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Rare genetic disorders affect as many as 3%–5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole‐genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first‐tier NBS technique at least for those disorders without appropriate high‐throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders. The diagnostic odyssey for rare diseases begins with the development of symptoms, but often requires significant time and financial expenses before a diagnosis is ultimately made. Use of genomic technology, originally whole‐exome sequencing, but increasing whole‐genome sequencing shortcuts this odyssey by introducing comprehensive genetic analysis into clinical practice early in the evaluation of an individual without a clear diagnosis after an abbreviated clinical assessment.

What is Newborn Screening? Your baby has arrived and what an exciting event! While you are getting to know the newest member of your family, many things are happening in [...]

DR. HOWELL: Max, thank you, very much. It's my pleasure to be here today to talk about newborn screening with this distinguished group of LC researchers and clinicians. This afternoon, [...]

IMPORTANCE: Newborn screening (NBS) identifies infants with specific congenital disorders for which earlier intervention cannot only prevent a lifetime of chronic disability but also, most importantly, save lives. In this article, we discuss complexities associated with NBS processes in the United States, with a focus on challenges in neuromuscular disorders. OBSERVATIONS: As new interventions for neuromuscular disorders become available, the clinical community must prepare to overcome the challenges of adding new diseases to screening panels and understand the rigorous evidence review at the federal level and the complex process of state-level implementation. In this regard, NBS programs for Pompe disease and spinal muscular atrophy can guide the path of Duchenne muscular dystrophy and other neuromuscular disorders as future candidates for NBS. CONCLUSIONS AND RELEVANCE: The availability of advanced screening methods, the emergence of effective treatment, and the support of professional organizations may facilitate the expansion of NBS, such that an increasing number of infants can be identified in the newborn period who will benefit from life-saving interventions.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2has been shown to decrease disease severity in a dose-dependent manner, SMN2copy number is predictive of disease severity. To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2copy number. A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines. The overarching recommendation is that all infants with two or three copies of SMN2should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation. The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process.

Technological advances in recent years have made it possible for newborn infants in the United States to be screened for more than two dozen conditions. The first genetic screen for [...]

Newborn screening has long been considered one of the most successful public health programs in the United States. The Centers for Disease Control and Prevention has recognized improvements in new [...]

The Alpha-1 Foundation convened a workshop to consider the appropriateness of newborn screening for -1-antitrypsin (AAT) deficiency.

The Alpha-1 Foundation convened a workshop to consider the appropriateness of newborn screening for a-1-antitrypsin (AAT) deficiency. A review of natural history and technical data was conducted. Homozygous ZZ AAT deficiency is a common genetic disease occurring in 1 in 2000 to 3500 births; however, it is underrecognized and most patients are undiagnosed. AAT deficiency can cause chronic liver disease, cirrhosis, and liver failure in children and adults, and lung disease in adults. The clinical course is highly variable. Some neonates present with cholestatic hepatitis and some children require liver transplantation, but many patients remain well into adulthood. Some adults develop emphysema. There is no treatment for AAT liver disease, other than supportive care and liver transplant. There are no data on the effect of early diagnosis on liver disease. Avoidance of smoking is of proven benefit to reduce future lung disease, as is protein replacement therapy. Justifying newborn screening with the aim of reducing smoking and reducing adult lung disease-years in the future would be a significant paradigm shift for the screening field. Recent passage of the Genetic Information Nondiscrimination Act (GINA) and the Affordable Care Act may have a major effect on reducing the psychosocial and financial risks of newborn screening because many asymptomatic children would be identified. Data on the risk–benefit ratio of screening in the new legal climate are lacking. Workshop participants recommended a series of pilot studies focused on generating new data on the risks and benefits of newborn screening.

Newborn screening programs are state based with variable policies. Guidance regarding the retention, storage, and use of portions of newborn screening dried blood spots that remain after screening (residual specimens) was first published in 1996. Since then, newborn screening programs have paid increased attention to specimen storage and usage issues. Standard residual specimen uses include quality assurance and program evaluation, treatment efficacy, test refinement, and result verification. In all cases, privacy and security are primary concerns. In general, two distinct state practices regarding the storage and use of residual newborn screening specimens exist: (1) short-term storage (<3 years), primarily for standard program uses and (2) long-term storage (>18 years), for standard program uses and possible important public health research uses. Recently, there have been concerns in some consumer communities regarding both the potential uses of residual specimens and patient (newborn and family) privacy. To assist in policy improvements that can protect the individual's privacy and allow for important public health uses of residual newborn screening specimens, the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children has developed recommendations (with requested action by the Secretary where applicable). This report presents the Committee's recommendations and reviews the pertinent associated issues.

Abstract: The Secretary's Advisory Committee on Heritable Disorders in Newborns and Children is charged with evaluating conditions nominated for addition to the uniform screening panel and consequently making recommendations to the secretary of the US Department of Health and Human Services. This report describes the framework by which the committee approaches its task. Key decision nodes include initial review of every nomination to determine whether conditions are amenable for systematic evidence review, review of systematic evidence reviews conducted by the committee's external review group, and deliberation and formal recommendation for addition or exclusion to the uniform panel. Data analyzed include the accuracy and specificity of screening and diagnostic tests for nominated disorders, the extent of predicted health benefits, harms impact on disease course, and cost from early diagnosis and treatment. The committee process is guided by approaches used by similar entities, but more flexible criteria are sometimes needed to accommodate data limitations stemming from the rarity of many of these conditions. Possible outcomes of committee review range from recommendation to add a nominated condition to the uniform panel; provide feedback on specific gaps in evidence that must be addressed before making a decision; or rejection of a nomination (e.g., because of identified harms). The committee's structured evidence-based assessment of nominated conditions supports a consistently rigorous, iterative and transparent approach to its making recommendations regarding broad population-based screening programs for rare conditions in infants and children.

Primary health care providers will play an increasingly important role in delivering genetics-related services for women and children along the reproductive continuum. However, most primary health care providers have received little training in genetics or medical genomics to incorporate such services into routine care. A workshop was convened by the National Institutes of Health, the Centers for Disease Control and Prevention, and the Health Resources and Services Administration to identify practical strategies to educate primary care physicians involved in maternal and child health. These included developing a targeted curriculum for residency training programs, incorporating assessments of genetics and genomic medicine into the initial board certification process and the process for maintenance of certification, providing continuing medical education opportunities at national meetings, establishing an Internet-based repository of recommendations for primary care providers, and forming a learning collaborative to link primary care providers and specialists to evaluate strategies to improve care. Workgroup members underscored the importance of assessing the impact of these interventions on the process and outcomes of health care delivery. The recommendations from this workshop were presented to the United States Secretary for Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children Subcommittee on Education and Training. The Subcommittee reviewed the report and put forth recommendations to the Committee, which were adopted by the Committee in September 2009.

The second conference of the Middle East and North Africa newborn screening initiative: partnerships for sustainable newborn screening infrastructure and research opportunities was held in Cairo, Arab Republic of Egypt on April 12 to 14, 2008. Policy makers, health ministry representatives, health care providers, and experts from the region, Europe, Asia, and North America participated. The primary outcome was development of country plans of action to implement or expand newborn screening programs. Country representatives were grouped by current levels of national newborn screening activities based on a Needs Assessment Survey for national newborn screening programs and assisted by international technical experts. The Needs Assessment Survey provided information on the level of newborn screening in each country, strengths and barriers to implementation of newborn screening programs, and identified areas for research. Newborn screening programs require an integrated system of laboratories, health care providers, and educators, thus, the infrastructure put in place to screen for one condition should support expansion to other conditions. Congenital hypothyroidism was selected for initiating newborn screening programs because of its high prevalence, availability of screening methods, and cost-effective intervention. To this end, the conference provided technical sessions on screening and treatment of congenital hypothyroidism, performance standards, quality assurance, follow-up interventions, and patient management. In addition, presentations highlighted the value of integrating research into newborn screening programs as they are established and in evaluating outcomes. Research opportunities were identified at a postconference workshop sponsored by the US Civilian Research Development Foundation.

There are thousands of rare genetic diseases and many genetic and nongenetic contributors to common genetic diseases. The evidence base that is currently available about the great majority of these conditions is limited to case studies and relatively small observational study sets derived from one or several institutions. Hence, the statistical power in any one study is usually quite limited. Further, in the absence of organized registries and data collection on particular patient groups, the information available is weak and the patient resources that are available are limited. It is only through organized and coordinated clinical investigation systems that a sufficient number of patients with these diseases can be accumulated to provide the statistical power needed to inform about clinical history of treated and untreated forms, provide the resources needed for clinical trials of new tests and treatments, provide a sufficiently powered evidence base for public health decision-making and other uses. The meeting in which these issues were raised resulted in a set of proposed principles and associated recommendations as to how best to achieve the vision of creating an extensive and comprehensive collaboration of professional and lay communities to enable translational research to improve clinical care and therapies for persons with rare genetic diseases.

Background: States vary widely in their use of newborn screening tests, with some mandating screening for as few as three conditions and others mandating as many as 43 conditions, including varying numbers of the 40+ conditions that can be detected by tandem mass spectrometry (MS/MS). There has been no national guidance on the best candidate conditions for newborn screening since the National Academy of Sciences report of 1975†and the United States Congress Office of Technology Assessment report of 1988,2despite rapid developments since then in genetics, in screening technologies, and in some treatments.Objectives: In 2002, the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA) of the United States Department of Health and Human Services (DHHS) commissioned the American College of Medical Genetics (ACMG) to: Conduct an analysis of the scientific literature on the effectiveness of newborn screening.Gather expert opinion to delineate the best evidence for screening for specified conditions and develop recommendations focused on newborn screening, including but not limited to the development of a uniform condition panel.Consider other components of the newborn screening system that are critical to achieving the expected outcomes in those screened.Methods: A group of experts in various areas of subspecialty medicine and primary care, health policy, law, public health, and consumers worked with a steering committee and several expert work groups, using a two-tiered approach to assess and rank conditions. A first step was developing a set of principles to guide the analysis. This was followed by developing criteria by which conditions could be evaluated, and then identifying the conditions to be evaluated. A large and broadly representative group of experts was asked to provide their opinions on the extent to which particular conditions met the selected criteria, relying on supporting evidence and references from the scientific literature. The criteria were distributed among three main categories for each condition: The availability and characteristics of the screening test;The availability and complexity of diagnostic services; andThe availability and efficacy of treatments related to the conditions.A survey process utilizing a data collection instrument was used to gather expert opinion on the conditions in the first tier of the assessment. The data collection format and survey provided the opportunity to quantify expert opinion and to obtain the views of a diverse set of interest groups (necessary due to the subjective nature of some of the criteria). Statistical analysis of data produced a score for each condition, which determined its ranking and initial placement in one of three categories (high scoring, moderately scoring, or low scoring/absence of a newborn screening test).In the second tier of these analyses, the evidence base related to each condition was assessed in depth (e.g., via systematic reviews of reference lists including MedLine, PubMed and others; books; Internet searches; professional guidelines; clinical evidence; and cost/economic evidence and modeling). The fact sheets reflecting these analyses were evaluated by at least two acknowledged experts for each condition. These experts assessed the data and the associated references related to each criterion and provided corrections where appropriate, assigned a value to the level of evidence and the quality of the studies that established the evidence base, and determined whether there were significant variances from the survey data. Survey results were subsequently realigned with the evidence obtained from the scientific literature during the second-tier analysis for all objective criteria, based on input from at least three acknowledged experts in each condition. The information from these two tiers of assessment was then considered with regard to the overriding principles and other technology or condition-specific recommendations. On the basis of this information, conditions were assigned to one of three categories as described above: Core Panel;Secondary Targets (conditions that are part of the differential diagnosis of a core panel condition.); andNot Appropriate for Newborn Screening (either no newborn screening test is available or there is poor performance with regard to multiple other evaluation criteria).ACMG also considered features of optimal newborn screening programs beyond the tests themselves by assessing the degree to which programs met certain goals (e.g., availability of educational programs, proportions of newborns screened and followed up). Assessments were based on the input of experts serving in various capacities in newborn screening programs and on 2002 data provided by the programs of the National Newborn Screening and Genetics Resource Center (NNSGRC). In addition, a brief cost-effectiveness assessment of newborn screening was conducted.Results: Uniform panel – A total of 292 individuals determined to be generally representative of the regional distribution of the United States population and of areas of expertise or involvement in newborn screening provided a total of 3,949 evaluations of 84 conditions. For each condition, the responses of at least three experts in that condition were compared with those of all respondents for that condition and found to be consistent. A score of 1,200 on the data collection instrument provided a logical separation point between high scoring conditions (1,200– 1,799 of a possible 2,100) and low scoring (<1,000) conditions. A group of conditions with intermediate scores (1,000–1,199) was identified, all of which were part of the differential diagnosis of a high scoring condition or apparent in the result of the multiplex assay. Some are identified by screening laboratories and others by diagnostic laboratories. This group was designated as a “secondary target” category for which the program must report the diagnostic result.Using the validated evidence base and expert opinion, each condition that had previously been assigned to a category based on scores gathered through the data collection instrument was reconsidered. Again, the factors taken into consideration were: 1) available scientific evidence; 2) availability of a screening test; 3) presence of an efficacious treatment; 4) adequate understanding of the natural history of the condition; and 5) whether the condition was either part of the differential diagnosis of another condition or whether the screening test results related to a clinically significant condition.The conditions were then assigned to one of three categories as previously described (core panel, secondary targets, or not appropriate for Newborn Screening).Among the 29 conditions assigned to the core panel are three hemoglobinopathies associated with a Hb/S allele, six amino acidurias, five disorders of fatty oxidation, nine organic acidurias, and six unrelated conditions (congenital hypothyroidism (CH), biotinidase deficiency (BIOT), congenital adrenal hyperplasia (CAH), classical galactosemia (GALT), hearing loss (HEAR) and cystic fibrosis (CF)). Twenty-three of the 29 conditions in the core panel are identified with multiplex technologies such as tandem mass spectrometry (MS/MS) or high pressure liquid chromatography (HPLC). On the basis of the evidence, six of the 35 conditions initially placed in the core panel were moved into the secondary target category, which expanded to 25 conditions. Test results not associated with potential disease in the infant (e.g., carriers) were also placed in the secondary target category. When newborn screening laboratory results definitively establish carrier status, the result should be made available to the health care professional community and families. Twenty-seven conditions were determined to be inappropriate for newborn screening at this time.Conditions with limited evidence reported in the scientific literature were more difficult to evaluate, quantify and place in one of the three categories. In addition, many conditions were found to occur in multiple forms distinguished by age-of-onset, severity, or other features. Further, unless a condition was already included in newborn screening programs, there was a potential for bias in the information related to some criteria. In such circumstances, the quality of the studies underlying the data such as expert opinion that considered case reports and reasoning from first principles determined the placement of the conditions into particular categories.Newborn screening program optimization – Assessment of the activities of newborn screening programs, based on program reports, was done for the six program components: education; screening; follow-up; diagnostic confirmation; management; and program evaluation. Considerable variation was found between programs with regard to whether particular aspects (e.g., prenatal education program availability, tracking of specimen collection and delivery) were included and the degree to which they are provided. Newborn screening program evaluation systems also were assessed in order to determine their adequacy and uniformity with the goal being to improve interprogram evaluation and comparison to ensure that the expected outcomes from having been identified in screening are realized.Conclusions: The state of the published evidence in the fast-moving worlds of newborn screening and medical genetics has not kept up with the implementation of new technologies, thus requiring the considerable use of expert opinion to develop recommendations about a core panel of conditions for newborn screening. Twenty-nine conditions were identified as primary targets for screening from which all components of the newborn screening system should be maximized. An additional 25 conditions were listed that could be identified in the course of screening for core panel conditions. Programs are obligated to establish a diagnosis and communicate the result to the health care provider and family. It is recognized that screening may not have been maximized for the detection of these secondary conditions but that some proportion of such cases may be found among those screened for core panel conditions. With additional screening, greater training of primary care health care professionals and subspecialists will be needed, as will the development of an infrastructure for appropriate follow-up and management throughout the lives of children who have been identified as having one of these rare conditions.Recommended actions to overcome barriers to an optimal newborn screening system include: The establishment of a national role in the scientific evaluation of conditions and the technologies by which they are screened;Standardization of case definitions and reporting procedures;Enhanced oversight of hospital-based screening activities;Long-term data collection and surveillance; andConsideration of the financial needs of programs to allow them to deliver the appropriate services to the screened population.

The Maternal and Child Health Bureau commissioned the American College of Medical Genetics to outline a process for the standardization of outcomes and guidelines for state newborn screening programs and to define responsibilities for collecting and evaluating outcome data, including a recommended uniform panel of conditions to include in state newborn screening programs. The expert panel identified 29 conditions for which screening should be mandated. An additional 25 conditions were identified because they are part of the differential diagnosis of a condition in the core panel, they are clinically significant and revealed with screening technology but lack an efficacious treatment, or they represent incidental findings for which there is potential clinical significance. The process of identification is described, and recommendations are provided.

Disclaimer: ACMG standards and guidelines are designed primarily as an educational resource for physicians and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from these standards and guidelines.

Pompe disease, a disorder caused by a deficiency in the lysosomal enzyme acid alpha glucosidase, is frequently overlooked as a cause of floppy baby syndrome. The accurate diagnosis of floppy baby syndrome requires the sequential evaluation of medical causes (e.g., hypothyroidism, sepsis, malnutrition, malabsorption, congenital heart disease), neurologic etiologies (central [cerebral] and peripheral [lower motor unit]) and anatomic characteristics of the abnormality. Cardiomegaly on chest x-ray in a patient with floppy baby syndrome should alert the pediatrician to suspect Pompe disease. Based on this finding, further work-up or referral to a specialist can be considered. Pompe disease requires immediate attention. Symptomatic intervention of this disorder should be initiated at the earliest time possible to maximize the potential benefit from therapy and to prevent irreversible organ damage. Moreover, early diagnosis is important for providing parents with realistic information about their child's prognosis, and where appropriate, professional genetic counseling. Enzyme replacement therapy (ERT) with recombinant human GAA is currently being evaluated in clinical trials; the future availability of this option makes early identification of this condition even more critical. This article presents a unified view on the optimal approach to the accurate diagnosis of Pompe disease and to its recognition as one of the possible and treatable causes of floppy baby syndrome.

Purpose: To summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice.Methods: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed.Results: Judged by published criteria, prenatal cystic fibrosis screening is suitable for introduction. Screening can be performed cost-effectively by identifying racial/ethnic groups at sufficient risk and then using either of two models for delivering laboratory services. Validated educational materials exist. Ethical issues are not unique.Conclusions: Once adequate facilities for patient and provider education, testing, counseling, quality control, and monitoring are in place, individual programs can begin prenatal screening for cystic fibrosis.

In older patients with glucose-6-phosphatase deficiency, adenomatous nodules develop within the liver parenchyma. Investigation of eight such patients, age 3 to 28 years, using radioisotopic scans, has demonstrated areas of depressed isotope uptake in the liver in all except the one preteenaged child. Three patients were further studied with hepatic angiograms and liver biopsy specimens. A diffuse nodularity, more widespread than apparent on isotopic scans, was demonstrated on angiograms. Although initial histologic study in each case showed adenomatous tissue without evidence of neoplasm, the development of hepatocellular carcinoma in one of our patients and in others from the literature suggests that the nodules may be premalignant.(JAMA 236:1481-1484, 1976)

Acatalasia, a disease due to homozygosity for a Mendelian gene, is characterized by the absence of the enzyme catalase from the tissues of the human body. Red cells from heterozygotes have enzyme activities about one-half normal. In this paper, the development of cell lines from skin biopsies on an affected homozygote, a heterozygote, and eight control patients is described. The cell type is the euploid "fibroblast." It was found that acatalasic cells lacked the enzyme, even after growing for many months in a medium rich in catalase. The control lines all had mean catalase activities double or more that of the heterozygous line. Selection experiments, in which the growth of cells exposed for 20 minutes to varying concentrations of hydrogen peroxide was measured, did not provide a system for preferentially eliminating acatalasic cells. Certain other experiments bearing on the enzymatic defect in this disease were performed.

Prenatal diagnosis of chromosomal and many enzymatic-metabolic diseases is now possible, with little apparent risk. Studies may be carried out on the supernatant amniotic fluid, on the amniotic fluid cells directly, and on cultivated amniotic fluid cells.

THE PURPOSE of this paper is to present, for the first time, the ocular pathological manifestations of infantile or type 1 GM1-gangliosidosis (also known as generalized gangliosidosis). In addition, the clinical aspects of this disease will be discussed, since it has important ocular manifestations, but has received only one brief mention in the ophthalmic literature.1GM1-gangliosidosis is one of the inborn errors of metabolism, associated with the abnormal storage of two substances, one a ganglioside, and the other a mucopolysaccharide. More than 20 established cases now appear in the literature.2-15 In none of these were the eyes examined histopathologically.The earliest well-documented reports of GM1-gangliosidosis appeared in 1959,2,3 followed by seven cases in 1964.5 However, it was not until 1965 that a storage substance was identified as a ganglioside by O'Brien et al.6 An abnormally high accumulation of the ganglioside was

Many rare genetic, congenital, and functional disorders in neonates can be identified by newborn screening (NBS). Among the most successful of public health programs, NBS ensures early management and appropriate follow-up for affected infants. Each state has the responsibility to develop and implement policies in their NBS programs, and there is considerable variation among states policies. In 1996, the first report was published providing guidance for the retention, storage, and use of residual NBS specimens. Although significant improvements occurred in individual state policies for NBS as a result of this report, several important issues have not been addressed.

The US Secretary of Health and Human Services' Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children provides guidance to reduce the morbidity and mortality associated with heritable disorders, with a special emphasis on those conditions detectable through newborn screening. Although long-term follow-up is necessary to maximize the benefit of diagnosis through newborn screening, such care is variable and inconsistent. To begin to improve long-term follow-up, the Advisory Committee has identified its key features, including the assurance and provision of quality chronic disease management, condition-specific treatment, and age-appropriate preventive care throughout the lifespan of affected individuals. There are four components central to achieving long-term follow-up: care coordination through a medical home, evidence-based treatment, continuous quality improvement, and new knowledge discovery.

• A female newborn infant with Marfanlike habitus experienced lethargy and hypothermia associated with tyrosinemia that was not corrected by the administration of ascorbic acid at 50 mg/day but that subsequently responded to ascorbic acid at 500 mg/day. Cerebrospinal fluid analysis for neurotransmitter metabolites showed elevated concentrations of homovanillic acid and 5-hydroxyindoleacetic acid when the child was symptomatic and normal concentrations after successful ascorbic acid therapy. These observations suggest that a high level of tyrosine in serum can affect the metabolism in the brain of dopamine and serotonin.(Am J Dis Child 134:492-494, 1980)

After a single injection of radioactive orotic acid and a "chase" of nonradioactive precursor, the specific activity of ribosomal RNA in rat liver decreases logarithmically at a rate corresponding to a half-life of about 5 days. The possible significance of this result is discussed with regard to control of protein synthesis.

Histidinemia was detected in a Negro girl through a multiple screening process which selected out families having more than one child with learning disorders. Studies of 18 randomly selected asymptomatic Negro children failed to demonstrate a significant racial variation in blood histidine levels; the mean for the group studied was 0.92 mg/100 ml compared to a range of 0.49 to 1.66 mg/100 ml previously recorded among populations of mixed racial origin.

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.

ALTHOUGH uricase is absent from the tissues of the human being, there is nevertheless evidence that uric acid is destroyed in man. Benedict, Forsham and Stetten1first demonstrated by intravenous injection of isotopically labelled urate that only two-thirds to three-fourths of the daily urate turn-over of the body actually appears as urinary uric acid. Furthermore, the total recovery of the injected isotopically labelled uric acid in urinary uric acid over a 7-day period is similarly reduced2. The missing isotope has been demonstrated in a variety of metabolites in the urine, including ammonia, urea, allantoin, allantoic acid, respiratory carbon dioxide and fæcal bacterial bodies, after intravenous administration of uric acid labelled with nitrogen-15 and uric acid-2-14C (refs. 3, 4).

Sir.—I have just read the brief article dealing with juvenile gouty arthritis.1 The patients presented certainly are interesting, and the material presented leaves little doubt that they probably did have gouty arthritis.Unfortunately, I think this article contributes very little to the literature because no data are presented that would rule in or out a variety of underlying causes for hyperuricemia during childhood. I feel rather strongly that these two patients should not have been presented until some fairly careful looks had been made to consider the variety of underlying causes for hyperuricemia in childhood.

Amikacin is an aminoglycoside antibiotic that is effective against gram negative bacilli which are resistant to other aminoglycoside antibiotics. Pharmacokinetic data of amikacin in pediatric patients are scant. The pharmacokinetics of amikacin were evaluated in 30 hospitalized children (5 to 14 years of age) with malignancies. Children receiving 15 or 20 mg/kg/24 hr administered every 8 to 6 hours, respectively had peak serum concentrations of 16.9±3.67 µg/ml (mean ± SD) at the end of a one hour infusion. Six and 8 hour serum concentrations were 1.27±1.26 and 0.64±0.92 µg/ml, respectively. The t½ was 78±43.8 minutes and the total clearance was 133±43 ml/min/1.73 m2. The mean volume of distribution was 0.26±0.08 1/kg. No accumulation of amikacin was noted and no side effects occurred. A 9% inactivation of amikacin occurred when incubated in normal donor sera at 37°C for 72 hours with varying concentrations of ticarcillin. Due to the rapid renal clearance and short half life of amikacin in these children, the currently recommended dose of amikacin should be increased and the frequency of administration shortened.