ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:2493–2501 (2007) Research Review Sibling Phenotype Concordance in Classical Infantile Pompe Disease Wendy E. Smith, 1 * Jennifer A. Sullivan-Saarela, 2 Jennifer S. Li, 3 Gerald F. Cox, 4,5 Deyanira Corzo, 4,5 Yuan-Tsong Chen, 2 and Priya S. Kishnani 2 1 Division of Genetics, The Barbara Bush Children’s Hospital, Maine Medical Center, Portland, Maine 2 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 3 Division of Cardiology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 4 Division of Genetics, Children’s Hospital, Boston, Massachusetts 5 Clinical Research, Genzyme Corporation, Cambridge, Massachusetts Received 20 March 2007; Accepted 8 June 2007 Pompe disease (acid-a-glucosidase deficiency) encompasses a clinical spectrum, ranging from severe infantile-onset disease with clinical symptoms appearing before 1 year of age with rapid progression to an early death, to late-onset disease with a much more variable age at onset and disease course. Sibling phenotype discordance has been reported for late-onset Pompe disease, but has not been studied in classical infantile disease. We reviewed the medical literature for affected sibships in which at least one sibling had clinical and pathology or biochemical findings consistent with infantile Pompe disease including symptoms beginning in infancy, early hypotonia, cardiomegaly documented by 6 months of age, and early death. The age at symptom onset, age at death, and clinical course were compared between probands and affected siblings. Our results showed that since 1931, publications document 13 families with 31 affected infants (11 probands; 20 affected siblings). The median age at symptom onset for all affected infants was 3 months (range 0–6 months) with significant correlation (R ¼ 0.60, P ¼ 0.04) between probands and affected siblings. The median age at death for all affected infants was 6 months (range 1.5–13 months); probands were slightly older at death than their siblings. The median length of disease course for all affected infants was 3 months (0– 10 months) and was slightly longer for probands. Unlike late- onset Pompe disease, there appears to be minimal pheno- typic and lifespan variation among siblings with infantile Pompe disease. This prognostic information is vital for families with affected infants and allows for appropriate genetic counseling. ß 2007 Wiley-Liss, Inc. Key words: Pompe disease; siblings; phenotype; concor- dance; infants How to cite this article: Smith WE, Sullivan-Saarela JA, Li JS, Cox GF, Corzo D, Chen Y-T, Kishnani PS. 2007. Sibling phenotype concordance in classical infantile Pompe disease. Am J Med Genet Part A 143A:2493 – 2501. INTRODUCTION Pompe disease, also termed glycogen storage disease type II (GSD II) or acid maltase deficiency (AMD), results from a deficiency of acid-a-glucosi- dase, a lysosomal enzyme necessary for the break- down of glycogen within lysosomes. All affected individuals share the same general disease course with ongoing accumulation of glycogen primarily within muscles leading to progressive debilitation, organ failure and often death. Infantile and late-onset (previously termed juvenile and adult onset) forms of GSD II have been described and are recognized by age at disease onset, course of disease progression, clinical symptoms, and age at death. These clinical presentations generally correlate with the amount Conflict of Interest: PSK, JAS, and YTC have received honoraria and research/grant support from Genzyme Corporation. PSK is a member of the Pompe Disease Advisory Board for Genzyme Corporation. YTC has served as a consultant for Genzyme Corporation. If therapy for Pompe disease proves successful commercially, Duke University and the inventors of the cell line used to generate the enzyme used for therapy may benefit financially pursuant to the Duke University’s Policy on Inventions, Patents, and Technology Transfer. GFC and DC are employed by Genzyme Corporation. *Correspondence to: Wendy E. Smith, M.D., Maine Pediatric Specialty Group, 887 Congress Street, Suite 300, Portland, ME 04102. E-mail: smithw@mmc.org DOI 10.1002/ajmg.a.31936