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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 469 records · Page 26Linked to original sources
PubMed1990

Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators.

Linkage analysis in twenty-five families with acute (type I) spinal muscular atrophy (SMA) showed that the mutant gene responsible for the disorder is tightly linked to the D5S39 locus. The mutation(s) causing the intermediate (type II) and juvenile chronic (type III) forms of SMA were also mapped to DNA marker D5S39 on chromosome 5 (5q12-q14). Thus, the three forms, which have been differentiated clinically on the basis of age of onset and clinical course, are most probably due to different mutations at a single locus on chromosome 5. Prenatal diagnosis of SMA type I will now be possible.

Acute Disease↗
PubMed1990

Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X.

Rett syndrome (RS) was diagnosed in a girl with a t(X;22) (p11.22;p11). This translocation was also present in her unaffected mother and her sister affected by a neurological disorder compatible with a "forme fruste" of RS. Different etiological mechanisms are considered: gene disruption, X inactivation disturbance, metabolic interference. Whatever this may be, the localization of a RS related gene to the short arm of chromosome X is likely.

Child↗
PubMed1990

Clinical and genetic heterogeneity in retinitis pigmentosa.

The clinical course of defective vision and blindness has been investigated in relation to different modes of genetic transmission in a large series of 93 families with retinitis pigmentosa (RP). For autosomal dominant RP, two clinical subtypes could be distinguished according to the delay in macular involvement. In the severe form, macular involvement occurred within 10 years, while in the mild form, macular involvement occurred after 20 years. Interestingly, a significant increase of mean paternal age (38.8 years, mean controls in France = 29.1 years, P less than 0.001) was found in this form of RP, a feature which is suggestive of new mutations. For autosomal recessive RP, four significantly different clinical subtypes could be recognized, according to both age of onset and the pattern of development (P less than 0.001), namely cone-rod dystrophy and early-onset severe forms on the one hand (mean age of onset = 7.6 years), late-onset mild forms and senile forms on the other. Similarly, two significantly different clinical subtypes could be recognized in X-linked RP, according to both mode and age of onset, which were either myopia (mean age = 3.5 +/- 0.5 years) or night blindness (mean age = 10.6 +/- 4.1 years. P less than 0.001). By contrast, no difference was noted regarding the clinical course of the disease, which was remarkably severe whatever the clinical subtype (blindness before 25 years). In addition, all obligate carriers in our series were found to have either severe myopia or pigment deposits in their peripheral retina. Finally, sporadic RP represented the majority of cases in our series (42%). There was a considerable heterogeneity in this group, and at least three clinical forms could be recognized, namely cone-rod dystrophy, early onset-severe forms and late onset moderate forms. At the beginning of the disease, the hereditary nature of the sporadic forms was very difficult to ascertain (especially between 7-10 years) and only the clinical course could possibly provide information regarding the mode of inheritance. However, the high level of consanguinity, and the high sex ratio in early onset and severe sporadic forms (including cone-rod dystrophy), was suggestive of an autosomal or X-linked recessive inheritance, while increased paternal age in late onset forms was suggestive of autosomal dominant mutations.

Adolescent↗
PubMed1990

A probable sex difference in mutation rates in ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency is an X-linked disease with possible manifestations in heterozygous females. Using segregation analysis in families from the literature pooled with a French series, the penetrance could be estimated to be 17% in heterozygous females (15% with severe and 2% with milder symptoms). Using these estimates, the proportion of sporadic cases among heterozygous females and hemizygous males could be derived. This proportion is 57% in females. In males, it depends on mutation rate values: assuming equal mutation rates in sperm and eggs, this proportion should be 40%. However, this value can be strongly rejected based on the proportion of isolated cases in male sibships. In both sets of data, segregation analysis provided no evidence for sporadic affected males, suggesting that there are virtually no mutations in eggs. The upper limit of the confidence interval, 0%-16%, can be taken as the maximum prior probability that an affected male occurs as the result of a new mutation in his mother's germ cells.

Female↗
PubMed1990

Carrier detection in a partially dominant X-linked disease: ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disease responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes (15%). Increased orotic acid excretion occurs in both symptomatic and asymptomatic carriers, especially under protein loading tests. The disease is therefore partially dominant with neonatal lethality in the hemizygous male; the fraction of new mutations has previously been estimated to be low in males (point estimation = 0, upper bound of the confidence interval = 0.16) and 57% in females. Genetic counseling in this disease is difficult because it is not clear whether a negative protein loading test rules out carrier status. In an attempt to determine how reliable the test is for carrier detection, we investigated ten obligate carriers for orotic acid excretion; considering all data available, we concluded that the test is rarely negative in obligate carriers (8%). Consequently, a negative test in a mother decreases the minimum risk of being a carrier from 84% a priori to 30% if she had an affected son and from 43% a priori to 5% if she had a heterozygous daughter. Finally, the diagnosis of a new mutation in the germ cells of the maternal grandfather in one particular family could be ascertained by extensive DNA analysis.

Bayes Theorem↗
PubMed1990

The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states.

A 24-h fasting test was performed in 48 control children, in 9 hypoketotic patients with inherited defects of fatty acid oxidation and in 2 hyperketotic patients with inherited defects of ketolysis. The control group was then divided into three age groups on the basis of different adaptation to fasting. Concentrations of blood glucose, lactate, free fatty acids (FFA), 3-hydroxybutyrate, acetoacetate and carnitine were measured after 15 h, 20 h and 24 h of fasting. Significant negative correlations were found in the control group between plasma total ketone bodies (KB) and plasma glucose (P less than 0.001), plasma carnitine (P less than 0.005) and the amplitude of glycaemic response to glucagon at the end of the fast (P less than 0.01). FFA/KB ratio and the product of final fasting values of glucose and ketones were useful to differentiate between hypoketotic or hyperketotic patients and normal subjects. In children with a suspected or definite hyperketotic or hypoketotic disorder, a fasting test must only be performed in healthy patients, in good nutritional condition with non-diagnostic basal biochemical investigations. Carefully supervised fasting should be continued sufficiently to allow ketogenesis and ketolysis to become activated.

3-Hydroxybutyric Acid↗
PubMed1990

Clinical approach to inherited metabolic disorders in neonates.

Most inborn errors of intermediary metabolism presenting in the neonatal period fall schematically into three clinical categories: (1) those which lead to a neurological distress 'intoxication type' with a symptom-free interval, vomiting, comas, hypertonia, abnormal movements and frequent humoral disturbances (organic acidaemias, congenital urea cycle defects); (2) those which lead to a neurological distress 'energy deficiency' type. Frequent symptoms in this group include hyperlactacidaemia, severe hypotonia, cardiomyopathy, failure to thrive and malformations (congenital lactic acidaemias, fatty acid oxidation defects, peroxysomal disorders); (3) those which present evidence of liver dysfunction and hepatomegaly (glycogenesis, neoglucogenesis defects, galactosaemia, fructosaemia, tyrosinaemia type I). According to these three major clinical presentations and according to the proper use of few screening tests (blood gases, glucose, ammonia, lactic acid, electrolytes, acetest), we propose a method of diagnosis which groups these children into five schematical syndromes: type I MSUD; type II organic acidaemias; type III; congenital lactic acidosis; type IVa, urea cycle defects; type IVb, non-ketotic hyperglycinaemia, sulfite oxidase deficiency, peroxisomal disorders; type V liver dysfunctions. Once the above classification has been made, sophisticated and specific investigations can be planned (amino acid chromatography, organic acid chromatography, enzymatic studies, etc).

Acidosis, Lactic↗
PubMed1990

Usher syndrome type I is not linked to D1S81 (pTHH 33): evidence for genetic heterogeneity.

Usher syndrome is an autosomal recessive disease associating congenital sensorineural deafness and retinitis pigmentosa. Two clinical forms have been recognized, namely a) congenital and severe (type I) and b) later and moderate (type II). A linkage of the D1S81 probe (THH 33) with the gene for type II has been recently demonstrated by Kimberling et al. 1990. Here, a panel of 29 individuals from 6 kindreds with Usher syndrome type I has been tested for possible allelism at the D1S81 locus. A negative lod-score was found with this probe and close linkage to this region could be excluded. These different results support the view that the clinical heterogeneity in Usher syndrome is accounted for by an obvious genetic heterogeneity.

Blotting, Southern↗
PubMed1990

Exclusion of linkage between D3S47 (C17) and ADRPII gene in two large families of moderate autosomal dominant retinitis pigmentosa: evidence for genetic heterogeneity.

Autosomal dominant forms of retinitis pigmentosa appear among the most frequent types of retinal degenerations. Two clinical subtypes have been recognized, namely the early onset, severe form (type I) and the late onset, moderate form (type II). A linkage between the D3S47 probe (C17) with the gene of the type I has been recently demonstrated by Humphries et al., 1989. Here, two families with type II of the disease have been tested for possible allelism at the D3S47 locus. A negative lod-score was found with this probe and a linkage with this region could be excluded. These results support the hypothesis of a genetic heterogeneity in autosomal dominant forms of retinitis pigmentosa.

Genes, Dominant↗
PubMed1989

Apolipoprotein-E-gene expression in rat liver during development in relation to insulin and glucagon.

An apolipoprotein-E (apo-E) cDNA probe, cloned by immunoscreening of a lambda GT11 rat liver cDNA library, was used to further characterize the expression of the apo-E gene in rat liver during development, in relation to plasma insulin and glucagon levels. The apo-E mRNA level was low in fetus liver, then abruptly increased at birth and rose further during the suckling period. It returned to the level at birth in 10-week-old adults. These variations were paralleled with dramatic changes in plasma glucagon, which rose at birth and remained high during suckling. At the same time, the insulin/glucagon molar ratio fell. Administration of N6,O2-dibutyryl cAMP to 5-day-old rats resulted in a significant induction of liver apo-E mRNA. Moreover, liver apo-E mRNA rose in 10-h-fasted suckling rats as compared to controls, while plasma glucagon increased and the insulin/glucagon ratio decreased. Conversely, glucose feeding of suckling rats did not induce any increase in liver apo-E mRNA, the insulin/glucagon ratio was 10-fold higher than in fasted animals. Our results are consistent with liver apo-E gene expression being under the control of plasma glucagon and of the glucagon/insulin balance.

Animals↗
PubMed1989

Clinical approach to inherited metabolic diseases in the neonatal period: a 20-year survey.

Every newborn with unexplained neurological deterioration, ketosis, metabolic acidosis or hypoglycaemia should be suspected of having an inherited error of intermediary metabolism. Many of these conditions can be diagnosed clinically with the aid of simple laboratory investigations. Since a substantial number of these diseases respond well to treatment but may otherwise be fatal, and in order to assure adequate prenatal diagnosis in subsequent pregnancies, a high index of suspicion and rapid diagnosis are necessary in the face of the clinical presentations described. According to three major clinical presentations observed in 218 neonates with inborn errors of intermediary metabolism (neurological distress 'intoxication' type, neurological distress 'energy-deficiency' type and hypoglycaemia with liver dysfunction) and according to the proper use of few laboratory investigations, we propose a method of diagnosis which groups these children into five categories. Initial therapy, and sophisticated investigations can be planned on the basis of this grouping.

Energy Metabolism↗
PubMed1989

CpG dinucleotides are mutation hot spots in phenylketonuria.

The coding region of the phenylalanine hydroxylase (PAH) gene contains 22 CpG dinucleotides, including five doublets in the seventh exon of the gene. We hypothesized that CpG doublets could represent mutation hot spots in PAH deficiencies and we carried out the systematic sequence analysis of exon 7 in 20 unrelated PAH-deficient kindreds of Mediterranean ancestry. This procedure resulted in the detection of two novel missense mutations whose location and nature (CG to CA and CG to TG) were consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet (codon 261arg----gln and codon 252arg----trp). Moreover, the codon 261 mutation was found to be associated with mutant restriction fragment length polymorphism (RFLP) haplotype 1, the most frequent mutant RFLP haplotype at the PAH locus in the studies reported thus far. However, since the mutation was detected in only 36% of haplotype 1 mutant alleles, it appears that this haplotype at the PAH locus is genotypically heterogeneous in Mediterranean countries.

Amino Acid Sequence↗
PubMed1989

[Respiratory chain diseases in infancy. Clinical presentation and diagnosis].

Nineteen children with defects of the mitochondrial respiratory chain are described. First symptoms appeared during the first two years of their lives. Four types of clinical pictures were identified: 1/neonatal hypotonia. 2/cardiomyopathy. 3/progressive neurological deterioration. 4/multisystem disease. A study of pyruvate and fatty acids metabolism and a skeletal muscle biopsy were performed in all cases. Elevation of beta-hydroxybutyrate/acetoacetate and lactate were the most frequent biochemical abnormalities. Muscular biopsy in light microscopy showed in most cases abnormal lipid storage.

Biopsy↗
PubMed1989

Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency.

We report the characterization of a mutation in the phenylalanine hydroxylase (PAH) gene associated with partial residual activity of the enzyme. This point mutation (280glu----lys) was found by sequencing a mutant cDNA clone derived from a needle biopsy of the liver in a child with variant form of phenylketonuria. There is a strict concordance between homozygosity for the mutation and this particular phenotype. The (280glu----lys) mutation is linked to an original and rare RFLP haplotype at the PAH locus found in south Europe and North Africa. So far, this genotype-haplotype association is both inclusive and exclusive. Thirty-three PAH-deficient patients were screened for the mutation by using polymerase chain-reaction amplification of their genomic DNA extracted from Guthrie cards. Since a large number of patients can be screened for a particular mutation by using Guthrie cards, the possibility arises of using these samples collected by national newborn screening centers for prospective and retrospective detection of other mutations in the human genome.

Amino Acid Sequence↗