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Biomedical subjects

J Letarte

Publications and source records attributed to J Letarte.

At least 37 records · Page 2Linked to original sources
PubMed1986

Postnatal maturation of enterocytes in sparse-fur mutant mice.

In adult sparse-fur mutant mice, ornithine transcarbamylase (OTC) activity represents only 14% of the normal values. We studied the development of this activity from birth to adult period and demonstrated that the enzyme deficiency is already fully expressed at birth, in both the liver and the small intestine of mutants. Since OTC catalyzes the conversion of ornithine to citrulline, in the presence of carbamoyl-phosphate, the effect of a disturbed ornithine metabolism on the postnatal development of the small intestine has been evaluated. The normal appearance of sucrase as well as the normal increase of glucoamylase, trehalase, and alkaline phosphatase activities are delayed in sparse-fur mice compared with controls. Moreover, normal adult values are never attained. In contrast, the normal decline of lactase activity is impaired while leucylnaphthylamidase activity is unaffected. Cell proliferation, as evaluated by [3H]thymidine incorporation into DNA and mitotic index, is less active during the 3rd wk of life in mutants. These phenomena are closely associated with a transient weak arginase and ornithine decarboxylase activity in the small intestine. Since arginase catalyzes the conversion of arginine to orthithine, thus ensuring the availability of this substrate for ornithine decarboxylase activity, these results indicate a disturbance of polyamine metabolism in mutant enterocytes with a consequent delay in postnatal differentiation and proliferation. Sparse-fur mutant mouse may therefore represent a useful animal model for evaluating the role of ornithine metabolism in the maturation process of the small intestine.

Animals↗
PubMed1986

Auditory brainstem response audiometry in congenitally hypothyroid children under early replacement therapy.

Using auditory brainstem response audiometry, we evaluated 34 congenital hypothyroidism children under thyroid hormone therapy and 24 age- and sex-matched controls between 5 and 12 yr of age. Two main auditory brainstem response abnormalities were encountered: first, prolonged wave I latencies, secondary to a peripheral impairment, were found in seven congenital hypothyroidism children (20%): three of these showed signs of serious otitis media, unilaterally in two and bilaterally in the other, at the time of the evaluation. Second, shortened I-V interpeak latencies were observed in 10 children (29%). No correlation was found between the interpeak latencies and the L-thyroxine serum values at the time of the test or just prior to treatment initiation. Also, there was no correlation with estimated bone age at treatment initiation or with the Griffiths global mental development quotients assessed at 5 yr of age. These preliminary results suggest a significant incidence of auditory brainstem response abnormalities in treated hypothyroid children.

Audiometry↗
PubMed1986

Significance of transported glycine in the conjugation of sodium benzoate in spf mutant mice with ornithine transcarbamylase deficiency.

3H-glycine and 14C-serine were injected intraperitoneally, during treatment of spf mutant mice with 2% sodium benzoate in drinking water. Urinary hippurate was separated by thin layer chromatography and counted for 3H and 14C labels representing transported and newly synthesized glycine, respectively. The specific activity of 3H-hippurate increased significantly in mutant and normal groups, while the increase of 14C was seen only in mutants. The ratio of specific activity 3H:14C showed significant increases in normal (0.99 to 1.93; p less than 0.01) and mutant (1.53 to 3.05; p less than 0.05) groups, which shows that glycine transported from body pools played a significantly greater role in the conjugation of benzoate, compared to glycine synthesized de novo from serine. In spf mice, benzoate treatment also resulted in a decrease in orotate excretion, indicating amelioration of the hyperammonemic state. It is postulated that the elimination of glycine transported from body pools may be the primary mechanism for the reduction of ammoniagenicity in benzoate therapy, and that the de novo synthesis of glycine may have a secondary effect.

Animals↗
PubMed1986

[Variability of enzyme activity and urinary orotic acid in ornithine transcarbamylase deficient spf/+ heterozygotic mice].

Urinary orotate excretion is used as a clinical parameter to distinguish female carriers of X-linked ornithine transcarbamylase deficiency. The value of this test has been considered doubtful due to a lack of knowledge about the true variability of hepatic enzyme activity and its effect on orotate synthesis. We have used a purebred population of spf/+ heterozygous females (n = 90), with an X-linked structural mutation of ornithine transcarbamylase, to study this variability in comparison with normal +/+ females (n = 19) and hemizygous spf/Y males (n = 20). Our results show that spf/+ heterozygotes have a mean hepatic enzyme activity equal to 64% of the normal group, as compared to 44-56% reported previously. They have a very wide variability (range 28-107 mumol/h/mg protein) which overlap the normal distribution curves of +/+ and spf/Y groups. Similar overlapping is shown in the distribution of urinary orotate excretion. The correlation studies indicate that the urinary orotate level as an index of hepatic enzyme deficiency is of value only in heterozygotes having an activity less than 50% of normal. This parameter cannot, therefore, be used to screen for all heterozygotes. However, it would still be valuable in distinguishing female-children at risk of developing hyperammonemic symptoms.

Animals↗
PubMed1985

Guanidino compounds in plasma, urine and cerebrospinal fluid of hyperargininemic patients during therapy.

The concentrations of guanidino compounds were determined in urine, plasma and cerebrospinal fluid of two patients with hyperargininemia during dietary therapy. alpha-Keto-delta-guanidinovaleric acid, N-alpha-acetylarginine, argininic acid and gamma-guanidinobutyric acid were increased in urine. In plasma, these compounds together with creatine, guanidinoacetic acid, arginine and homoarginine were also increased. In cerebrospinal fluid, only arginine, homoarginine and argininic acid were increased. Trace amounts of alpha-keto-delta-guanidinovaleric acid were found in cerebrospinal fluid of the patient treated with only a low-arginine diet. The concentrations of guanidinosuccinic acid are decreased in urine, plasma and cerebrospinal fluid. During a low-arginine diet, together with sodium benzoate therapy, the plasma and cerebrospinal fluid arginine values returned to normal. There was also a normalization of plasma guanidinoacetic acid and a marked decrease in plasma N-alpha-acetylarginine and argininic acid.

Adolescent↗
PubMed1985

Hepatotoxicity of sodium valproate in ornithine transcarbamylase-deficient mice.

Susceptibility to sodium valproate (SV) hepatotoxicity was investigated in male sparse-fur mutant (spf/Y) mice with X-linked ornithine transcarbamylase (OTC) deficiency, as compared to normals (+/Y). SV was given in drinking water, in increasing concentrations of 0, 0.05, 0.15 and 0.25%. Actual SV intake was similar in both groups. There were no significant changes in orotate excretion, but alpha-amino nitrogen increased progressively with SV intake in both groups. Valproate-treated animals also had a significant increase in hepatic carbamyl phosphate synthetase-I (CPS-I) activity. OTC-deficient spf/Y mice showed 33% mortality and morbidity at 0.05-0.15% valproate, while normal mice remained non-symptomatic. spf/Y Mice also showed a higher incidence of hepatocellular necrosis, microvesicular steatosis and polymorphic infiltration. Centrilobular necrosis was seen only in symptomatic OTC-deficient mice, indicating an idiosyncratic hepatotoxic response which may be different from the dose-related effects seen in all SV-treated mice. Electron microscopy of liver sections from severely affected spf/Y mice showed marked abnormalities of mitochondria, which appeared swollen or rounded. The rough endoplasmic reticulum was dilated and filled with a flocculent material. It is postulated that the idiosyncratic response in OTC-deficient mice may be caused by an interaction between a metabolic aberration of mitochondria and toxic metabolites of valproate.

Animals↗
PubMed1985

Expression of ornithine transcarbamylase deficiency in the small intestine and colon of sparse-fur mutant mice.

Sparse-fur mutant mice have an X-linked deficiency of liver ornithine transcarbamylase (OTC), similar to congenital hyperammonemia type II seen in children. The purpose of the present study was to see whether the expression of enzyme deficiency in the small intestine and colon was similar to that in the liver. Our results show that the level of residual OTC activity in duodenal, jejunal, and ileal mucosa is not significantly different from that of the liver, both in mutant heterozygous female and hemizygous male mice. A highly significant (p less than 0.001) positive correlation was seen between the enzyme activity from all segments of the normal and mutant intestine and that of the liver. pH dependence of mucosal OTC was similar to liver enzyme, when compared within normal or hemizygous mutant mice. Apparent Km (ornithine) of the enzyme from normal or mutant small intestine did not show any significant differences when compared with OTC from normal or mutant livers, respectively. Apparent Km (carbamyl phosphate) from both organs of normal mice was also similar. However, Km (carbamyl phosphate) of mutant intestine and liver gave variable results on statistical comparisons. The specific activity in the proximal and distal colon of mutant mice was significantly lower (p less than 0.001) than normal mice, and showed a similar expression of enzyme deficiency as seen in the small intestine. The similarity of OTC deficiency in the intestine and liver of sparse-fur mice would provide a basis for investigating the use of mucosal biopsies in the confirmation and characterization of human disease.

Animals↗
PubMed1983

A new French-Canadian family affected by hyperargininaemia.

A new French-Canadian family from the province of Quebec is reported, in which a male child was diagnosed as hyperargininaemic after showing positive tests for cystinuria on neonatal screening. The child has no residual activity of erythrocyte arginase, and a plasma arginine level of 633 mumol/l. Both parents have 32-38% of arginase activity. A newborn sister has normal enzyme levels. The propositus did not show abnormal plasma ammonia elevation even after a protein tolerance test (1.5 g protein/kg body weight) but excretes high levels of urinary orotate (845 mg/g creatinine). At 3 1/2 years of age the hyperargininaemic child had started showing abnormal gait, ataxia and slowing of intellectual development. It is suggested that all newborn children showing cystinuria-lysinuria pattern of amino acid excretion be tested for arginase deficiency.

Adult↗
PubMed1983

Preliminary results on the mental development of hypothyroid infants detected by the Quebec Screening Program.

A prospective study of the mental development of hypothyroid infants detected by the Quebec Network for Genetic Medicine began in January, 1976. The mean age at initiation of thyroid hormone therapy was 27 days. Forty-five hypothyroid infants and 37 normal control subjects were assessed at age 12 months with the Griffiths mental development test; 77 and 41, respectively, were assessed at age 18 months, and 59 and 40, respectively, at 36 months. There were no statistically significant differences in the various test scores between the two populations at age 12 months, but at age 18 and 36 months the hypothyroid infants had lower scores in hearing-speech performance scales and practical reasoning (36 months) which also decreased their global quotient. The mean scores were still above 100 and only nine were below 85. Further assessment of the influence of early therapy on mental development at age 6 years is needed before definitive statements can be made about the long-term mental development in these subjects.

Child, Preschool↗
PubMed1982

Activity of orotate metabolizing enzyme complex and various urea-cycle enzymes in mutant mice with ornithine transcarbamylase deficiency.

The overall activity of the enzyme complex consisting of orotate phosphoribosyl transferase and orotidine monophosphate decarboxylase, and of various enzymes of the urea cycle, has ben studied in sparse-fur (spf) mutant mice with ornithine transcarbamylase deficiency. The enzyme complex has a lower overall activity, which could be caused by disturbed pyrimidine metabolism due to hyperammonemia. Other enzymes of the urea cycle do not show any significant change.

Animals↗
PubMed1982

Cataracts and ketotic hypoglycemia.

Of 40 patients with ketotic hypoglycemia, 15 (nine boys and six girls) developed cataracts. The mean age at onset of the first hypoglycemic attack was 20 months, and the average age at the time the cataracts were discovered was 3 1/4 years. The average birth weight of 14 children was 2060 g. The cataracts were bilateral in all but one case. Seven patients (11 eyes, bilateral in four patients) developed complete cataracts. Despite aphakic correction and occlusion therapy, the major cause of visual loss after cataract surgery was stimulus deprivation amblyopia. Other ocular abnormalities included strabismus and jerky horizontal nystagmus. Neurologic impairment--epilepsy, psychomotor retardation, and/or electroencephalographic abnormalities--was present in over one half of the patients. All children with ketotic hypoglycemia should be referred promptly for an ophthalmic examination so that appropriate therapy can be implemented early.

Age Factors↗
PubMed1982

Cardiac dimensions and myocardial function of infants with congenital hypothyroidism. An echocardiographic study.

This study was undertaken to evaluate the cardiac dimensions and various indices of myocardial function, determined by echocardiography, in a group of 12 infants with congenital hypothyroidism. Left ventricular systolic and diastolic dimensions, posterior wall thickness, enddiastolic and systolic volumes were all significantly lower in the hypothyroid infants compared with 25 normal infants of the same age. No pericardial effusion was found. Hypothyroid infant had a lower heart rate with a reduced cardiac output. The mean velocity of circumferential fibre shortening and the shortening fraction of the left ventricle were normal. The pre-ejection period of the left ventricle (PEP), however, was abnormally prolonged as well as the ratio PEP over left ventricular ejection time (PEP/ET). This ratio correlated inversely with the end-diastolic volume, suggesting that the increased PEP/ET could be partly the result of decreased preload.

Cardiac Volume↗
PubMed1982

[Neonatal electrocardiographic manifestations of congenital hypothyroidism. Correlation with echocardiographic data].

Twelve infants, average age 5, 4 weeks (range 3 to 8 weeks) with congenital hypothyroidism were studied. In addition to routine evaluation including plasma T3, T4 and TSH estimation and the establishment of a clinical index of hypothyroidism on electrocardiogram and an echocardiogram were performed. The following variables were analysed: heart rate, QRS axis in the frontal plane, PR interval in Lead II, corrected QT interval in V5, amplitude of the P waves in Lead II, R waves in V3R, V1, V5 and V6; S waves in V1, V2 and V4 and T wave in V6. The ventricular activation time in V5 and QRS duration in V3R, V1 and V6 were also measured. The presence of pericardial effusion, left ventricular posterior wall and septal thickness, and left ventricular internal diastolic and systolic dimensions were determined by echocardiography. The following conclusions were drawn: 1. The ECG of hypothyroidism in the neonatal period is characterised by the low amplitude of the left ventricular potentials while increased conduction times were much less evident; 2. Only the sum of R + S in V2, the amplitude of the T wave in V6 and increase in QRS duration in V3R were influenced by severity of hypothyroidism; 3. Left ventricular microvoltage is not due to pericardial effusion which was absent in all our cases.

Congenital Hypothyroidism↗