PubMed Health⌕ Search

Biomedical subjects

H Mandel

Publications and source records attributed to H Mandel.

At least 55 records · Page 3Linked to original sources
PubMed1997

Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping.

Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.

Alaska↗
PubMed1997

Profound biotinidase deficiency caused by a point mutation that creates a downstream cryptic 3' splice acceptor site within an exon of the human biotinidase gene.

Biotinidase recycles the vitamin biotin from biocytin upon the degradation of the biotin-dependent carboxylases. We have identified a novel point mutation within the biotinidase gene that encodes the signal peptide in two unrelated individuals with profound biotinidase deficiency. Sequence analysis of genomic DNA from these individuals revealed a G to A transition (G100-->A) located 57 bases downstream of the authentic splice acceptor site in exon B. Although this mutation predicts a G34S substitution, it also generates a 3' splice acceptor site. Sequence of the PCR-amplified cDNA from the homozygous child revealed that all the product was shorter than that of normal individuals and was the result of aberrant splicing. The aberrantly spliced transcript lacked 57 bases, including a second in-frame ATG, that encode most of the putative signal peptide and results in an in-frame deletion of 19 amino acids. The mutation results in failure to secrete the aberrant protein into the blood. This is the first reported example in which a point mutation creates a cryptic 3' splice acceptor site motif that is used preferentially over the upstream authentic splice site. The preferential usage of the downstream splice site is not consistent with the 5'-3' scanning model, but is consistent with the exon definition model of RNA splicing.

Amidohydrolases↗
PubMed1997

Progressive familial intrahepatic cholestasis among the Arab population in Israel.

BACKGROUND: Progressive familial intrahepatic cholestasis, which constitutes a heterogeneous group of imperfectly delineated syndromes and appears to be inherited as an autosomal recessive condition, has not been hitherto reported from the Middle East, in spite of the high rate of consanguineous marriage in this region. METHODS: Sixteen affected children from six Israeli Arab families were evaluated over 30 years. All were born to consanguineous parents. RESULTS: Jaundice appeared during the first 3 weeks of life in 15 babies. When first referred, 10 had hepatomegaly and nine had splenomegaly. A progression toward cirrhosis was the rule. Serum levels of conjugated bilirubin, liver enzymes, and alkaline phosphatase were raised; gamma-glutamyl transpeptidase levels were normal in all three infants in whom it was examined, but elevated in two siblings of another family at ages 2 and 3 years. No abnormal bile acids were detected in the serum and urine of patients. Histologic examination of the liver showed giant-cell transformation, paucity of intrahepatic bile ducts, cholestasis, fibrosis, or cirrhosis. The pattern of liver pathology differed at times among affected members within the same family. Therapeutic trials with phenobarbital, cholestyramine, or ursodeoxycholic acid were ineffective. Survival of the patients was from 5 to 18 months in four families; in the other two families, three children received liver transplants, and one is awaiting liver transplantation. CONCLUSIONS: Progressive familial intrahepatic cholestasis should be included in the differential diagnosis of infants with cholestatic jaundice of unknown etiology, especially those born to consanguineous Arab parents.

Arabs↗
PubMed1996

Interstitial deletion (6)q13q15.

We report on a 2-year-old child with psychomotor retardation, facial and urogenital anomalies. His chromosome constitution was 46,XY, del(6)(q13q15). This case further contributes to the karyotype-phenotype correlation of proximal deletion 6q syndromes.

Abnormalities, Multiple↗
PubMed1996

Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis.

BACKGROUND: Venous and arterial thromboembolism occurs in only about one third of patients homozygous for homocystinuria, which suggests that other, contributory factors are necessary for the development of thrombosis in these patients. Factor V Leiden, an R506Q mutation in the gene coding for factor V, is the most common cause of familial thrombosis and could be a potentiating factor. METHODS: We determined activated partial-thromboplastin times in the presence and absence of activated protein C and tested for the factor V Leiden mutation in 45 members of seven unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. RESULT: Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (age, 0.2 to 8 years). All six also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden has received warfarin therapy since birth and has not had thrombosis (age, 18 months). Of four patients with homocystinuria who did not have factor V Leiden, none had thrombosis (ages at this writing, 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. CONCLUSIONS: Patients with concurrent homocystinuria and factor V Leiden can have an increased risk of thrombosis. Screening for factor V Leiden may be indicated in patient with homocystinuria and their family members.

Adolescent↗
PubMed1996

First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency).

In Smith-Lemli-Opitz syndrome (SLOs), 7-dehydrocholesterol (7-DHC) accumulated because there is a block in the pathway for synthesis of cholesterol via 7-DHC. Prenatal diagnosis of SLOs has been achieved by analysis of 7-DHC in amniotic fluid obtained at 16-18 wk from pregnancies at risk. The purpose of this study was to investigate 7-DHC and cholesterol concentrations in chorionic villus (CV) samples with a view to performing first trimester prenatal diagnosis. Using a sensitive gas chromatography-mass spectrometry assay it was possible to detect 7-DHC in CV samples obtained as early as 7 wk of gestation. The ration of 7-DHC to cholesterol in placental tissue was shown to be relatively constant over the gestational period of 7-18 wk. We therefore proceeded to analyze the 7-DHC/cholesterol ration in CV samples taken at 10-12 wk of gestation from three pregnancies at risk for SLOs. The results were as follows: patient A, 1.10 x 10(-3); patient B, 1.80 x 10(-3); patient C, 0.091; control range for CVS (8-12 wk), 3.10 x 10(-4) to 1.62 x 10(-3) (mean +/- 2SD; n = 5). The fetus of patient C was diagnosed as affected by SLOs, and the parents requested termination. Analysis of cultured skin fibroblasts confirmed the diagnosis. Pregnancies A and B were diagnosed unaffected, and this was confirmed first by amniocentesis and then by the birth of normal infants at term. We conclude that synthesis of cholesterol via 7-DHC is occurring in the placenta and/or fetus at 10 wk of gestation and that prenatal diagnosis by CV biopsy is possible.

Amniocentesis↗
PubMed1996

Glutaric aciduria type I in the Arab and Jewish communities in Israel.

Mutation analysis was performed in eight families (16 patients) with glutaric aciduria type I (GA-I), which were all the families diagnosed in Israel in the years 1987-1994. Six families were of Moslem origin and two were non-Ashkenazi Jews. The entire coding region of the cDNA of the glutaryl-CoA dehydrogenase gene was sequenced in one patient of each family. Seven new mutations were identified in 15 of 16 mutated alleles, including six point mutations: T416I (4 alleles), G390R (1 allele), and S305L, A293T, L283P, and G1O1R (2 alleles each). In addition, a 1-bp deletion at position 1173 was identified in two alleles. These findings do not provide a molecular basis for the clinical variability in GA-I families. The occurrence of multiple novel mutations in a small geographic area may be explained by their recent onset in isolated communities with a high consanguinity rate.

Adult↗
PubMed1996

Congenital permanent diabetes: a different type of diabetes?

OBJECTIVE: To investigate two related children with congenital permanent diabetes. SUBJECTS AND METHODS: Two related male patients of Arab origin with congenital permanent diabetes were studied for immunological and genetic markers, insulin and glucagon secretion, thiamine levels, pancreatic ultrasounds studies and developmental characteristics. RESULTS: Both patients developed normally. The immunological markers were negative, there was no ketosis at diagnosis, and both patients were negative for diabetes susceptibility alleles at the HLA locus. Insulin levels were undetectable, glucagon secretion, thiamine levels and pancreatic ultrasound studies were normal. CONCLUSIONS: Congenital permanent diabetes is an extremely rare entity that differs from type I or type II diabetes. Our patients have a unique disorder with isolated beta cell defect and no additional manifestations. Autosomal recessive inheritance is suggested.

Child↗
PubMed1995

Polymorphisms in the alanine:glyoxylate aminotransferase gene and their application to the prenatal diagnosis of primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the hepatic alanine:glyoxylate aminotransferase enzyme encoded by the AGXT gene on chromosome 2. Prenatal diagnosis of PH1 either by measurement of hepatic enzyme activity or DNA analysis provides a valuable contribution to the management of pregnancies at risk for the severe infantile form of this disease. DNA analysis is preferred because it can be performed earlier in pregnancy and eliminates difficulties encountered in measurement of tissue enzyme activity, particularly those related to sample instability. We have assessed the clinical value of two polymorphisms located in introns 1 and 4 of the AGXT gene as linkage markers for the prenatal diagnosis of PH1 in 12 families. Eight of the twelve families were informative when either one or a combination of the two polymorphisms was used and prenatal diagnosis has been performed in two of these. The remaining four families were only partially informative. Five additional linkage markers on chromosome 2 have been identified which are co-inherited with the AGXT gene. Assays to detect these markers are currently under development.

Alanine Transaminase↗
PubMed1995

Macrophage uptake of oxidized LDL inhibits lysosomal sphingomyelinase, thus causing the accumulation of unesterified cholesterol-sphingomyelin-rich particles in the lysosomes. A possible role for 7-Ketocholesterol.

Macrophage uptake of oxidatively modified LDL (Ox-LDL), unlike the uptake of acetylated LDL (Ac-LDL), resulted in lysosomal accumulation of unesterified cholesterol (UC). As sphingomyelin (SM) binds UC with high affinity, we considered whether lysosomes also accumulate Ox-LDL-derived SM, and if such a phenomenon could be involved in the lysosomal trapping of Ox-LDL-derived UC. Incubation of J-774 A.1 macrophages with Ox-LDL increased the lysosomal accumulations of UC by 75% and SM by 63% compared with the effect of Ac-LDL. The addition of chlorpromazine, an inhibitor of lysosomal sphingomyelinase (SMase), to macrophages that were incubated with [3H]cholesteryl ester-labeled Ac-LDL also led to lysosomal accumulation of both SM and UC. 7-Ketocholesterol (7-KC), the major oxysterol in Ox-LDL, inhibited lysosomal SMase in a cell-free system. The addition of 7-KC to cells in the presence of [3H]choline- or [3H]cholesteryl ester-labeled Ac-LDL led to macrophage accumulation of SM or UC, respectively. Niemann-Pick type C disease (NP-C) is an inherited cholesterol-storage disease in which lysosomal SMase activity is attenuated after uptake of LDL. Incubation of monocyte-derived macrophages from two NP-C patients with Ac-LDL or Ox-LDL resulted in an accumulation of UC in the lysosomes, whereas normal monocyte-derived macrophages accumulate UC in their lysosomes after incubation with Ox-LDL but not Ac-LDL. These results suggest that inhibition of lysosomal SMase in NP-C cells or by 7-KC is required for lysosomal accumulation of UC. Analysis of the macrophage lysosomal extract (following cell incubation with Ox-LDL) by density-gradient ultracentrifugation and gel-filtration chromatography revealed the presence of a particle consisting of UC, SM, 7-KC, and apoB-100. We conclude that 7-KC in Ox-LDL can inhibit lysosomal SMase, thus leading to the accumulation of SM, which binds UC avidly and inhibits its further cellular processing out of the lysosome. As UC-SM particles of lysosomal origin exist in the atherosclerotic lesion, the formation of such particles may result from an impaired processing of Ox-LDL by arterial wall macrophages during early atherogenesis.

Animals↗
PubMed1995

Peroxisome mosaicism in the livers of peroxisomal deficiency patients.

Peroxisomal deficiency disorders, which are genetically transmitted, are assumed to be expressed in all cells, and the use of cultured skin fibroblasts for diagnosis and research is based on this assumption. We describe three patients with clinical, biochemical, and microscopic evidence of a peroxisomal disorder. However, their liver displays mosaicism, i.e., parenchymal cells with peroxisomes are adjacent to cells without peroxisomes. Ten percent (volume), 8%, and less than 1% of the parenchyma possessed peroxisomes that can be identified in immunocytochemical tests for six matrix and membrane proteins performed by light and electron microscopy. In the bulk of the parenchyma, catalase is localized in the cytoplasm, and in such cells no peroxisomes are evident by electron microscopy and immunolabeling for the 43-kd peroxisomal membrane protein (PMP) in two patients; in the third case, peroxisomal membrane ghosts are present. Immunoblots of peroxisomal beta-oxidation enzymes show a pattern similar to that from patients with a generalized peroxisomal deficiency. In contrast to the clinical and biochemical signs of peroxisomal dysfunction and hepatic histopathology, cultured fibroblasts from two patients demonstrate normal peroxisomal functions, including very-long-chain fatty acid oxidation and plasmalogen synthesis.

Bile Acids and Salts↗
PubMed1995

Reduced cellular cholesterol content in peroxisome-deficient fibroblasts is associated with impaired uptake of the patient's low density lipoprotein and with reduced cholesterol synthesis.

Mammalian cells acquire cellular cholesterol by de novo synthesis as well as by uptake of low density lipoprotein (LDL). Peroxisomes contain enzymes involved in the synthesis of cholesterol, and peroxisome-deficient (PD) patients have been shown to have hypocholesterolemia and abnormal LDL. We therefore decided to study whether cholesterol synthesis and cellular uptake of LDL are impaired in cultured PD fibroblasts. The present study demonstrates a significantly lower cellular cholesterol mass in fibroblasts from three PD patients, as compared to control cells (41-59% of controls). The rate of cholesterol synthesis was also reduced in all three PD cell lines, being 16-20% of the control values. LDL binding and degradation by fibroblasts were 3- to 5-fold higher in the PD cells as compared to control cells. Similarly, enrichment of normal fibroblasts with tetracosanoic acid (C-24:0), a situation that could mimic the in vivo accumulation of very long chain fatty acid (VLCFA) in PD cells, caused LDL binding and degradation to be 4-fold higher than in non-treated cells. On the other hand, the uptake of LDL derived from PD patients by normal fibroblasts was markedly reduced (by up to 67%) in comparison to the cellular uptake of normal LDL. Similar results were obtained in PD cells. This study demonstrates a lower cellular cholesterol content and reduced cholesterol synthesis rate in PD cell lines. In addition, we demonstrate that regulation of the uptake of normal LDL by cellular LDL receptors is operative in PD cells, whereas LDL derived from PD patients is not recognized normally by the LDL receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol↗
PubMed1995

Immunolocalization of a 43 kDa peroxisomal membrane protein in the liver of patients with generalized peroxisomal disorders.

The presence of peroxisomal membrane ghosts was examined in liver biopsies from eleven patients presenting the clinical and biochemical picture of a generalized peroxisomal disorder (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and variants of these syndromes). A polyclonal antibody raised against the membrane of human liver peroxisomes and recognizing a 43 kDa peroxisomal membrane protein (PMP) was used. In human control liver the antibodies react in a distinct and specific way with the peroxisomal membrane. Two types of organelles with an immunoreactive membrane were identified in the liver parenchymal cells of the patients: organelles containing an electron-dense core and organelles with electron transparent contents. Both types may co-occur in the same patient; in two patients they were found in the same cell. The organelles are rare, and their number varies between patients. The first type possibly corresponds to the previous morphological description of aberrant peroxisomes in the liver of patients with Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. The empty looking organelles have not been reported previously in the liver, some of the "empty" organelles seem to be enclosed by a double membrane. Morphometrical analysis in three patients indicated that both types of organelles (corrected mean d-circle 0.271-0.306 micron for the "empty" and the dense core organelles, respectively) are smaller than the peroxisomes in postnatal control liver and in fetal liver. In one patient (infantile Refsum disease) immunoreactive organelles were not detected. The organelles with the electron-dense core were not found in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Further studies on erythrocyte thiamin transport and phosphorylation in seven patients with thiamin-responsive megaloblastic anaemia.

Erythrocyte thiamin metabolism and transport were investigated in 7 patients from Brazil, Israel and Italy suffering from thiamin-responsive megaloblastic anaemia (TRMA) associated with diabetes mellitus and sensorineural deafness. All patients discontinued thiamin therapy for 4-7 days before the investigation. TRMA patients showed invariably reduced total thiamin levels in erythrocytes (percentage reduction compared with healthy controls, -46.8 +/- 3%; mean +/- SEM). The proportions of individual thiamin compounds, expressed as a percentage of total thiamin content, were within the normal range, whereas their absolute amounts were significantly decreased in the following order: thiamin monophosphate > thiamin pyrophosphate > thiamin. Thiamin pyrophosphokinase activity was also reduced as compared with controls (mean reduction +/- SEM, -25.9 +/- 1%). The saturable, specific component of thiamin uptake, which normally prevails at physiological concentrations of thiamin (< 2 mumol/L), was absent in erythrocytes obtained from TRMA patients, while the non-saturable (diffusive) component of uptake was normally present. These results confirm observations made previously in two patients and demonstrate that TRMA is consistently associated with a state of thiamin deficiency, which is presumably secondary to reduced thiamin cellular transport and absorption (caused by lack of a membrane-specific carrier), and to impaired intracellular pyrophosphorylation.

Anemia, Megaloblastic↗