easy sampling and shipping and stability of samples, DBS has evident advantages over other laboratory methods and can be particularly helpful in the early identification of affected LSD patients through neonatal screening, high-risk population screening or family screening.

12. Pediatr Neurol. 2011 Sep;45(3):141-8.

Early infantile krabbe disease: results of the world-wide krabbe registry.

Duffner PK, Barczykowski A, Jalal K, Yan L, Kay DM, Carter RL.

Abstract

New York State began screening for Krabbe disease in 2006 to identify infants with Krabbe disease before symptom onset. Because neither galactocerebrosidase activity nor most genotypes reliably predict phenotype, the World Wide Registry was developed to determine whether other clinical/neurodiagnostic data could predict early infantile Krabbe disease in the newborn screening population. Data on disease course, galactocerebrosidase activity, DNA mutations, and initial neurodiagnostic studies in 67 symptomatic children with early infantile Krabbe disease were obtained from parent questionnaires and medical records. Initial signs included crying/irritability, cortical fisting, and poor head control. Galactocerebrosidase activity was uniformly low. Eight of 17 manifested novel mutations. Ninety-two percent (n= 25) exhibited elevated cerebrospinal fluid protein; 76% (n= 42) demonstrated abnormal magnetic resonance images; 67% (n= 15) exhibited abnormal computed tomography findings; 43% (n= 28) produced abnormal electroencephalogram findings; 100% (n= 5) demonstrated abnormal nerve conduction velocities; 83% (n= 6) produced abnormal brainstem evoked responses; and 50% (n= 6) exhibited abnormal visual evoked responses. One, 2, and 3 year survivals were 60%, 26%, and 14%, respectively. Although most symptomatic patients with the early infantile phenotype manifested abnormal cerebrospinal fluid protein, magnetic resonance imaging, brainstem evoked responses, and nerve conduction velocities, studies of affected children may be normal. Other biomarkers are needed to predict phenotype in the newborn screening population.