ORIGINAL ARTICLE S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes Randall Grubbs & Oliver Vugrek & Jeremy Deisch & Conrad Wagner & Sally Stabler & Robert Allen & Ivo Barić & Marko Rados & S. Harvey Mudd Received: 29 April 2010 / Revised: 17 June 2010 / Accepted: 5 July 2010 / Published online: 18 September 2010 # SSIEM and Springer 2010 Abstract This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S-adenosylhomo- cysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p. Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respi- ratory failure. Metabolic abnormalities included elevated plasma S-adenosylhomocysteine, S-adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain. Abbreviations AdoHcy S-adenosylhomocysteine AdoMet S-adenosylmethionine AHCY S-adenosylhomocysteine hydrolase tHcy total homocysteine Communicated by: K. Michael Gibson Competing interest: None declared. R. Grubbs Pediatrix Medical Group of Texas, Fort Worth, TX, USA O. Vugrek Department of Molecular Medicine, Institute “Ruđer Bošković”, Zagreb, Croatia J. Deisch University of Texas Southwestern Medical Center, Dallas, TX, USA C. Wagner Department of Biochemistry, Vanderbilt University, Nashville, TN, USA S. Stabler : R. Allen University of Colorado Health Sciences Center, Denver, CO, USA I. Barić Department of Pediatrics, University Hospital Center and School of Medicine, Zagreb, Croatia M. Rados Department of Radiology, University Hospital Center and Zagreb School of Medicine, and Croatian Institute for Brain Research, Zagreb, Croatia S. H. Mudd (*) Laboratory of Molecular Biology, National Institute of Mental Health, Building 10, Room 2D46, 9000 Rockville Pike, Bethesda, MD 20892, USA e-mail: muddh@mail.nih.gov J Inherit Metab Dis (2010) 33:705–713 DOI 10.1007/s10545-010-9171-x