Biomedical subjects

Mordechai Shohat

Publications and source records attributed to Mordechai Shohat.

29 records · Page 2Linked to original sources

PubMed2004

Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3.

Phenotypic expression of the deafness-associated mitochondrial A1555G mutation in the 12S rRNA gene is influenced by aminoglycosides and complex inheritance of nuclear-encoded modifier genes. The position of a major nuclear modifier gene has been localized to chromosome 8p23.1, but the identification of this gene has remained elusive. Recently, we identified a second modifier gene, mitochondrial transcription factor B1 (TFB1M), involved in mitochondrial rRNA modification. In the present study, we tested three genes involved in mitochondrial tRNA or rRNA modification, and two genes associated with non-syndromic deafness, for linkage and linkage disequilibrium (LD) in 214 DNA samples from Spanish, Italian, and Arab-Israeli families with maternally inherited non-syndromic hearing loss. The multipoint non-parametric linkage analysis and transmission disequilibrium test testing were done using all families combined as well as divided based on linkage to the chromosome 8 locus and ethnicity. Two genes, MTO1 and GTPBP3, showed strongly suggestive linkage and significant LD results. Since both genes, as well as TFB1M, are involved in the process of mitochondrial RNA modification, it appears that the modification of mitochondrial RNA is an important regulatory pathway in the phenotypic expression of the deafness-associated mitochondrial A1555G mutation. This conclusion was supported by comparing linkage results of simulated genotypes with actual results for the four genes involved in mitochondrial RNA modification.

Carrier Proteins↗

PubMed2004

Prenatal diagnosis in Li-Fraumeni syndrome.

PURPOSE: The hallmark of Li-Fraumeni syndrome (LFS), a familial cancer syndrome, is constitutional TP53 mutation. The authors addressed the complex question of predictive prenatal genetic testing for cancer risk associated with inheritance of TP53 mutation. METHODS: A classic LFS family including the proband (a 20-month-old boy with rhabdomyosarcoma), his 36-year-old father with osteosarcoma, and his 40-year-old paternal aunt with bilateral breast cancer were identified as carriers of a TP53 germline mutation, a novel 1 base pair deletion in exon 5. A few years later, the mother became pregnant twice, and the parents requested prenatal diagnosis on each occasion. Genetic counseling, psychological evaluation, and support were provided by a multidisciplinary team including a pediatric oncologist, a geneticist, a psychosocial worker, a prenatal care provider, and an ethical representative. After providing overall information on LFS, including the high risk of developing secondary multiple neoplasms in LFS survivors, the committee approved prenatal diagnosis at the request of the family. RESULTS: In the two pregnancies, the two fetuses were found to be carriers of the same mutation. Nine years from diagnosis of the first tumor, the proband, and a month later his father, developed second tumors, multifocal osteosarcoma and leiomyosarcoma, respectively. CONCLUSIONS: Children with primary tumors belonging to LFS should be considered for screening for germline mutations and genetic counseling by a multidisciplinary team. Whether family members are found to be positive or negative as carriers, such measures may provide, by reducing uncertainty, psychological benefit to high-risk families.

Adult↗

PubMed2004

Familial central precocious puberty suggests autosomal dominant inheritance.

The prevalence of precocious puberty is higher in certain ethnic groups, and some cases may be familial. The aim of this study was to investigate the mode of inheritance of familial precocious puberty and to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to our center for suspected precocious puberty between January 1, 1997, and December 31, 2000, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy) (27.5%). Data of the familial and sporadic cases were compared. The familial group was characterized by a significantly lower maternal age at menarche than the sporadic group (mean, 11.47 +/- 1.96 vs. 12.66 +/- 1.18 yr; P = 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs. 78.1%; P = 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0.38 (0.45 after exclusion of young siblings) assuming incomplete penetrance and 0.58 (0.65 after exclusion of young siblings) assuming complete ascertainment. These results suggest autosomal dominant transmission with incomplete, sex-dependent penetrance.

Adult↗

PubMed2004

844ins68 in the cystathionine beta-synthase gene in Israel and review of its distribution in the world.

The 844ins68 allele in the cystathionine beta-synthase gene is always found in cis with the T833C mutation further indicating that its origin is monophyletic and that it might be a useful anthropogenetic marker. Its frequency was examined in 1087 randomly chosen subjects from Israel (twelve Jewish communities and Palestinians), and found to range from 0.034 to 0.125. The heterogeneity among the Jewish communities spans most of the range encountered among Caucasoid populations and is in accordance both with other genetic markers examined in the Jewish communities and with genetic distance and discriminant analyses. 844ins68 cannot distinguish between various European regions, because of the marked heterogeneity of the allele frequency distribution in Europe. This distribution of the insertion does not follow a recognised pattern of any known colonisation process. Its use as a reliable anthropogenetic marker discriminating between the major human groups may also be problematic until more populations are sampled.

Arabs↗

PubMed2003

Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study.

Mutations in GJB2, the gene encoding connexin-26 at the DFNB1 locus on 13q12, are found in as many as 50% of subjects with autosomal recessive, nonsyndromic prelingual hearing impairment. However, genetic diagnosis is complicated by the fact that 10%-50% of affected subjects with GJB2 mutations carry only one mutant allele. Recently, a deletion truncating the GJB6 gene (encoding connexin-30), near GJB2 on 13q12, was shown to be the accompanying mutation in approximately 50% of these deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Here, we present data from a multicenter study in nine countries that shows that the deletion is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%-20.9% after screening for the del(GJB6-D13S1830) mutation. Our results also suggest that additional mutations remain to be identified, either in DFNB1 or in other unlinked genes involved in epistatic interactions with GJB2. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in Western Europe. These results have important implications for the diagnosis and counseling of families with DFNB1 deafness.

Connexin 26↗

PubMed2003

Prenatal diagnosis of Down syndrome: ten year experience in the Israeli population.

Second trimester maternal serum biochemical markers, introduced between 1990 and 1995, were supplemented with new ultrasound methods at 14-16 weeks and first trimester biochemical markers between 1995 and 2000. This study evaluated the effectiveness of a Down syndrome (DS) prevention program among the Israeli Jewish population between 1990 and 2000. We collected data on the total number of prenatal tests performed on Israeli Jewish women, DS cases detected prenatally and DS livebirths in Israel during these years. We also studied the use of the newer screening tests in 1990, 1992, and 2000. Between 1990 and 1995, use of chromosomal studies for DS in this population increased from 11.3% to 21.6% and the percentage of cases detected prenatally from 53% to 70%. However, between 1996 and 2000, even with the new screening methods, the utilization rate remained similar (20.7% and 19.8%, respectively) and the percentage detected prenatally decreased to 61% in 2000. The total cost per case detected increased from $47,971 US dollars in 1990 to $75,229 US dollars in 1992, and to $190,171 US dollars in 2000. Between 1990 and 1995, improvement in the percentage of cases detected prenatally was associated with a significant increase in the amniocentesis rate-both are attributed to the introduction of second trimester maternal serum biochemical marker tests. Unexpectedly, the introduction between 1995 and 2000 of new genetic methods to assess the DS risk did not improve the percentage detected or reduce the amniocentesis rate, and was accompanied by an increased cost per case detected.

Chorionic Gonadotropin↗

PubMed2003

Brachyolmia and spinal stenosis.

Brachyolmia is a rare short-trunk short stature skeletal dysplasia characterized by generalized platyspondyly without significant epiphyseal or metaphyseal changes in the long bones. This group of skeletal dysplasia is heterogeneous and four types have been differentiated on the basis of radiological and genetic findings. We report on two siblings with Hobaek-type brachyolmia complicated by spinal stenosis. This combination has never been reported in the literature and suggests further genetic heterogeneity within brachyolmia.

Adult↗

PubMed2003

New syndrome of simplified gyral pattern, micromelia, dysmorphic features and early death.

We report two sisters with a new syndrome of simplified gyral pattern, normal head circumference at birth but with subsequent development of microcephaly, intractable seizures, and early death. Dysmorphic features included coarse face, hypertrichosis, short nose, paranasal widening, long philtrum, short neck, upper limb micromelia, single transverse palmar lines, and clasp thumbs. The proband had repeated convulsions from shortly after birth and she required continuous artificial ventilation. Neurological examination showed absent sucking, rooting, Moro and grasping reflexes. MRI revealed a diffuse simplified gyral pattern with apparent agyria over the frontal lobes. Biochemical screening gave normal results. Her older sister had bilateral renal pelvic dilatation on prenatal ultrasound. She also developed severe convulsions on the first day of life, and she had to be artificially ventilated for 38 days. She had severe developmental retardation and neurological examination showed absence of spontaneous movements and Moro reflex, weak sucking reflex, and hypertonicity. CT scan of the brain showed a simplified gyral pattern. At 3 months, she developed hypocalcemia and hyperphosphatemia with normal levels of vitamin D and alkaline phosphatase, and parathyroid hormone level was low. Other biochemical tests gave normal results. She died at 5 months due to a massive aspiration event. Based on the unique clinical and radiological features found in our patients, we propose that this is a new syndrome.

Brain Diseases↗

PubMed2003

Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults.

BACKGROUND: Transcobalamin II is a serum transport protein for vitamin B12. Small variations in TC-II affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B12 deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes. OBJECTIVES: To study 23 members of a four-generation family with hereditary vitamin B12 deficiency and neurologic disorders. METHODS: Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members. RESULTS: Partial TC-II deficiency was found in 19 subjects. Apo TC-II (free TC-II unbound to vitamin B12) and total unsaturated B12 binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B12) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B12 levels but were not anemic. Low serum B12 levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B12 injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency. CONCLUSIONS: We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances--despite normal serum vitamin B12 levels. Low serum UBBC and apo TC-II should confirm the diagnosis. Early vitamin B12 therapy may prevent irreversible neurologic damage.

Adolescent↗

PubMed2002

Branchial cyst, sensorineural deafness, congenital heart defect, and skeletal abnormalities: Branchio-oto-cardio-skeletal (BOCS) syndrome?

This article describes a boy with an unusual combination of features, namely, intrauterine growth retardation, short stature, branchial cyst, sensorineural hearing loss, congenital heart defect, rib and vertebral abnormalities, micromelia, brachymesophalangia, and absence of phalanges. We suggest that these findings comprise a new entity of combined branchio-oto and cardio-digital developmental field abnormalities, which we termed branchio-oto-cardio-skeletal syndrome. The pattern of inheritance remains uncertain.

Adult↗

PubMed2002

Plasma homocysteine, methylenetetrahydrofolate reductase genotypes, and age at onset of symptoms of myocardial ischemia.

Elevated fasting plasma homocysteine is a graded risk factor of coronary artery disease (CAD) and may accelerate onset of CAD. Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is commonly but inconsistently associated with hyperhomocysteinemia. In the present study we examined the possible relation between levels of fasting plasma homocysteine and age at CAD onset in different MTHFR genotypes. We studied 182 patients with CAD, 74 patients with early onset CAD (aged < or = 45 years), and 108 patients with later onset CAD (aged 46 to 65 years). Plasma homocysteine levels in 90 subjects without CAD were used for control. Fasting plasma homocysteine levels in T/T homozygotes with early onset CAD (20.2 +/-12.5 micromol/L) was markedly higher than in T/T homozygotes with later onset CAD (13.4 +/- 6.8 micromol/L) and in patients with early onset CAD who were not T/T homozygotes (11.9 +/- 3.7 micromol/L; p = 0.034 and p = 0.0001, respectively). CAD developed earlier in T/T homozygotes who were hyperhomocysteinemic (>15 micromol/L) than in the T/T homozygotes who were not (p = 0.036). Plasma homocysteine levels had no effect on age at onset of CAD in patients who were non-T/T genotypes. Homocysteine levels in control subjects and in patients who were non-T/T genotypes were comparable and were not influenced by age. The results reveal an inverse relation between the level of fasting plasma homocysteine and age at onset of CAD in T/T homozygotes as opposed to no association in patients who were non-T/T genotypes. Additionally, these results show that hyperhomocysteinemia and the T/T genotype have a stronger effect on the pathogenesis of CAD when they are combined, and that a marked increase (>15 micromol/L) in fasting plasma homocysteine in T/T homozygotes is a risk factor for early onset of CAD.

Adult↗