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Biomedical subjects

S Avigad

Publications and source records attributed to S Avigad.

At least 37 records · Page 2Linked to original sources
PubMed1994

Origins of hyperphenylalaninemia in Israel.

Mutations and polymorphisms at the phenylalanine hydroxylase (PAH) gene were used to study the genetic diversity of the Jewish and Palestinian Arab populations in Israel. PAH mutations are responsible for a large variety of hyperphenylalaninemias (HPAs), ranging from the autosomal recessive disease phenylketonuria to various degrees of nonclinical HPA. Seventy-two Jewish and 36 Palestinian Arab families with various HPAs, containing 115 affected genotypes, were studied by haplotype analysis, screening for previously known PAH lesions and a search for novel mutations. Forty-one PAH haplotypes were observed in this sample. Four mutations previously identified in Europe (IVS10nt546, R261Q, R408W and R158Q) were found, and were associated with the same haplotypes as in Europe, indicating possible gene flow from European populations into the Jewish and Palestinian gene pools. Of particular interest is a PAH allele with the IVS10nt546 mutation and haplotype 6, that might have originated in Italy more than 3,000 years ago and spread during the expansion of the Roman Empire. These results, together with previous identification of three PAH mutations unique to Palestinian Arabs [IVSnt2, Edel(197-205) and R270S], indicate that the relatively high genetic diversity of the Jewish and Palestinian populations reflects, in addition to genetic events unique to these communities, some gene flow from neighboring and conquering populations.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Genetic alterations involving chromosome 1p in children with neuroblastoma.

Neuroblastoma is a common childhood tumor of the sympathetic nervous system, characterized by N-myc amplification and loss of heterozygosity (LOH) for sequences on chromosomes 1p, 11q and 14q. Using restriction fragment length polymorphism analysis, the constitutional and tumor genotypes were compared for LOH on 1p in 25 children with neuroblastoma at diagnosis: 19 in stages III-IV, 5 in stages I-II and one in IVs. The genetic alterations observed on chromosome 1p were frequent in the early and advanced stages. Thirty-three percent of the alterations were found in patients under the age of 1 year, and in one patient with IVs. It is concluded that 1p alterations were identified in children with neuroblastoma in early stages and infants and thus of no prognostic relevance. 1p genetic alterations may be early events in neuroblastoma.

Blotting, Southern↗
PubMed1993

A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in north African Jews with phenylketonuria.

The majority of hyperphenylalaninemias (HPAs) result from mutations at the gene for phenylalanine hydroxylase (PAH). The broad phenotypic variability of these conditions, ranging from phenylketonuria (PKU) to mild benign HPA, is underlain by a wide spectrum of mutations giving rise to various genotypic combinations. Mutant PAH alleles, labeled by specific polymorphic haplotypes and mutations, are becoming useful markers in human population genetics. We report here a mutant PAH allele found in Jews from Morocco and Tunisia, marked by haplotype 4 and a missense mutation, TCASer-->CCAPro, at codon 349 in exon 10 of the gene. In vitro expression of the mutation showed normal levels of mRNA with virtually no enzymatic activity or protein immunoreactivity, pointing to a highly unstable protein. A homozygote for this mutation showed the most severe ("classical") type of PKU, while compound heterozygotes showed two other types of HPA--"atypical" PKU and "high benign" HPA--illustrating the interplay between different mutations that gives rise to various HPAs.

Base Sequence↗
PubMed1991

Compound heterozygosity in nonphenylketonuria hyperphenylalanemia: the contribution of mutations for classical phenylketonuria.

Hyperphenylalaninemia (HPA) results from defective hydroxylation of phenylalanine in the liver, in most cases because of defective phenylalanine hydroxylase. HPA is highly variable, ranging from moderate elevation of plasma phenylalanine with no clinical consequences to a severe disease, classical phenylketonuria (PKU). Non-PKU HPA was found in excess of PKU in Israel, while the opposite is true in Europe. To study the genetic basis of non-PKU HPA, we performed haplotype analysis at the phenylalanine hydroxylase locus in 27 families with non-PKU HPA. All individuals with this condition were compound heterozygotes. In six of these families, in which both PKU and non-PKU HPA were segregating, haplotype analysis showed that non-PKU HPA resulted from compound heterozygosity for a PKU mutation and a second mutation, with milder effect, which is probably expressed only when it interacts with the severe mutation. The involvement of PKU mutations in non-PKU HPA was further demonstrated in Jewish Yemenite families with non-PKU HPA, in which the individuals with this condition were carriers of the single PKU allele which exists in this community. In addition, two previously known PKU point mutations (R261Q and R408W) were found in individuals with non-PKU HPA. These mutations are associated, in our population, with the same haplotypes as those with which it is associated in Europe. Based on the above-mentioned genetic model for non-PKU HPA, successful prenatal diagnosis of this condition was performed in one family.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

A single origin of phenylketonuria in Yemenite Jews.

Phenylketonuria (PKU) is a metabolic disease caused by recessive mutations of the gene encoding the hepatic enzyme phenylalanine hydroxylase (PAH). The incidence of PKU varies widely across different geographic areas, and is highest (about 1 in 5,000 live births) in Ireland and western Scotland, and among Yemenite Jews. A limited number of point mutations account for most of the PKU cases in the European population. Here we report that a single molecular defect--a deletion spanning the third exon of the PAH gene--is responsible for all the PKU cases among the Yemenite Jews. Examination of a random sample of Yemenite Jews using a molecular probe that detects the carriers of this deletion indicated a high frequency of the defective gene in this community. Although the deleted PAH gene was traced to 25 different locations throughout Yemen, family histories and official documents of the Yemenite Jewish community showed that the common ancestor of all the carriers of this genetic defect lived in San'a, the capital of Yemen, before the eighteenth century.

Alleles↗
PubMed1989

[Carrier detection and prenatal diagnosis in phenylketonuria, cystic fibrosis and adrenal hyperplasia use of molecular biology techniques].

With the advent of molecular biology techniques the prenatal diagnosis of many inherited diseases is now possible. In our Division of Transplantation Immunology we provide prenatal diagnosis for phenylketonuria (PKU), cystic fibrosis (CF) and congenital adrenal hyperplasia (CAH). In CF and PKU the chromosome carrying the disease gene is identified by the molecular probe, while in CAH it can also be determined by HLA phenotyping. Accurate diagnosis of a disease is dependent on the physical distance on the chromosome between the probe and the disease gene. Chorionic villous sampling allows evaluation of embryos at 9-10 weeks of gestation and also identification of carriers. DNA prepared from white blood cells of members of 4 families with CAH was digested with restriction endonucleases. Southern transfers were hybridized with the probe for 21-hydroxylase, and with 3 HLA probes mapped to both sides of the gene for 21-OH. In 2 families the embryo was found to be normal and in 2 diseased. Using the same techniques, but with probe and endonucleases specific for PKU, prenatal diagnosis was provided for 11 families with that condition. An embryo with PKU was found in each of 2 families, normal ones in 7, and in the remaining 2 families the testing was not informative. As of the present, 6 normal and 2 diseased children have been born, all as predicted. In 8 families with CF, DNA was examined with 5 probes mapped to both sides of the CF gene. Carriers and healthy sibs were identified, and in 1 family prenatal diagnosis was provided.

Adrenal Hyperplasia, Congenital↗
PubMed1986

Well-compensated primary bile acid malabsorption presenting as chronic nonspecific diarrhea.

Increased fecal bile acid loss and defective in vitro ileal bile acid uptake were demonstrated in an 8-year-old boy with diarrhea starting in the neonatal period. His continuously normal physical development and good nutritional status are in keeping with a well-preserved cholic acid pool and normal duodenal bile acid concentration. Isolated bile acid malabsorption can remain well compensated and present as the chronic nonspecific diarrhea syndrome of childhood.

Bile Acids and Salts↗
PubMed1985

Assessment of intestinal and cardiorespiratory function in children with congenital heart disease on high-caloric formulas.

Fourteen infants with congenital heart disease were investigated for failure to thrive. Assessment of intestinal function revealed minor absorptive abnormalities (mild steatorrhea in three patients, bile salt loss in four patients), delayed gastric emptying, and abnormal triglyceride loading tests. Low caloric intake (88.3 +/- 19.3 kcal/kg/day) seemed the main reason for failure to gain weight. Weight accession and cardiorespiratory rates were monitored daily during voluntary intake, a high-caloric diet by mouth, and nasogastric tube feeding. Providing 169 +/- 29 kcal/kg/day by tube resulted in weight gain with mild and transient elevation of respiratory rate at the end of the meal and increased heart rate 90 min after the meal. This regimen is a metabolically inexpensive and efficient method of supporting weight gain in children with congenital heart disease.

Age Factors↗
PubMed1985

Ia-like antigens in the small intestinal mucosa of normal and celiac children.

The small-intestinal mucosa of normal children and of celiac patients was studied using the Class II DP (SB) Ia-like monoclonal antibody ILR-1 and an immunoperoxidase technique. Positive staining of the Golgi region of the epithelial cells of villi and crypts, and of the brush border of villous epithelium, was seen in the histologically normal mucosa. In active celiac disease with "flat" mucosa, the surface epithelium showed poor staining, but the crypt epithelium stained strongly in the Golgi region. We suggest that the Ia-like antigens are a product of the epithelial cells themselves, arising most likely in the Golgi apparatus, and that this staining pattern is altered in active celiac disease.

Celiac Disease↗
PubMed1983

Gluten-sensitive enteropathy: value of oral triglyceride loading test in the follow-up of patients on gluten challenge.

Oral triglyceride (TG) loading tests were performed in 31 patients with gluten-sensitive enteropathy (GSE) upon gluten challenge, and the results were compared with the mucosal histology. Of 19 prechallenge tests, 16 were in the normal range previously established in this laboratory (2-h postcibal plasma TG rise greater than or equal to 55 mg/dl) although values were lower (76 +/- 38 mg/dl, mean +/- SD) than those of healthy age-matched controls (116 +/- 34 mg/dl). Postchallenge tests performed in 29 patients (both symptomatic and asymptomatic) were all pathologic (postcibal TG rise 9 +/- 18 mg/dl). Three tests performed in two patients in whom GSE was ultimately not confirmed remained normal (postcibal TG rise 82 +/- 21 mg/dl) during a 24-mo follow-up. A significant correlation was demonstrated between the TG loading test and the mucosal pathology. The test is useful in the follow-up of patients of gluten challenge and in directing the postchallenge biopsy.

Administration, Oral↗
PubMed1982

alpha 1-antitrypsin deficiency in Israeli children: a five-year survey.

In order to elucidate the importance of alpha 1-antitrypsin (AAT) deficiency as a cause of liver disease in children in Israel, we conducted a retrospective 5-yr study. The screening of 51 liver biopsies for the presence of AAT inclusion bodies was performed using the immunoperoxidase technique. Serum AAT concentrations of 300 pediatric patients determined during the same period were reviewed. No case of AAT deficiency was detected. We conclude that AAT deficiency is rare in Israel.

Adolescent↗
PubMed1981

Immunogenetics of childhood celiac disease: the association with HDA DR3 and DR7 in unrelated patients with multiply affected families.

The association between childhood celiac disease and the histocompatibility complex was studied in five multiply affected families and 20 unrelated patients. The diagnosis of celiac disease (CD) was established by three consecutive jejunal biopsies: 1) at the initiation of the diagnosis; 2) following a gluten-free diet; and 3) after gluten provocation. The results of this study indicate that a significant association exists between celiac disease, DR3 (P less than 0.001) and DR7 (P less than 0.001). The relative risks for these antigens were 8.56 and 5.05, respectively. Segregation analysis in the families suggested that the susceptibility genes associated with the histocompatibility antigens are not inherited in either a dominant or a recessive pattern. While an intermediate type fits better into the genetic framework of CD, more than one susceptibility and protecting gene may be involved in the pathogenesis of this disease.

Adult↗
PubMed1980

Microvillous surface area in secondary disaccharidase deficiency.

Electron microscopy was used to measure microvillous surface area in seven small intestinal biopsies showing secondary disaccharidase deficiency and in five biopsies having normal disaccharidase levels. There were significant reductions in microvillous surface area in the enzyme deficient group, although the microvilli were not severely damaged. Histological abnormality was not always present with disaccharidase deficiency. There was no significant difference in intraepithelial lymphocyte counts between the two groups.

Adolescent↗
PubMed1979

Lactase degradation by human enteric bacteria.

Twelve non-pathogenic bacteria and two yeast strains isolated from the duodenal aspirate or mucosa of five children with diarrhoea were tested for their ability to degrade non-human lactase in vitro. Both yeast strains and eleven of the bacterial strains significantly reduced lactase activity. A similar action on human lactase could be a cause of lactose intolerance.

Bacteria↗
PubMed1979

Disturbed fat absorption following infectious gastroenteritis in children.

Fat absorption was studied in 10 patients recovering from an episode of acute infectious gastroenteritis who failed to gain weight despite adequate caloric intake. Three patients restudied after clinical improvement and three other infants with failure to thrive, unrelated to gastrointestinal problems, served as control subjects. Fat balance studies during the ingestion of a formula containing long-chain fatty acids demonstrated significant degrees of steatorrhea in patients (mean CFA 70.6 +/- 10.7 compared to 90.3 +/- 2.4 in control subjects). The administration of a test meal demonstrated a marked deficiency of duodenal bile acid concentration and of fat incorporation into the micellar phase in patients. Fecal bile acid excretion was significantly increased in patients (mean 33.9 +/- 11.6 microM/kg/day) as compared to control subjects (mean 13.5 +/- 3.1 microM/kg/day). Bacterial overgrowth and abnormalities of the small intestinal mucosa were not constant. Ileal dysfunction and associated bile acid loss are possible causes of disturbed fat assimilation following acute intestinal infection in children.

Acute Disease↗
PubMed1978

Small-intestinal mucosal antibodies against antigens of non-pathogenic luminal or mucosal bacteria in young children with and without diarrhoea.

Duodenal mucosal antibody against non-pathogenic bacteria, grown either from the luminal juices or the mucosa itself, was demonstrated for the first time in 7 of 8 children with diarrhoea and only 2 of 7 without diarrhoea. Neither group showed significant histological abnormalities on duodenal biopsy. An aetiological relation between the antibody and the persistence of postenteritis diarrhoea is possible.

Antibodies, Bacterial↗