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M Shohat

Publications and source records attributed to M Shohat.

At least 37 records · Page 2Linked to original sources
PubMed2001

Novel approach to the molecular diagnosis of Marfan syndrome: application to sporadic cases and in prenatal diagnosis.

Marfan syndrome is an autosomal dominant disorder affecting the skeletal, ocular, and cardiovascular systems. Defects in the gene that encodes fibrillin-1 (FBN1), the main structural component of the elastin-associated microfibrils, are responsible for the disorder. Molecular diagnosis in families with Marfan syndrome can be undertaken by using intragenic FBN1 gene markers to identify and track the disease allele. However, in sporadic cases, which constitute up to 30% of the total, DNA-based diagnosis cannot be performed using linked markers but rather requires the identification of the specific FBN1 gene mutation. Due to the size and complexity of the FBN1 gene, identification of a causative Marfan syndrome mutation is not a trivial undertaking. Herein, we describe a comprehensive approach to the molecular diagnosis of Marfan syndrome that relies on the direct analysis of the FBN1 gene at the cDNA level and detects both coding sequence mutations and those leading to exon-skipping, which are often missed by analysis at the genomic DNA level. The ability to consistently determine the specific FBN1 gene mutation responsible for a particular case of Marfan syndrome allows both prenatal and pre-implantation diagnosis, even in sporadic instances of the disease.

Adult↗
PubMed2001

Triple-test screening in in vitro fertilization pregnancies.

PURPOSE: To determine whether the results of triple-test analysis differ between spontaneous and IVF pregnancies. METHODS: The study population consisted of 140 women with singleton pregnancies, 70 by IVF, and 70 by spontaneous conception. The groups were matched for maternal age, gestational week, and laboratory batch. The levels of all triple-test markers--alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and unconjugated estriol (u-E3)--were compared between the groups. RESULTS: Significantly higher HCG levels were detected in the patients with IVF pregnancies than in the control group (1.31 +/- 0.8 vs. 0.95 +/- 0.5 multiple of the medians, respectively, (p < 0.006), but there were no significant differences in AFP or u-E3 levels. Overall, 18.5% of the IVF group were found to be screen-positive as compared with 11.4% of the control group (difference not statistically significant). Only 8 IVF pregnancies (11.4%) reached the lowest calculated risk possible (1:9999) compared with 17 (24.2%) in the control group (p < 0.05). CONCLUSIONS: Our findings support previous data demonstrating elevated maternal serum HCG in IVF patients in comparison with spontaneous ones.

Case-Control Studies↗
PubMed2001

Autosomal dominant nephritis with renal failure of non-Alport type: clinical and molecular studies.

BACKGROUND: Familial nephritis is a heterogeneous group of disorders caused by several genetic conditions such as Alport syndrome, glomerulonephritic syndromes, and unclassified nephritis without deafness or ocular defects. OBJECTIVES: To describe a family of Iraqi Jewish origin, several of whose members suffer from non-syndromic renal failure without deafness or ocular defects and where transmission is by autosomal dominant inheritance. We present the case histories of four family members and describe the molecular analysis performed in order to seek a possible linkage to one of the genes causing Alport or Alport-like syndromes. METHODS: We investigated all family members over the age of 18 for evidence of renal failure. We also extracted DNA and carried out molecular linkage analysis with polymorphic markers in each of the known loci involved in Alport and Alport-like syndromes. RESULTS: Histology of the renal biopsy specimens showed non-specific findings. Linkage was excluded for all the Alport and Alport-like syndrome loci. CONCLUSIONS: The condition suffered by several members of this family seems to represent a unique autosomal dominant type of progressive hereditary nephritis, characterized by hypertension and progressive renal failure without significant hematuria or proteinuria. The main histological changes are non-specific in the early stage of the disease. Our study rules out all the currently known genes that cause Alport syndrome as being responsible for the basic defect in this type of nephritis.

Adolescent↗
PubMed2000

A locus for an autosomal dominant form of progressive renal failure and hypertension at chromosome 1q21.

Linkage studies were performed in a large family with an autosomal dominant phenotype characterized by nephropathy and hypertension. In this family of Iraqi Jewish origin, the nephropathy develops into progressive renal failure. By performing a genomewide linkage search, we localized the disease gene to chromosome 1q21; the highest LOD score was obtained for the marker at locus D1S305, which yielded a maximum LOD score of 4.71 at a recombination fraction of 0. Recombination mapping defined an interval of approximately 11.6 cM, between the markers at loci D1S2696 and D1S2635, that contains the disease gene. Localization of the disease-causing gene in this family represents a necessary step toward isolation of the defective gene and toward a deeper understanding of the mechanisms of hypertension and progressive renal failure.

Adult↗
PubMed2000

Increased transmission of intermediate alleles of the FMR1 gene compared with normal alleles among female heterozygotes.

Fragile X syndrome (Fra X) is the most common heritable disease accounting for mental retardation and is caused by an expanded CGG repeat in the first exon of the FMR1gene. Previous studies have shown an increased fertility rate among fragile X carrier mothers and a preponderance of mentally retarded boys among the male offspring. In this study, we examined the transmission of the intermediate allele in the lower range of CGG repeats in carrier mothers found randomly in a screening program of the normal population. We tested 10,587 healthy women with no family history of mental retardation and identified 138 (1.3%) who were carriers of the intermediate allele (51-200 CGG repeats). Of these, 107 underwent prenatal testing during 108 pregnancies for Fra X in the fetus. Of the 108 pregnancies, the abnormal allele was transmitted in 67 (segregation ratio = 0.62, P < 0.012). We found a significant increase in the transmission of the abnormal allele by mothers who had between 51 and 60 repeats (segregation ratio = 0.69 [P < 0.007] for the group with 51-55 repeats, and 0.74 [P < 0.04] for the group with 56-60 repeats), but no increase by mothers who had more than 61 repeats. This suggests a genetic advantage for the abnormal allele in the 51- to 60-repeat range.

Alleles↗
PubMed2000

Candidate locus for a nuclear modifier gene for maternally inherited deafness.

Maternally inherited deafness associated with the A1555G mutation in the mitochondrial 12S ribosomal RNA (rRNA) gene appears to require additional environmental or genetic changes for phenotypic expression. Aminoglycosides have been identified as one such environmental factor. In one large Arab-Israeli pedigree with congenital hearing loss in some of the family members with the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewide search has indicated the absence of a single major locus having such an effect. Thus it has been concluded that the penetrance of the mitochondrial mutation appears to depend on additive effects of several nuclear genes. We have now investigated 10 multiplex Spanish and Italian families with 35 members with the A1555G mutation and sensorineural deafness. Parametric analysis of a genomewide screen again failed to identify significant evidence for linkage to a single autosomal locus. However, nonparametric analysis supported the role of the chromosomal region around marker D8S277. The combined maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result. We suggest that this region should be considered a candidate for containing the first human nuclear modifier gene for a mitochondrial DNA disorder. The locus operates in Arab-Israeli, Spanish, and Italian families, resulting in the deafness phenotype on a background of the mitochondrial A1555G mutation. No obvious candidate genes are located in this region.

Arabs↗
PubMed2000

Pathological fractures in spondyloenchondrodysplasia: case report.

We present a patient with spondyloenchondrodysplasia who sustained two pathological fractures of long bones in a period of 6 months. This complication of spondyloenchondrodysplasia has not been described previously. Since both fractures occurred with mild trauma, it would appear that spondyloenchondrodysplasia can be associated with a tendency towards pathological fractures and, therefore, it would be advisable to warn people suffering from this condition to avoid activities that put excessive strain on the limbs.

Adolescent↗
PubMed2000

The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population.

Connexin 26 (GJB2) mutations lead to hearing loss in a significant proportion of all populations studied so far, despite the fact that at least 50 other genes are also associated with hearing loss. The entire coding region of connexin 26 was sequenced in 75 hearing impaired children and adults in Israel in order to determine the percentage of hearing loss attributed to connexin 26 and the types of mutations in this population. Age of onset in the screened population was both prelingual and postlingual, with hearing loss ranging from moderate to profound. Almost 39% of all persons tested harbored GJB2 mutations, the majority of which were 35delG and 167delT mutations. A novel mutation, involving both a deletion and insertion, 51del12insA, was identified in a family originating from Uzbekistan. Several parameters were examined to establish whether genotype-phenotype correlations exist, including age of onset, severity of hearing loss and audiological characteristics, including pure-tone audiometry, tympanometry, auditory brainstem response (ABR), and transient evoked otoacoustic emissions (TEOAE). All GJB2 mutations were associated with prelingual hearing loss, though severity ranged from moderate to profound, with variability even among hearing impaired siblings. We have not found a significant difference in hearing levels between individuals with 35delG and 167delT mutations. Our results suggest that, in Israel, clinicians should first screen for the common 167delT and 35delG mutations by simple and inexpensive restriction enzyme analysis, although if these are not found, sequencing should be done to rule out additional mutations due to the ethnic diversity in this region.

Adult↗
PubMed2000

Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis leading to renal failure is the most severe complication in untreated patients. In Israel FMF is most frequent among Jews of North African origin. Recently the causative gene (MEFV) has been found and the common mutations characterised. The aim of this study was to investigate the carrier rates of the common MEFV mutations among 400 healthy members of four different ethnic groups (100 in each group) in Israel, and to compare the distribution of the different mutations between FMF carriers and patients. We found a high frequency of carriers among Jews from the various ethnic groups. In North African Jews it was 22%, in Iraqi Jews 39%, in Ashkenazi Jews 21%, and in Iranian Jews 6%. The distribution of the four most common MEFV mutations among healthy individuals (M694V 29%, V726A 16%, M6801 2% and E148Q 53%) was significantly different (P < 0.003) from that found in patients (M694V 84.4%, V726A 9.0%, M6801 0% and E148Q 6.6%). Six healthy asymptomatic individuals were found to carry mutations in both alleles: two homozygotes for E148Q and four compound heterozygotes E148Q/other. These results demonstrate a very high carrier rate among all Jewish ethnic groups. They confirm that mutation E148Q is associated with a milder phenotype, which explains the lower prevalence of FMF among the Ashkenazi and Iraqi Jews. This study raises the question of the need for molecular screening for M694V homozygotes in the Israeli North African Jewish community.

Adult↗
PubMed2000

Renal outcome and vascular morbidity in systemic lupus erythematosus (SLE): lack of association with the angiotensin-converting enzyme gene polymorphism.

OBJECTIVES: The angiotensin-converting enzyme (ACE) gene polymorphism has been associated with worse outcome in various chronic glomerular disorders and in hypertension. Because nephritis and vascular morbidity are prominent determinants of outcome in systemic lupus erythematosus (SLE), we studied the distribution and prognostic effect the ACE genotype might have on the outcome of SLE. METHODS: Fifty-six consecutive Israeli SLE patients and 48 (sex and ethnic origin matched) healthy individuals were evaluated for the ACE genotype by a polymerase chain reaction-based assay. The clinical and laboratory parameters of the patients as well as the SLE disease activity index (SLEDAI) and the presence of hypertension, diabetes mellitus, ischemic heart disease, congestive heart failure, and stroke were correlated with the ACE genotype. RESULTS: The distribution of the ACE genotype D/D, D/I, and I/I in the lupus group was 59%, 36%, and 5%, respectively, similar to the distribution in the control group (54%, 31%, and 15%, respectively). We failed to find any significant association between the ACE genotype and disease manifestations, SLEDAI, renal function, or cardiovascular and cerebrovascular morbidity. The clinical and laboratory parameters associated with renal outcome and vascular morbidity in our cohort are described. CONCLUSIONS: No difference was found between the distribution of the ACE genotype in lupus patients and the general population in Israel. Renal function as well as cardiovascular and cerebrovascular morbidity among Israeli patients with SLE are disease-related and independent of the ACE gene polymorphism.

Adolescent↗
PubMed2000

Familial Mediterranean fever: effects of genotype and ethnicity on inflammatory attacks and amyloidosis.

OBJECTIVE: The gene causing familial Mediterranean fever (FMF)-an autosomal recessive disease characterized by recurrent short episodes of fever associated most commonly with peritonitis, pleuritis, and arthritis-has recently been found and several mutations identified. The most severe complication of the disease is amyloidosis, which can lead to renal failure. The aim of this study was to investigate the role of genetic versus nongenetic factors on the phenotype as well as on the development of amyloidosis in FMF in a large and heterogeneous group of patients. METHODOLOGY: We studied 382 patients from 4 ethnic origins living in different environments: North African Jews, other Jews, Turks, Armenians living in the United States, and Armenians from Yerevan, Armenia. Information regarding amyloidosis was available for 371 patients. We examined the association between the mutation M694V and the development of amyloidosis, and we also compared the clinical characteristics of the inflammatory attacks in patients from different ethnic origins, while controlling for the type of mutation. RESULTS: A significant association was found between amyloidosis and the most common mutation in exon 10 of the FMF gene (MEFV), M694V (for M694V homozygotes, relative risk = 1.77; 95% CI = 1.16-2.71). Amyloidosis was present in 44 of 171 homozygous FMF patients (25.7%), in 22 of 143 compound heterozygous FMF patients (15.4%), and in 7 of 57 patients carrying other mutations (12.3%). In homozygotes for M694V who had not been treated with colchicine before 20 years of age, the risk of amyloidosis developing before this age was 61.0%. In our series, there were no cases of amyloidosis in 16 patients carrying the common mutation E148Q. We found that the type and severity of the FMF inflammatory symptoms were associated with both the genotype and the country of residence of the patient. CONCLUSIONS: In the light of the high frequency of amyloidosis in homozygotes for the mutation M694V, colchicine treatment should be given to this group irrespective of the severity of the inflammatory attacks to prevent the development of amyloidosis. Our findings also suggest that factors other than genotype, such as environment or genes other than MEFV, play a role in the determination of the severity of the inflammatory attacks in FMF. amyloidosis, specific mutation, phenotype-genotype correlation, ethnicity.

Age of Onset↗
PubMed2000

Gender differences in the reactogenicity of measles-mumps-rubella vaccine.

BACKGROUND: In trials comparing different formulations of measles vaccine, excess non-specific mortality occurred in female children who received high titer vaccine. These findings suggest a gender-specific effect of measles vaccine. OBJECTIVES: To determine whether gender differences exist in the rates of adverse reactions and morbidity in the month following immunization with measles-containing vaccine, and to evaluate whether there is a gender-specific association between the humoral immune response to measles vaccination and post-vaccination morbidity. METHODS: Parents completed questionnaires on the health status of 755 infants aged 15-20 months, during the month preceding and the month following the measles-mumps-rubella vaccination. Blood samples were tested for measles antibody titers in a subsample of 237 infants. RESULTS: After controlling background morbidity in the infants, the relative risk of fever and rash following vaccination was 2.35 in females and 1.36 in males. The geometric mean antibody titers against measles were similar in both sexes and there was no significant association between antibody titer and post-vaccination morbidity in either sex. CONCLUSIONS: Our findings demonstrate higher rates of adverse effects in females following vaccination with MMR vaccine, irrespective of the humoral response. This study emphasizes the need to consider possible gender differences when evaluating new vaccines.

Antibodies, Viral↗
PubMed2000

Reaching the diagnosis of cystic fibrosis--the limits of the spectrum.

BACKGROUND: Cystic fibrosis is the most common life-limiting autosomal recessive genetic disorder in Caucasians. Typically it is a multisystem disease diagnosed by increased chloride levels on sweat testing, with mortality due mainly to progressive respiratory disease. The clinical spectrum of CF has recently been much expanded. Genetic testing for mutant CF transmembrane regulator has revealed atypical cases where sweat test results are borderline or normal. In other patients, genetic mutations cannot be identified but abnormal CFTR function is shown using nasal potential difference measurement. OBJECTIVES: To highlight the diagnostic and therapeutic dilemmas in cases of atypical cystic fibrosis. METHODS: We reviewed patients with atypical CF and widely varying phenotype who are managed at Schneider Children's Medical Center of Israel. RESULTS: Two patients had severe lung disease but little expression in other organs. Accurate diagnosis was essential to enable aggressive therapy in a specialized center. Four other patients are in excellent general health but have symptoms limited to male infertility, heat exhaustion, pancreatitis or transient liver dysfunction, while lung disease is minimal. For these patients, careful counseling is needed to avoid unnecessary upheaval, inappropriately aggressive management, and the psychosocial implications of a CF diagnosis. These dilemmas have increased considerably in our center, as in others worldwide. CONCLUSION: It is our obligation as clinicians--at the level of both primary physician and referral center--to maintain an ever higher index of suspicion for CF, tempered by a rational program of counseling and management appropriate to the individual.

Adult↗
PubMed2000

Blood pressure measurements in Israeli Arab children and adolescents.

BACKGROUND: Hypertension is one of the most prevalent vascular diseases in the adult population. It is an important determinant of atherosclerosis in adolescents and young adults. There is to date no information on blood pressure in children of the Israeli Arab population. OBJECTIVES: To study blood pressure in Israeli Arab children and adolescents. METHODS: Blood pressure measurements were taken in the supine position in 4,488 Israeli Arab children and adolescents of both sexes aged 6-17 years. Height and weight were also determined. Correlation was investigated between systolic and diastolic blood pressure, body mass index, gender, and age. RESULTS: The systolic and diastolic blood pressures were similar in both sexes for all age groups up to 14 years of age. Systolic blood pressure was significantly (P < 0.001) higher in males aged 15-17 years (120 +/- 13 vs. 111 +/- 12 mmHg, 123 +/- 13 vs. 113 +/- 14.0 mmHg, and 123 +/- 18 vs. 111 +/- 14 mmHg, respectively). Diastolic blood pressure was higher in males aged 15-17, with a statistically significant difference for age 17 only (75 +/- 12 vs. 69 +/- 13 mmHg). Blood pressure was elevated in 322 students in the initial screening (7.17%), with a decrease to 2.18% when this group was rescreened 2 weeks later. The systolic blood pressure in our group is higher than that in Jewish Israeli children of Asian and North African origin, and in American children. It is similar to the systolic blood pressure of European children and Jewish children born in Israel. The diastolic blood pressure in our group is higher than that in all groups of Israeli Jewish children and American children of different ethnic groups. CONCLUSIONS: Israeli Arab children and adolescents have higher blood pressure levels than their Israeli Jewish counterparts. Further studies are required to confirm this observation.

Adolescent↗
PubMed2000

Achondroplasia in diverse Jewish and Arab populations in Israel: clinical and molecular characterization.

BACKGROUND: Achondroplasia is the most frequent form of disproportionate short stature, characterized by rhizomelic shortening of the limbs. This disorder is inherited as an autosomal dominant trait, although most of the cases are sporadic, a result of a de novo mutation. A recurrent glycine to arginine mutation at codon 380 (G380R) in the transmembrane domain of the fibroblast growth factor receptor 3 gene was found to cause achondroplasia among different populations. This is most uncommon in other autosomal dominant genetic diseases. OBJECTIVES: To determine whether this mutation is also common among Jewish patients from diverse ethnic groups and among the Arab population in Israel. METHODS: We examined the G380R mutation (G > A and G > C transition) and the mutation G375C (G > T transition at codon 375) in 31 sporadic patients and in one family diagnosed clinically to have achondroplasia. RESULTS: We found the G > A transition at codon 380 in 30 of our patients and the G > C transition in one patient. We were not able to detect any of the three mutations in two patients with an atypical form of achondroplasia. CONCLUSIONS: Our results further support the unusual observation that nucleotide 1138 of the FGFR3 gene is the most mutable nucleotide discovered to date across different populations.

Achondroplasia↗
PubMed1999

Methylenetetrahydrofolate reductase genotypes and early-onset coronary artery disease.

BACKGROUND: Homozygosity for the common (677C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with hyperhomocysteinemia, but there is uncertainty as to the association between this mutation and coronary artery disease (CAD). This study examined the association between MTHFR genotypes and age at onset of CAD. METHODS AND RESULTS: Patients (n=169) with documented myocardial infarction or angiographically documented CAD who were aged < or = 55 years at onset of CAD symptoms and DNA samples from control subjects (n=313) were studied. The prevalence of homozygosity among patients with early CAD onset (aged < or = 45 years) was 28%, which was significantly higher than that in patients with later onset (13%) and in control subjects (14%) (odds ratio 2.4, 95% CI 1.24 to 4.69, P=0.006, and odds ratio 2.7, 95% CI 1.15 to 6.42, P=0.01, respectively). Plasma folate was lower in TT homozygotes who had early CAD onset than in those with later onset (P=0.005). Among patients with plasma folate in the lowest quintile (< or = 12.6 nmol/L), 31% were homozygotes, as were 45% of those with low plasma folate and early CAD onset. There was no difference in the prevalence of traditional risk factors among genotypes. The frequency of homozygosity in patients with < or = 1 risk factor was higher than in those with > or = 2 risk factors (30% versus 12%, P<0.05). In multiple regression analysis, TT homozygosity and plasma folate were independently associated with CAD, but the impact of folate was small. CONCLUSIONS: Homozygosity for the 677C-->T mutation of MTHFR is common and is associated with an increased risk of premature CAD in this population.

Age of Onset↗