Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005-2009: a prospective population-based cohort study.

BACKGROUND: Spinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program. METHODS AND FINDINGS: This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968. CONCLUSION: The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling.

Delayed treatment of diagnosed pulmonary tuberculosis in Taiwan.

BACKGROUND: Mycobacterium tuberculosis infection is an ongoing public health problem in Taiwan. The National Tuberculosis Registry Campaign, a case management system, was implemented in 1997. This study examined this monitoring system to identify and characterize delayed treatment of TB patients. METHODS: Records of all tuberculosis cases treated in Taiwan from 2002 through 2005 were obtained from the National Tuberculosis Registry Campaign. Initiation of treatment more than 7 days after diagnosis was considered a long treatment delay. RESULTS: The study included 31,937 patients. The mean day of delayed treatment was 3.6 days. Most patients were treated immediately after diagnosis. The relationship between number of TB patients and days of delayed treatment after diagnosis exhibited a Power-law distribution. The long tail of the power-law distribution indicated that an extreme number occur cannot be neglected. Tuberculosis patients treated after an unusually long delay require close observation and follow up. CONCLUSION: This study found that TB control is generally acceptable in Taiwan; however, delayed treatment increases the risk of transmission. Improving the protocol for managing confirmed TB cases can minimize disease transmission.

Beta-thalassemia major births after National Screening Program in Taiwan.

OBJECTIVE: A National Thalassemia Screening Program was adopted in Taiwan in 1993. This report examined that program's results and impact. METHODS: Patients with beta-thalassemia major born between 1994 and 2003 were recruited through the help of all thalassemia clinics in Taiwan. A structured questionnaire was designed to collect the reasons for affected births. RESULTS: There were 97 affected births from 1994 to 2003.These births resulted after informed choice (n = 4), screening problems (n = 83), and undetermined causes (n = 10). Approximately 83% (5/6) of affected births in 2003 came from interracial marriages. CONCLUSIONS: This report has identified several areas that might improve the thalassemia-screening program, including carrier screening in high school rather than in early pregnancy and the involvement of genetic counselors, providing care of new female immigrants.

Survival, mortality, and complications in patients with beta-thalassemia major in northern Taiwan.

BACKGROUND: Advances in treatment have improved the prognosis in beta-thalassemia major. We present the survival and complications pattern of those patients in northern Taiwan born after 1970. PROCEDURE: One-hundred and sixty patients with beta-thalassemia major born after 1970 were collected. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Cox regression models were used to examine the associations of bone marrow transplantation (BMT), time of BMT procedure, and time of complications with survival. RESULTS: Better survival was observed for patients born after 1980 (P = 0.0121). Heart disease, BMT-related deaths, and infections were the main causes of death. Among the living patients over age 15, hypogonadotropic hypogonadism, HCV infection, diabetes, heart failure, and arrhythmia were the common complications. No patients under age 15 had complications. CONCLUSIONS: Survival for patients with beta-thalassemia major has improved significantly in Taiwan. More time is required to demonstrate whether these modalities added to the treatment of these patients will impact favorably on their outcome. Our success with BMT is improving and we are now in a position to offer this curative alternative.

Impact of a national beta-thalassemia carrier screening program on the birth rate of thalassemia major.

BACKGROUND: In Taiwan, the prevalence of beta-thalassemia trait is at least 1.1%. The Taiwan government initiated a National Screening Program in 1993. Herein we examine the differences before and after the initiation of this program. PROCEDURE: Data consisting of the total number of patients and the birth prevalence beta-thalassemia major were collected. Ninety-one patients with transfusion-dependent thalassemia treated in our hospitals were included for analysis. DNA analysis was performed for 86 patients. RESULTS: In Taiwan 361 patients exist. The birth prevalence of per 100,000 births was 5.6% in 1994 and declined to 1.21 in 2002. Fourteen patients were born after the program's initiation. DNA analysis of them revealed a new mutation (IVS-1-5 (G-C)), which was introduced through an inter-racial marriage. Otherwise, the remainder was the common beta-thalassemia mutations found in Taiwan. CONCLUSIONS: Despite how successful the National Screening Program is, a few doctors still failed to detect parents at risk. In addition, we are concerned about the emerging problem of the increase of interracial marriages where parents may not have appropriate screening. Hence, postgraduate education programs for physicians, health education for the general population, and timely screening of inter-racial marriage should become a priority.

Hypogonadotropic hypogonadism and hematologic phenotype in patients with transfusion-dependent beta-thalassemia.

OBJECTIVE: To determine the prevalence and risk factors of hypogonadotropic hypogonadism in transfusion-dependent patients with thalassemia. PATIENTS AND METHODS: The authors examined 29 patients with thalassemia major aged 15 years or older. Luteinizing hormone-releasing hormone tests were performed and beta-thalassemia mutations were analyzed by direct sequencing. RESULTS: The prevalence of hypogonadotropic hypogonadism was 72%. Failure of puberty was observed in 5 of 11 (45%) boys and 7 of 18 (39%) girls. Arrested puberty was noted in two boys (18%) and five girls (28%). Ten girls (56%) did not menstruate, two (11%) had regular menstrual cycles, one (6%) had irregular menstrual cycles, and five (28%) developed secondary amenorrhea. Twenty-one and eight patients had the beta 0/beta 0 and beta 0/beta+ hematologic phenotypes, respectively. beta 0-thalassemia mutation alleles involved IVS II-654 (C-T), codons 41/42 (-TCTT), codons 27/28 (+C), and codons 17 (A-T). beta+-thalassemia mutations alleles were -28 (A-G) and HbE (codons 26(GAG-AAG)). Hematologic phenotype (odds ratio, 28.50; P = 0.002) was the only risk factor identified in the logistic regression analysis. CONCLUSIONS: In patients with thalassemia major, genetic differences may influence their susceptibility to hypogonadotropic hypogonadism, possibly as a result of differences in the amounts of blood transfused and/or their vulnerability to free radical damage. The hematologic phenotype is a main determinant of the severity of thalassemia major; hence, it may influence the need for and frequency of blood transfusion and the patient's iron-overload status.

Severe bacterial infection in transfusion-dependent patients with thalassemia major.

The incidence and clinical spectrum of severe bacterial infection were studied in 89 patients with thalassemia major that was diagnosed between January 1971 and March 2002. There were 20 patients with 24 episodes of severe bacterial infection, resulting in an incidence of 1.6 infections per 100 patient-years. The clinical spectrum included liver abscess (6 cases), septicemia (6 cases), soft-tissue infection (2 cases), osteomyelitis (2 cases), corneal ulcer (1 case), enteritis (1 case), and abscesses of the lung, kidney, intra-abdominal region, retropharynx, gums, and buttocks (1 case each). The leading causal microorganisms were gram-negative bacilli, especially Klebsiella pneumoniae (10 of 20 isolates). Other responsible pathogens were Pseudomonas aeruginosa (2/20), Vibrio vulnificus (2/20), Acinetobacter baumanii (1/20), Streptococcus intermidius (1/20), Yersinia enterocolitica (1/20), Staphylococcus aureus (1/20), Escherichia coli (1/20), and Salmonella species (1/20). Splenectomy and delays in the start of iron-chelating therapy were 2 independent risk factors.

Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia.

PURPOSE: To determine the prevalence of hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. PATIENTS AND METHODS: A total of 28 transfusion-dependent patients with beta-thalassemia were interviewed, and their serum calcium, phosphate, magnesium, and intact parathyroid hormone levels were checked. Serum ferritin levels were measured to monitor the effect of chelation therapy. Blood urea nitrogen, creatinine, total protein, and albumin were measured in patients with undetectable or low intact parathyroid hormone levels. RESULTS: The prevalence of hypoparathyroidism was 10.7% (3/28). Mean age at diagnosis was 18 years. The serum ferritin levels of patients with hypoparathyroidism were 1,032, 2,102, and 7,680 microg/L. Only one patient had clinical symptoms of hypocalcemia. All three of the patients with hypoparathyroidism had hypogonadism, and 66.7% (2/3) of the patients had insulin-dependent diabetes mellitus. CONCLUSIONS: Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia seems to be accompanied by other endocrinopathies. Serum ferritin may not have been a reliable indicator of iron overload in the three patients with hypoparathyroidism. Severe iron overload would easily explain these multiple endocrinopathies. This pattern is commonly seen in iron-overloaded patients with thalassemia elsewhere.