Genetic metabolic disorders

Using cutting edge genetic technologies, we have discovered a number of disease genes for rare genetic disorders, some of which are world firsts, some of which led to institution of specific therapies, and all of which have improved our understanding of the genetic risks to other family members.

We have developed a new approach to treating the inborn error of metabolism, phenylketonuria (PKU).  All babies in Australia are screened for PKU.  Our new therapy, a genetically modified probiotic, is currently undergoing preclinical trials, and is showing promising results.  This research is being undertaken in collaboration with Associate Professor Kevin Carpenter from the NSW Biochemical Genetics Service.

The research team

> Dr Kaustuv Bhattacharya, Head of Genetic Metabolic Disorders Service

> Other Research Team Members

• Associate Professor Kevin Carpenter, Dept Head and Principal Scientist, NSW Biochemical Genetics Service
• Clinical A/Professor Carolyn Ellaway
• Dr Shanti Balasubramaniam
• Dr Minal Menezes, Research Officer

Key publications

Menezes MJ, Guo Y, Zhang J, Riley LG, Cooper ST, Thorburn DR, Li J, Dong D, Li Z, Glessner J, Davis RL, Sue CM, Alexander SI, Arbuckle S, Kirwan P, Keating BJ, Xu X, Hakonarson H, Christodoulou J (2015) Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Hum Mol Genet 24(8):2297-307

Gold WA, Lacina TA, Cantrill LC, Christodoulou J (2015) MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can be restored using HDAC6 inhibitors. J Mol Med (Berl) 93(1):63-72

Guo Y, Menezes MJ, Menezes MP, Liang J, Li D, Riley LG, Clarke NF, Andrews PI, Tian L, Webster R, Wang F, Liu X, Shen Y, Thorburn DR, Keating BJ, Engel A, Hakonarson H, Christodoulou J, Xu X (2015) Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect. Neuromuscul Disord 25(3):257-61

Gold WA, Williamson SL, Kaur S, Hargreaves IP, Land JM, Pelka GJ, Tam PP, Christodoulou J (2014) Mitochondrial dysfunction in the skeletal muscle of a mouse model of Rett syndrome (RTT): implications for the disease phenotype. Mitochondrion 15:10-7

Miller, DK*, Menezes MJ*, Simons C, Riley LG, Cooper S, Grimmond S, Thorburn D, Christodoulou J, Taft R (2014) Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. PLoS One 9(8): e104879

Menezes MJ, Riley LG, Christodoulou J. (2014) Mitochondrial respiratory chain disorders in childhood: insights into diagnosis and management in the new era of genomic medicine. Biochim Biophys Acta 1840(4):1368-79

Riley LG, Menezes MJ, Rudinger-Thirion J, Duff R, de Lonlay P, Rotig A, Tchan MC, Davis M, Cooper ST, Christodoulou J (2013) Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia. Orphanet J Rare Dis ;8:193

Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim MJ, Lin JP, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, et al. (2014) Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 137(1):44-56

Williamson SL, Giudici L, Kilstrup-Nielsen C, Gold W, Pelka GJ, Tam PP, Grimm A, Prodi D, Landsberger N, Christodoulou J (2012) A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the
predominant transcript in brain. Hum Genet 131(2):187-200

Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, Lim SC, Thorburn D, Ryan MT, Giegé R, Bahlo M, Christodoulou J (2010) Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. Am J Hum Genet 87(1):52-9