Metabolic Anomalies in Cri du Chat Syndrome (5 p-) Lymphocytes and de Novo Purine Synthesis

Marie A. Peeters, Marie Odile Réthoré, André Megarbane, Jérôme Lejeune, Institut de Progrenèse, Paris, France.


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To test the hypothesis that the clinical features of cri du chat syndrome may be in relation with a defect of purine metabolism we used an in vitro assay examining variation of the mitotic index in the presence or absence of various inhibitors or metabolites of purine synthesis. Sixteen peripheral blood cultures from a total of twelve patients with cri du chat were cultured for 72 hours according to standard culture techniques. The drugs, added on initiation of the culture which showed significant results were: L-Alanosine (0.062 mg/L) and HAT medium (62.5 µM hypoxanthine, 0.25 µm aminopterin, 10 µM thymidine). Controls used for the analysis were: 136 normal adults, 91 patients with documented Trisomy 21, 30 patients with Fragile-X syndrome and 83 patients with mental retardation of another etiologies. Results were analyzed by comparing the mitotic index of each experiment to the patient's own control culture and expressed as the percentage increment or decrease in mitotic index. We found a paradoxical increase in the mitotic index in the presence of L-Alanosine in lymphocyte cultures of patients with 5p- who were on no medication, as well as particularly severe toxicity in HAT medium. This response, apparently characteristic for 5p-syndrome was highly significant when compared to the one observed in the control population. When patients with cri du chat syndrome were given inosine with folinic acide as in vivo medication, their in vitro lymphocyte assay showed an inversion of the response to L-Alanosine (decrease in mitotic index) as well as a normalization of their response to HAT medium. These findings suggest that the deletion of 5p14-5pl5 leads to impairment of de novo purine synthesis which could account for the characteristic failure to thrive as well as for the abnormal brain development and function. We suggest that genes coding for enzymes intervening in the final stages of de novo purine synthesis should be sought for on the 5p14-5p15 segment. Were this the case, early substitutive therapy with inosine and perhaps folic acide derivatives might be of benefit to these children.

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Elevated TSH Levels in Infants with Down Syndrome: Normalization by Supplemental Folic Acide

Marie A. Peeters, Jérôme Lejeune, Institut de Progenèse, Paris, France.

There is a well known association between thyroid disorders and Down syndrome. Recently it has been suggested that thyroid dysfunction may be age-related and that it is encountered predominantly in Down syndrome infants less than three years of age. We studied 91 infants with documented trisomy 21, aged less than three years at the time of their thyroid function studies, who were seen at the Genetics Clinic Hôpital des Enfants Malades (Paris): 29 infants (16 males, 13 females; mean age 17.5±12.6 months) had their thyroid studies done at the time of their first visit, prior to any therapy. Twenty-two infants were less than two years of age. - 62 infants (33 males, 29 females; mean age: 14±7 months) of whom 56 were less than two years of age, had their thyroid studies done after at least two months of therapy: folic acide supplementation (0.5-1mg/kg/day) plus A) - pediatric mufti-vitamins (at standard recommended doses); 30 patients; B) - pediatric mufti-vitamins and methionine (50-100mg/kg/day); 21 patients; c) - pediatric mufti-vitamins and vitamin 12: 11 patients. The incidence of thyroid dysfunction in the group of patients receiving therapy was 16%, whereas it was 55% in the group receiving no therapy (X2 =13,2; p<0.001). In the group receiving no therapy, TSH decreased after folic acids supplementation in most patients. Ultimately only 10% of patients (in both groups) required L-thyroxine therapy for persistence of elevated TS H levels. Thirty-nine patients were started on folic acide and pediatric multivitamins prior to six months of age. Only 2 (5%) ultimately received L-thyroxine therapy. It has been suggested that TSH elevation in Down syndrome infants is due to delayed maturation of feed-back control system of the thyroid gland responsiveness. Delayed maturation of other biological systems have been documented in Down syndrome. Our findings suggest that folic acide in association with pediatric mufti-vitamins especially when given prior to six months of age may be a modulator of thyroid function and play a role in the maturation process.

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Excessive Glutamine Sensitivity in Alzheimer Disease and Down Syndrome Lymphocytes

Marie A. Peeters; Marie Odile Réthoré, Jérôme Lejeune, Institut de Progenèse, Paris; A. Arzimanoglou, D. Laplane, Service Neurologie, Hôpital Pitié-Salpetrière, Paris, France

Alzheimer disease (AD) is a progressive, degenerative form of dementia, affecting more than 11% of the population aged over 65 years. Adult Down syndrome (DS) patients all develop the cerebral histological changes characteristic of AD and dementia is common. In addition to these clinical and neuropathological similarities, there is genetic and biochemical data suggesting common disease mechanism. There is some evidence that the glutamine/glutamate cycle may be involved in AD. Using an in vitro assay examining variations of the mitotic index in the presence or absence of various inhibitors or metabolites of purine synthesis, we studied 8 patients with clinical AD, 12 patients with DS and AD. Controls used for this study were 12 age-matched normal controls, 135 normal adult controls and 75 patients with Down syndrome without AD. Peripheral blood lymphocytes were cultured for 72 hours according to standard methods in TC 199 medium, 25% human AB serum, PHA-C and antibiotics. Only glutamine (95mg/L) added on initiation of culture showed significant results. AD: Results showed a highly significant (p<0.001) decrease in the mitotic index (MI) (-26%±15.3) in the presence of glutamine when compared to both normal controls (+3.1%±23.2) and to normal aged-matched controls (+12.2%±24.7). In the normal control population 13% demonstrated a decrease in MI similar (greater than -20%) to that observed in AD patients. DS: Adult DS patients with clinical AD also showed a decrease in MI (-29%±13.3) in the presence of glutamine which was highly significant when compared to normal controls but which was not significantly different from that observed in AD patients. When compared to patients with DS but without AD, the difference was also significant (0.01 <p<0.005). In the DS control group 7/22 (32%) decreased their MI more than -20%. An age-related effect cannot be excluded (the difference in response to glutamine between DS with AD was more marked in the DS population aged less than 14 years). These findings suggest that glutamine sensitivity may play a role in the pathogenesis of AD. This would have significant implications in the development of preventive strategies.