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Biomedical subjects

C Laberge

Publications and source records attributed to C Laberge.

At least 37 records · Page 2Linked to original sources
PubMed1989

Prospective ascertainment of complete and partial serum biotinidase deficiency in the newborn.

We screened 163,000 newborn filter-paper blood samples for serum biotinidase deficiency (McKusick 25326) and found 15 probands: three had complete deficiency (incidence 18.4 cases per million live births, 95% confidence interval 4-54 cases per million); the others had partial deficiency. The positive predictive value of the test for either form of biotinidase deficiency was 9.86%. We found seasonal variation in biotinidase activity in filter-paper blood samples. The cost per test was Can.$0.27 (1987 dollar value) and per case of complete deficiency ascertained, $15,500. Family studies indicated that complete serum biotinidase deficiency is a homozygous phenotype and partial deficiency is the heterozygous form. Homozygous cases were treated with biotin and have shown no clinical manifestations (55 patient-months of observation). None of the heterozygotes (n = 42, age 3 months - 62 years) has clinical manifestations. The number of heterozygotes found by screening was much less than predicted probably because the screening test detects mainly the samples with very low (outlier) biotinidase activity. The variant allele(s) for biotinidase deficiency was more common in French Canadians than in other ethnic groups in Quebec; there was no evidence of regional clustering or founder effect.

Amidohydrolases↗
PubMed1989

Myotonic dystrophy in Quebec: geographical distribution and concept of genetic homogeneity.

The geographical distribution relative to place of residence of patients with myotonic dystrophy (MD) and admitted to a Quebec hospital during a five year period (1980-1984) is presented and discussed. The sample consists of 72 males and 68 females of varying ages over 10 years. Analysis of the data shows a North Shore distribution of patients in a cline from Saguenay-Lac-St-Jean, through Québec City and to Montréal. However, a low prevalence is apparent on the South Shore, east of Québec City, for which an historical and genealogical explanation are discussed. This geographic distribution favours the hypothesis of genetic homogeneity for the MD gene in the Québec population. A stronger second argument comes from genealogical studies of 10 families sampled from the Chicoutimi Muscular Dystrophy Clinic. Genealogical paths traced to ancestors who founded Charlevoix for these 10 families go back to a cluster of 25 founders, one of whom must have been the carrier of the MD gene. The probative third argument for genetic homogeneity comes from the allelic distribution of the apolipoprotein E (ApoE) gene in the Québec City, Saguenay and in families with MD. The ApoE locus is on chromosome 19 and closely linked to MD. In MD-affected individuals there is a linkage disequilibrium for the epsilon 4 allele while non-MD members of these families show allelic frequencies not differing significantly from the control population.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Hypertriglyceridemia and lower LDL cholesterol concentration in relation to apolipoprotein E phenotypes in myotonic dystrophy.

Plasma lipid, lipoprotein levels and apolipoprotein apo E phenotypes were determined in 70 patients with myotonic dystrophy (MyD) and 81 controls. Marked differences were noticed in the apo E phenotype frequencies between the two groups. Plasma triglycerides and VLDL cholesterol were higher in MyD than controls, but only the latter was related to differences in the apo E phenotypes between two groups. Accordingly, the ratio of VLDL cholesterol/plasma triglycerides was increased significantly in MyD, suggesting accumulation of intermediary density particles due to lower affinity of E2 containing lipoproteins for lipoprotein cell receptors. The LDL cholesterol concentration was lower in MyD than controls and was related to differences in the apo E phenotype frequencies between the two groups. These results indicate increased removal of LDL particles in the apo E2 phenotypes, perhaps due to upregulation of LDL (B, E) receptor activity. Plasma cholesterol and HDL cholesterol concentrations were similar in both groups. Another feature of the study was lower levels of plasma cholesterol, triglycerides, VLDL and LDL cholesterol in the homozygous E4:E4 phenotype. These results suggest increased clearance rate of both VLDL and LDL particles and support the concept that apo E4-containing lipoproteins have higher in vivo affinity for ape E and/or B, E receptors.

Adolescent↗
PubMed1989

Myotonic dystrophy: linkage with apolipoprotein E and estimation of the gene carrier status with genetic markers.

The genes for myotonic dystrophy (MD) and for apolipoprotein E (ApoE) belong to a chromosome 19 synthenic group of markers. A familial linkage analysis between MD and ApoE was performed using the J Ott LIPED program (IBM PC/XT, April 1984) to estimate the genetic distance between these 2 genes. Of a total of 136 individuals in 11 MD families, 81 were confirmed to be affected by the disease and 41 were asymptomatic. ApoE phenotypes were determined in 115 of these 122 individuals. No recombinant was observed out of 74 meioses which were informatives for both MD and the ApoE isoproteins. A global maximal lod score Z of 19.00 was obtained at the recombination fraction theta = 0. The upper theta value at the confidence interval corresponding to the peak lod score (Z max) - 1 was 0.03. This suggests that the loci for MD and ApoE are at a distance of 0 to 0.03 Morgan. Since ApoE and apolipoprotein C2 (ApoC2) have been shown by others to be about 40 kb apart, our data are therefore consistent with the distance estimate of 0.02 Morgan reported between MD and ApoC2. The D19S19 (LDR152) polymorphic DNA sequence is also tightly linked to MD on chromosome 19. The segregation of ApoE isoproteins and of ApoC2 and D19S19 DNA polymorphism was utilized for evaluating the probability for individuals at risk of inheriting the disease gene in MD families. Data are presented on 3 families to emphasize the usefulness of genetic markers to estimate the MD gene carrier status of asymptomatic individuals and also for those presenting a partial syndrome. The limitations of such approach are also discussed.

Apolipoproteins E↗
PubMed1989

Novel PKU mutation on haplotype 2 in French-Canadians.

We analyzed DNA from nine French-Canadian probands from eastern Quebec province; all had hyperphenylalaninemia (phenylketonuria [PKU] or non-PKU forms) caused by mutations at the phenylalanine hydroxylase locus. Analysis of RFLP haplotypes and mutations revealed a novel mutation, an A-to-G transition (met----val) in codon 1 (the translation-initiation codon). It occurred on 5 of the 18 mutant chromosomes and was associated each time with haplotype 2. A proband homozygous for this mutation had the PKU phenotype. In other probands, the codon 1 mutation was inherited once with the splice junction mutation in exon 12 (on haplotype 3), conferring PKU, and was inherited twice with a mutation on haplotype 1, conferring PKU in one proband and non-PKU hyperphenylalaninemia in the other. The other five probands carried mutations, conferring PKU, on the following haplotype combinations: 1/3 (twice), 1/9, 3/4, and 1/1. The mutations on haplotypes 1, 4, and 9 are not yet characterized. This preliminary study reveals a novel PKU mutation and considerable genetic heterogeneity at the phenylalanine hydroxylase locus in French-Canadians.

Exons↗
PubMed1988

A study on the inheritance of thyroxine-binding globulin (TBG) deficiency from data obtained in 13 families detected by a neonatal screening program.

Thirteen families with thyroxine-binding globulin deficiency, detected through probands screened by the Quebec Network of Genetic Medicine, were investigated. These families were divided into two groups, depending on whether hemizygous males had low or undetectable serum thyroxine-binding globulin levels. Five families belonged to the low (hypo-TBGnemic) type while the remaining 8 families belonged to the absent (a-TBGnemic) type. On pedigree analysis, 10 families satisfied the requirements for an X-linked co-dominant mode of transmission. Three families, 2 a-TBGnemic and 1 hypo-TBGnemic, did not satisfy these requirements and three hypotheses had to be put forward to explain these situations: an autosomal recessive mode of transmission, a spontaneous mutation, or an extreme lyonisation of the defective X. Since the thyroxine-binding globulin gene has been localized to the X-chromosome, the two latter explanations appear to be the most plausible.

Female↗
PubMed1987

Feasibility of chemical screening of urine for neuroblastoma case finding in infancy in Quebec.

Neuroblastoma is the most common fatal solid tumour of childhood. Studies in Japan suggest that screening urine at 6 months for tumour-derived metabolites greatly improves early case finding and prognosis. The incidence rate of neuroblastoma in Quebec is at least 1 per 10,330 live births, higher than that of all other diseases responding to early treatment except congenital hypothyroidism screened for in the Quebec Network of Genetic Medicine. The feasibility of chemical screening of urine for elevated levels of homovanillic acid and vanillylmandelic acid in Quebec was assessed. The cost-effectiveness of screening 100,000 infants per year would be high (cost-benefit ratio 2.4), with a net saving of about $280,000 and eight lives per year. The estimated cost of adding neuroblastoma screening to the existing urine metabolite screening program is $70,700. The apparent sensitivity of the proposed test is 0.859 and the rate of false-positive results about 0.1%, both acceptable values. The attitude of potential participants toward the present urine screening program and the addition of a "tumour test" was positive. The results indicate that a pilot study of neuroblastoma screening in Quebec could be undertaken.

Attitude to Health↗
PubMed1987

A new probe for the diagnosis of myotonic muscular dystrophy.

Myotonic muscular dystrophy (DM) is the most common muscular dystrophy, affecting adults as well as children. It is inherited as an autosomal dominant trait and is characterized by variable expressivity and late age-of-onset. Linkage studies have established the locus on chromosome 19. In order to identify tightly linked probes for diagnosis as well as to define in detail the DM gene region, chromosome 19 libraries were constructed and screened for restriction fragment length polymorphisms tightly linked to DM. A genomic clone, LDR152 (D19S19), was isolated that is tightly linked to DM; recombination fraction = 0.0 (95% confidence limits 0.0-0.03); lod score, 15.4.

Adult↗
PubMed1987

The Hartnup phenotype: Mendelian transport disorder, multifactorial disease.

The Hartnup mutation affects an amino acid transport system of intestine and kidney used by a large group of neutral charge alpha-amino acids (six essential and several nonessential). We compared developmental outcomes and medical histories of 21 Hartnup subjects, identified through newborn screening, with those of 19 control sibs. We found no significant differences in means of growth percentiles and IQ scores between Hartnup and control groups (but all low academic performance scores were found in the Hartnup group, and various skin lesions occurred in five Hartnup subjects), no significant difference between means of the summed plasma values for amino acids affected by the Hartnup gene in Hartnup and control groups, two Hartnup subjects with clinical manifestations--impaired somatic growth and IQ in one, impaired growth and a "pellagrin" episode in the other--who had the lowest summed plasma amino acid values in the Hartnup group; the corresponding values for their sibs were the low outliers in the control group, and two tissue-specific forms of the Hartnup (transport) phenotype: renal and intestinal involvement (15 families) and renal involvement alone (one family), both forms having been inherited as autosomal recessives (the symptomatic probands had the usual form). Whereas deficient activity of the "Hartnup" transport system is monogenic, the associated plasma amino acid value (measured genotype) is polygenic. The latter describes the parameter of homeostasis and liability to disease. Cause of Hartnup disease is multifactorial.

Amino Acids↗
PubMed1986

Hereditary tyrosinemias (type I): a new vista on tyrosine toxicity and cancer.

Review of the literature of the past 40 years on tyrosine and its toxicity shows that no direct link between this aromatic amino acid and carcinogenesis has been well established. Ten years ago, studies of tyrosine toxicity in mice suggested the formation of an epoxide adduction product presumably derived from tyrosine by way of the liver microsomal detoxification system. Another study showed an increased frequency of hepatomas following long-term treatment with para-hydroxyphenyllactic acid, a tyrosine derivative occurring in the absence of p-hydroxyphenylpyruvate oxydase activity. Recently, studies on hereditary tyrosinemias (Type I) have indicated that the primary enzyme defect in these diseases is a deficiency of liver and renal fumarylacetoacetase. This results in an accumulation of natural alkylating derivatives of homogentisic acid such as maleyl- and fumarylacetoacetate in liver. Adduction of these compounds by glutathione is demonstrated by the presence of the mercapturic acid S-2-fumaryl-acetone-N-acetylcysteine in urine of patients. This adduct is also present in the urine of a number of heterozygote carriers after oral loads consisting of small quantities of homogentisic acid. In this report, we present the results of preliminary animal studies on the biochemical nature of the toxic effects of these tyrosine derivatives in these diseases along with preliminary data on the influence of fumarylacetone on protein synthesis in cultured eucaryotic cells. Fumarylacetone reacts as a natural alkylating agent and may, along with maleylacetoacetate, be responsible for the high incidence of late-onset hepatoma in the clinical chronic forms of hereditary tyrosinemias.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Purification of mRNA coding for the enzyme deficient in hereditary tyrosinemia, fumarylacetoacetate hydrolase.

As a step towards the cloning of the gene for fumarylacetoacetate hydrolase (FAH), we have purified the FAH mRNA from rat liver by specific immunoadsorption of polysomes. The relative abundance of this mRNA has been estimated to be 0.14%. The major in vitro translation product of the purified mRNA preparation is specifically precipitated by a rabbit anti-rat FAH antiserum and it is, furthermore, undistinguishable by criteria of mass and charge from purified rat FAH.

Amino Acid Metabolism, Inborn Errors↗
PubMed1982

Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinemia.

A technique designed to measure quantitatively succinylacetone (4,6-dioxoheptanoic acid) is presented. It essentially involves the inhibition of delta-aminolevulinate dehydratase (EC 4.2.1.24) by succinylacetone. Prior to their use in the assay, the samples are heated at 100 degrees C for 30 min in order to transform all succinylacetoacetate (3,5-dioxooctanedioic acid) to succinylacetone. By this transformation of the first abnormal metabolite specific to hereditary tyrosinemia to the second and last one, which is a powerful inhibitor of delta-aminolevulinate dehydratase, we determine in one sensitive assay the total amount of both. Succinylacetone was measured in sera and urines from 19 patients with hereditary tyrosinemia. All sera and urines contained succinylacetone at concentrations ranging, respectively, from 2 to 100 mumol/l and from 190 to 6000 mumol/g creatinine. The technique was also adapted to dried blood spots on paper and was used as a test complementary to blood tyrosine determination in mass screening for hereditary tyrosinemia. A total of 2412 samples having concentrations of 60 mg/l or more of tyrosine were assayed, and ten showed the presence of succinylacetone. These were all from newborns with hereditary tyrosinemia. The test has proven to virtually eliminate false positives, and, thereby, much clerical work and parental anxiety.

Amino Acid Metabolism, Inborn Errors↗
PubMed1982

Prenatal diagnosis of hereditary tyrosinaemia: measurement of succinylacetone in amniotic fluid.

A method is proposed for prenatal diagnosis in pregnancies at risk of hereditary tryosinaemia. Affected fetuses were detected on the basis of the abnormal presence in the amniotic fluid of succinylacetone, a metabolite previously identified in sera and urines of patients suffering from hereditary tyrosinaemia. Our data show that the forty amniotic control samples had no detectable succinylacetone, while succinylacetone was found in three out of the thirteen cases at risk. Following the parents' decision, these three fetuses were aborted. The ten other mothers who brought their pregnancies to term had normal infants. Enzymatic analysis from two of their aborted fetuses' livers revealed an absence or a low activity of fumarylaceto-acetate hydrolase (EC 3.7.1.2) compared with control fetal livers of the same age.

Amniotic Fluid↗
PubMed1981

Ammonia metabolism in a family affected by hyperargininemia.

A French-Canadian family, with a 14-year old mentally retarded girl, was investigated for hyperargininemia. The girl showed a fasting plasma ammonia N concentration of 100 micrograms/dl (normal : 50.5 +/- 13 micrograms/dl), and a two-hour post protein load level of 183 micrograms/dl (normal : 51.6 +/- 17.6 micrograms/dl). Plasma urea N was lower than normal in the post-load sample. Arginine concentrations were 11 times normal in the plasma, 47 times normal in the urine and 4 times normal in erythrocytes. Measurement of erythrocyte arginase showed only 1% activity in the propositus, and 52-54% in the parents and a sibling as compared to controls. In heterozygous members of the family, the Km (arginine) was similar to controls. Column chromatography of serum amino acids in the propositus showed arginine to be 17.6 S.D. higher than the normal mean. A characteristic cystine-lysinuria pattern of urinary amino acids was also seen. Measurement of other urinary nitrogenous metabolites showed low urinary urea and excessive orotic aciduria. On "normal" food intake, the patient excreted 122 mg of orotic acid/24 h, as against 3.7 mg by the sibling and 3.9 mg by the mother. It is postulated that the level of ornithine in hepatocyte mitochondria is critical to the disposal of carbamyl phosphate. The lack of normal regeneration of ornithine by liver arginase, and an excessive urinary excretion may be responsible for its low mitochondrial concentration. This would cause diversion of unmetabolised carbamyl phosphate towards orotic acid synthesis or ammonia production.

Adolescent↗