Biomedical subjects
Publications and source records attributed to J Lejeune.
A technique is described by which unstained metaphases may be observed using phase contrast microscopy. The cells are fixed on a cover slip which then is turned over and onto a slide, leaving a thin air layer sandwiched between. Observation in phase contrast shows metaphases comparable to those observed after Giemsa staining.
Cri du chat disease and trisomy 8p were observed in a male patient. His father was carrier of a balanced de novo t(5;8)(p1409p12).
Observation of a patient with r(14) mosaicism together along with 18 previously published observations define the syndrome as follows: mental deficiency, seizures, microcephaly (usually), and facial dysmorphism showing a narrow, elongated face, short palpebral fissures, a flat nasal bridge, and retrognathia. A retinal dystrophia which may be specific of the syndrome consists of a hyperpigmentation and, in three patients, yellow-white spots of the macula. The brain shows mild dilation of the lateral ventricles.
Forty-two patients with the fragile-X syndrome have been treated with oral folic acid, 0.5 mg/kg/d. An improvement of the behavior was observed in the majority of the cases, and evolution of the IQ showed a favorable tendency at the border of statistical significance. On the contrary, the addition to the treatment regime of methionine or of carnitine (carriers of methyl radicals) had unfavorable effects. In view of the few preliminary convergent observation recorded in literature, a continued trial of folic acid treatment seems justified. Simultaneously, however, research is indicated on monocarbon metabolism, probably affected in these patients.
Trisomy 17p resulting from a parental translocation t(10;17)(q26.3;p11) was observed in a 22-month-old boy. Analysis of five cases of trisomy 17p from the literature indicates a common malformation pattern: microcephaly, excessive development of the median part of the frontal region, mandibular hypoplasia, permanent opening of the mouth, a high-arched palate, a short, webbed neck, hypotonia, growth retardation, and severe mental retardation. Three abnormal features emphasized by the authors are permanent myosis due to a structural anomaly of the iris; an unusually low blood folate concentration; and an unusual hand configuration, the first four fingers flexed and the little finger extended.
The increase in frequency of the Xq27 gap is investigated after addition to the culture medium of two inhibitors of dihydrofolate reductase : trimethoprim (TMP) and pyrimethamine (PMT). Neither antibiotic induced the gap in ten normal subjects. In five Xqfra, mentally retarded, untreated boys, TMP (26,7 mg/l) and PMT (1,25 mg/l) increased equally the gap frequency. In two out of four women carrying the Xqfra and in three out of four Xfra mentally retarded boys, treated for a few months, with oral folic acid (one milligram/kg/day), TMP increased the frequency of the gap, while PMT was practically inactive. PMT is a much more powerful inhibitor of dihydrofolate reductase than TMP : it was concluded therefore that TMP could also act on some other steps of the monocarbons' metabolism. The only patient who reacted strongly to both TMP and PMT had previously suffered a severe neurologic regression during an antibiotherapy with TMP. It is stressed that dihydrofolate reductase inhibitors should be avoided when treating Xqfra patients.
Two cousins with trisomy for the distal third of 16q due to a familial translocation, t(16;21)(q22.2;q22.2), are reported. The APRT gene locus could be assigned to 16q22.2 to 16qter. The phenotypic similarities of the first patient, who had trisomy 16q22.3 to 16qter and monosomy 21q22.3, to six other patients with partial trisomy 16q reported in literature allows the delineation of a syndrome due to trisomy 16qter. In the second patient, with trisomy 16q22.3 to 16qter and trisomy 21pter to 21q22.2, similar features are present, but in association with the classical symptoms of trisomy 21.
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Two cousins with trisomy for the distal third of 16q due to a familial translocation, t(16;21)(q22.2;q22-2), are reported. The APRT gene locus could be assigned to 16q22.2 to 16qter. The phenotypic similarities of the first patient, who had trisomy 16q22.3 to 16qter and monosomy 21q22.3, to six other patients with partial trisomy 16q reported in literature allows the delineation of a syndrome due to trisomy 16qter. In the second patient, with trisomy 16q22.3 to 16qter and trisomy 21pter to 21q22.2 similar features are present but in association with the classical symptoms of trisomy 21.
Severe clinical regression was observed in a patient carrier of a fragile X after treatment trimethoprime. This prompted us to examine the effect of this antibiotic in lymphocyte cultures: a dose ranging from 13 mg/l to 53 mg/l increases considerably the frequency of the Xq27 gap in four fragile-X patients; a dose of 13 mg/l allows a normal growth, without appearance of the Xq27 gap, in 19 normal, non-carrier subjects; a dose of 82 mg/l totally inhibits cell division in 10 normal, non carrier subjects. The reversibility of the blockade was demonstrated, either by washing out the trimethoprime before the 50th hour of incubation or by adding 5-formyl-tetrahydrofolate (0.125 mg/l). It is concluded that one of the steps of monocarbon metabolism is inhibited by trimethoprime. This antibiotic, which must be avoided when treating patients carrier of the fragile X can be utilized in vitro for cytogenetic investigations.
A decrease of frequency of a gap at the extremity of the long arm of the X chromosome (fragile site Xq27) is obtained by adjonction of monocarbons precursors to lymphocytes cultures. The efficacity of the treatments is precised by the analysis of 44 629 mitoses. For the first time, in one patient, parenteral administration of 5-formyl-tetrahydrofolate lead to a clinical improvement with concomitant disappearance of the gap.
A systematic review of the biochemical troubles associated with Trisomy 21 lead to three constatations: 1) There must be an important perturbation of the oxygen metabolism (Excess of S.O.D.I. and of G.P.X.) 2) There is probably a shift in the regulation of non essential amino acids (Comparison with other forms of mental deficiencies) 3) In conformity with a general hypothesis, an abnormality of the monocarbon metabolism could be the consequence of 1) and 2) and could represent the actual cause of mental deficiency.
Trisomy-19 mosaicism was observed in lymphocytes of a newborn male with facial dysmorphism (upward slanting palpebral fissures, pointed nose, short upper lip, prominent antitragus), laryngeal stridor, and leucothrombopenia, and who died on day 13. Autopsy revealed no other major malformation but poor development of the cerebral sulci.
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After confirming the increase of the fragility of the site Xq27 by methotrexate and its decrease by 5-formyltetrahydrofolate, it is observed that L-serine, 5-amino-levulinate and L-4-hydroxy-proline at millimolar concentrations, reduce considerably the frequency of the anomaly in lymphocyte cultures. The possible relationships between this chromosomal marker, the one carbon cycle,and mental deficiency of the patients, are discussed.
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The R-banding of more than 1100 lymphocytes and fibroblasts from 11 patients with ataxia telangiectasia (AT) showed rearrangements of chromosomes 7 and/or 14 in about 7% of the cells. Among these rearrangements, pericentric inversion of chromosome 7 was the most frequent, and the paracentric inversion of chromosome 14 not very rare. These inversions are believed to be fairly specific of AT, and their absence in the previously reported literature may be due to technical problems. Inversions were also observed in the lymphocytes of presumed heterozygote carriers with a lower frequency, and may be of some help for the detection of healthy heterozygote carriers of the AT gene.