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Mutations in the potassium channel-related gene KCTD7 were described so far in a single family with progressive myoclonus epilepsy. We describe a unique phenotype: acute onset of myoclonus and ataxia, associated with abnormal opsoclonus-like eye movements; improvement of clinical symptoms under steroid treatment; and appearance of epileptic activity on EEG 2 years later without overt seizures. After excluding possible genetic causes, whole-genome exome sequencing was performed in order to identify the causative gene. One heterozygous missense mutation (R84W) was detected by exome sequencing and a large heterozygous deletion of exons 3 and 4 by MLPA analysis. The father is heterozygous for the R84W mutation and the mother is heterozygous for the exon 3+4 deletion. The mutation affects a highly conserved segment of the predicted protein, changing a basic amino acid into neutral. The large deletion probably results in a truncated protein. The different phenotype broadens the spectrum of KCTD7-related diseases. Therefore, patients diagnosed as having opsoclonus-myoclonus with an atypical course should be evaluated for KCTD7 mutations.

Acute myeloid leukemia (AML) with a complex karyotype (CK) has frequent alterations in TP53 and a very poor prognosis. We examined whether a prompt and simple fluorescence in situ hybridization (FISH) analysis for 17p13 deletion at diagnosis has a predictive value for response to therapy and overall survival in subgroups of AML. In 15 patients with a normal karyotype the TP53 FISH analysis was normal, whereas in 16 patients with CK 75% had only one copy of the TP53 allele. The deletion was also detected in 33% of six patients with monosomy or partial monosomy of chromosome 5, 7, 9, or 12. This loss of TP53 correlated significantly with a poor response to chemotherapy, and the median survival time of these patients was shorter. TP53 FISH analysis carried out at diagnosis has a predictive value with respect to chemotherapy response and can therefore facilitate a rapid decision on treatment strategies.

Summary Introduction X-linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by mutations or complete deletion of the NR0B1 gene that encodes the DAX-1 protein, an orphan member of the nuclear receptor superfamily. AHC is characterized by adrenal insufficiency in infancy and early childhood. Later, hypogonadotropic hypogonadism (HH) manifests as pubertal failure. Patients and methods We evaluated the clinical, endocrine and molecular characteristics of 12 AHC patients from 5 families diagnosed between 1984 and 2007 in Israel. Results Most of the boys (10/12) presented with signs of adrenal insufficiency such as salt wasting and failure to thrive during the neonatal period. Aldosterone deficiency usually preceded cortisol deficiency requiring early mineralocorticoid therapy. Serum cortisol levels in the first weeks of life varied from very low to high levels ( 1776 nmol/l). Five boys showed signs of precocious sexual development during infancy and childhood, including enlargement of the penis and testes. In four patients the initial diagnoses were erroneous. Molecular analysis of the NR0B1 gene identified point mutations in six patients including a novel splice site mutation in one patient and his family (IVS1-1G→C). Contiguous gene deletion was found in six patients from two families who manifested impaired mental development. Conclusions In X-linked AHC caused by different molecular defects in NR0B1 gene, the clinical spectrum of the disease is quite variable and precocious sexual development is a prominent feature. Genetic testing is indicated in boys presenting with salt-wasting with or without cortisol deficiency if congenital adrenal hyperplasia has been ruled out.

Sinonasal carcinomas, including nonkeratinizing (NK) squamous cell carcinoma (SCC) and sinonasal undifferentiated carcinoma (SNUC), are uncommon malignant neoplasms arising from the Schneiderian respiratory epithelium of the nasal cavity and paranasal sinuses. Due to their low frequency, the cytogenetic data on these tumors is limited.Seventeen patients who were operated on in our institution for extirpation of paranasal carcinomas were enrolled in this study. Fourteen pathologically confirmed samples of sinonasal carcinomas were cytogenetically analyzed using G-banding techniques after short-term culture. Three samples did not grow on culture.Five of the 14 sinonasal carcinomas had an abnormal karyotype (36%). Of the 9 NK SCCs, 3 had abnormal karyotypes with numerical and structural chromosomal anomalies. Of the 5 patients with SNUC, 2 had an abnormal karyotype. One case of SNUC had a diploid complex karyotype. Another case of SNUC had a near triploid composite karyotype with 60-69 chromosomes. The chromosome arms that involved frequent breakpoint and rearrangements were: 1p, 6p, 7p, and 12q. We found that 3 of the 3 patients who died of disease displayed an abnormal karyotype, whereas 2 of the 11 patients who are alive displayed an abnormal karyotype (P = 0.027).The study revealed that more than a third of the paranasal carcinomas carry an abnormal karyotype. No specific common aberrations were found in these tumors. To our knowledge this is the first attempt to investigate sinonasal squamous and undifferentiated carcinomas on a genetic level using G-banding technique. Additional studies are required in order to determine whether cytogenetic data may serve as an adjunct to conventional pathology for the diagnosis and prognosis assessment of these rare and highly aggressive tumors.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by hereditary sensory and autonomic neuropathies. Although extremely rare in most populations, FD is common among Ashkenazi Jews (AJ), with a calculated carrier frequency of 1 in 30, based on disease prevalence. The gene for FD was recently identified as IKBKAP. One major mutation (IVS2 + 6T --C) is responsible in99.5% of cases among AJ. The purpose of this study was to determine the actual frequency of FD carriers in the AJ population in Israel and to determine whether carriers are more frequent among a subpopulation of AJ from Poland. The study group included 1267 Jews of Ashkenazi origin who were referred for routine DNA screening tests. These included 1100 individuals who were full AJ and 167 who were part AJ. None had a family history of FD. Mutation analysis for (IVS2 + 6T --C) was performed by PCR amplification followed by restriction enzyme analysis. All positive cases were confirmed by DHPLC WAVE( trade mark ). Among the 1100 full AJ tested, 34 were found to be FD carriers (1:32). The incidence of mutation carriers was significantly higher in AJ of Polish descent (1:18) compared to AJ of non-Polish descent (1:99). Among the 167 individuals who were part AJ, there were 3 carriers (1:56). The incidence of FD among AJ, particularly those of Polish background, warrants population screening. Population screening may be performed by denaturing high-performance liquid chromatography.

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and adaptive regression with autistic features, loss of acquired skills, and stereotypic hand movements that almost exclusively affects females. It is an X-linked dominant disorder, with presumed lethality in males. Nonetheless, there are a few descriptions of males suspected of having Rett syndrome. With the recent discovery that the MECP2 gene is responsible for most cases of Rett syndrome, it is possible to molecularly assess cases of affected males by direct sequencing analysis. We describe an Israeli family consisting of a female having classic Rett syndrome and a male sibling with severe neonatal encephalopathy. Molecular analysis revealed that both sister and brother have the same MECP2 gene mutation; however, their mother does not. This case, as well as other published studies of males with MECP2 mutations, reveals that the clinical manifestations in viable males vary from neonates with severe encephalopathy to adults with mental retardation and demonstrate genotype-phenotype correlations. (J Child Neurol 2002;17:20-24).

Familial adenomatous polyposis (FAP) is an uncommon, but widespread genetic disorder that develops multiple colonic adenomatous polyps and, if untreated, can lead to large bowel cancer. Little is known about its occurrence and characteristics in the Israeli population. Aims: To evaluate FAP prevalence, phenotypic manifestations and compliance for diagnosis and follow-up in our registry. Methods: Since 1993 approximately one-half of FAP patients in Israel have been seen and followed-up by us before and/or after colectomy. They and their families were encouraged to have mutation analysis, genetic and/or endoscopic screening. Results: 37 pedigrees were identified, including 2 non-Jewish. The Jewish ethnic distribution was similar to that of the general population and the point prevalence rate estimated as 28.4/one million Jewish inhabitants. There were 461 first-degree relatives at-risk for FAP. Genetic screening was completed and successful in 28 pedigrees (87.5%), and 73 FAP patients entered the registry. Marked intra-familial phenotypic variations with minimal disease manifestation were noted in 11 patients belonging to 4 pedigrees. Cancer occurred in 15.1% (11 patients), in 10 before FAP diagnosis or during follow-up elsewhere, but one non-compliant patient developed duodenal cancer. One other patient died from a massive, neglected, intra-abdominal desmoid. Compliance for evaluation and follow-up of pedigree members and individual FAP patients was inadequate in 29% and 27%, respectively. Conclusions: FAP occurs in the Israeli Jewish population at the expected rate, but is inadequately recognized in non-Jews. The inadequate compliance for screening and post-surgical follow-up needs to be addressed by educating the public, health care workers and Health Insurers.

Fragile X syndrome, a common cause of intellectual disability, is usually caused by CGG trinucleotide expansion in the FMR1 gene. CGG repeat size correlates with expansion risk. Premutation alleles (55–200 repeats) may expand to full mutations in female meiosis. Interspersed AGG repeats decrease allele instability and expansion risk. The carrier rate and stability of FMR1 alleles were evaluated in large cohorts of Ashkenazi and non-Ashkenazi women. A total of 4,344 Ashkenazi and 4,985 non-Ashkenazi cases were analyzed using Southern blotting and polymerase chain reaction between 2004 and 2011. In addition, AGG interruptions were evaluated in 326 Ashkenazi and 298 non-Ashkenazi women who were recruited during 2011. Both groups had major peaks of 30 and 29 repeats. Ashkenazi women had a higher frequency of 30 repeats and a lower frequency of other peaks (P < 0.0001). A higher rate of premutations in the 55–59 repeats range (1:114 vs. 1:277) was detected among the Ashkenazi women. Loss of AGG interruptions (

Duchenne muscular dystrophy (DMD) is a relentless progressive disorder, leading to severe disability during childhood and death in adolescence or early adulthood. In most families, prenatal diagnosis is readily achieved by molecular detection of DNA deletions using chorionic villi or amniocytes, or by linkage analysis. In some cases, however, molecular methods fail to provide a definitive diagnosis and in such cases in utero fetal muscle biopsy may serve as a diagnostic option. We describe three families in whom fetal muscle biopsy was performed, focusing on the prenatal diagnostic dilemmas, the indications and timing for in utero fetal muscle biopsy, and the difficulties encountered.

Turcot's syndrome is a rare heritable complex that is characterized by an association between a primary neuroepithelial tumor of the central nervous system and multiple colonic polyps. The aim of this study was to analyze genetic alterations in a case of Turcot's syndrome in a 10.5-year-old boy in whom a colorectal tumor developed 3.5 years following astrocytoma. An APC germline non-sense mutation at codon 1284 leading to a truncated protein was identified, as was a somatic p53 mutation in the colorectal carcinoma in exon 7, codon 244. The latter was not identified in the primary astrocytoma. However, immunohistochemistry revealed high p53 protein expression in both tumors, suggesting an additional p53 mutation in the primary astrocytic tumor. The diverse p53 mutations observed in this unique syndrome in two different sites and stages of the disease may shed light on the multistep progression of the malignant events.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by small stature, immunodeficiency, chromosomal instability, and a predisposition to different types of cancer. Although extremely rare in the general population, BS is seen in about 1 in 48,000 Ashkenazi Jews. Mutation analysis of seven Ashkenazi BS probands has shown that all were homozygous for the same mutation in the BLM gene: 2281delATCTGAinsTAGATTC, also known as blmAsh. This finding, along with the increased incidence of BS among Ashkenazi Jews, suggests a founder effect for BS in this population. The purpose of this study was to determine the frequency of blmAsh mutation carriers in a randomly sampled Ashkenazi Jewish population in Israel. The initial study group included 1,613 Ashkenazi Jews who were referred for routine DNA screening tests (cystic fibrosis, Gaucher, Canavan, fragile X). None had a family history of BS. A group of 552 non-Ashkenazi Jews served as controls. Mutation analysis was performed by PCR amplification followed by analysis of a specific BstN1 restriction site, created by the blmAsh mutation. All positive carriers were confirmed by direct sequencing. Sixteen blmAsh carriers were detected among 1,613 Ashkenazi Jews (1 in 101), compared to none among 552 non-Ashkenazi individuals. In this study, Ashkenazi Jews of biparental Polish descent had a significantly higher proportion of the blmAsh mutation (1 in 37) compared to Ashkenazi Jews of non-Polish descent. These results provide further evidence that a founder effect is responsible for the increased incidence of Bloom syndrome among Ashkenazi Jews, particularly those of Polish descent.

A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. "Idiopathic" hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggest that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these to exons 44-45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes.

Purpose: To determine the frequency of SMN1 deletion carriers in the Israeli population and to assess the feasibility of population screening for spinal muscular atrophy. Methods: A total of 6394 individuals without family history of spinal muscular atrophy underwent genetic screening by multiplex ligation-dependent probe amplification, designed to detect SMN1 exon 7 and exon 8 copy number. Results: One hundred fifty-nine individuals carried an SMN1 heterozygous exon 7 deletion, yielding a carrier frequency of 1:40. About 10.8% of individuals were found to carry two or more SMN1 exon 7 copies on the same chromosome (cis configuration). This implies that some deletion carriers may not be detected by multiplex ligation-dependent probe amplification or similar quantitative methods. The acceptance of spinal muscular atrophy screening among women undergoing testing for fragile X syndrome and cystic fibrosis reached 93%. Conclusions: Currently used molecular techniques cannot detect about 5% of spinal muscular atrophy carriers with a cis configuration or individuals with SMN1 sequence mutations and de novo deletions. Thus, it is estimated that the spinal muscular atrophy carrier detection rate is about 90%. Given the severity of spinal muscular atrophy, the relatively high carrier frequency, and the estimated detection rate, we conclude that population-based screening for spinal muscular atrophy is feasible and acceptable.

Duchenne muscular dystrophy (DMD) results from mutations in the X-linked gene coding for the muscular protein dystrophin. The isolation of genomic and cDNA probes for this gene has greatly facilitated the detection of DMD carriers, which previously relied mainly on measurements of serum creatine kinase (CK), and has enabled prenatal diagnosis of this disease. However, the relatively large size of the gene and the high frequency of recombination and mutation events within the dystrophin locus continue to pose difficulties in the genetic counselling and prenatal diagnosis of DMD, and render the conclusions of molecular analysis less clear cut. This communication presents examples of two such difficulties: the distinction between sporadic and inherited cases in families with a single patient and normal CK levels in all females, and the distinction between mutant and normal dystrophin alleles in families in which the patients have died. The combined use of genomic and cDNA probes allows one to make these distinctions. An additional complicating factor, gonadal mosaicism, is demonstrated.

Background. Skull base tumors are rare neoplasms and the cytogenetic data on these tumors are limited. The authors cytogenetically analyzed a large series of tumors and compared the findings with patients' pathologic data. Methods. The karyotypes of pathologically confirmed samples of 101 patients, who were operated for oncological extirpation of tumors, were analyzed using G-banding and spectral-karyotyping techniques. Results. Of the 67 malignant tumors, 32 (48%) had chromosomal aberrations, some with complex numerical and structural chromosomal anomalies. Recurrent chromosomal breakpoints were identified in squamous cell carcinomas, adenoid cystic carcinomas (ACCs), sinonasal undifferentiated carcinomas, chordomas, and sarcomas. Specific breakpoints established the diagnosis of various soft tissue sarcomas. Novel chromosomal aberrations were found in various other malignant and benign tumors. Conclusion. This study highlights the value of cytogenetic analysis for diagnosis of skull base tumors. The data add further information on the biological behavior of these rare neoplasms. © 2007 Wiley Periodicals, Inc. Head Neck, 2008

Objective: Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused in most patients by homozygous deletion of the SMN1 gene. For a carrier couple at a 25% risk of affected offspring, preimplantation genetic diagnosis (PGD) offers an alternative to prenatal diagnosis and termination of affected pregnancies. Our objective was to develop an accurate and reliable single-cell multiplex nested PCR analysis for PGD of SMA. Methods: The method was developed on single blood leukocytes, obtained from healthy controls and an adult SMA type III patient with a known homozygous deletion of SMN1 exon 7 and 8. Multiplex nested PCR on single cells was used to co-amplify exons 7 and 8 of SMN. Additional multiplexing was performed with the ZFX/ZFY gene for sexing. Following successful establishment of the multiplex nested PCR protocol in single leukocytes, the technique was employed for PGD in 4 patients for a total of 7 cycles. In 2 patients, sexing was simultaneously performed using ZFX/ZFY. Results: 220 single leukocytes from a normal individual and 220 from an SMA patient were analyzed. Exon 7 of SMN1 was amplified in 99% of normal single leukocytes and in none of the SMA-affected leukocytes. Exon 7 of SMN2 was amplified in 100% of both normal and SMA-affected leukocytes. Exon 8 of SMN1 was amplified in 98% of normal cells and in none of the SMA-affected leukocytes. Exon 8 of SMN2 was amplified in 96% of both normal and SMA-affected leukocytes. Amplification efficiency was 99% for ZFX/ZFY. There were no false-negative results and no contamination was detected in all wash-drop blanks tested. Seven PGD cycles were performed in 4 SMA-carrier couples with successful molecular analysis of 34 embryos and a total of 15 normal embryos transferred in 7 cycles. One clinical pregnancy has resulted in the delivery of a healthy male. Amniocentesis performed at 17 weeks confirmed the correct diagnosis for both SMA and sexing. Conclusions: These results suggest that our multiplex nested PCR protocol offers an efficient and accurate method for PGD of SMA while enabling the simultaneous analysis of an additional loci.

This report describes molecular analysis of the MECP2 gene in 37 Israeli patients suspected of having Rett syndrome (RTT). The patients were from various Jewish ethnic groups and from Arabic origin. Of the 17 patients with classical RTT, bi -directional sequencing of the coding exons revealed MECP2 mutations in 14 patients. About 66% of the mutations were located in prev iously described hot-spots. One case presented a novel mutation (141insA). Mutation-negative patients were further analyzed by Southern blot, which detected a novel gross rearrangement in another classical case. Altogether, detection rate in classical cases was 88%. In a non-classical case, a novel missense mutation (1451G>C) was detected in an affected girl and in her normal father, suggesting that this is a non-pathogenic alteration. Another variant (1461+96insA) was detected in an affected girl and in he r healthy mother and also in another affected girl and her healthy father, suggesting that this variant too, is non-pathogenic. No significant difference in mutation type was noted among the different ethnic groups. In one familial case, the same mutation was detected in two sibs but not in their mother, suggesting germ-line mosaicism. Our results suggest that mutation-negative cases should be further assessed for gross rearrangements and that molecular analysis of the parents is often required when previously undescribed sequence alterations are detected. © ?2002 Wiley-Liss, Inc.

The Fragile X syndrome is the most common cause of inherited mental retardation. For a female premutation carrier, the risk of having a child with a full mutation is positively correlated with the size of the premutation. The current study was performed to evaluate the risk of premutation expansion in the offspring of average-risk carriers detected by general prenatal screening. Over a 4-year period, 9,660 women underwent DNA screening for FMR1 mutation/premutation at the Tel Aviv Sourasky Medical Center. A premutation was defined as a CGG repeat number50 in the 5' untranslated region (UTR) of exon 1 in the FMR1 gene. The study included only individuals with no family history of X-linked mental retardation or known FMR1 mutations. A premutation was found in 85 women (1 in 114), 68 of whom consented to have prenatal diagnoses in 74 pregnancies. The abnormal allele was transmitted to the offspring in 44 pregnancies. Of these, no change in allele size was noted in 35 pregnancies (79.6%), and expansion within premutation range was evident in 4 pregnancies (9%). In 5 pregnancies (11.4%), expansion to the full mutation was noted. This occurred only in carriers having more than 90 repeats. We conclude that the likelihood of Fragile X premutation expansion to full mutation is significantly lower in individuals ascertained by general prenatal carrier testing than in those from known Fragile X families.

Background & Aims: Israeli Jews of European birth, i.e., Ashkenazim, have the highest colorectal cancer incidence of any Israeli ethnic group. The I1307K APC gene variant was found in 6.1% of American Jews, 28% of their familial colorectal cancer cases, but not in non-Jews. We assessed the I1307K prevalence in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Methods: DNA samples from 500 unrelated Jews of European or non-European origin, with or without a personal and/or family history of neoplasia, were examined for the I1307K variant by the allele-specific oligonucleotide (ASO) method. Results: In persons at average risk for colorectal cancer, I1307K was found in 5.0% of 120 European and 1.6% of 188 non-European Jews ( P = 0.08). It occurred in 15.4% of 52 Ashkenazi Israelis with familial cancer ( P = 0.02) and was not detected in 51 non-European Jews at increased cancer risk. Colorectal neoplasia occurred personally or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia. Conclusions: The I1307K APC variant may represent a susceptibility gene for colorectal, or other, cancers in Ashkenazi Jews, and partially explains the higher incidence of colorectal cancer in European Israelis. GASTROENTEROLOGY 1999;116:54-57

We describe two brothers with clinical and histological findings of type 2 spinal muscular atrophy (SMA) associated with small head circumference (

We have examined the expression of several Duchenne muscular dystrophy (DMD) gene products in amniotic fluid (AF) and chorionic villus sampling (CVS) cells. Variable amounts ofdystrophin could be detected in most CVS and AF samples by immunoprecipitation followed by Western blot analysis. PCR analysis demonstrated the presence of the muscle type dystrophin mRNA in all AF cell cultures. The brain type dystrophin mRNA was also detected in some of these cultures. These DMD gene transcripts are of fetal origin and are produced by most or all clonable AF cells. The results may facilitate the development of a method for prenatal diagnosis of DMD, based on the expression of the gene in AF and CVS cells.

Abstract 2617 Poster Board II-593 In recent years, a number of studies emphasized AML with complex aberrant karyotype as a distinct biological entity which is characterized by a unique gene expression pattern, with very frequent alteration in TP53 and a median overall survival (OS) of less than 6 months. However, the definition of a complex karyotype (CK) or whether monosomal karyotype (MK) provides a better prognostic prediction than CK is not well established. In the present study, we examined whether a prompt and simple Fluorescence in situ hybridization (FISH) test for TP53 deletion (presence or absence of 17p13) at diagnosis, has a predictive value for response to therapy and overall survival in AML patients (pts) with CK or chromosomal deletions (either complete or partial of any other chromosome). Between 2000 and 2009 we analyzed 38 patients with newly diagnosed AML, with age ranged from 18 to 82 years (median 52 years). On cytogenetic analysis from bone marrow at diagnosis, 16 (42%) pts had a CK (≥3 chromosome abnormalities), 16 pts (42%) had a normal karyotype (NK) and 6 (16%) pts had other monosomy or deletion of any chromosomal region. Seven patients had a post myelodysplastic syndrome AML and 1 post therapy for a prior malignancy. For induction treatment patients received idarubicine, 12 mg/m2/d (age 18– 55y) or mitoxantron 10 mg/m2/d intravenous (IV) on days 1-3 (age 55–68y) and cytarabine, 100mg/m2/d by continuous IV infusion on days 1 through 7. Pts entering complete remission (CR) received three courses of consolidation with high dose cytarabine. Patients with a histocompatibale donor, which did not received CR or relapsed, were allografted. Elderly patients, 69–82 years old, were treated with one induction chemotherapy which included Mylotarg (3mg/m2/2h on day 1) plus cytarabine (100 mg/m2/24h on days 2-8). Patients at this group of age did not received consolidation therapy. Of the16 pts with CK AML, 14 were treated with chemotherapy but only 3 pts (21%) achieved CR, 4 pts died during induction therapy. By comparison, of the 16 pts with NK AML, 15 pts were treated with chemotherapy, 11 pts achieved CR (73%), 3 pts died during induction therapy. Of the 6 AML pts with monosomy or deletion in cytogenetic analysis, 3 pts (50%) achieved CR (p =0.0067). In all NK AML patients examined the TP53 FISH was normal (mean 4% of cells examined), where as in patient with CK 75% of pts had TP53 deletion (mean 51%), and in the group with chromosomal deletion 50% of pts showed a loss of one TP53 (mean 18%) p=0.0016. Of note, in 13 pts (34%) with TP53 deletion by FISH analysis, cytogenetic analysis found no anomaly of 17p chromosome. In a stepwise logistic regression model FISH groups significantly entered the model in first step, and no other variable did (p=0.0056, C=0.833). In pts in which two copies of TP53 were found in FISH analysis ('10%) the median survival time is 440 days, whereas in pts with TP53 deletion was detected the median survival time was 189 days. The OS in pts with deletion of TP53 was significantly shorter as compared to pts that TP53 deletion was not found (p=0.025). However, a multivariate analysis including age, karyotype, deletion of TP53 and allogeneic transplantation showed that only CK and allogeneic transplantation are independent prognostic factors in this analysis. In conclusion, TP53 status by FISH at diagnosis is important due to the following findings: The test is sensitive, rapid and simple. 2. TP53 deletions are frequent in AML with CK and tend to segregate with additional chromosomal deletions. TP53 status at diagnosis has a predictive value with respect to chemotherapy response and OS in AML pts with CK and chromosomal deletions. Disclosures: No relevant conflicts of interest to declare.

Familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. This study included 71 Israeli families referred for molecular analysis of the APC gene. Analysis was performed by the protein truncation test (PTT) of exon 15, and if negative, by direct sequencing of exon 1 to 14. Mutations were found in 36 (50.7%) probands. Mutation detection rates depended on the pattern of referral, such that among the 40 probands referred from the Service for Hereditary Cancer the mutation detection rate was 70%, whereas among the 31 probands referred by other gastroenterologists detection rate was significantly lower (25.8%). Of the 36 mutations detected, 21 were within exon 15, 13 within exons 1 to 14 and 2 were newly-described splicing mutations in introns 9 and 14. A relatively high proportion of the mutations was detected in exon 9 (6/36), five of them newly described. Altogether, we describe here 17 new mutations. Within the two major ethnic groups in Israel, patients of Ashkenazi and non-Ashkenazi origin, there was no significant differences in the mutation detection rate or the distribution of mutations within the APC gene. No founder mutation was detected in any of these populations. Our data confirm that higher detection rates may be expected in patients referred by clinical services specializing in hereditary colon cancer. These results further underscore the importance of complete analysis of all exons and exon/intron boundaries, in order to achieve maximal detection rate in patients suspected of FAP.

Emery-Dreifuss Muscular Dystrophy (EMD or EDMD) is a rare X-linked recessive disorder, characterized by progressive muscle wasting and weakness, contractures, and cardiomyopathy, manifesting as heart block. Mutation analysis at the EMD gene locus was performed in 4 unrelated Israeli families with X-linked EMD and in one sporadic case. In the 4 families 4 different mutations were found, 3 of which were novel. These included two frame shift mutations in exon 2 (333delT and 412insA) and one base pair substitution at the consensus +1 donor splice in intron 5 (1429GA). The fourth mutation in exon 6 (1675-1678delTCCG) has been previously described. No mutations were identified in the one sporadic case. Two of the three novel mutations were found in exon 2. A summary of the previously published mutations described in the EMD Mutation Database (http://www.path.cam.ac.uk/emd/) as well as the mutations described in our study suggest that the distribution of mutations in EMD gene is not entirely random and that exon 2 is prone to mutations. Hum Mutat 17:522, 2001. © 2001 Wiley-Liss, Inc.

The capping of lymphocytes from normal pregnant women is diminished. Decreased capping is observed for both anti-Ig and for Con A receptors. The altered capping response appears between the tenth and the twelfth week of pregnancy. The diminution in capping persists until about 2 weeks after delivery. The possible association between the decreased capping response and the altered immune responses known to occur during pregnancy is discussed. The factors underlying the altered capping response in pregnancy may be related to the factors responsible for the parallel phenomenon in pathological conditions.

Monobromobimane labels red cell membrane protein thiol groups; bands exhibit fluorescence after sodium dodecyl sulfate acrylamide gel electrophoresis and correspond to almost all of those staining with Coomassie blue. The response of membrane protein thiol groups to oxidative challenge and the dynamics of recovery of the thiol groups may be followed. Diminished labeling is found after oxidation with diamide, with both intrachain and interchain disulfide bond formation demonstrated by sodium dodecyl sulfate acrylamide gel electrophoresis. Regeneration of thiol groups under physiological conditions (incubation with glucose) after a moderate degree of diamide oxidation is shown to be complete (with respect to thiol group content and degree and distribution of bimane label) in normal human red blood cell membranes. Even after oxidation of almost half of the membrane protein thiol groups (maximum degree of oxidation achieved), regeneration of thiol groups is almost complete; a minor fraction resides in the form of disulfide-linked high molecular weight proteins (demonstrated by the electrophoretic profile) which may be reduced completely with dithiothreitol. Bimane fluorescent labeling provides a convenient and sensitive method for following membrane thiol group status under physiological conditions.