Search

Background Fabry disease is an X-linked lysosomal storage disorder that causes progressive complications within the kidneys, brain, and heart. Ocular manifestations of this disease are often present at a very young age, thereby facilitating early diagnosis, before the signs and symptoms of renal disease, stroke, or hypertrophic cardiomyopathy. Early diagnosis by the eye care provider may eventually reduce the morbidity and mortality of this disease through the institution of therapy before the development of sclerotic end organ damage. This study evaluated 23 Fabry-affected members of a single cohort for the presence of ocular signs of Fabry disease. Methods Twenty-three patients of a single family were seen on a single day. Patients were given comprehensive ophthalmic examinations and completed a health and lifestyle questionnaire. Results Eight hemizygous men (mean age, 32.3 years) and 15 heterozygous women (mean age, 26.9 years) from a single family of 43 known Fabry patients were evaluated. Corneal verticillata was present in all patients. Additional findings in the male patients included anterior capsule opacity (25% total) and Fabry cataract (12.5%). Thinning of the retinal nerve fiber layer was observed in one man whose medical history was significant for stroke. Conjunctival and/or retinal vessel tortuosity was present in the majority of patients (62.5% and 75% of hemizygotes, respectively; 40% and 13.3% heterozygotes, respectively). Additional findings in the women included anterior capsule opacity. The majority of patients (87.5% hemizygotes, 60% heterozygotes) felt Fabry disease had an impact on their quality of life. Conclusions All evaluated patients who had Fabry disease had corneal verticillata, which generally does not affect vision and is readily recognizable by slit lamp examination. Greater than 60% showed conjunctival and/or retinal vessel tortuosity. The eye care provider can play a crucial role in the early recognition of ocular manifestations of Fabry disease and decrease both the time to accurate diagnosis and the delay in the institution of disease-modifying therapy.

CONTEXT: Severe combined immunodeficiency (SCID) is a group of disorders that leads to early childhood death as a result of severe infections. Recent research has addressed potential newborn screening for SCID. OBJECTIVE: To conduct a systematic review of the evidence for newborn screening for SCID, including test characteristics, treatment efficacy, and cost-effectiveness. METHODS: We searched Medline and the OVID In-Process & Other Non-Indexed Citations databases. We excluded articles if they were reviews, editorials or other opinion pieces, or case series of fewer than 4 patients or if they contained only adult subjects or nonhuman data. The remaining articles were systematically evaluated, and data were abstracted by 2 independent reviewers using standardized tools. For topics that lacked published evidence, we interviewed experts in the field. RESULTS: The initial search resulted in 719 articles. Twenty-six met inclusion criteria. The results of several small studies suggested that screening for SCID is possible. Interviews revealed that 2 states have begun pilot screening programs. Evidence from large case series indicates that children receiving early stem-cell transplant for SCID have improved outcomes compared with children who were treated later. There is some inconclusive evidence regarding the need for donor-recipient matching and use of pretransplant chemotherapy. Few data on the cost-effectiveness of a SCID-screening program. CONCLUSIONS: Evidence indicates the benefits of early treatment of SCID and the possibility of population-based newborn screening. Better information on optimal treatment and the costs of treatment and screening would benefit policy makers deciding among competing health care priorities.

SUMMARY This article describes the background, development, and ini-tial implementation of new procedures for the systematic reviewof key issues in newborn screening. Building on the work ofother systematic review efforts, the ERG described here hasaimed to develop consistent and transparent strategies for evi-dence review. This process has helped to strengthen a complexanalysis and decision system by providing balanced evi-dence, taking into account available high-quality data, expertopinion, and other levels of evidence, in a transparent man-ner. The methods developed and the identification of areas ofmissing data may also help investigators begin to standardizethe clinical and laboratory data they collect pertaining to thenewborn screening and diagnosis of rare disorders and theiroutcomes and focus future research efforts in the mostneeded areas.ACKNOWLEDGEMENTSThis review was made possible by subcontract number SC-07-028 to Massachusetts General Hospital, Center for Child andAdolescent Health Policy under prime contract numberHHSP23320045014XI to Altarum Institute, from the Maternaland Child Health Bureau (MCHB) (Title V, Social SecurityAct), Health Resources and Services Administration (HRSA),U.S. Department of Health and Human Services (DHHS).REFERENCES

OBJECTIVE: Our objective was to describe how parents consider disease and test characteristics when making decisions about newborn screening. METHODS: We conducted focus groups with parents from primary care clinics and interviews of parents from a genetics clinic (total of 45 participants). Participants discussed 7 vignettes about newborn screening that we developed and refined with the assistance of an expert panel. Two coders coded the data independently, compared coding, and resolved disagreements through discussion. Using framework analysis, we analyzed the data and identified how parents' preferences varied according to disease characteristics, test characteristics, and perceptions of the associated risks and benefits. RESULTS: Study participants strongly supported population-wide screening for disorders with well-defined, effective treatments, even if the treatment (eg, a bone marrow transplant) had significant morbidity. However, particularly among primary care clinic participants, there were more-varied preferences and greater difficulty making decisions about disorders associated with older age at onset, less-accurate screening tests, or less-effective treatment. In those cases, many participants suggested optional screening. For all disorders, participants expressed a desire for more information to facilitate decision-making. CONCLUSIONS: Participants supported newborn screening for treatable disorders but suggested optional screening for other disorders. The variable influences on parents' decision-making suggest that parents with diverse experiences, if they were included in decision-making regarding screening policies, could provide critical perspectives and help screening programs address parents' preferences and meet parents' information needs.

NRXN1 is highly expressed in brain and has been shown recently to be associated with ASD, schizophrenia, cognitive and behavioral abnormalities, and alcohol and nicotine dependence. We present three families, in whom we identified intragenic rearrangements within NRXN1 using a clinical targeted oligonucleotide array CGH. An approximately 380 kb deletion was identified in a woman with Asperger syndrome, anxiety, and depression and in all four of her children affected with autism, anxiety, developmental delay, and speech delay but not in an unaffected child. An approximately 180 kb tandem duplication was found in a patient with autistic disorder and cognitive delays, and in his mother and younger brother who have speech delay. An approximately 330 kb tandem duplication was identified in a patient with autistic features. As predicted by conceptual translation, all three genomic rearrangements led to the premature truncation of NRXN1. Our data support previous observations that NRXN1 may be pathogenic in a wide variety of psychiatric diseases, including autism spectrum disorder, global developmental delay, anxiety, and depression.

OBJECTIVE: The objective was to evaluate the relationships between all types of fetal fatty acid oxidation defects and maternal liver disease, including acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. METHODS: This was a case–control study comparing fetal fatty acid oxidation defects to the outcome of maternal liver disease. Fifty case infants with fatty acid oxidation defects were identified, with 25 matched controls collected per case. This generated a total of 50 case infants and 1,250 control infants. Pregnancies were evaluated for the presence of maternal liver disease (comprised of acute fatty liver of pregnancy, HELLP syndrome, and preeclampsia evolving into HELLP syndrome) using a conditional logistic regression model. Subgroup analysis compared long chain to short and medium chain fatty acid defects. RESULTS: Maternal liver disease was noted in 16.00% of all fatty acid oxidation defect pregnancies compared with 0.88% in the general population (odds ratio 20.4, 95% confidence interval 7.82–53.2). These pregnancies demonstrated an 18.1-fold increase in maternal liver disease when compared with our matched population controls with unaffected fetuses. All classifications of fatty acid oxidation defects were at high risk of developing maternal liver disease. Long chain defects were 50 times more likely than controls to develop maternal liver disease and short and medium chain defects were 12 times more likely to develop maternal liver disease. CONCLUSION: Maternal liver disease is significantly higher across the entire spectrum of fatty acid oxidation defects pregnancies compared with the matched control population. Notably, there is significant risk to the pregnancies with fetuses affected with short and medium chain defects, not just those with fetal long chain fatty acid oxidation defects as previously reported. Future studies should examine the pathophysiology of all infant fatty acid oxidation defects and its implications for maternal liver disease for improved future health outcomes.