Changes in Spina Bifida Lesion Level after Folic Acid Fortification in the US.

OBJECTIVE: To assess whether the severity of cases of spina bifida changed after the institution of mandatory folic acid fortification in the US. STUDY DESIGN: Six active population-based birth defects programs provided data on cases of spina bifida for 1992-1996 (prefortification period) and 1999-2016 (postfortification period). The programs contributed varying years of data. Case information included both a medical record verbatim text description of the spina bifida diagnosis and spina bifida codes (International Classification of Diseases, Clinical Modification, or a modified birth defects surveillance coding system). Comparing the prefortification and postfortification periods, aORs for case severity (upper-level lesions [cervical, thoracic] vs lower-level lesions [lumbar, sacral]) and prevalence ratios (PRs) were estimated. RESULTS: A total of 2593 cases of spina bifida (out of 7 816 062 live births) met the inclusion criteria, including 573 cases from the prefortification period and 2020 cases from the postfortification period. Case severity decreased by 70% (aOR, 0.30; 95% CI, 0.26-0.35) between the fortification periods. The decrease was most pronounced for non-Hispanic White mothers. Overall spina bifida prevalence declined by 23% (PR, 0.77; 95% CI, 0.71-0.85), with similar reductions seen across the early, mid, and recent postfortification periods. A statistically significant decrease in upper-level lesions occurred in the postfortification period compared with the prefortification period (PR, 0.28; 95% CI, 0.22-0.34), whereas the prevalence of lower-level lesions remained relatively similar (PR, 0.94; 95% CI, 0.84-1.05). CONCLUSIONS: The severity of spina bifida cases decreased after mandatory folic acid fortification in the US. Further examination is warranted to better understand the potential effect of folic acid on spina bifida severity.

A SOX3 duplication and lumbosacral spina bifida in three generations.

Chromosomal aneuploidies, microduplications and microdeletions are the most common confirmed genetic causes of spina bifida. Microduplications of Xq27 containing the SOX3 gene have been reported in 11 cases, confirming the existence of an X-chromosomal locus for spina bifida. A three generation kindred reported here with a SOX3 duplication has been identified in one of 17 kindreds with recurrences in the 29 years of the South Carolina Neural Tube Defect Prevention Program. Other recurrences during this time period included siblings with an APAF1 mutation, siblings with a CASP9 mutation, siblings with a microdeletion of 13q, and two sets of siblings with Meckel syndrome who did not have genetic/genomic studies performed.

Neural Tube Defects and Associated Anomalies before and after Folic Acid Fortification.

OBJECTIVE: To examine the prevalence and types of neural tube defects and the types of anomalies co-occurring with neural tube defects in 6 years before fortification of cereal grain flour with folic acid (1992-1998) and 20 years after fortification (1999-2018) in South Carolina, a state with a historically high prevalence of these birth defects. STUDY DESIGN: The prevalence of neural tube defects was determined by active and passive surveillance methods in South Carolina since 1992. The types of neural tube defects and co-occurring malformations were determined by prenatal ultrasound and post-delivery examination. RESULTS: In the 6 prefortification years, 363 neural tube defects were identified among 279 163 live births and fetal deaths (1/769), 305 (84%) of which were isolated defects of the calvaria or spine. In the 20 fortification years, there were significant reductions in the prevalence and percentage of isolated defects: 938 neural tube defects were identified among 1 165 134 live births and fetal deaths (1/1242), 696 (74.2%) of which were isolated. The current prevalence of neural tube defects in South Carolina (0.56/1000 live births and fetal deaths) is comparable with that nationwide. CONCLUSIONS: The continued occurrence of neural tube defects, the majority of which are isolated, after folic acid fortification of cereal grain flours suggests that additional prevention measures are necessary to reduce further the prevalence of these serious defects of the brain and spine.

Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects.

Neural tube defects (NTDs) remain one of the most serious birth defects, and although genes in several pathways have been implicated as risk factors for neural tube defects via knockout mouse models, very few molecular causes in humans have been identified. Whole exome sequencing identified deleterious variants in key apoptotic genes in two families with recurrent neural tube defects. Functional studies in fibroblasts indicate that these variants are loss-of-function, as apoptosis is significantly reduced. This is the first report of variants in apoptotic genes contributing to neural tube defect risk in humans.

When folic acid fails: Insights from 20 years of neural tube defect surveillance in South Carolina.

Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence.

Long term maintenance of neural tube defects prevention in a high prevalence state.

OBJECTIVE: To assess the efficacy of folic acid (FA) supplementation and fortification in preventing neural tube defects (NTDs) in a high prevalence region of the United States. STUDY DESIGN: Active and passive surveillance methods were used to identify all fetuses/infants affected with an NTD in South Carolina. Prevalence rates were compared with FA intake to determine the effects of increased intake on NTD occurrence and recurrence. RESULTS: From 1992 to 2009, 916 NTD cases occurred in South Carolina, with isolated defects comprising 79% of cases. The NTD rate decreased 58% during this period. There was one NTD-affected pregnancy in 418 subsequent pregnancies (0.2%) in mothers with earlier NTD-affected pregnancies who consumed periconceptional FA supplements, and there were 4 NTDs in 66 pregnancies (6.1%) in which the mother did not take FA supplements. FA supplementation increased from 8% to 35% from 1992 to 2007, and knowledge of the protective benefits of FA increased from 8% to 65% in women of childbearing age. CONCLUSIONS: Increased periconceptional intake of FA appeared to reduce NTDs in a high-prevalence region. The rate of spina bifida and anencephaly in South Carolina is now essentially the same (0.69 cases per 1000 live births and fetal deaths) as the 1998 to 2005 US rate (0.69).

Economic evaluation of a neural tube defect recurrence-prevention program.

BACKGROUND: Women with a pregnancy affected by a neural tube defect (NTD) are encouraged to take folic acid prior to a subsequent pregnancy, but it is unknown whether organized attempts to identify and counsel such women to prevent recurrent NTDs are cost effective. METHODS: Data from the South Carolina recurrence-prevention program for October 2001-September 2002 were analyzed between October 2002 and December 2003 to calculate costs. Cost-effectiveness modeling of the program during 1992-2006 was conducted during 2007. Results were calculated for three scenarios based on recurrence risk, supplement use, and the effectiveness of folic acid in preventing recurrences. For each scenario, quality-adjusted life years (QALYs) were calculated separately using prevented NTD-affected live births; prevented NTD-affected births (including fetal deaths); and all prevented NTD-affected pregnancies. RESULTS: The prevention program cost approximately $155,000 per year in 2003 dollars to protect 35 pregnancies and prevent approximately one NTD. The direct costs associated with an NTD depend on type and outcome, but are approximately $560,000 in 2003 dollars for a live birth with spina bifida. The base-case cost-effectiveness ratio was $39,600 per QALY gained from avoided NTD-affected live births and stillbirths, and $14,700 per QALY gained from the avoidance of all NTD-affected pregnancies. The baseline NTD recurrence risk and the use of folic acid supplements by women who are at high risk for an NTD-affected pregnancy were influential parameters. CONCLUSIONS: The South Carolina NTD recurrence-prevention program appears comparable in cost effectiveness to other preventive services. Other states might consider including NTD recurrence prevention in birth defect-prevention programs.

Neural tube defects and associated anomalies in South Carolina.

BACKGROUND: Neural tube defects (NTDs) occur as isolated malformations and in the company of other birth defects. This study was conducted to determine the frequency of coexisting anomalies and the relationship between them. METHODS: Since 1992, NTDs have been identified through prenatal and postnatal surveillance activities in South Carolina. The type of NTD and presence of associated anomalies were determined by prenatal ultrasound, postnatal and/or postmortem examination. RESULTS: During the ten-year period from 1992 to 2002, 564 NTDs were identified by the surveillance system. Seventeen percent of NTDs (98/564) had associated malformations. In approximately half (n = 51) of these cases, the NTDs and associated anomalies were components of a recognizable syndrome. In the remaining cases (n = 47), no syndrome was identified or suspected, but the associated anomalies were believed in most instances to be secondary to space limitation or neural crest abnormalities imposed by the NTD. CONCLUSION: Seventeen percent of NTDs in South Carolina have associated malformations. In most cases, the associated anomalies are considered either components of a multiple malformation syndrome or secondary to the NTD.

Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome.

OBJECTIVE: The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM 260920) is caused by recessive mutations in the mevalonate kinase gene (MVK), which encodes an enzyme involved in cholesterol and nonsterol isoprenoid biosynthesis. HIDS is characterized by persistently elevated polyclonal IgD and recurrent febrile episodes. Although abnormalities in tumor necrosis factor alpha (TNF alpha) are not the primary cause of HIDS, plasma TNF alpha levels are elevated in HIDS patients during attacks and thus may be a therapeutic target. This study assessed the effects of etanercept, a soluble p75 TNF alpha receptor-Fc fusion protein, in 2 patients with HIDS. METHODS: We performed biochemical and molecular genetic analyses on 2 girls with periodic episodes of fever, skin rash, abdominal pain, and arthralgia, of whom 1 had elevated levels of serum IgD. After the diagnosis of HIDS was made, treatment with etanercept was initiated in both patients. Clinical response was recorded in a standardized diary, and serum levels of cytokines and their decoy receptors were serially measured in 1 of the 2 patients. RESULTS: Urinary mevalonate levels were elevated in both girls. Patient 1 was heterozygous for a known MVK missense mutation (V377I) and a novel mutation that led to skipping of exon 3. Patient 2 was found to have V377I and a new missense mutation, S329R. Neither patient had mutations in TNFRSF1A or MEFV, the genes for the TNF receptor-associated periodic syndrome and familial Mediterranean fever, respectively. Etanercept reduced the frequency and severity of symptoms in both patients, whereas the levels of serum IgD and urine mevalonate remained unchanged. CONCLUSION: Our favorable experience with etanercept for the treatment of HIDS suggests that further investigation of this therapy is warranted.

Periconceptional multivitamin folic acid use, dietary folate, total folate and risk of neural tube defects in South Carolina.

PURPOSE: To investigate whether dietary folate or multivitamin folic acid taken 3 months before conception and during the first 3 months of pregnancy reduces the risk of isolated occurrent neural tube defect (NTD)-affected pregnancies. METHODS: This population-based case control study conducted between 1992 and 1997 included 179 women with NTD-affected pregnancies and 288 randomly selected controls. Women completed a food frequency questionnaire and were interviewed about lifestyle behaviors, pregnancy histories and use of multivitamins. RESULTS: Use of 0.4 mg or more of multivitamin folic acid at least 3 times per week during the periconceptional period showed no statistically significant reduction in NTD risk [adjusted odds ratio (AOR) = 0.55, 95% confidence interval (CI) = 025, 1.22]. After adjusting for covariates, protective effects for NTDs were observed at the highest quartiles of dietary folate and total folate (daily dietary folate plus daily multivitamin folic acid); the respective odds ratios were 0.40 (95% CI = 0.19, 0.84) and 0.35 (95% CI = 0.17, 0.72). CONCLUSIONS: This study illustrates some of the difficulties in determining effects of folic acid and dietary folate in a population where the consumption of foods rich in folate and the use of multivitamins are increasing and the rate of NTDs is declining. Studies are needed to monitor future changes in folate levels and their effect on health.

The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.

The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions). Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.

Complementary therapies follow Hippocrates.

Things have changed considerably since Claire Rayner qualified in 1954.