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Biomedical subjects

J Zlotogora

Publications and source records attributed to J Zlotogora.

At least 19 recordsLinked to original sources
PubMed2003

Otoacoustic emissions and brainstem evoked potentials in compound carriers of connexin 26 mutations.

This study compares the effects of mutations in the gap junction protein connexin 26 (Cx26), on outer hair cells (OHCs), inner hair cells (IHCs) and auditory nerve/brainstem among carriers of these mutations. One hundred and twenty eight individuals, from a village with widespread consanguinity and congenital deafness, due to three Cx26 mutations, were selected among relatives of deaf persons, and divided into non-carriers, carriers of one mutation, homozygous to one mutation, or compound heterozygous carriers of two different mutations. Distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs) and audiometric evaluation were compared in these genetic groups. Hearing loss among homozygotes and compound heterozygotes was comparable and ranged from mild to profound. Most ABRs from these groups showed no responses or partial responses (peaks III, V) with prolonged latencies, but some individuals had all peaks at normal latencies. DPOAEs were absent, except sporadic responses. Carriers of one mutation had significantly smaller DPOAEs compared to non-carriers, although normal pure tone audiograms and ABRs were found in these groups. In conclusion, based on DPOAEs, Cx26 mutations may impact OHC function among carriers of one or two Cx26 mutations. IHC/nerve impairment among homozygotes and compound heterozygotes is variable. OHCs may be more susceptible to Cx26 mutations compared to IHCs and the auditory nerve and brainstem pathway activated by them.

Adolescent↗
PubMed2002

The effects of a connexin 26 mutation--35delG--on oto-acoustic emissions and brainstem evoked potentials: homozygotes and carriers.

The purpose of this study was to examine whether outer hair cells (OHCs), inner hair cells and the brainstem auditory pathway are impaired due to a mutation in a gap junction protein, connexin 26 (Cx26), 35delG. Fifty-six individuals, from a village with widespread consanguinity and profound, non-syndromic congenital deafness, due to 35delG mutation, were selected among relatives of deaf people. The individuals were either non-carriers (n=20), heterozygous (n=20) or homozygous (n=16) for the mutation. Distortion product oto-acoustic emissions (DPOAEs) and auditory brainstem evoked potentials (ABEPs) in mutation non-carriers, in heterozygotes (carriers) and in subjects homozygous for the mutation were compared in addition to audiometric evaluation. Most deaf homozygotes had no DPOAEs, except some sporadic responses at 1000, 8000 and 10000 Hz. This was also observed in audiometry which showed profound hearing loss in most cases. Two cases were unique: one had moderate to severe hearing loss and the other had severe to profound hearing loss. A significant difference was found between non-carriers and carriers of 35delG: non-carriers had larger DPOAE responses than heterozygotes at all frequencies. The prevalence of responses got lower with higher frequencies in both groups, but between 6000 and 10000 Hz 50-70% of the carriers had no DPOAE responses, compared to 30-60% of non-carriers. In both groups responses diminished with age, but no significant interaction was found between age and the genetic group. ABEPs among homozygotes were variable: in most homozygotes ABEPs were absent or partial (waves III, V) with prolonged latencies, but two subjects had ABEPs within normal limits, in one ear. ABEPs were normal with no differences between carriers and non-carriers. We suggest that OHC function is affected by the 35delG mutation in Cx26. In addition, the hearing of carriers of this mutation may be impaired at very high frequencies (8000-10000 Hz), which are not assessed in routine audiometry or ABEP testing.

Adolescent↗
PubMed2001

Prenatal diagnosis of sex chromosome aneuploidy: possible reasons for high rates of pregnancy termination.

Sex chromosome aneuploidy (SCA), when detected in amniocentesis, is usually an unexpected result of a test carried out for another purpose. For most SCAs, the prognosis is milder and less predictable than trisomy 21, and therefore parents are faced with a difficult decision regarding the option of pregnancy termination. While studies from Europe and the USA report a declining trend in termination rates for SCA, our local experience is different. During the period 1989-1998, we diagnosed 60 SCA (including mosaics) in 20 106 amniocenteses (0.29%) and 48 (80%) of these pregnancies were terminated, a significantly higher proportion than has been reported in Europe and the USA. The present study shows that the difference between our experience and others' may be related to differences in cultural norms and values. Thirty women were interviewed, of whom 23 terminated and seven continued the pregnancy. Interview analyses showed that the main reason behind the decision to terminate the pregnancy was associated with the parents' fear of non-specific abnormality of the child, and concerns about abnormal sexual development. Although genetic counseling practised in our center aims to be non-directive, 56% of the women reported that the counseling was either directive towards termination, or that they at least felt that the counselor's attitude was pro-termination. Most women (93%) reported themselves as having come to terms with their decision.

Abortion, Induced↗
PubMed2000

Genetic disorders among Palestinian Arabs: 3. Autosomal recessive disorders in a single village.

Autosomal recessive diseases are common in the Arab population of Israel, mostly as a result of the high rate of consanguinity. They represent a major factor in the mortality and morbidity of the population. Since the distribution of genetic disorders in this population is not uniform, the present study was performed to determine the frequency and impact of recessive disorders within a single village. We demonstrate the existence of at least 19 autosomal recessive disorders in a village of about 8,600 inhabitants chosen at random. Since most of the disorders were chronic, the prevalence of recessive conditions in the village at the time of the study was at least 1/70, leading to a very high burden to the population and the health services.

Arabs↗
PubMed2000

Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfatase A allele carrying a E312D missense mutation and characterize the effects of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activity can be expressed from arylsulfatase A cDNAs coding for the D255H substituted enzyme, whereas Y201C and E312D mutations were associated with low amounts of residual enzyme activity. All amino acid substitutions lead to a decreased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment.

Adolescent↗
PubMed2000

Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia.

Cleft lip, with or without cleft palate (CL/P), is one of the most common birth defects, occurring in 0.4 to 2.0 per 1,000 infants born alive. Approximately 70% of CL/P cases are non-syndromic (MIM 119530), but CL/P also occurs in many single-gene syndromes, each affecting a protein critical for orofacial development. Here we describe positional cloning of the gene responsible for an autosomal recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously ED4; ref. 2), which we identify as PVRL1, encoding nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpesviruses (HveC; ref. 7), and the high frequency of CLPED1 on Margarita Island in the Caribbean Sea might result from resistance of heterozygotes to infection by these viruses.

Amino Acid Sequence↗
PubMed2000

Screening for genetic disorders among Jews: how should the Tay-Sachs screening program be continued?

The screening program in Israel for Tay-Sachs disease has proven very successful, giving Jewish couples a choice not to have affected children. The technology of carrier detection is now possible in several other severe genetic diseases that are relatively frequent among Jews. Due to the current confusion, a policy is needed to determine how the TSD screening program should be continued in the Israeli Jewish population. We propose that such a screening program include only mutations agreed by consensus as causing a disease severe enough to warrant the possibility of therapeutic abortion. We also propose that general screening include only mutations that are relatively frequent, taking into account the carrier frequencies in the Israeli Jewish population.

Arabs↗
PubMed1999

Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Abnormalities, Multiple↗
PubMed1998

Selection for carriers of recessive diseases: a common phenomenon?

Several autosomal recessive disorders are present in high frequency in isolated populations because of either multiple allelic mutations or mutations in different genes. These observations are best explained by selection, which may be an important mechanism in the determination of the distribution of genetic disorders.

Genes, Recessive↗
PubMed1998

Prenatal testing for genetic disorders among Arabs.

Since, at least in the near future, prenatal testing and abortion of affected fetuses will remain the main way of the prevention of genetic diseases, knowledge about the way of its acceptance in different cultures is important. The Israeli population includes two major groups: Jewish and Arabs, but while there is wide experience about the Jewish population and its attitude towards prenatal testing, little is known about the Arab population. This knowledge is particularly important, since genetic disorders are relatively frequent in the Arab world (Teebi and Farag, 1997). From 1992 to 1996, 816 prenatal tests were performed in our department on Arab women [143 chorionic villus sampling (CVS) procedures and 673 amniocenteses]. The indication for an early prenatal test was a high risk for a monogenic disorder in 140 out of the 146 tests performed (143 CVS procedures and three early amniocenteses). In 26 cases, the fetus was found to be affected and early abortion was chosen by the couple in 25 cases (96 per cent). The 670 late prenatal tests were done for various reasons including monogenic disorders (13 per cent), increased risk because of a previous child affected with Down syndrome or a neural tube defect (4.8 per cent), and an increased risk for a chromosomal aberration (78 per cent). In 31 cases of a late prenatal test, the fetus was found to be affected and only 21 couples (70 per cent) opted for an abortion. The major reason for this observation is probably related to religious and cultural factors. Since Arab women do not wish to have prenatal testing for only knowledge or reassurance, these factors should be taken into consideration during pre-amniocentesis counselling.

Abortion, Induced↗