Is the prevalence of Down syndrome births in Hawai'i increasing?

PURPOSE: In response to a study published by the Centers for Disease Control and Prevention (CDC) in 2009, which indicated that the prevalence of Down syndrome births was increasing in the 10 regions studied, this study examined whether a similar trend was occurring in Hawai'i. METHODS: Data were obtained from the Hawai'i State Department of : Health Birth Defects Program for the years 1997-2005. The information was analyzed by numbers of live births and outcomes of Down syndrome pregnancies, by ratio of terminations to live births, by age of mother (< 35 years or ≥ 35 years), by maternal ethnicity, and by whether the baby was born with a congenital heart defect (a frequent concomitant condition of babies born with Down Syndrome). These results were compared with previously published studies on the prevalence of Down syndrome births and pregnancies in Hawai'i and were also compared with recently published data of the CDC. FINDINGS: THE STUDY FOUND THAT THE PREVALENCE OF DOWN SYNDROME : births for Hawai'i over the nine-year period did not change significantly. Thus, this finding did not match the findings of the CDC study. Additionally, the data showed that the prevalence of congenital heart defects was higher in Hawai'i than in other areas. However, because of changes in the resources available to the Hawai'i Birth Defects Program, fully comparing in all respects data from the 1997-2005 period with studies conducted earlier in Hawai'i was not possible. CONCLUSIONS: THE DATA IDENTIFIED A NUMBER OF AREAS IN NEED OF FURTHER : study. These areas include the following: 1) an examination of the kinds of information and counseling given by primary care providers to women following a prenatal diagnosis of Down syndrome; 2) analysis of the characteristics, values, and choices made by these women to terminate the pregnancy or continue it to term; and 3) determination of why the prevalence of congenital heart defects appears higher among births of babies with Down syndrome in Hawai'i than elsewhere.

A multisite study to examine the efficacy of the otoacoustic emission/automated auditory brainstem response newborn hearing screening protocol: introduction and overview of the study.

PURPOSE: This article is the 1st in a series of 4 articles on a recently completed multistate study of newborn hearing screening. METHOD: The study examined the efficacy of the 2-stage otoacoustic emission/automated auditory brainstem response (OAE/A-ABR) protocol for identifying hearing loss in newborns. RESULTS: The study found that the 2-stage OAE/A-ABR protocol did miss a significant number of babies who exhibited a permanent hearing loss by 1 year of age. Three subsequent articles will describe the research design and results in detail, discuss the behavioral assessment of infants, and summarize the implications of the study for policy, practice, and research.

A multisite study to examine the efficacy of the otoacoustic emission/automated auditory brainstem response newborn hearing screening protocol: research design and results of the study.

PURPOSE: Most newborns are screened for hearing loss, and many hospitals use a 2-stage protocol in which all infants are screened first with otoacoustic emissions (OAEs). In this protocol, no additional testing is done for those passing the OAE screening, but infants failing the OAE are also screened with automated auditory brainstem response (A-ABR). This study evaluated how many infants who failed the OAE and passed the A-ABR had permanent hearing loss (PHL) at 8-12 months of age. METHOD: A total of 86,634 infants were screened at 7 birthing centers using a 2-stage OAE/A-ABR hearing screening protocol. Of infants who failed the OAE but passed the A-ABR, 1,524 were enrolled in the study. Diagnostic audiologic evaluations were performed on 64% of the enrolled infants (1,432 ears from 973 infants) when they were 8-12 months old. RESULTS: Twenty-one infants (30 ears) who passed the newborn A-ABR hearing screening were identified with PHL when they were 8-12 months old. Most (71%) had mild hearing loss. CONCLUSIONS: If all infants were screened for hearing loss using a typical 2-stage OAE/A-ABR protocol, approximately 23% of those with PHL at 8-12 months of age would have passed the A-ABR.

A multisite study to examine the efficacy of the otoacoustic emission/automated auditory brainstem response newborn hearing screening protocol: results of visual reinforcement audiometry.

PURPOSE: This 3rd of 4 articles on a study of the efficacy of the 2-stage otoacoustic emission/automated auditory brainstem response (OAE/A-ABR) newborn hearing screening protocol describes (a) the behavioral audiometric protocol used to validate hearing status at 8-12 months of age, (b) the hearing status of the sample, and (c) the success of the visual reinforcement audiometry (VRA) protocol across 7 sites. METHOD: A total of 973 infants who failed OAE but passed A-ABR, in one or both ears, during newborn screening were tested with a VRA protocol, supplemented by tympanometry and OAE screening at age 8-12 months. RESULTS: VRA audiograms (1.0, 2.0, and 4.0 kHz) were obtained for 1,184 (82.7%) of the 1,432 study ears. Hearing loss was ruled out in another 100 ears by VRA in combination with OAE, for a total of 88.7% of the study sample. Permanent hearing loss was identified in 30 ears of 21 infants. Sites differed in their success with the VRA protocol. CONCLUSIONS: Continued monitoring of hearing beyond the newborn period is an important component of early detection of hearing loss. Using a structured protocol, VRA is an appropriate test method for most, but not all, infants. A battery of test procedures is often needed to adequately delineate hearing loss in infants. Examiner experience appears to be a factor in successful VRA.

A multisite study to examine the efficacy of the otoacoustic emission/automated auditory brainstem response newborn hearing screening protocol: recommendations for policy, practice, and research.

PURPOSE: This article examines whether changes in hearing screening practices are warranted based on the results of the recent series of studies by J. L. Johnson, K. R. White, J. E. Widen, J. S. Gravel, B. R. Vohr, M. James, T. Kennalley, A. B. Maxon, L. Spivak, M. Sullivan-Mahoney, Y. Weirather, and S. Meyer (Johnson, White, Widen, Gravel, James, et al., 2005; Johnson, White, Widen, Gravel, Vohr, et al., 2005; White et al., 2005; Widen et al., 2005) that found a significant number of infants who passed an automated auditory brainstem response (A-ABR) screening after failing an initial otoacoustic emission (OAE) screening later were found to have permanent hearing loss in one or both ears. METHOD: Similar to the approach used by F. H. Bess and J. Paradise (1994), this article addresses the public health tenets that need to be in place before screening programs, or in this case, a change in screening practice (use of a 2-step screening protocol) can be justified. RESULTS: There are no data to suggest that a 2-step OAE/A-ABR screening protocol should be avoided. CONCLUSION: Research is needed before any change in public policy and practice surrounding current early hearing detection and intervention programs could be supported.

Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH.

Molybdenum cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. All forms of molybdenum cofactor deficiency are inherited as autosomal recessive traits. The cofactor is an unstable reduced pterin with a unique four-carbon side chain, synthesized by a complex pathway that requires the products of at least four different genes (MOCS1, MOCS2, MOCS3, and GEPH). Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 and MOCS2 have a bicistronic architecture; i.e., each gene encodes two proteins in different open reading frames. The protein products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by independent translation of a bicistronic mRNA. The gephyrin protein, encoded by a third locus, is required during cofactor assembly for insertion of molybdenum. A total of 32 different disease-causing mutations, including several common to more than one family, have been identified in molybdenum cofactor-deficient patients and their relatives.

Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients.

We report twelve novel mutations in patients with isolated sulfite oxidase deficiency. The mutations are in SUOX, the gene that encodes the molybdohemoprotein sulfite oxidase. These include two frameshift mutations, a four-basepair deletion (562del4) and a single-basepair insertion (113insC), both resulting in premature termination. Nonsense mutations predicting Y343X and Q364X substitutions were identified in a homozygous state in three patients, the latter in two sibs. The remaining eight are missense mutations generating single amino acid substitutions. From the position of the substituted residues, seven of these mutations are considered to be causative of the enzyme deficiency: I201L, R211Q, G305S, R309H, K322R, Q339R, and W393R. The eighth, a C>T transition, predicts an R319C substitution, which could affect the binding of the molybdenum cofactor and thus severely reduce sulfite oxidase activity. This mutation, however, is downstream of a frameshift mutation and is therefore not the causative mutation in this individual.

Universal newborn hearing screening: a goal being achieved in Hawaii.

This article describes the importance of early identification of hearing loss in newborns, the current status of newborn hearing screening in the United States, and the leadership that Hawaii has contributed to that effort. Described are events that may help the nation reach the Year 2010 Health Goals for newborn hearing screening, identification, and intervention.

A multicenter evaluation of how many infants with permanent hearing loss pass a two-stage otoacoustic emissions/automated auditory brainstem response newborn hearing screening protocol.

OBJECTIVE: Ninety percent of all newborns in the United States are now screened for hearing loss before they leave the hospital. Many hospitals use a 2-stage protocol for newborn hearing screening in which all infants are screened first with otoacoustic emissions (OAE). No additional testing is done with infants who pass the OAE, but infants who fail the OAE next are screened with automated auditory brainstem response (A-ABR). Infants who fail the A-ABR screening are referred for diagnostic testing to determine whether they have permanent hearing loss (PHL). Those who pass the A-ABR are considered at low risk for hearing loss and are not tested further. The objective of this multicenter study was to determine whether a substantial number of infants who fail the initial OAE and pass the A-ABR have PHL at approximately 9 months of age. METHODS: Seven birthing centers with successful newborn hearing screening programs using a 2-stage OAE/A-ABR screening protocol participated. During the study period, 86634 infants were screened for hearing loss at these sites. Of those infants who failed the OAE but passed the A-ABR in at least 1 ear, 1524 were enrolled in the study. Data about prenatal, neonatal, and socioeconomic factors, plus hearing loss risk indicators, were collected for all enrolled infants. When the infants were an average of 9.7 months of age, diagnostic audiologic evaluations were done for 64% of the enrolled infants (1432 ears from 973 infants). RESULTS: Twenty-one infants (30 ears) who had failed the OAE but passed the A-ABR during the newborn hearing screening were identified with permanent bilateral or unilateral hearing loss. Twenty-three (77%) of the ears had mild hearing loss (average of 1 kHz, 2 kHz, and 4 kHz < or =40-decibel hearing level). Nine (43%) infants had bilateral as opposed to unilateral loss, and 18 (86%) infants had sensorineural as opposed to permanent conductive hearing loss. CONCLUSIONS: If all infants were screened for hearing loss using the 2-stage OAE/A-ABR newborn hearing screening protocol currently used in many hospitals, then approximately 23% of those with PHL at approximately 9 months of age would have passed the A-ABR. This happens in part because much of the A-ABR screening equipment in current use was designed to identify infants with moderate or greater hearing loss. Thus, program administrators should be certain that the screening program, equipment, and protocols are designed to identify the type of hearing loss targeted by their program. The results also show the need for continued surveillance of hearing status during childhood.

Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency.

Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with severe neurological symptoms resulting from a lack of sulfite oxidase activity. The deficiencies can be diagnosed prenatally by monitoring sulfite oxidase activity in chorionic villus sampling (CVS) tissue. In those families in which the specific defects have been identified, diagnosis can be achieved by mutation analysis or linkage studies directed at affected genes. These include MOCS1, MOCS2 or GEPH, in cases of molybdenum cofactor deficiency, or SUOX in patients with isolated sulfite oxidase deficiency.

The 1.2 A structure of the human sulfite oxidase cytochrome b(5) domain.

The molybdenum- and iron-containing enzyme sulfite oxidase catalyzes the physiologically vital oxidation of sulfite to sulfate. Sulfite oxidase contains three domains: an N-terminal cytochrome b(5) domain, a central domain harboring the molybdenum cofactor (Moco) and a C-terminal dimerization domain. Oxidation of the substrate sulfite is coupled to the transfer of two electrons to the molybdenum cofactor. Subsequently, these electrons are passed on, one at a time, to the b(5) heme of sulfite oxidase and from there to the soluble electron carrier cytochrome c. The crystal structure of the oxidized human sulfite oxidase cytochrome b(5) domain has been determined at 1.2 A resolution and has been refined to a crystallographic R factor of 0.107 (R(free) = 0.137). A comparison of this structure with other b(5)-type cytochromes reveals distinct structural features present in the sulfite oxidase b(5) domain which promote optimal electron transport between the Moco of sulfite oxidase and the heme of cytochrome c.

Pulsed EPR studies of nonexchangeable protons near the Mo(V) center of sulfite oxidase: direct detection of the alpha-proton of the coordinated cysteinyl residue and structural implications for the active site.

Pulsed electron nuclear double resonance (ENDOR) spectra of nonexchangeable protons in the vicinity of the Mo(V) center of the high pH (hpH) and low pH (lpH) forms of native chicken liver sulfite oxidase (SO) and recombinant human SO have been obtained and analyzed for the first time. The close similarity of the spectra for the chicken and human enzymes indicates that the structures of their molybdenum centers are essentially identical. For lpH SO, the closest nonexchangeable proton is found to be approximately 2.8 A from the Mo atom. To more accurately determine the distance to this proton and facilitate its assignment, the C-band electron spin-echo envelope modulation (ESEEM) spectra of lpH SO were also analyzed. From the obtained distance and comparison with the X-ray structure, this closest nonexchangeable proton is assigned to the alpha-proton of the coordinated conserved cysteinyl residue (Cys185 in chicken, Cys207 in human). The closest Mo...H distance for the nonexchangeable protons of hpH SO is found to be approximately 3.3 A. For the cysteinyl alpha-proton, such an increase in the Mo...H distance only requires a very small change in torsional angles. This study demonstrates that details of the enzyme structural rearrangements with pH can be monitored by ENDOR spectroscopy and suggests that a similar approach may be routinely used to probe the orientation of the coordinated cysteinyl residue in mutant forms of SO that are catalytically compromised.