ß 2006 Wiley-Liss, Inc. American Journal of Medical Genetics 140A:878–882 (2006) Clinical Report Non-Lethal Congenital Hypotonia Due to Glycogen Storage Disease Type IV T. Andrew Burrow, 1 Robert J. Hopkin, 1 * Kevin E. Bove, 2 Lili Miles, 2 Brenda L. Wong, 3 Arabinda Choudhary, 4 Deeksha Bali, 5 Sing Chung Li, 6 and Yuan-Tsong Chen 5 1 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 2 Department of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 3 Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 4 Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 5 Duke University Medical Center, Durham, North Carolina 6 Taipei Medical University, Taipei, Taiwan Received 12 September 2005; Accepted 2 January 2006 Glycogen storage disease type IV (GSD-IV) is an autosomal recessive genetic disorder due to a deficiency in the activity of the glycogen branching enzyme (GBE). A deficiency in GBE activity results in the accumulation of glycogen with fewer branching points and long, unbranched outer chains. The disorder results in a variable phenotype, including musculoskeletal, cardiac, neurological, and hepatic involve- ment, alone or in continuum, which can be identified at any stage of life. The classic form of GSD-IV is a hepatic presentation, which presents in the first 18 months of life with failure to thrive, hepatomegaly, and cirrhosis that progresses to liver failure, resulting in death by age 5 years. A severe congenital musculoskeletal phenotype with death in the neonatal period has also been described. We report an unusual case of congenital musculoskeletal presentation of GSD-IV with stable congenital hypotonia, gross motor delay, and severe fibro-fatty replacement of the musculature, but no hepatic or cardiac involvement. Molecular analysis revealed two novel missense mutations with amino acid changes in the GBE gene (Q236H and R262C), which may account for the mild phenotype. ß 2006 Wiley-Liss, Inc. Key words: glycogen storage disease (GSD); congenital myopathy; glycogen branching enzyme (GBE); Andersen disease INTRODUCTION Glycogen storage disease type IV (GSD-IV; OMIM 232500), also known as Andersen disease, is an autosomal recessive genetic disorder that results from a deficiency in the activity of the glycogen branching enzyme, a-1,4-glucan:a-1,4-glucan 6 gly- cosyl-transferase [Chen, 2001]. The glycogen branch- ing enzyme catalyzes the last step in glycogen biosynthesis by attaching short glucosyl chains in a-1,6 glucosidic links to naked peripheral chains of nascent glycogen [Bruno et al., 1999; Tay et al., 2004], resulting in a branched polymer with increased water solubility. The effect of abnormal branching enzyme function is an abnormal glycogen structure with fewer branching points and long, unbranched outer chains. The human glycogen branching enzyme gene (GBE1) located at chromosome 3p12, codes for the glycogen branching enzyme and has a coding sequence of 2106 base pairs. Mutations in the GBE1 gene result in glycogen storage disease type IV [Bao et al., 1996; Bruno et al., 1999; Bruno et al., 2004]. The phenotype is variable with hepatic, cardiac, neuro- logic, and musculoskeletal involvement, alone or in continuum [McConkie-Rosell et al., 1996; Bruno et al., 1999; Maruyama et al., 2004; Tay et al., 2004]. Congenital to adulthood presentations have been described. Affected persons demonstrate a broad spectrum of severity and organ involvement. Thus, many variants of GSD-IV have been described, resulting in a rather confusing classification system. We report on a child with a congenital neuromus- cular phenotype of GSD-IV characterized by con- genital hypotonia, and severe replacement of muscles with fat and fibrous tissue. To date, there *Correspondence to: Dr. Robert J. Hopkin, Cincinnati Children’s Hospital Medical Center, Division of Human Genetics, 3333 Burnet Avenue, MLC 4006, Cincinnati, Ohio 45229. E-mail: Rob.Hopkin@cchmc.org DOI 10.1002/ajmg.a.31166