Toxicity of leukaemia therapy in children with down syndrome

M.A. PEETERS (*),A. POON (**), A. ZIPURSKY(**), J. LEJEUNE (*)

The Lancet, November 29, 1986.


Sir, - Dr Blatt and her colleagues (Oct 18, p 914) report excessive chemotherapy-related myelotoxicity in children with Down syndrome and acute lymphoblastic leukaemia. We have had the same experience,1.2. in 24 patients unusual clinical presentations and unexpected methotrexate (MTX) toxicity were observed. All patients had severe toxicity at standard MTW doses. Mouth ulcerations and bone marrow depression were seen regardless of the route of administration (oral, intrathecal, or intravenous). A 30-50 % reduction of the standard dose war tolerated. Methotrexate absorption and clearance were studied in 2 patients and were normal. The toxicity may be due to a gene dosage effect for the three enzymes known to be on chromosome 21 and intervening in purine metabolisme.3.4. Increased purine synthesis implies greater tetrahydrofolic acid demands and therefore greater sensitivity to an antifolate agent. This clinical study war confirmed by the in vitro demonstration that trisomy 21 patients were twice as sensitive to MTX as ware age-matche controls. This war demonstrated by a decrease in the mitotic index which war proportional to the square of the dose of MTX.5 The toxicity observed by Blatt et al in Down syndrome patients receiving low-dose co-trimoxazole is noteworthy. Trimethoprim, which is also an inhibitor of dihydrofolate reductase, has in vitro toxicity in another syndrome in which mental retardation is prominent-indeed it increases the expression of the Xq27 fragile site in patients wirth Martin-Bell or fragile X syndrome.6 A systematic study of the one-carbon cycle an of transmethylation mechanisms in patients with mental retardation7 is urgently required.



1. Peeters M. Poon A., Zipursky A., Olive D. Down's syndrome and leukaemia : Unusual clinical presentation ; unexpected methotrexate sensitivity Eur J. Paediatr 1985; 144: 115 (abstr 63).

2. Peeters M., Poon A. Down syndrome and leukaemia : Unusual clincal aspects and unexpected methotrexate sensitivity. Eur J Paediatr (in press).

3. Patterson D. Graw S, Jonez C. Demonstration by somatic cell genetics of coordinate regulation of genes for two enzymes of purine synthesis assigned to human chromosome 21 Proc Natl Accad Sci USA 1981; 78: 405-09.

4. Hards RG, Benkovic SJ, Van Keuren ML, Graw SL, Drabkin HA, Patterson D. Assignment of a third purine biosynthetic gene (glycinamide ribonucleotide transformylase) to human chromosome 21. Am J Hum Genet 1986; 39; 179-85.

5. Lejeune J, Réthoré MO, de Blois MC, et al. Monocarbon's metabolisme and trisomy 21 : Sensitivity to methotrexate. Ann Génét 1986; 29: 16-19.

6. Calva-Mercado MP, Maunoury C, Réthoré MO, Lejeune J. Fragile X and inhibition of dihydrofolate reductase. Compared effects of two antibiotics : trimethoprim and pyrimethamine. Ann Génét1983; 26: 147-49.

7. Lejeune J. Le métabolisme des monocarbones et la débilité de l'intelligence. In: Lejeune J. Ed Debilité mentale. Paris: Masson, 1983; 3-18.