An update of Gaucher mutations distribution in the Ashkenazi Jewish population: prevalence and country of origin of the mutation R496H.

BACKGROUND: Gaucher disease is the most prevalent inherited disorder among Ashkenazi Jews (carrier frequency of about 6%) and six mutations account for about 96% of their mutant alleles. Two mutations, N370S and R496H, have been reported only in mildly affected or asymptomatic patients. Due to the rarity of R496H, it was recommended that it be excluded from screening programs. OBJECTIVES: To verify the frequency and trace the origin of Gaucher mutations in screened individuals whose Ashkenazi ethnicity was confirmed by the birthplace of their grandparents. METHODS: We conducted a retrospective analysis of the screened results for the period 2006-2011. Mutations were identified by restriction analysis, Tag-It detection system, Pronto diagnostic kit and Nanogen technology (NanoChip 400). RESULTS: The heterozygote frequency of eight mutations was estimated in a cohort of 16,910 alleles. Two mutations, N370S and R496H, were the most frequent in our population. However, while the occurrence of N370S carriers was similar to other reports (1:19.4), that of R496H carriers was considerably elevated (1:207). Examination of the screened individuals' ethnicity showed a significant difference in the distribution pattern of the country of origin between the carriers of these two mutations. CONCLUSIONS: The origin pattern differences between the two groups of heterozygotes might reflect a separate geographic region of introduction for various mutations. As a result, secondary subgroups could be formed within the Ashkenazi population. This might clarify the dissimilarities in the occurrence of R496H mutation reported by various centers.

Rhythmic profiles of cell cycle and circadian clock gene transcripts in mice: a possible association between two periodic systems.

The circadian system shapes the rhythms of most biological functions. The regulation of the cell cycle by a circadian clock was suggested to operate via stages S, G2 and G2/M. This study investigated a possible time link at stages G1 and G1/S as well. The daily expression profiles of cell cycle markers (Ccnd1, Ccne1 and Pcna) and circadian clock genes (Per2 and Clock) were monitored in liver and esophagus (low and high proliferation index, respectively) of BALB/c mice. Locomotor activity displayed a 24 h rhythm, establishing the circadian organization of the suprachiasmatic nucleus. In the liver, the mRNA level of Per2 and Clock fitted the circadian rhythm with a 7.5 h shift. This temporal pattern suggests that the liver harbors a functional circadian clock. The rhythm of the analyzed cell cycle genes, however, was of low significance fitness and showed an opposite peak time between Pcna and Clock. These results indicate a weak regulatory role of the circadian clock. In the esophagus, the rhythms of Clock and Per2 mRNA had a similar peak time and non-circadian periods. These results suggest either that the esophagus does not harbor a functional circadian apparatus or that the phenotypes stem from differences in phase and amplitude of the rhythms of its various cell types. The similarity in the rhythm parameters of Clock, Ccne1 and Pcna transcripts questions the control of the circadian clock on the cell cycle along the G1 and G1/S stages. Yet the G1/S transition may play a role in modulating the local clock of proliferating tissues.

The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population.

Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population.

Pyrimethamine increases ß-hexosaminidase A activity in patients with Late Onset Tay Sachs.

OBJECTIVE: To assess whether or not pyrimethamine (PMT) can be used to enhance ß-hexosaminidase A activity (HexA) in subjects with Late Onset Tay Sachs (LOTS), we studied the effect of incremental doses of PMT in vivo in 9 LOTS patients carrying the αG269S/c.1278insTACT mutations. METHODS: PMT treatment was initiated at a dose of 6.25 mg, increasing gradually up to a maximal allowable dose of 75 mg daily at 4-6 weeks intervals for a total of up 10 months. Mean patients' age was 37.9±16.1 yrs (range 20-67 years). RESULTS: Lymphocyte HexA activity rose in all subjects, peaking at 78±30% over baseline activity (mean±SD; range 36-114%). The optimal PMT dose varied considerably, averaging at 30±24.1 mg (range-6.25-75 mg, daily). Further increase in PMT beyond the optimal dose was associated with gradual loss of effect on lymphocyte HexA. Improvement in speech was seen within several weeks in 4 out of 9 subjects, mostly paralleling the initial increment in HexA. Mood stabilization was also perceived in 3 subjects, but this was more difficult to assess due to the concomitant use of psychotropic/mood stabilizing agents. Reversible decline in motor activity manifesting predominantly in more frequent falls was seen in 3 subjects when the PMT dose was increased beyond the peak effect generating dose. CONCLUSIONS: PMT therapy can increase HexA activity in LOTS in vivo. Optimal doses should be tailored individually to avoid loss of biochemical effects. Clear cut neurological and psychiatric effects are difficult to discern at this time, mostly due to short term study follow up and large inter-individual variability.

The single cell as a tool for genetic testing: credibility, precision, implication.

PURPOSE: To investigate the influence of amplicons size and cell type on allele dropout and amplification failures in single-cell based molecular diagnosis. METHODS: 730 single lymphocytes and amniotic cells were collected from known heterozygotes individuals to one of the common Ashkenazi Jewish mutations: 1278+TATC and IVS12+1G>C which cause Tay Sachs Disease, IVS20+6T and 854A>C which underlie Familial Dysautonomia and Canavan Disease. DNA was extracted and analyzed by our routine methods. RESULTS: Reduced rates of allele dropout and amplification failure were found when smaller amplification product were designed and in amniotic cultured cells compared to peripheral lymphocytes. Cultured lymphocytes, induced to divide, demonstrated significantly less allele dropout than non induced lymphocytes suggesting the role of division potential on amplification efficiency. CONCLUSION: Single cell based diagnosis should be designed for each mutation. Minimal sized amplicons and cell having division potential should be preferred, as well as sensitive techniques to detect preferential amplification.

Thrombophilic polymorphisms in Israel.

Three thrombophilic polymorphisms, FV G1691A, FII G20210A and MTHFR C677T were investigated in Israeli populations by FRET, (fluorescence resonance energy transfer) real-time PCR. We observe extensive variability in the frequencies of each of the polymorphisms, as has been observed in the study of other polymorphisms in these populations. Very high allele frequencies for FV G1691A (the highest 0.087 in Turkish and Greek Jews) and FII G20210A (the highest 0.061 in Georgian Jews) in some of the Israeli populations justify a clinical investigation to assess their risk for venous thrombosis. Principal Coordinates Analysis demonstrates that the Jewish populations are interspersed among the non-Jewish populations. The resemblance of some Jewish populations to certain non-Jewish populations coincides with findings based on classical markers.

Rapid detection of fetal Mendelian disorders: Tay-Sachs disease.

Tay-Sachs disease is an autosomal recessive storage disease caused by the impaired activity of the lysosomal enzyme hexosaminidase A. In this fatal disease, the sphingolipid GM2 ganglioside accumulates in the neurons. Due to high carrier rates and the severity of the disease, population screening and prenatal diagnosis of Tay-Sachs disease are routinely carried out in Israel. Laboratory diagnosis of Tay-Sachs is carried out with biochemical and DNA-based methods in peripheral and umbilical cord blood, amniotic fluid, and chorionic villi samples. The assay of hexosaminidase A (Hex A) activity is carried out with synthetic substrates, 4-methylumbelliferyl-6-sulfo-N-acetyl-beta-glucosaminide (4-MUGS) and 4-methylumbelliferil-N-acetyl-beta-glucosamine (4-MUG), and the DNA-based analysis involves testing for the presence of specific known mutations in the alpha-subunit gene of Hex A. Prenatal diagnosis of Tay-Sachs disease is accomplished within 24-48 h from sampling. The preferred strategy is to simultaneously carry out enzymatic analysis in the amniotic fluid supernatant or in chorionic villi and molecular DNA-based testing in an amniotic fluid cell-pellet or in chorionic villi.

Typing classical polymorphisms by real-time PCR: analysis of the GPT and ALAD protein polymorphisms in the Jewish populations.

Expanding the already extensive data array on classical polymorphisms in new populations is beneficial to full characterization of the intricate relationships between human populations. This can be done in a short time on a large-scale by using real-time PCR. The red-cell enzymes Delta-aminolevulinate dehydratase (ALAD) and glutamate pyruvate transaminase (GPT) have each two alleles that can be separated by protein electrophoresis. They were previously characterized by protein electrophoresis in some of the Jewish populations. We designed primers and probes for fluorescence resonance energy transfer detection of the ALAD and GPT alleles to type Jewish populations including some in which these polymorphisms have not been studied in the past. The methods described here allow fast and efficient determination of these common classical polymorphisms. When used in large-scale population studies, these methods are not only faster, but also cheaper than amplification followed by restriction enzyme digestion and gel electrophoresis. The frequency of ALAD*1 among Jews ranges from 0.781 to 0.960 and that of GPT*1 from 0.412 to 0.773. A maximum likelihood tree based on the ALAD and GPT polymorphisms and five other red-cells enzymes polymorphisms depicts quite accurately the known historic, anthropological, and geographic relations between the Jewish populations.

Carrier screening for Gaucher disease: lessons for low-penetrance, treatable diseases.

CONTEXT: The aim of carrier screening is to prevent severe, untreatable genetic disease by identifying couples at risk before the birth of an affected child, and providing such couples with options for reproductive outcomes for affected pregnancies. Gaucher disease (GD) is an autosomal recessive storage disorder, relatively frequent in Ashkenazi Jews. Carrier screening for GD is controversial because common type 1 GD is often asymptomatic and effective treatment exists. However, screening is offered to Ashkenazi Jews worldwide and has been offered in Israel since 1995. OBJECTIVE: To examine the scope and outcomes of nationwide GD screening. DESIGN, SETTING, AND PARTICIPANTS: All Israeli genetic centers provided data on the number of individuals screened for GD, the number of carriers identified, the number of carrier couples identified, and the mutations identified in these couples between January 1, 1995, and March 31, 2003. Carrier couples were interviewed via telephone between January 21, 2003, and August 31, 2004, using a structured questionnaire for relevant outcome measures. MAIN OUTCOME MEASURES: Screening scope (number of testing centers, tested individuals, and carrier couples), screening process (type of pretest and posttest consultations), and screening outcomes (utilization of prenatal diagnosis and pregnancy terminations). RESULTS: Between January 1, 1995, and March 31, 2003, 10 of 12 Israeli genetic centers (83.3%) offered carrier screening. Carrier frequency was 5.7%, and 83 carrier couples were identified among an estimated 28,893 individuals screened. There were 82 couples at risk for offspring with type 1 GD. Seventy of 82 couples (85%) were at risk for asymptomatic or mildly affected offspring and 12 of 82 couples (15%) were at risk for moderately affected offspring. At postscreening, 65 interviewed couples had 90 pregnancies, and prenatal diagnosis was performed in 68 pregnancies (76%), detecting 16 fetuses with GD (24%). Pregnancies were terminated in 2 of 13 fetuses (15%) predicted to be asymptomatic or mildly affected and 2 of 3 fetuses (67%) with predicted moderate disease. There were significantly fewer pregnancy terminations in couples who in addition to genetic counseling had medical counseling with a GD expert (1 of 13 [8%] vs 3 of 3 with no medical counseling [100%], P = .007). CONCLUSIONS: In this study of GD screening among Ashkenazi Jewish couples in Israel, most couples did not terminate affected pregnancies, although screening was associated with a few pregnancy terminations. The main possible benefit was providing couples with knowledge and control. The divergence of these outcomes from stated goals of screening programs is likely to confront carrier screening programs for low-penetrance diseases.

Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.

BACKGROUND: Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of ß-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. METHODS: In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). RESULTS: HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. CONCLUSIONS: Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.

Chemotoxicity and survival of tumor-bearing mice under exposure to randomized photoperiodic regimen.

Although disruption of the circadian rhythm had been traditionally considered as a pathological sign, there is an increasing recognition that an existence of internal disorder (or chaos) in the organism's homeostasis is, to some degree, essential to the organism's well being. In this study we explored the effects of rhythm scrambling by exposure to random light/dark (RLD) alternation or by hydrocortisone administration. The variables measured were the toxicity of Adriamycin, Vincristin, Cisplatinum and Cyclophosphamide in C57Bl/6J mice and the survival of EL4 lymphoma-bearing mice, before and after chemotherapy. Rhythm alterations were determined by WBC counts and plasma Alkaline Phosphatase activity. Injections of Adriamycin, Cisplatinum and Vincristin in RLD conditions resulted in a better survival than in control groups of mice kept in LD illumination regimen, although the differences between the groups were significant only for injection of Adriamycin. RLD conditions imposed a "protective" effect on survival of tumor-bearing mice. On the 94th day, 20% of the injected mice in RLD conditions still survived while, there were no survivors beyond 38 days in control group. Chemotherapy had a more prominent beneficial effect on survival in RLD group, as compared to LD group. The injections of hydrocortisone had detrimental effect on survival in both illumination schedules. However, the survival in the RLD group was still better than in the LD group. These experiments indicate that temporal disorganization has beneficial effects on lymphoma-bearing mice and could be used for development of new therapeutic modalities.

Circadian variation of nitric oxide synthase activity in mouse tissue.

Endogenous nitric oxide (NO) is an important mediator in the processes that control biological clocks and circadian rhythms. The present study was designed to elucidate if NO synthase (NOS) activity in the brain, kidney, testis, aorta, and lungs and plasma NOx levels in mice are controlled by an endogenous circadian pacemaker. Male BALB/c mice were exposed to two different lighting regimens of either light-dark 14:10 (LD) or continuous lighting (LL). At nine different equidistant time points (commencing at 09:00h) blood samples and tissues were taken from mice. The plasma and tissue homogenates were used to measure the levels of NO2 + NO3- (NOx) and total protein. The NOx concentrations were determined by a commercial nitric oxide synthase assay kit, and protein content was assessed in each homogenate tissue sample by the Lowry method. Nitric oxide synthase activity was calculated as pmol/mg protein/h. The resulting patterns were analyzed by the single cosinor method for pre-adjusted periods and by curve-fitting programs to elucidate compound rhythmicity. The NOS activity in kidneys of mice exposed to LD exhibited a circadian rhythm, but no rhythmicity was detected in mice exposed to LL. Aortic NOS activity displayed 24h rhythmicity only in LL. Brain, testis, and lung NOS activity and plasma NOx levels displayed 24h rhythms both in LD and LL. Acrophase values of NOS activity in brain, kidney, testis, and lungs were at midnight corresponding to their behavioral activities. Compound rhythms were also detected in many of the examined patterns. The findings suggest that NOS activity in mouse brain, aorta, lung, and testis are regulated by an endogenous clock, while in kidney the rhythm in NOS activity is synchronized by the exogenous signals.

Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel.

BACKGROUND: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi's anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4 + 4AT for Fanconi's anemia complementation group C. OBJECTIVES: To provide additional verification of the mutation rate of BLM and FACC in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation. METHODS: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto kit to verify the results in 244 samples and there was an excellent match. RESULTS: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population. CONCLUSIONS: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.

Cisplatin effects on rhythmic functions of mice: strain and tissue dependence.

The competence to preserve the optimal timing relationships between rhythmic variables enables adaptation of mammals to alternate environmental conditions. The capability to re-entrain depends on genetic factors and the nature of imposed time cues. In the present study, the authors examined in rodent models, following a cancer chronochemotherapy, cisplatin (CP), the rhythm patterns of locomotor activity and of a few biochemical variables (alkaline phosphatase and creatinine phosphokinase in kidney tissue and plasma, kidney urea nitrogen, and white blood cell count). Males of two inbred mice strains, BALB/c and c57Bl/6J, received 10 consecutive daily intraperitoneal (i.p.) injections of either saline or CP at zeitgeber time 22 (ZT22). CP administration altered the rhythms of each examined function in both strains. The type and extent of the changes varied among variables, tissues/plasma, and mouse strain. Yet, the effect of CP was not detected on all parameters, but only in ∼60% of them. In addition, in the majority of the studied parameters, BALB/c and c57Bl/6J mice differed in their response to CP. The temporal parameters of period and peak time were more affected by CP than were the level ones of mesor (time series mean) and amplitude of variation. This observation may indicate the involvement of independent pathways of action upon each of the rhythm parameter sets. As a result, the rhythm phenotype of each function was modified and novel timing relationships were shaped. The results show that the circadian systems of BALB/c and c57Bl/6J mice failed to re-entrain after cessation of CP injections (tested on the first day following the 10 d course of CP administration), pointing to a direct effect of the medication on the tissues. The findings imply that optimal chemotherapeutic protocols should be tailored individually, according to the current temporal order rather than administered at a fixed predetermined circadian time. Further studies are necessary to determine which variables and rhythmic parameters could be useful to determine the optimal timing of chronochemotherapy.

Three peaks in the polymerase chain reaction fragile X analysis.

OBJECTIVE: To report and discuss the observation of three fragments on polymerase chain reaction (PCR) in routine carrier screening for fragile X. METHODS: From 2005 through 2010, 34,500 women underwent prenatal screening for fragile X. PCR was carried out to amplify the repeat segment. The resulting fragments were scanned by a genetic analyser. RESULTS: Three PCR peaks representing three different-sized fragments were found in 25 of the 34,500 women (1:1380 or 0.072%). Karyotype analysis was performed in 16 subjects. Full triple X was found in three women, while two had triple X mosaicism. Of the 16 karyotyped women, five (31%) had a finding of XXX (full or mosaic). CONCLUSIONS: Triple X (full or mosaic) is the most frequently encountered mechanism responsible for three peaks on fragile X PCR testing.

The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis.

OBJECTIVE: To assess the frequency of the D1152H mutation in the CFTR gene in normal individuals, in cystic fibrosis (CF) patients and in the setting of prenatal diagnosis. SETTING: A database analysis of sequential screening results seen at the Sheba Medical Center, Israel, between 2001 and 2010. METHODS: We retrospectively analyzed the frequency of D1152H in a large cohort of healthy individuals who were screened as part of a routine prenatal care programme, in individuals referred due to CF-related symptoms and in the setting of prenatal diagnosis. RESULTS: We found one asymptomatic homozygous female and 195 D1152H carriers among 49,940 healthy individuals screened, establishing a carrier rate of 1:255 for this mutation. We detected D1152H in nine of 103 individuals referred due to CF-related symptoms. Four suffered from respiratory symptoms and five from congenital bilateral absence of the vas deferens (CBAVD). During this period D1152H was detected in three pregnancies, two of which were aborted. CONCLUSION: The increased frequency of D1152H in individuals referred due to CF-related symptoms compared with healthy individuals included in the CF carrier screening programme (P < 0.001) clearly indicates that it is a disease-causing mutation.

Preconceptional and prenatal screening for fragile X syndrome: experience with 40,000 tests.

OBJECTIVES: To determine the carrier frequency of fragile X syndrome, and the rate of expansion from premutation (PM) carrier to full mutation (FM) fetus. METHODS: Results were analyzed on women with no family history of fragile X syndrome, or who were PM/FM carriers, who were tested between January 1994 and June 2004. PM was defined 55-199 repeats, FM above 200. RESULTS: Out of 40 079 women screened, 5 FM and 255 PM carriers were detected. There was no significant difference in carrier frequency between those with versus those without family history of mental retardation or developmental abnormalities: 1 in 128 (28/3596) versus 1 in 157 (232/36 483). However, the median of repeats differed significantly: 58 and 66 repeats, respectively, (P < 0.0001). Invasive prenatal diagnosis was carried out in 370 pregnancies (7 FM and 363 PM). Thirty FM fetuses were detected. There was a lower expansion rate in cases without a family history: 10% (17/169 PMs) compared to 50% (11/22 PMs) in those with a history, but this could be accounted for by the difference in allele size. CONCLUSION: There is now sufficient information on screening parameters and prenatal diagnosis of fragile X syndrome to offer testing to women of reproductive age.

Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis.

The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

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.

Hexosaminidase A deficiency is an uncommon cause of a syndrome mimicking amyotrophic lateral sclerosis.

Patients with adult hexosaminidase A (Hex A) deficiency may have clinical manifestations similar to amyotrophic lateral sclerosis (ALS). Mutations in the hexosaminidase A (HEXA) gene are common in the Jewish Ashkenazi population in Israel. Serum samples of 115 Israeli patients with sporadic ALS were screened for enzymatic activity to detect "enzyme-based carriers." Fifteen samples with low (< 50%) enzymatic activity were subjected to mutation analysis, which included the two common mutations in the HEXA gene among Ashkenazi Jews (+1278TATC and IVS12+1G-->C). Three "enzymatic carrier" patients of Moroccan origin were checked for two additional mutations (DeltaF304/305 and Arg170-->Gln), specific to this ethnic group. Two "enzymatic carrier" patients of Iraqi origin were analyzed for the mutation Gly250-->Val, specific to this population. The mutation Gly 269-->Ser was screened in carriers of Ashkenazi origin only (n = 10). The only abnormalities found were heterozygous +1278TATC mutations in two Ashkenazi patients. Their clinical presentation was not different from that usually encountered in ALS. The frequency of mutations in the HEXA gene among Israeli ALS patients was not higher than in the healthy Israeli population. Therefore, Hex A deficiency seems to be a very unlikely cause of an ALS-mimic syndrome.