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Biomedical subjects

M Kaback

Publications and source records attributed to M Kaback.

18 recordsLinked to original sources
PubMed1996

The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.

Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations.

Adult↗
PubMed1994

The Ashkenazi Jewish Fanconi anemia mutation: incidence among patients and carrier frequency in the at-risk population.

Fanconi anemia (FA) is an autosomal recessive disease for which at least four complementation groups exist. Recently the gene that corrects the defect in Fanconi anemia complementation group C cells (FACC) has been cloned. We have previously identified a common mutation in the FACC gene, which accounts for a majority of FA cases in Ashkenazi Jewish individuals. We here describe the use of allele-specific oligonucleotide (ASO) hybridization to determine the frequency of this mutation among additional Jewish FA patients and to determine the carrier frequency in the Jewish population. The common IVS4 + 4A-->T allele was found on 19/23 (83%) Jewish FA chromosomes, indicating that it is indeed responsible for most cases of FA among Ashkenazi Jews. The carrier frequency was 2/314 for Jewish individuals and the mutant allele was not detected in 130 non-Jewish controls.

Fanconi Anemia↗
PubMed1993

Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network.

OBJECTIVES: To provide an update of the international experience with carrier screening and prenatal diagnosis for Tay-Sachs disease (TSD), to assess the impact of these efforts, and to review the recent developments in DNA technology with application to TSD carrier detection and screening. DESIGN: Through the International TSD Testing, Quality Control, and Data Collection Center, all testing centers in the world were surveyed annually to assess overall experience with carrier testing and prenatal diagnosis. Quality control and laboratory surveillance of testing centers were performed through an annual assessment, using samples provided by the center. SETTING: Tay-Sachs disease testing centers around the world. PARTICIPANTS: Nearly 1 million young adults from both Jewish and non-Jewish populations. INTERVENTION: Gene product screening (enzyme testing) and DNA-based mutation analysis (in some populations). MAIN OUTCOME MEASURE: Impact of screening program on disease incidence. RESULTS: Data from all centers in the international TSD network on experience with TSD carrier testing and prenatal diagnosis since 1974 indicated that more than 36,000 heterozygotes were identified and 1056 couples found to be at risk for TSD in their offspring. A total of 2416 pregnancies at increased risk for TSD were monitored by amniocentesis or chorionic villus sampling. A dramatic decrease in the incidence of TSD in the Jewish populations was demonstrated. With both serum and leukocyte proficiency testing, there have been only 16 instances (of 845 cumulative laboratory evaluations) of one or more errors reported by a laboratory since 1983 resulting in nonaccreditation. CONCLUSIONS: This analysis represents a prototypic effort in coordinating adult education, carrier testing, and genetic counseling directed toward prospective prevention of a uniformly fatal childhood disease and demonstrates that such an effort can dramatically affect disease incidence.

Clinical Enzyme Tests↗
PubMed1993

A Pst+ polymorphism in the HEXA gene with an unusual geographic distribution.

A polymorphic variant in the human HEXA gene is described. This gene encodes the alpha-subunit of hexosaminidase A, the enzyme which is deficient in Tay-Sachs disease (TSD). In individuals carrying the polymorphism there is a T-->C transition at position -6 in intron 13. The substitution creates a site for the restriction endonuclease Pst1. This variant has an unusual ethnogeographic distribution. It occurs on 1.4% of non-TSD carrier chromosomes in Ashkenazi Jews. All individuals ascertained carrying the Pst+ allele have ancestry in Lithuania, Belarus and Ukraine. By contrast, no individuals carrying the Pst+ allele have been detected among non-Jewish Lithuanians, Jews of Sephardic origin or in several other ethnic groups. Two unrelated non-Jewish families have been identified in which the Pst+ variant occurs. In both cases the variant occurs on a chromosome carrying a novel TSD mutation (G772C) association with the B1 phenotype. The Pst+ G772C chromosomes are of Scots-Irish descent.

Alleles↗
PubMed1992

A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation.

Three novel Tay--Sachs Disease (TSD) mutations have been identified in two unrelated, non-Jewish compound heterozygous patients. A G772C transversion mutation causing an Asp258His substitution is shared by both patients. The mutant enzyme had been characterized, on the basis of previous kinetic studies (1) as a B1, or alpha-subunit active site mutation. This is the first B1 mutation not found in codon 178 (exon 5). A C508T transition causing an Arg170Trp substitution also occurred in one of the patients. The third mutation is a two base deletion occurring in exon 8 involving the loss of either nts 927-928 or 929-930 in codon 310. The deletion creates an inframe termination codon 35 bases downstream. The Arg170Trp mutation was also detected in a third unrelated TSD patient. In both families this allele was traced to French Canadian ancestors originating in the Estrie region of the province of Quebec. This mutation is the third TSD allele unique to the French Canadian population and the ancestral origins of the carrier parents are distant from the center of diffusion of the more common 7.6 kb deletion mutation which is in the eastern part of the province.

Alleles↗
PubMed1991

A 7-year old white-male boy with progressive neurological deterioration.

A 9-month-old boy presented with rapid deterioration of psychomotor development. He developed seizures at 2 months, and shortly thereafter lost motor skills and developed feeding difficulties, increased startle response, red maculas, and decreased vision. His measurements, including head circumference, were greater than the 95th centile. No organomegaly was found. Serum determination of the hemoxsaminidases confirmed the diagnosis of Sandhoff disease.

Brain↗
PubMed1987

Tay-Sachs disease with hexosaminidase A: characterization of the defective enzyme in two patients.

Cases of infantile Tay-Sachs disease (TSD) with high residual hexosaminidase A (Hex A) activity have recently been described. The clinical presentation of the disease in these patients is identical to that found among Ashkenazi-Jewish patients. Fibroblasts from two such TSD patients had Hex A activity comprising 16% of total Hex when measured by thermal fractionation and quantitation with 4-methylumbelliferyl-beta-D-N-acetylglucosamine (4MUG). Hydrolysis of 4-methylumbelliferyl-beta-D-N-acetylglucosamine-6-SO4 (4MUGS) by patient fibroblast extracts is catalyzed by an enzyme activity that comprises less than 1% of total Hex. Kinetic analysis of patient Hex A by using 4MUGS revealed Km's similar to that of control Hex A but Vmax's significantly different from that of the control enzyme. The inhibitors N-acetylglucosamine and N-acetylglucosamine-6-PO4 were used to distinguish between active sites associated with the two different subunits of Hex A. A beta-subunit site with little activity toward 4MUGS is sensitive to N-acetylglucosamine but resistant to N-acetylglucosamine-6-PO4. This site accounts for most of the hydrolysis of 4MUG. By contrast, an alpha-subunit site that is sensitive to N-acetylglucosamine-6-PO4 but resistant to N-acetylglucosamine accounts for almost all of the hydrolysis of 4MUGS. In mutant cells, this site retains the ability to bind substrate but is deficient in catalytic activity toward 4MUGS. The pH optima of patients' Hex A is shifted to a more acidic range, and the enzymes are significantly more thermostable than control Hex A. By using the thermal fractionation procedure for serum isozyme discrimination, one parent of each patient is unambiguously classified as heterozygous for the TSD gene whereas the other parent has test values in the grey zone. When parents are tested by use of 4MUGS, however, all four parents are classified as heterozygotes. Comparison of the results of both assay procedures allows the carrier of the atypical TSD allele to be recognized and identifies the probands as compound heterozygotes.

Alleles↗
PubMed1978

Sampling the fetoplacental circulation. III. Combined laparoscopy-fetoscopy in the pregnant macaque for hemoglobin identification.

To demonstrate increased technical experience with fetoscopy and fetal blood sampling, two groups of macaques were compared to control animals. Group 2 had a perinatal mortality rate that was not significantly different from that of the control group. A 2.7 mm. Hopkins rod lens endoscope encased in an eccentric cannula, 3.8 mm. outside diameter, was used. When compared to the earlier test group (Group 1), the later test group (Group 2) showed greater adequacy of the fetal blood sample for laboratory analysis (P less than 0.01). Anthropometric and hematologic data collected at term births compared favorably in test and control groups, with the exception of the white blood cell count, which was significantly lower with fetoscopy (P less than 0.01). This is the first report of experimental fetoscopy with the use of a control group to provide precise data to aid in clarification of the ethical issues yet unresolved in this technology.

Animals↗
PubMed1978

The Axenfeld syndrome and the Rieger syndrome.

A family is reported in which both the syndrome of Axenfeld and the eye malformations of the syndrome of Rieger occur, indicating that both may be expressions of the same gene. We also review the associated anomalies already reported, emphasise their high incidence, suggest that these are not accidental associations, and propose some possible explanations for the high incidence.

Anterior Chamber↗
PubMed1977

Pseudophakic pupillary-block glaucoma.

Four cases of iris-supported pseudophakic pupillary-block glaucoma were presented. Pupillary-block glaucoma is the first postoperative complication seen following the implantation of an intraocular lens, and in our series occurred at an incidence of 3-8%. A short review was made of pupillary-block glaucoma with all types of intraocular lenses, with emphasis on the iris-supported lens. The role of inflammation, haemorrhage, and vitreous and lens material in obstructing aqueous flow at the pupil and peripheral iridectomy site was emphasised. Pitfalls in the diagnosis and management of this condition were reviewed. Methods of prevention and treatment were reviewed with emphasis on early mydriasis, along with carbonic anhydrase inhibitors and hyperosmotic agents as a primary medical treatment. Iridectomy, laser iridotomy, or transfixation of the iris was mentioned as a surgical treatment.

Aged↗
PubMed1975

Chromosomal mosaicism in amniotic cell culture. A diagnostic Dilemma.

Chromosomal mosaicism, with supernumerary C or C group elements, was observed in the cultured amniotic fluid cells of four fetuses undergoing prenatal diagnosis. There were discrepancies in the karyotypes of cells from different culture flasts of a single fluid sample, between cultures from successive uterine aspirations, and between cultures of amniotic fluid and fetal tissues obtained by pregnancy interruption. Most alarming was the finding, in one case, of identical mosaicism in different culture flasks as well as in repeated amniocenteses derived from a phenytypically normal fetus. In each instance, the aborted fetus or newborn infant proved to be phenotypically and cytogenetically normal. This suggests that mosaicism, demonstrated in cultured amniotic fluid cells, may not reflect the chromosomal constitution of the fetus and may pose a dilemma regarding an accurate diagnosis.

Abortion, Induced↗