Jacques Letarte

Preliminary report on a mass screening program for neonatal hypothyroidism

We have recently developed an immunoassay that can measure thyroxine rapidly and accurately in the eluate of 40 mul of dried blood spotted on filter paper at the fifth day of life. The method is completely automated and by using the samples received by the Central Laboratory of the Quebec Network for Genetic Medicine and their follow-up facilities, we are now screening every newborn in the province of Quebec for neonatal hypothyroidism. To date, from 47,000 measurements, three newborn infants with abnormally low TBG and seven hypothyroid infants have been detected. From these data we conclude that the frequency of congenital hypothyroidism is about one in 7,000 births and that our method is effective in detecting thyroid hormone abnormalities with an acceptable percentage of false positive measurements; no false negative results have occurred to our knowledge.

Useful parameters to predict the eventual mental outcome of hypothyroid children

ABSTRACT: The Quebec Network for Genetic Medicine has followed the development of some 100 hypothyroid children treated by 1 month of age and evaluated at 18 months, 3 and 5 yr and the Griffiths Mental Development Scales, then at 7 and 9 yr with the Wechsler Intelligence Scale for Children Revised. Results show that the children as a group reach scores within the normal range of the tests. However, a few patients have low scores at each evaluation. Previously, we showed a correlation between a low serum thyroxine concentration, or a relatively retarded bone maturation before treatment, and low mental scores. To better characterize the significance of this relationship we correlated these pretreatment factors and the Wechsler Intelligence Scale for Children Revised results of 43 subjects reaching the age of 7 yr. Again, the same correlation was observed. Calculating a predictive factor (low thyroxine, <2 μg/dl and retarded bone surface, <0.05 cm2) from data recorded before therapy initiation, 10 of 13 children were correctly predicted to have I.Q. values <90. The use of these parameters might permit early intervention, and allow specific guidance of the more affected subjects.

Ornithine transcarbamylase deficiency in mutant mice I. Studies on the characterization of enzyme defect and suitability as animal model of human disease.

Summary: Eighty-four young mice born from matings of four sparse-fur (spf)/+ females and two 22A +/Y males, were classified according to spf phenotype for males and orotic acid excretion and ornithine transcarbamylase (OTC) activity for females. The OTC activity of 15.2 ± 1.32 μmole citrulline/mg protein/hr shown by hemizygous affected males was 13% of that of normal males. Heterozygous females showed a much wider variation with a mean activity of 56% of normals.Apparent Km and Vmax of the liver OTC in respect of carbamyl phosphate (CP) and ornithine (ORN) were measured for the hemizygous affected males, heterozygous females, and normal males and females. Km and Vmax (CP) for hemizygous affected males were significantly lower than normal males, normal females, and heterozygous females. Mean Km and Vmax (CP) values of heterozygous females were also significantly different from normal groups and hemizygous affected males. There were no significant differences for the values of Km (ORN) among various groups. However, the Vmax (ORN) of hemizygous males was significantly lower than the other three groups. Vmax (ORN) of the heterozygous females was also lower than the normal groups.Mean value of 18.38 ± 5.13 μmole orotic acid/mg creatinine, excreted by spf/Y males, was significantly higher than all other groups. The average excretion of 7.38 ± 5.63 μmole by heterozygous females was also significantly higher than normal males (0.72 ± 0.23 μmole) and females (0.54 ± 0.27 μmole). The high orotic acid excretion by mutant mice underlines the basic similarity of these animals to the human counterpart.There was no significant difference in the excretion of urinary urea between normal males and affected hemizygous males, or between normal females and heterozygous females.Speculation: Lower Km for carbamyl phosphate might be a characteristic of OTC from mutant mice with spf gene, which could be detected by urinary orotic acid measurement. These mice would prove to be useful animal models for studying nutritional and therapeutic measures to alleviate the consequences of OTC deficiency in children. Characterization of the defect of a mutant enzyme in an animal model should lead to greater understanding of the human disease counterpart. These studies would also be helpful in investigation of other inherited hyperammonemic syndromes.

Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B

Eight infants presented with a malabsorption syndrome, normal fasting triglycerides, hypocholesterolemia (64.3 +/- 10.0 mg/dl), and deficiency of vitamins A and E. Plasma low-density lipoprotein, apolipoprotein B, and apolipoprotein A-I were decreased. After a fatty meal, plasma triglycerides did not increase and chylomicrons could not be identified. Lipoprotein composition was characterized by normal apoproteins, high phospholipids, and low cholesterol. Increased triglycerides were present in low-density lipoproteins. Immunoperoxidase localization of apolipoprotein B on fasting biopsy specimens showed increased staining of the lipid-laden intestinal epithelial cells compared to normals. On electron microscopy after a fat load, the enterocytes contained large numbers of fat particles vesiculating the endoplasmic reticulum. These particles, morphologically similar to chylomicrons, were also present as aggregates of well-individualized lipid droplets within dilated vesicles in the Golgi zone, but were not seen in the intercellular spaces and lacteals. This recessively transmitted condition differs from abetalipoproteinemia and from the homozygous form of hypobetalipoproteinemia and may be caused by a defect in the final assembly of chylomicrons or in the mechanism of their exocytosis.

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.

Guanidino Compound Analysis as a Complementary Diagnostic Parameter for Hyperargininemia: Follow-Up of Guanidino Compound Levels during Therapy

ABSTRACT: The aim of this collaborative study was to investigate whether guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange Chromatographie system with a fluorescence detection method. The serum arginine, homoarginine, α-keto-δ-guanidino-valeric acid, argininic acid, and N-α-acetylarginine levels of all the hyperargininemic patients are higher than the normal range. Similar increases were seen for the urinary excretion of α-keto-δ-guanidinovaleric acid and argininic acid. Untreated hyperargininemic patients have the highest guanidino compound levels in cerebrospinal fluid. However, even under therapy, the arginine, homoarginine, α-keto-δ-guanidinovaleric acid, and argininic acid levels in cerebrospinal fluid are still increased. Protein restriction alone is not sufficient to normalize the hyperargininemia, but protein restriction together with supplementation of essential amino acids with or without sodium benzoate decreases further the arginine levels. However, whereas the argininemia can be normalized, the catabolites of arginine are still increased. We conclude that the urinary amino acid levels may remain normal in hyperargininemia, whereas consistent increases of the guanidino compounds are observed. Thus, guanidino compound analyses can be used as a complementary biochemical diagnostic parameter for hyperargininemia. Although the argininemia can be normalized by therapy, the levels of the catabolites of arginine are still elevated.

Carbohydrate intolerance in children and adolescents with Turner syndrome

Carbohydrate homeostasis was evaluated in 41 girls, 6 to 20 years of age, with Turner syndrome by means of oral and intravenous glucose tolerance tests, as well as intravenous tolbutamide. Mean (±SE) glucose levels following oral glucose were higher at 60 minutes (162±5 vs 134±6 mg/dl, 2 P P P

A twenty-year experience with thyroid carcinoma in children

During the past 20 years, 23 patients (7 males, 16 females) were operated on for thyroid carcinoma in our institution. The average age was 13.6 years (range, 22 months to 27 years). Our series includes papillary carcinoma in 11, follicular carcinoma in four, and medullary thyroid carcinoma in eight patients. Follow-up ranged from 8 months to 20.3 years, with an average of 7.5 years for well-differentiated carcinomas and 4.3 years for medullary thyroid carcinomas. All patients are presently alive with no evidence of progressive disease. Patients with papillary and follicular carcinomas underwent partial thyroidectomy; those with medullary carcinoma underwent total thyroidectomy. Serious complications included three permanent hypoparathyroidism and two tracheostomies, all after secondary neck explorations. The overall results observed in our series of patients seem to support the current conservative approach to well-differentiated thyroid carcinoma, reserving total thyroidectomy for medullary cancer of the thyroid. A more aggressive search for familial medullary carcinoma through use of pentagastrin stimulation leads to early detection and more effective therapy.

Effect of Stress and Hypothalamic Deafferentation on the Secretion of Growth Hormone in the Rat

Stressful stimuli are known to inhibitthe secretion of radioimmunoassayable rat growth hormone (RGH). Groups of adult male rats submitted to one of three different types of hypothalamic deafferentation (total, incomplete, or frontal) were exposed to ether and auditory stresses at 1 week intervals. Ether and auditory stresses were equally effective in inhibiting the RGH secretion in controls and frontally deafferented rats. Ether stress inhibited the RGH values of completely deafferented animals, while auditory stress left these values unchanged; α-MT pretreatment blocked the effect of ether stress in such animals. Neither stress was able to modify the already low values of the incompletely deafferented rats; pentobarbital anesthesia induced a marked rise of RGH plasma levels in these animals. Base-line levels of RGH were significantly higher in frontally deafferented, and significantly lower in incompletely deafferented rats than those of controls. These data seem to indicate that ether stress is transmitted through a humoral, dopa-minergic pathway, while auditory stress follows a nervous pathway. In addition, extra-hypothalamic influences seem to modulate the secretion of RGH through frontal inhibitory and postero-lateral stimulatory nervous pathways.

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

ABSTRACT. 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.