Dr Rathi Prasad

Profile

Dr Rathi Prasad graduated in Medicine in 2004 from Imperial College London, thereafter training in Paediatrics and sub-specialising in Paediatric Endocrinology. She commenced her PhD at the Centre for Endocrinology in 2010, initially funded by a Barts and the London Charity Research Fellowship and thereafter a Wellcome Trust Research Training Fellowship. She was awarded her PhD on the role of oxidative stress in the pathogenesis in Triple A Syndrome and familial glucocorticoid deficiency (FGD), in 2014. This work included the description of a novel form of FGD secondary to mutations in TXNRD2, a component of the thioredoxin antioxidant system.

She was appointed as a Consultant in Paediatric Endocrinology and Diabetes at the Royal London Children’s Hospital, Barts Health NHS Trust in 2016. Her clinical practice incorporates all areas of Paediatric Diabetes and Endocrinology, with particular interest in adrenal disorders, puberty, differences in sex development and familial paraganglioma syndrome.

Her research interest is in genetic disorders of primary adrenal insufficiency including the description of a new multi-systemic disorder of sphingolipid metabolism incorporating adrenal disease, nephrotic syndrome and wider endocrinopathy secondary to SGPL1 mutations. Her current research, funded by an MRC Clinical Academic Research Partnership, is focused in deciphering mechanisms of disease related to Sphingosine-1-phosphate lyase deficiency, in particular the endocrinopathy associated with the condition.

Research

Group members:

Ruth Kwong (PhD Student), Jack Williams & Chris Smith (Post Docs with L. Metherell)

Summary

Natural history of the disease in patients with Sphingosine-1-phosphate lyase (S1P Lyase) deficiency
S1P Lyase deficiency is associated with a multi-systemic disorder incorporating endocrinopathy (primary adrenal insufficiency (PAI), primary hypothyroidism, gonadal failure), steroid resistant nephrotic syndrome, ichthyosis, and neurological deficit. This is the most recent published disorder of sphingolipid metabolism (2017). There is a broad phenotypic spectrum, even amongst affected members of the same kindred. In addition to identifying new patients through genetic screening of cohorts with PAI (Metherell group), congenital nephrotic syndrome (Saleem group), 100,000 genome study (Metherell in Rare Endocrine Diseases GeCIP), we continue to collect prospective clinical information of patients from ongoing collaboration with referring clinicians.

Role of S1P Lyase in steroidogenesis and adrenal and gonadal disease.
This novel condition has highlighted the importance of the sphingolipid pathway in steroidogenesis with potential impact on adrenal and gonadal development. Sphingolipid species have a myriad of effects on cell signalling and organelle function. Current work is focused on delineating the sphingolipid signature of S1P lyase deficiency and the subsequent effects on adrenal/ gonadal development, steroidogenesis and organelle function in both in vitro models of disease and Sgpl1 null mouse model. Molecular programmes that underpin adrenal homeostasis can be involved in adrenocortical carcinoma (ACC) progression and more recently we have been investigating S1P lyase as a novel regulator of ACC and potential therapeutic target.

Deciphering mechanisms of disease in S1P lyase deficiency
Together with a consortium of collaborators we are interrogating the role of S1P lyase deficiency in other aspects of the disease including thyroid disease and ichthyosis.

Key Publications

• Williams J, Smith C, Hall C, Khaled Z, Maharaj A, Kwong R, Pittaway J, Casas J, Parvanta L, Abdel-Aziz T, Palazzo F, Chung T-T, Guasti L, Metherell L*, Prasad R* Elevated SGPL1 leads to increased metabolism and reduced survival in adrenocortical carcinoma. European Journal of Endocrinology (2023)
• Maharaj A*, Kwong R*, Williams J, Smith C, Storr H, Krone R, Braslavsky D, Clemente M, Ram N, Banerjee I, Çetinkaya S, Buonocore F, Güran T, Achermann J, Metherell L, Prasad R. A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review. Endocrine Connections (2022)
• Maharaj A, Güran T, Buonocore F, Achermann J, Metherell L, Prasad R*, Semra Çetinkaya S*. Insights from long term follow-up of a girl with adrenal insufficiency and sphingosine-1-phosphate lyase deficiency. J Endocr Soc. (2022)
• Maharaj A, Williams J, Bradshaw T, Güran T, Braslavsky D, Casas J, Chan LF, Metherell LA, Prasad R. Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction. J Steroid Biochem Mol Biol (2020); 202: 105730
• Weaver KN, Sullivan B, Hildebrandt F, Strober J, Cooper M, Prasad R, Saba J. Sphingosine Phosphate Lyase Insufficiency Syndrome. Gene Reviews (2020)
• Maharaj A, Theodorou D, Banerjee I, Metherell L, Prasad R, Wallace D. A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy. Front Pediatr. (2020)
• Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergadá I et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. (2017) 127(3):942-953
• The above publication was highlighted research in Nature Reviews Nephrology, and awarded Society for Endocrinology Early Career Top Scoring Basic Science Oral Communication 2016.
• Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. (2014) 99(8): E1556-63.
• Prasad R, Kowalczyk JC, Meimaridou E, Storr HL, Metherell LA. Oxidative stress and adrenocortical insufficiency. J Endocrinol. (2014) 221(3): R63-73.
• Prasad R, Metherell LA, Clark AJ, Storr HL. Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis. Endocrinology (2013) 154(9):3209-18.
• Prasad R, Nicholas A, Schoenmakers N, Barton J. Haploinsufficiency of NKX2-1 in Brain-Lung-Thyroid Syndrome with Additional Multiple Pituitary Dysfunction. Horm Res Paediatr. (2019) 92:340-344
• Awarded ESPE-Hormone Research in Paediatrics Prize in 2020
• Maharaj A, Maudhoo A, Chan LF, Novoselova T, Prasad R, Metherell LA, Guasti L. Isolated glucocorticoid deficiency: Genetic causes and animal models. J Steroid Biochem Mol Biol. (2019) 189:73-80.
• Maharaj A, Buonocore F, Meimaridou E, Ruiz-Babot G, Guasti L, Peng HM, Capper CP, Burgos-Tirado N, Prasad R,  Hughes C, Maudhoo A, Crowne E, Cheetham T, Brain C,  Suntharalingham J, Striglioni N, Yukse Bl, Gurbuz F,Sangay Gupta S, Lindsay R,  Couch R, Spoudeas H, Guran T, Johnson S, Fowler D, Conwell L, McInerney-Leo A, Drui D, Cariou B, Lopez-Siguero J, Harris M, Duncan E, Hindmarsh P, Auchus R, Donaldson M, Achermann J, Metherell L. Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing. J Endocr Soc. (2018) 3(1):201-221.
• Prasad R, Brewer C, Burren CP. Hartsfield syndrome associated with a novel heterozygous mutation in FGFR1 and incorporating tumoral calcinosis. Am J Med Genetics A (2016) 170: 2222-2225
• Storr HL, Prasad R, Temple IK, Metherell LA, Savage MO, Walker JM. Heterogeneity of the growth phenotype and birth size in acid-labile subunit (ALS) deficiency. J Endocrinol Investigation (2014) 38: 407-412
• Prasad R, Johnston L.B., Savage M.O., Martin L., Perry L.A., Storr H.L. Paediatric endocrine screening for Von Hippel-Lindau disease: benefits and the challenge of compliance. J Endocrinol. Investigation (2010) 34:296-9.

Collaborators

Internal: Professor Lou Metherell, Dr Leo Guasti 

External: Dr Fina Casas (RUBAM, Barcelona), Professor Moin Saleem (University of Bristol, UK), Professor Julie Saba (UCSF, USA), Professor Paul Van Veldhoeven (KU Leuven, Belgium), Professor Serge Nef (University of Geneva, Switzerland), Dr Rod Mitchell (University of Edinburgh, UK), Dr Nadia Schoenmakers (University of Cambridge, UK), Professor Edel O’Toole (QMUL, UK)