Bee C Chen1, Shanti Balasubramaniam2, Ivan N McGown3, J Patrick O'Neill4, Gaik S Chng1, Wee T Keng1, Lock H Ngu1, John A Duley5. 1. Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia. 2. 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. 3. Mater Health Services and Mater Medical Research Institute, Brisbane 4101, Australia. 4. Department of Pediatrics, University of Vermont Genetics Laboratory, Burlington, VT 05405, USA. 5. Mater Health Services and Mater Medical Research Institute, Brisbane 4101, Australia; School of Pharmacy, The University of Queensland, Brisbane 4101, Australia.
Abstract
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. AIM: 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. DISCUSSION: 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. Crown
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. AIM: 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. DISCUSSION: 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. Crown
Authors: Jacob A S Vorstman; Jeremy R Parr; Daniel Moreno-De-Luca; Richard J L Anney; John I Nurnberger; Joachim F Hallmayer Journal: Nat Rev Genet Date: 2017-03-06 Impact factor: 53.242