Treatment of Lesch-Nyhan disease with S-adenosylmethionine: experience with five young Malaysians, including a girl.
BACKGROUND
Lesch-Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment.


OBJECTIVE
For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy.


RESULTS
Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy.


CONCLUSIONS
Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G-protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies.
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
Bee C
BC
Chen
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia; Metabolic Unit, Department of Pediatric and Adolescent Medicine, Princess Margaret Hospital, 6008 Perth, Western Australia. Electronic address: Shanti.Balasubramaniam@health.wa.gov.au.
Shanti
S
Balasubramaniam
Mater Health Services and Mater Medical Research Institute, Brisbane 4101, Australia.
Ivan N
IN
McGown
Department of Pediatrics, University of Vermont Genetics Laboratory, Burlington, VT 05405, USA.
J Patrick
JP
O'Neill
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
Gaik S
GS
Chng
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
Wee T
WT
Keng
Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
Lock H
LH
Ngu
Mater Health Services and Mater Medical Research Institute, Brisbane 4101, Australia; School of Pharmacy, The University of Queensland, Brisbane 4101, Australia.
John A
JA
Duley
D000293:Adolescent; D000374:Aggression / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004421:Dystonia / Q000188:drug therapy; D005260:Female; D006801:Humans; D007223:Infant; D007926:Lesch-Nyhan Syndrome / Q000188:drug therapy*; D008296:Malaysia; D008297:Male; D010375:Pedigree; D011687:Purines / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000627:therapeutic use*; D016728:Self-Injurious Behavior / Q000188:drug therapy
D011687:Purines; D012436:S-Adenosylmethionine; C030985:purine
Aggression; Dystonia; HGPRT; HPRT1; Lesch–Nyhan disease; S-adenosylmethionine; Self-injury