Changes of serum hexosaminidase for the presumptive diagnosis of type I Gaucher disease in Tay-Sachs carrier screening

Although reduced acid β-glucosidase activity appears to be the primary enzyme defect in type I Gaucher disease, patients with this disorder also have marked elevation of serum acid phosphatase and β-hexosaminidase activities but with a normal level of lactic dehydrogenase activity. Moreover, there is a characteristic alteration in the hexosaminidase isozyme distribution with a striking increase in hexosaminidase B. Since these changes appear to be consistent and unlike those associated with other disorders or the hormonally induced alterations associated with pregnancy, routine serum testing for the Tay-Sachs carrier state may offer a useful approach for the presumptive diagnosis and screening for Gaucher disease. Unlike the changes in affected homozygotes, there are no characterisitic alterations of acid phosphatase or hexosaminidase in heterozygotes for Gaucher disease.     

Genetic screening for Krabbe disease: learning from the past and looking to the future

In Israel, Krabbe disease is frequent in two Moslem Arab villages in the Jerusalem area. In this paper we present our experience of almost four decades with diagnosis of Krabbe disease, carrier screening and prenatal diagnosis. The screening program is well accepted by the community, and there is a clear trend towards premarital testing. The screening program and prenatal diagnosis have led to a decrease in the incidence of Krabbe disease from 1.6 per 1,000 live births to 0.82 per 1,000.     

Attitudes and opinions of pregnant women who are not offered cystic fibrosis carrier screening

Cystic fibrosis (CF) is the most common severe, autosomal recessive disease among Caucasians. A population-based CF carrier screening programme was implemented in Victoria, Australia, in 2006. Carrier screening for CF is currently only offered in the private health system. The aim of this study was to determine the attitudes and opinions of pregnant women in the public health system, towards screening for CF. Pregnant women were recruited in the antenatal clinics of two public hospitals, and invited to participate in the study. Results of this study were compared with previous studies where screening for CF carrier status was offered. Of the participants (n=158), the majority were aged 25–34 years old (66.1%) and were Caucasian (45.8%). Compared with those who were offered screening (reported in previous studies) participants in the current study were younger, had a lower level of education and a lower income. Knowledge was significantly lower in those who were not offered screening compared with those who were offered screening. The majority of participants believe CF carrier screening should be offered in the public health system (80.5%) and almost half would have liked to receive an offer of screening during their current pregnancy (49.7%). In order for the programme to be equitable, screening for CF carrier status needs to be offered in both the public and private health system and ideally should be at no cost to the user.     

Carrier screening for cystic fibrosis: Test acceptance and one year follow-up

We identified 124 carriers among 4,879 patients of prenatal care providers in the Rochester region. Six factors were identified that together permitted a correct classification regarding test acceptance for 77.5% of all subjects. For those pregnant, the most influential of these factors was a more accepting attitude toward abortion. As an indication for abortion, cystic fibrosis (CF) ranked between mild and moderate mental retardation. Of the 124 carrier women identified, we obtained 1-year follow-up information on 100. Mean score for CF knowledge at 1 year (77.4 ± 13.2%), although significantly lower than immediately after counseling (84 ± 12.4%), was still significantly higher than after detection but before counseling (51.1% ± 20.7%). Anxiety about having a child with CF significantly declined from 25.8 ± 8.0 SD immediately after counseling to 18.9 ± 7.8 at 1 year (Spielberger State Anxiety Scale). Although 15 carriers regretted having been tested, 83% believed that they benefited from testing, 83% would make the same decision to be tested over again, and 79% would recommend testing to a friend. We conclude that, for most women, CF carrier screening accomplished its purpose: most carriers detected came for counseling, had their partners tested, and, if their partners were also carriers, had prenatal diagnosis. The major undesirable outcomes were that many women testing negative did not understand that a negative result did not exclude being a carrier and that three women found to be carriers did not have their partners tested because of anxiety or the unacceptability of pregnancy termination and therefore may not have carefully considered their decision to be tested. Both of these undesirable outcomes could have been avoided by greater attention to pretest patient education by the primary care provider. Am. J. Med. Genet. 73:378–386, 1997. © 1997 Wiley-Liss, Inc.     

Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease‐causing variants

The Ashkenazi Jewish (AJ) population has an increased risk for a variety of recessive diseases due to historical founder effects and genetic drift. For some, the disease‐causing founder mutations have been identified and well‐characterized, but for others, further study is necessary. The purpose of this study is to assess the carrier frequencies of 85 pathogenic variants causative of 29 recessive conditions in the AJ population. Up to 3000 AJ individuals were genotyped by Luminex MagPlex^®‐TAG^? bead array or Agena Bioscience^? MassARRAY assays. We identified seven conditions with carrier frequencies higher than 1 in 100, nine between 1 in 100 and 1 in 200, and four between 1 in 200 and 1 in 500. Variants in nine conditions had a detected carrier rate of less than 1 in 500 or were not identified in approximately 2000 AJ individuals. We assessed the combined AJ carrier frequency for 18 relatively prevalent diseases to be 1 in 6, and the risk of AJ individuals to be a carrier couple for one of these 18 diseases as 1 in 441. We note additional recessive genetic conditions should be considered for AJ carrier screening panels.     

The D409H variant in GBA1: Challenges in predicting the Gaucher phenotype in the newborn screening era

Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries. Early on, clinical features of GD2 can overlap with GD3; hence, predicting outcome is challenging. As NBS for GD becomes more available, the increased detection of GD in neonates is inevitable. As a result, health care providers and families will be faced with uncertainty with respect to clinical management. Since more severe GBA1 variants are generally associated with neuronopathic GD, there has been an increased dependence on genotypic information. We present an infant detected by NBS with genotype D409H(p.Asp448His)/RecNciI (p.Leu483Pro; p.Ala495Pro;p.Val499=). To assist in genetic counseling, we performed a retrospective review of other patients in our cohort carrying D409H and reviewed the literature. The study illustrates the challenges faced in counseling for infants with neuronopathic GD, even with known GBA1 variants, and the tough management decisions that can ensue from detection in newborns.     

Carrier testing in the fragile X syndrome: Attitudes and opinions of obligate carriers

This study surveyed obligate carriers of the fragile X syndrome fra(X) to ascertain opinions and attitudes regarding carrier testing. Female carriers of fra(X) syndrome were recruited during their visits to the Fragile X Clinic at Duke University Medical Center. Twenty-eight obligate carriers completed a 48 question structured interview and a visual analog scale (VAS). Strong trends in the responses were identified. Fra(X) syndrome was viewed as a very serious problem and the risk to offspring high. Subjects reported that prior knowledge of carrier status would have changed their reproductive plans. All felt that relatives should be informed about the inheritance of fra(X) syndrome; the mean age given for preferred age to inform their children of the inheritance of fra(X) syndrome was 12 years, and mean age given for optimal timing of carrier testing was 10 years. The women interviewed indicated that growing up with knowledge of their carrier status would have been preferable to learning this information as adults and they endorsed an aggressive approach to informing and testing their children. Further investigation is warranted to determine the psychological consequences of carrier testing for fra(X) syndrome in order to develop appropriate guidelines for testing and informing individuals at risk for fra(X) syndrome. Am. J. Med. Genet 68:62–69, 1997 © 1997 Wiley-Liss, Inc.     

The centralized prenatal genetics screening program of New York City: I. Developmental phase

The increasing demand in New York City for prenatal diagnosis of genetic disorders has necessitated the development of a large-scale, centralized prenatal genetic screening program. The objective of this program is eventually to serve 3,000 to 4,000 at-risk New York City pregnant women annually. Through the teamwork of a task force comprising representatives from the New York Scientists' Committee for Public Information (SCPI), the Medical and Health Research Association of New York City, Inc. (MHRA), the New York State and New York City Departments of Health, and five different advisory committees, the centralized Prenatal Diagnosis Laboratory of New York City (PDL) was designed and established. While this program aims to provide high quality, centralized laboratory service for the prenatal detection of chromosome abnormalities and open neural tube defects, it also emphasizes quality-controlled services in genetic counseling, amniocentesis, ultrasound monitoring, obstetric care, and patient follow-up. Genetic counseling by PDL-employed counselors is made available to patients whenever the participating hospital lacks such service or cannot handle their patient load. In addition, PDL has launched a vigorous public health education program. A detailed guideline for the program was prepared describing the highest standards of quality for each component. The initial step was the developmental phase that included establishing the advisory committees, searching for sponsors, preparing guidelines, developing the health education program, renovating the laboratory site, purchasing and installing equipment, and recruiting of staff. The experience gained from this endeavor will be value in the development of similar large-scale prenatal diagnosis programs.     

Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants

Glucosylceramide and glucosylsphingosine isolated from spleen, liver and brain were quantitated and characterized in two unrelated patients with Gaucher disease, neither of whom had clinical or neuropathologic evidence of neuronal involvement. Visceral glucosylceramide accumulation did not differ in the two patients. Hepatic glucosylsphingosine content was 2-fold greater in a young severely affected 3-year-old American Black patient compared to that in a 56-year-old Ashkenazi Jewish patient. In contrast, significant differences in glycosphingolipid content and composition were observed in the brains of these two cases. Cerebral and cerebellar cortical glucosylceramide accumulated to a greater extent (3-fold) in the severely affected 3-year-old patient compared to that in the older case. The compositions of the acyl and sphingosyl base residues of glucosylceramide in the cerebral and cerebellar cortices from the Ashkenazi Jewish patient were similar to those in normal individuals. In comparison, the gray matter glucosylceramide in the severely affected patient had increased percentages of stearic acid (18:0) and eicosasphingenine (d20:1), suggesting that the accumulated substrate was derived from the brain ganglioside pool. Glucosylsphingosine was found in large amounts only in cerebral and cerebellar cortices from the severely affected patient. The glycolipid content and composition in this patient was similar to that found in the Norrbottnian (Type 3) form of Gaucher disease. The differences in glucosylceramide acyl and sphingosyl base composition in gray matter from the severely affected patient and that in the Ashkenazi Jewish patient suggested that the accumulated substrates were metabolized differently by the residual enzymes in each case.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlating liver stiffness with disease severity scoring system (DS3) values in Gaucher disease type 1 (GD1) patients

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease. In addition to being time consuming for the clinician to calculate the scores, some of the assessments are subjective and may falsely increase or decrease disease severity. The purpose of this study was to determine if there is a correlation between liver stiffness values obtained from MR elastography (MRE) and the GD-DS3 score.An IRB approved, HIPAA compliant retrospective study was performed. All patients with type 1 GD imaged with MRE between 2011 and 2016 were included in this study. Clinical and imaging data was collected. Two pediatric radiologists analyzed MR images from abdomen and thigh studies independently to determine bone marrow involvement using a semi-quantitative scoring system with one reviewer analyzing a subset of studies to determine inter-observer reliability. The collected data was used to calculate a GD-DS3 score for all patients. GD-DS3 scores were compared with liver MRE stiffness values.Clinical MRE scores were plotted against GD-DS3 severity scores for 31 patients (15 males, 16 females; median age 27 years, age range: 4–67 years). The median GD-DS3 score was 4 (range: 1–10.1) and median MRE value was 2.43 kPa (range: 1.30–5.20 kPa). A significant positive correlation was found between MRE and GD-DS3 scores; Pearson's correlation coefficient value of r = 0.47, p < 0.001 for all scores, r = 0.68, p < 0.001 for complete scores and r = 0.46, p < 0.07 for incomplete scores. The inter-observer variation of bone marrow burden showed only fair agreement with a Kappa coefficient of 0.26.There is a significant positive correlation between increasing liver stiffness and increasing composite GD-DS3 scores. This supports the use of MRE, a non-invasive reproducible quantitative test, as both an additional assessment and independent marker for monitoring disease severity and progression in GD.     

Activity of glucocerebrosidase in extracts of different cell types from type 1 Gaucher disease patients

Glucocerebrosidase activity in extracts of leukocytes, Epstein-Barr virus transformed lymphocytes and fibroblasts from Portuguese Type 1 Gaucher disease patients was studied. The residual glucocerebrosidase activity in all extracts from patients was less than 25% if measured in the presence of bile salt taurocholate. However, if measured in the absence of bile salt the residual enzyme activity in extracts from patients was cell type specific: it was severely reduced in the case of fibroblasts, mildly reduced in the case of lymphoblasts and not significantly reduced in the case of leukocytes. The glucocerebrosidase activity in extracts from all control cell types was stimulated by taurocholate. In the patients the enzyme activity in fibroblasts extracts was also stimulated but that in lymphoblasts and leukocytes was inhibited by the bile salt. The differences in glucocerebrosidase activity (in the absence of taurocholate) in extracts from different cell types from Gaucher disease patients are attributable to differences in the proportion of glucocerebrosidase present as a monomer with low activity (form I) and as a highly active aggregate (form II) that may also contain sphingolipid activator protein 2 (SAP-2). In extracts from leukocytes and lymphocytes from Type 1 Gaucher disease patients, but not in those from fibroblasts, a relatively high proportion of enzyme is present in aggregated form with near normal specific activity.     

Pulmonary involvement in type 1 Gaucher disease: functional and exercise findings in patients with and without clinical interstitial lung disease

Pulmonary disease is a well-known complication of Type 1 Gaucher disease (GD), although its incidence is not well established and its severity varies. The purpose of this study was to determine the frequency and extent of pulmonary involvement in patients with GD. Pulmonary involvement was assessed by history, physical examination and chest radiograph in 150 consecutive patients with Type 1 GD presenting at a specialized center for genetic diseases. Five patients were noted to have clinical evidence of pulmonary involvement. Full pulmonary function tests were performed in these five patients and in an additional 13 patients randomly selected from the remaining 145. Many of the 18 patients also underwent radionuclide body imaging with 67 Gallium citrate and 111Indium-tagged leucocyte scans, as well as incremental cardiorespiratory exercise tests. Lung biopsies were available in two patients with lung disease, and a second examination of lung tissue was performed in one of these two patients post-mortem. Clinical lung disease was detected in five patients. All five had dyspnea, diffuse infiltrates, restrictive impairment and low single breath CO diffusing capacity (DLCOSB). Two of these patients underwent exercise testing and showed abnormalities consistent with lung disease (ventilatory limitation, excessive ventilation and increased dead space) as well as decreased VO2 max. and anaerobic threshold (AT). In contrast, in the other 13 patients, physical examination, chest radiographs and pulmonary function were normal (except for a low DLCOSB in one patient). Responses on exercise testing (performed in six of the 13 patients) were consistent with a circulatory impairment (decreased VO2 max. and AT). Our study found that <5% of patients with Type 1 GD have clinical interstitial lung disease. In addition, we found that some patients, without evident lung involvement, may experience limitations in physical exertion and are easily fatigued; this is attributable to impaired circulation.     

“It's about having the choice”: Stakeholder perceptions of population‐based genetic carrier screening for fragile X syndrome

This project explored, the views of key stakeholders regarding population‐based genetic carrier screening for fragile X syndrome (FXS). Interviews and focus groups were conducted with healthcare providers, relatives of individuals with FXS and members of the general population. Data were transcribed verbatim and coded into themes. 188 individuals took part in this study. Perceived benefits of carrier screening included: learning the risk of having a child with FXS; learning the risk of fragile X‐associated primary ovarian insufficiency; and the opportunity for carriers to access reproductive options. Concerns included: the emotional impact of screening and receiving a carrier result; the predictive testing nature of the carrier test with respect to fragile X‐associated tremor/ataxia syndrome; potential confusion created by receiving an intermediate result; and implications of genetic screening for society. Overall, population‐based genetic carrier screening was perceived to be acceptable provided it is optional and offered at an appropriate stage of life. With the support of the participants to promote individual choice by offering a population‐based carrier screening program for FXS, it is essential to carefully consider how screening might be offered in order to ensure broad accessibility and facilitation of decision‐making. © 2012 Wiley Periodicals, Inc.     

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study

Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48-month, prospective, non-randomized, open-label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase-naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre-treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual-energy X-ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near-normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.     

Dilemmas of genetic counseling during prenatal diagnosis of Fabry disease

Summary The authors analyze the process of genetic counseling and sociopsychological aspects of a decision making situation on the basis of the prenatal diagnosis of Fabry disease with manifestation in the family. It is suggested that genetic counseling comprises both prevention and follow-up. Psychotherapeutic measures mainly supportive forms and the presence of self-help groups are. To reach this goal, the medical team must develop an accepting attitude.