Eirini Manoli, M.D., Ph.D.
Metabolic Medicine Branch
National Human Genome Research Institute
M.D., National and Kapodistrian University, Athens, Greece
Ph.D., National and Kapodistrian University, Athens, Greece
Dr Manoli is a pediatrician, clinical and biochemical geneticist in the Organic Acid Research Section of the Metabolic Medicine Branch at NHGRI. She earned her medical degree, a Masters and PhD from the University of Athens in Greece; she completed her pediatric residency at John Radcliffe Hospital in Oxford, England and University Children’s Hospital in Athens, Greece. She then moved to the US and joined NIH in 2002 for a postdoctoral research fellowship (NCCAM), followed by clinical and biochemical genetics training through the combined NHGRI and Children’s National Hospital program, and was board certified in 2009. She continued as a Staff Clinician in the Organic Acid Research Section and became a Clinician Associate Investigator in 2016. She is a member of the faculty of the Metropolitan Washington D.C. Medical Genetics and Genomic Medicine Training Program and the NIH Institutional Review Board and co-chairs the NHGRI Scientific Review Committee. She has over 70 publications in the areas of clinical and biochemical genetics and is a co-inventor of 7 patents.
Dr Manoli’s research combines clinical studies with molecular genomics and animal models to explore the pathophysiology and develop new therapies for genetic and metabolic disorders. During her training as a clinical and biochemical genetics fellow, she worked on hereditary inclusion body myopathy, co-developed a patent on N-acetylmannosamine for the treatment of disorders related with hyposialylation and participated in the care of patients across NHGRI protocols including for the Undiagnosed Disease Program. Inspired by her postdoctoral work on mitochondrial stress she joined the Organic Acid Research Section (OARS), NHGRI, in 2009 to understand the pathophysiology of metabolic stress in methylmalonic acidemia (MMA). She studied the effects of dietary challenges, cold exposure or fasting in liver- and muscle-specific transgenic MMA mice and modeled clinically relevant disease manifestations, identified disease-related biomarkers and tested diagnostic methods and therapeutic interventions. Her clinical research on the MMA natural history protocol led to the recognition of errors in the design and implementation of medical nutrition therapy in MMA and cobalamin C deficiency, which resulted in the re-evaluation of long-standing dietary guidelines and clinical practices worldwide. She helped expand the phenotypic spectrum of inborn errors in the propionate oxidation and intracellular cobalamin metabolism, and the discovery of new genes in these pathways, including ACSF3 and HCFC1.
With support from an NIH CC bench to bedside award she developed a 1-13C-propionate oxidation breath test, to be used as a pharmacodynamic measure in upcoming clinical trials on methylmalonic and propionic acidemias. She is the lead Associate Investigator for the first-in-human systemic AAV8 liver-targeted gene therapy and is also involved with the AAV9 gene therapy clinical trials targeting propionic acidemias in partnership with NCATS, NIH, and the Bespoke gene therapy consortium (BGTC).
In addition to her basic and clinical research on organic acidemias, she served as the NIH PI on an extramural-intramural collaborative grant on Moebius syndrome and related facial weakness disorders, with investigators at Icahn School of Medicine at Mount Sinai and Boston Children’s Hospital. This led to the identification of myomaker (MYMK) as the causative gene for Carey-Fineman-Ziter syndrome, and heterozygous non-coding variants (duplications and SNVs) in a neuron-specific GATA2 regulatory as the cause for autosomal dominant hereditary congenital facial paresis, type 1 (HCFP1).
Tenney AP, Di Gioia SA, Webb BD, Chan WM, de Boer E, Garnai SJ, Barry BJ, Ray T, Kosicki M, Robson CD, Zhang Z, Collins TE, Gelber A, Pratt BM, Fujiwara Y, Varshney A, Lek M, Warburton PE, Van Ryzin C, Lehky TJ, Zalewski C, King KA, Brewer CC, Thurm A, Snow J, Facio FM, Narisu N, Bonnycastle LL, Swift A, Chines PS, Bell JL, Mohan S, Whitman MC, Staffieri SE, Elder JE, Demer JL, Torres A, Rachid E, Al-Haddad C, Boustany RM, Mackey DA, Brady AF, Fenollar-Cortés M, Fradin M, Kleefstra T, Padberg GW, Raskin S, Sato MT, Orkin SH, Parker SCJ, Hadlock TA, Vissers LELM, van Bokhoven H, Jabs EW, Collins FS, Pennacchio LA, Manoli I, Engle EC. Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis. Nat Genet. 2023 Jul;55(7):1149-1163.
Manoli I, Gebremariam A, McCoy S, Pass AR, Gagné J, Hall C, et al. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia (MMA). J Inherit Metab Dis. 2023 Jul;46(4):554-5572.
Head PE, Myung S, Chen Y, Schneller JL, Wang C, Duncan N, Hoffman P, Chang D, Gebremariam A, Gucek M, Manoli I, Venditti CP. Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin. Sci Transl Med. 2022 May 25;14(646).
Manoli I, Pass AR, Harrington EA, Sloan JL, Gagné J, McCoy S, et al. 1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA). Genet Med. 2021;23(8):1522-1533.
Lehky T, Joseph R, Toro C, Wu T, Van Ryzin C, Gropman A, Facio FM, Webb BD, Jabs EW, Barry BS, Engle EC, Collins FS, Manoli I. Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies. Muscle Nerve. 2021; 63(4):516-524.
Whitman MC, Barry BJ, Robson CD, Facio FM, Van Ryzin C, Chan WM, Lehky TJ, Thurm A, Zalewski C, King KA, Brewer C, Almpani K, Lee JS, Delaney A, FitzGibbon EJ, Lee PR, Toro C, Paul SM, Abdul-Rahman OA, Webb BD, Jabs EW, Moller HU, Larsen DA, Antony JH, Troedson C, Ma A, Ragnhild G, Wirgenes KV, Tham E, Kvarnung M, Maarup TJ, MacKinnon S, Hunter DG, Collins FS, Manoli I*, Engle EC*. TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early onset peripheral neuropathy. Hum Genet. Dec 2021;140 (12):1709-1731.
Sadeghi N*, Hutchinson E, Van Ryzin C, FitzGibbon EJ, Butman JA, Webb BD, Facio F, Brooks BP, Collins FS, Jabs EW, Engle EC, Manoli I*, Pierpaoli C. Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry. Brain Commun. 2020;2(1):fcaa014.
Manoli I, Sysol JR, Epping MW, Li L, Wang C, Sloan JL, et al. FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI Insight. 2018;3(23).
Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bönnemann CG, Olson EN, Carey JC*, Robertson SP, Manoli I*, Engle EC*. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017;8:16077.
Manoli I, Myles JG, Sloan JL, Carrillo-Carrasco N, Morava E, Strauss KA, et al. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency. Genet Med. 2016;19(4):396-404.
Manoli I, Myles JG, Sloan JL, Shchelochkov OA, Venditti CP. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med. 2016;18(4):386-95.
Manoli I, Sysol JR, Li L, Houillier P, Garone C, Wang C, et al. Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci U S A. 2013;110(33):13552-7.
Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. 2005 Aug 16 [updated 2022 Sep 8]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.
Last updated: November 8, 2023