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Biomedical subjects

Margaret M McGovern

Publications and source records attributed to Margaret M McGovern.

17 recordsLinked to original sources
PubMed2006

Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.

Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD.

Adult↗
PubMed2006

Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease.

OBJECTIVE: To document the prevalence of neurologic disease in Niemann-Pick disease (NPD) NPD-B. STUDY DESIGN: Sixty-four patients with NPD-B had detailed neurologic and ophthalmologic evaluations. The presence of neurologic abnormalities was compared with genotype. RESULTS: Nineteen of 64 patients (30%) had neurologic abnormalities, which were minor and nonprogressive in 14 (22%), and global and progressive in 5 (8%). In these five patients, the onset of neurologic difficulties occurred between 2 and 7 years of age and was associated with peripheral neuropathy, retinal abnormalities, and the Q292K mutation. No patients with at least one copy of DeltaR608 had neurologic involvement. CONCLUSIONS: The majority of patients with NPD-B have no neurologic abnormalities. In patients with neurologic abnormalities, the findings can be minor and static or severe and progressive. The latter phenotype follows a course distinct from that of classic NPD-A and is associated with the Q292K mutation and characteristic retinal findings. Thus, similar to other lysosomal storage disorders, there is a broad spectrum of neurologic abnormalities in acid sphingomyelinase deficiency, which makes the current classification scheme inaccurate.

Adolescent↗
PubMed2006

Use of standardized patients in, undergraduate medical genetics education.

BACKGROUND AND PURPOSE: To study the effectiveness of a standardized patient (SP) program in increasing the competence of medical students in assessing genetic risks and communicating genetic information to patients. METHODS: Third-year medical students at the Mount Sinai School of Medicine had two encounters from 2001 to 2003 with the same SP, who portrayed a woman at risk for hereditary breast cancer. Assessment instruments included student self-assessment of skills, SP assessment of student communication skills, an observer checklist, grading of the student-drawn pedigree, and a knowledge test. Students also completed an evaluation form after the debriefing session at the end of each of the SP sessions. RESULTS: The SP program was completed by 136 students. The student self-evaluation of skills instrument revealed that students who completed the SP program felt more competent in their ability to draw a pedigree, assess genetic risks based on family history and pedigree information, and communicate genetic risks compared to students at the same level of training who did not participate in the SP program. Of participating students, 90% agreed that the program allowed them to identify areas for improvement in their skills, and 95% agreed that the exercise increased their confidence for having a similar patient interaction in the future. CONCLUSIONS: The use of SPs in undergraduate medical genetics education may be one means for increasing the confidence of medical students in skills that are related to genetic encounters.

Clinical Competence↗
PubMed2005

Type B Niemann-Pick disease: findings at chest radiography, thin-section CT, and pulmonary function testing.

PURPOSE: To evaluate findings at radiography, computed tomography (CT), and pulmonary function testing in patients with type B Niemann-Pick disease. MATERIALS AND METHODS: The study was approved by the institutional review board or ethics committee at each study site and was compliant with HIPAA at the U.S. site. Written informed consent was obtained from each patient or guardian and minor assent was obtained from all children before any study-related procedures. Pulmonary involvement in 53 patients (27 male and 26 female patients; age range, 7-65 years; mean age, 23.3 years) with type B Niemann-Pick disease was evaluated with imaging and pulmonary function tests. All patients underwent chest radiography and thin-section CT, and images were independently interpreted by one of two radiologists. Spirometry (forced vital capacity [FVC] and forced expiratory volume in 1 second [FEV1]) was performed and diffusing capacity of lung for carbon monoxide (Dlco) was evaluated in all patients who could comply. A score for the degree of interstitial lung disease was derived at both radiography and CT, and the CT scores were then compared with results of pulmonary function testing and patient age by means of linear regression. CT scores were compared between the upper and lower lung zones by using the Wilcoxon signed rank test. RESULTS: Chest radiography and CT, respectively, revealed interstitial lung disease in 47 (90%) and 51 (98%) of the 52 patients who completed both imaging examinations. There was a basilar predominance of interstitial lung disease at CT. Six patients had pulmonary nodules, one of which was calcified at chest radiography. There were no statistically significant correlations between interstitial lung disease score at CT and age or percentage predicted FVC, FEV1, or Dlco values. CONCLUSION: Although pulmonary function test indexes may be abnormal, imaging findings do not necessarily correlate with pulmonary function in patients with type B Niemann-Pick disease.

Adolescent↗
PubMed2005

Referral and experience with genetic testing among women with early onset breast cancer.

The purpose of this study was to determine whether physicians refer women with early onset breast cancer for genetic testing for BRCA1 and BRCA2, and how women respond to being offered testing and use the results. A web-based survey was distributed to 1221 women with early onset breast cancer. The survey included 158 questions divided into the following sections: demographics, family history of cancer, medical history, treatment history, and experience with genetic testing. Of 551 women diagnosed since 1993 who responded to the survey (45.1%), less than half (45%, n = 246) had ever discussed genetic testing with their physician and/or been referred to see a genetic counselor. Women with a family history of cancer (53%) and Ashkenazi Jewish women (81%) were more likely to have been referred. Of those who had discussed testing, 60% had undergone or were interested in testing. Overall 92 women were tested and 19 (20.6%) of these tested positive for a deleterious BRCA1 or BRCA2 mutation. Fourteen (74%) who tested positive subsequently underwent prophylactic surgery. Satisfaction with counseling and the decision to be tested was high. Among women who were not offered testing, the fact that the test had not been offered by their physician (89%), and fear of discrimination (83%) were the two most frequently cited factors for lack of interest in testing. A substantial number of women are not being referred to genetic counseling and/or testing after a diagnosis of early onset breast cancer. Among those who were tested, there was high interest in prophylactic surgery after confirmation of a BRCA1/2 mutation.

Adult↗
PubMed2004

The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study.

OBJECTIVES: Type B Niemann-Pick disease (NPD-B) caused by acid sphingomyelinase deficiency is a rare, autosomal recessive, lysosomal storage disorder with a broad range of disease severity. The objectives of this study were to document the natural history of the disease in a large, clinically heterogeneous patient population that was followed for a period of 10 years and to determine how genotype influences phenotype. METHODS: Twenty-nine patients with NPD-B had serial evaluations at least 9 months apart. Organ volumes, hematologic indices, lipid concentrations, pulmonary function, and hepatic activity were studied, and individual phenotypic severity was compared with genotype. RESULTS: All patients with intact spleens had splenomegaly (mean value: 12.7 multiples of normal [MN]; range: 4.5-27.3 MN), and all but 1 had hepatomegaly (mean volume: 1.91 MN; range: 0.93-3.21 MN). At initial visit, 39% had thrombocytopenia and 3% had leukopenia. At final visit, the percentages increased to 54% and 34%, respectively. Mean annual decreases in platelet count and leukocyte count were 7 x 10(3) and 0.2 x 10(3) per mm3, respectively. The typical atherogenic lipid profile was worse in older patients. A total of 69% of patients had low diffusion capacity for carbon monoxide, and more than one third had low forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity at initial visit. All measurements of pulmonary function showed a gradual deterioration over time. Liver dysfunction was characterized by stable elevation of hepatic transaminases and bilirubin. Homozygotes for DeltaR608, P323A, and P330R had milder disease than patients with all other genotypes. CONCLUSIONS: The natural history of NPD-B is characterized by hepatosplenomegaly with progressive hypersplenism, worsening atherogenic lipid profile, gradual deterioration in pulmonary function, and stable liver dysfunction.

Adolescent↗
PubMed2004

Attitudes and psychosocial adjustment of unaffected siblings of patients with phenylketonuria.

Sibling illness may contribute to an increased risk of adjustment problems in healthy siblings. Previous studies have reported a variety of effects on healthy individuals who have an ill sibling, but the psychosocial effects of treatable inherited disease on healthy siblings have not yet been investigated. We report the results of a survey study conducted in families with both unaffected and affected children with classic phenylketonuria (PKU), an inherited inborn error of metabolism. The survey included a knowledge test about PKU, and four previously validated instruments designed to assess psychosocial adjustment of unaffected siblings compared to age and sex matched norms. The responses revealed that unaffected adolescent and adult siblings had gaps in their knowledge about the genetic basis of PKU, and had evidence for the presence of adverse psychosocial sequelae. These findings suggest a role for genetic services providers, including genetic counselors, in assisting all members of a family adjust, when the diagnosis of an inborn error of metabolism has been made.

Adaptation, Psychological↗
PubMed2004

Lipid abnormalities in children with types A and B Niemann Pick disease.

OBJECTIVE: To characterize the lipid profiles in patients with types A and B Niemann Pick disease (NPD) and determine if lipid abnormalities are associated with evidence of early cardiovascular disease or correlate with genotype. STUDY DESIGN: The study was a cross-sectional analysis of 10 patients with NPD type A and 30 patients with NPD type B that was carried out in the General Clinical Research Center. For each patient, fasting lipid profile and glucose, T4, height or length, weight, resting blood pressure, and acid sphingomyelinase deficiency genotype were measured. In type B patients, electrocardiograhic-gated helical computed tomography of the heart also was obtained. RESULTS: Lipid abnormalities included low (<35 mg/dL) high-density lipoprotein cholesterol in 100% of patients and hypertriglyceridemia and increased low-density lipoprotein cholesterol in 62% (25/40) and 67% (27/40) of patients, respectively. Coronary artery calcium scores were positive (>1.0) in 10 of 18 type B patients studied. There was no correlation of the Delta R608 genotype with a milder phenotype for the lipid abnormalities, as has been observed for a number of other NPD manifestations. CONCLUSIONS: Lipid abnormalities are part of the phenotype in types A and B NPD and may be associated with early atherosclerotic heart disease.

Calcium↗
PubMed2004

Ocular manifestations of Niemann-Pick disease type B.

PURPOSE: To investigate the ocular manifestations in Niemann-Pick disease type B (NPD-B). DESIGN: Observational case series. PARTICIPANTS: Forty-five patients (23 male and 22 female) with NPD-B from 37 unrelated families. METHODS: Serial clinical evaluations were carried out over a 2- to 14-year period, including a complete physical examination, neurologic assessment, and ophthalmologic examination. Genotyping of the specific mutations in the acid sphingomyelinase (ASM) gene was performed when possible for genotype-phenotype correlations. MAIN OUTCOME MEASURES: Fundus photographs to evaluate the retina, ASM genotype, and neurologic examination findings. RESULTS: Ophthalmoscopic examination revealed retinal stigmata in 15 of 45 patients, 3 with macular halos and 12 with cherry red maculae. Neurologic examinations did not reveal any evidence of neurodegeneration, and there was no consistent relationship between retinal findings and genotype. CONCLUSIONS: The presence of macular halos and/or cherry red maculae is not an absolute predictor of neurodegeneration, but should prompt a thorough evaluation to determine the underlying etiology and the precise diagnosis.

Adolescent↗
PubMed2003

Interaction of genetic counselors with molecular genetic testing laboratories: implications for non-geneticist health care providers.

The availability of molecular genetic tests for the identification of mutant gene carriers, and for assessing individual genetic response to pharmacologic agents, infectious agents, and other environmental exposures, is expected to result in the increased use of the molecular genetic testing laboratory by primary care physicians. However, a number of concerns have been raised about such testing including the need for safeguards to protect patient privacy, and if the interface between genetic testing laboratories and the ordering physician facilitates the appropriate clinical use of the test result. In this study, genetic counselors were surveyed to determine their practices with regard to the clinical issues of informed consent and confidentiality in the context of genetic testing, and to assess their level of satisfaction with the reporting practices of molecular genetic testing laboratories. The results of this survey revealed that there is variability in the practices of genetic counselors with regard to obtaining informed consent, and that there are areas for improvement with regard to molecular genetic test reports, particularly in terms of interpretation of results.

Counseling↗
PubMed2003

Growth restriction in children with type B Niemann-Pick disease.

OBJECTIVES: To compare growth of children with type B Niemann-Pick disease (NPD) with disease variables including genotype, organomegaly, bone age, and serum insulin-like growth factor-1 (IGF-1). STUDY DESIGN: A cross-sectional analysis of growth was performed in 23 children and adolescents with enzymatically and genotypically confirmed NPD. Liver and spleen volumes were measured by quantitative computed tomography and skeletal age by a wrist radiograph. RESULTS: The mean Z scores for height and weight were -1.24 (29th percentile) and -0.75 (34th percentile). The mean liver and spleen volumes were 2.06 and 13.46 times normal for weight, respectively. Skeletal age was delayed by an average of 2.5 years, and serum IGF-1 level was at or below the 2nd percentile in 8 of 12 patients. Short stature and low weight were significantly correlated with large organ volumes, delayed bone age, and low IGF-1 levels. In contrast to patients with other mutations, individuals homozygous for the DeltaR608 mutation had normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal IGF-1 levels. CONCLUSIONS: Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with type B NPD; however, homozygosity for DeltaR608 is associated with normal growth.

Adolescent↗
PubMed2003

Biochemical effect of intravenous arginine butyrate in X-linked adrenoleukodystrophy.

OBJECTIVES: To determine the biochemical and clinical effects of intravenous arginine butyrate in X-linked Adrenoleukodystrophy (X-ALD). STUDY DESIGN: Arginine butyrate was intravenously infused over a 4-month period in a patient with the rapid cerebral form of X-ALD. Very long chain fatty acids (VLCFA), complete blood counts, and serum chemistries were monitored, and serial MRI of the brain and clinical neurologic examinations were performed. RESULTS: All blood chemical and hematologic values remained within the normal range for age throughout the therapy. After completion of the first day of infusion, the C 26:0 value fell from 1.01 microg/mL to 0.445 microg/mL, which is below the mean value for an X-ALD heterozygote. Throughout the remainder of the trial, all C26:0 levels fell below the mean -1 SD for X-ALD hemizygotes (mean, 1.18 microg/mL, 1 SD = 0.53), ranging from 0.321 to 0.565 microg/mL. Despite reduction of the plasma VLCFA, the patient continued to deteriorate neurologically. CONCLUSIONS: Intravenous arginine butyrate resulted in a rapid decrease in plasma VLCFA but no effect on the neurologic progression of the disease in this patient. Additional studies are needed to determine minimum effective dosage and interval, what proportion of patients respond, and whether the agent can prevent neurologic degeneration.

Adrenoleukodystrophy↗
PubMed2003

Personnel standards and quality assurance practices of biochemical genetic testing laboratories in the United States.

CONTEXT: It has been suggested that specific regulation of laboratories performing genetic testing may be needed to ensure standards and quality assurance, and to safeguard the rights of patients with regard to confidentiality and providing informed consent. Previously, a comprehensive analysis of current practices of molecular genetic testing laboratories was conducted, the results of which have assisted in the assessment of the need for regulation and its impact on access to testing. However, a study designed to determine clinical laboratory practices with regard to biochemical genetic testing has not been carried out. OBJECTIVE: To collect and analyze data regarding availability of clinical biochemical genetic testing, personnel standards, and laboratory quality assurance practices. DESIGN: A mail survey of biochemical genetic testing laboratory directors and assignment of a quality assurance score based on responses to genetic testing process items. SETTING: Hospital-based, independent, and research-based biochemical genetic testing laboratories in the United States. PARTICIPANTS: Directors of biochemical genetic testing laboratories (n = 133; response rate 68.5%). MAIN OUTCOME MEASURE: Laboratory process quality assurance score based on the standards defined by the American College of Medical Genetics Laboratory Practice Committee. RESULTS: Personnel qualifications varied, although all directors had doctoral degrees. The mean quality assurance score was 77% (range 28%-100%). Higher scores were associated with the following variables: test director having an MD degree versus PhD degree (P = .002), director board certification in biochemical genetics (P = .002), research and hospital laboratory versus independent laboratory setting (P < .001), and participation in a proficiency testing program (P = .03). Twelve percent of participants had a confidentiality policy, and 19% required informed consent before testing. CONCLUSION: The finding that a number of laboratories had quality assurance scores that may reflect suboptimal laboratory practices, particularly with regard to reporting practices, suggests that personnel qualification and laboratory practice standards may be in need of improvement to ensure quality in clinical biochemical genetic testing laboratories, as well as the appropriate clinical use of the test results.

Genetic Diseases, Inborn↗
PubMed2002

The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.

We have collected demographic and/or mutation information on a worldwide sample of 394 patients with type B Niemann-Pick disease (NPD). The disorder is panethnic, with the highest incidence occurring in individuals of Turkish, Arabic, and North African descent. Only five of the 394 patients were Ashkenazi Jewish, revealing that, unlike the type A form of NPD, type B NPD does not occur frequently within this population. Mutation analysis of the acid sphingomyelinase (ASM) gene (designated "SMPD1") was performed on 228 patients (324 unique alleles), and several novel, "common" mutations were found. Among these were the L137P, fsP189, and L549P mutations, which accounted for approximately 75% of the alleles in Turkish patients, the H421Y and K576N mutations, which accounted for approximately 85% of the alleles in Saudi Arabian patients, the S379P, R441X, R474W, and F480L mutations, which accounted for approximately 55% of the alleles in Portuguese/Brazilian patients, and the A196P mutation, which accounted for approximately 42% of the alleles in Scottish/English patients. The previously reported DeltaR608 mutation occurred on approximately 12% of the alleles studied. Overall, a total of 45 novel mutations were found, and several new genotype/phenotype correlations were identified. In particular, the L137P, A196P, and R474W mutations were consistent with a less severe form of type B NPD, whereas the H421Y and K576N mutations led to an early-onset, more severe form that was specific to Saudi Arabia. These data provide the first extensive demographic assessment of this disorder and describe several new mutations that can be used to predict phenotypic outcome and to gain new insights into the structure and function of ASM.

Alleles↗
PubMed2002

A fluorescence-based, high-throughput sphingomyelin assay for the analysis of Niemann-Pick disease and other disorders of sphingomyelin metabolism.

Sphingomyelin is an important lipid component of cell membranes and lipoproteins that can be hydrolyzed by sphingomyelinases into ceramide and phosphorylcholine. The Type A and B forms of Niemann-Pick disease (NPD) are lipid storage disorders due to the deficient activity of the enzyme acid sphingomyelinase and the resultant accumulation of sphingomyelin in cells, tissues, and fluids. In this paper we report a new, enzymatic method to quantify the levels of sphingomyelin in plasma, urine, or tissues from NPD patients and mice. In this assay, bacterial sphingomyelinase is first used to hydrolyze sphingomyelin to phosphorylcholine and ceramide. Alkaline phosphatase then generates choline from the phosphorylcholine, and the newly formed choline is then used to generate hydrogen peroxide in a reaction catalyzed by choline oxidase. Finally, with peroxidase as a catalyst, hydrogen peroxide reacts with the Amplex Red reagent to generate a highly fluorescent product, resorufin. These enzymatic reactions are carried out simultaneously in a single 100-microl reaction mixture for 20 min. Use of a 96-well microtiter plate permits automated and sensitive quantification using a plate reader and fluorescence detector. This procedure allowed quantification of sphingomyelin over a broad range from 0.02 to 10 nmol, similar in sensitivity to a recently described radioactive method using diacylglycerol kinase and 50 times more sensitive than a colorimetric, aminoantipyrine/phenol-based assay. To validate this new assay method, we quantified sphingomyelin in plasma, urine, and tissues from normal individuals and from NPD mice and patients. The sphingomyelin content in adult homozygous or heterozygous NPD mouse plasma and urine was significantly elevated compared to that of normal mice. Moreover, the accumulated sphingomyelin in the tissues of NPD mice was 4 to 15 times higher than that in normal mice depending on the tissue analyzed. The sphingomyelin levels in plasma from several Type B NPD patients also was significantly elevated compared to normal individuals of the same age. Based on these results, we propose that this new, fluorescence-based procedure can provide simple, fast, sensitive, and reproducible sphingomyelin quantification in tissues and fluids from normal individuals and NPD patients. It could also be a useful tool for the study of other sphingomyelin-related diseases and in a variety of research settings where sphingomyelin quantification is required.

Animals↗
PubMed2002

Attitudes of pediatric residents toward ethical issues associated with genetic testing in children.

OBJECTIVE: To assess the attitudes of pediatric residents toward molecular genetic testing and some associated ethical issues that accompany its use in pediatric patients. METHODS: A questionnaire study of pediatric residents (n = 160; response rate: 40%) enrolled in training programs at 3 New York metropolitan area hospitals was designed to determine their attitudes toward genetic testing in children and adolescents. The study instrument presented 2 clinical vignettes that described scenarios where a pediatric patient was at risk for being affected with or a carrier of a genetic disorder. Residents returned the questionnaire anonymously. RESULTS: Most pediatric residents recognized the importance of educating family members (95%) and at-risk individuals (89%) about the inheritance pattern of the disorders they were at risk for. However, a substantial number would order predictive testing for Huntington disease in a child at the request of a parent (39% at age 10 and 52% at age 17), and more than half would order fragile X carrier studies on the cognitively normal sister of an affected male (56%). CONCLUSIONS: An effort must be made to educate all physicians during their residency training about the ethical issues associated with genetic testing. For pediatric residents, such education must include instruction on the complexities associated with offering such testing in this age group.

Adolescent↗