A multinational study of acute and long-term outcomes of Type 1 galactosemia patients who carry the S135L (c.404C > T) variant of GALT
Quinton S. Katler
Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorKarolina M. Stepien
Adult Inherited Metabolic Diseases Department, Salford Royal Foundation NHS Trust, Salford, UK
Search for more papers by this authorNathan Paull
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorSneh Patel
Neuroscience and Behavioral Biology Program, Emory University, Atlanta, Georgia, USA
Search for more papers by this authorMichael Adams
Division of Pediatric Genetics and Metabolism, UNC School of Medicine, Chapel Hill, North Carolina, USA
Search for more papers by this authorMehmet Cihan Balci
Department of Pediatric Metabolic Disease, Istanbul Medical School, Istanbul, Turkey
Search for more papers by this authorGerard T. Berry
Division of Genetics and Genomics, Department of Pediatrics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorAnnet M. Bosch
Division of Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorDidem Demirbas
Division of Genetics and Genomics, Department of Pediatrics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorJulianna Edman
Department of Pediatric Genetics, University of Illinois-Chicago, Chicago, Illinois, USA
Search for more papers by this authorCan Ficicioglu
Division of Human Genetics and Metabolism, The Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
Search for more papers by this authorMelanie Goff
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
Search for more papers by this authorStephanie Hacker
Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorIna Knerr
National Centre for Inherited Metabolic Disorders, Temple St. Children's University Hospital, Dublin, Ireland
Search for more papers by this authorKristen Lancaster
Division of Pediatric Genetics and Metabolism, UNC School of Medicine, Chapel Hill, North Carolina, USA
Search for more papers by this authorHong Li
Departments of Human Genetics and Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorBryce A. Mendelsohn
Department of Genetics, Oakland Medical Center, Kaiser Permanente, Oakland, California, USA
Search for more papers by this authorBrandi Nichols
Department of Clinical Nutrition, Arkansas Children's Hospital, Little Rock, Arkansas, USA
Search for more papers by this authorWladimir Bocca Vieira de Rezende Pinto
Division of Neuromuscular Diseases, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
Search for more papers by this authorJúlio César Rocha
Nutrition & Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
Reference Centre of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
Center for Health Technology and Services Research (CINTESIS), NOVA Medical School, Lisbon, Portugal, Lisbon, Portugal
Search for more papers by this authorM. Estela Rubio-Gozalbo
Department of Pediatrics, Department of Clinical Genetics, GROW-School for Oncology and Reproduction, European Reference Network for Hereditary Metabolic Disorders (MetabERN) member and United for Metabolic Diseases Member, Maastricht University Medical Centre, Maastricht, The Netherlands
Search for more papers by this authorMichael Saad-Naguib
Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorSabine Scholl-Buergi
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorSarah Searcy
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
Search for more papers by this authorPaulo Victor Sgobbi de Souza
Division of Neuromuscular Diseases, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
Search for more papers by this authorAngela Wittenauer
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorCorresponding Author
Judith L. Fridovich-Keil
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Correspondence
Judith L. Fridovich-Keil, Department of Human Genetics, Emory University School of Medicine, Room 325.2 Whitehead Building, 615 Michael St, Atlanta, GA 30322, USA.
Email: [email protected]
Search for more papers by this authorQuinton S. Katler
Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorKarolina M. Stepien
Adult Inherited Metabolic Diseases Department, Salford Royal Foundation NHS Trust, Salford, UK
Search for more papers by this authorNathan Paull
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorSneh Patel
Neuroscience and Behavioral Biology Program, Emory University, Atlanta, Georgia, USA
Search for more papers by this authorMichael Adams
Division of Pediatric Genetics and Metabolism, UNC School of Medicine, Chapel Hill, North Carolina, USA
Search for more papers by this authorMehmet Cihan Balci
Department of Pediatric Metabolic Disease, Istanbul Medical School, Istanbul, Turkey
Search for more papers by this authorGerard T. Berry
Division of Genetics and Genomics, Department of Pediatrics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorAnnet M. Bosch
Division of Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorDidem Demirbas
Division of Genetics and Genomics, Department of Pediatrics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorJulianna Edman
Department of Pediatric Genetics, University of Illinois-Chicago, Chicago, Illinois, USA
Search for more papers by this authorCan Ficicioglu
Division of Human Genetics and Metabolism, The Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
Search for more papers by this authorMelanie Goff
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
Search for more papers by this authorStephanie Hacker
Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorIna Knerr
National Centre for Inherited Metabolic Disorders, Temple St. Children's University Hospital, Dublin, Ireland
Search for more papers by this authorKristen Lancaster
Division of Pediatric Genetics and Metabolism, UNC School of Medicine, Chapel Hill, North Carolina, USA
Search for more papers by this authorHong Li
Departments of Human Genetics and Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorBryce A. Mendelsohn
Department of Genetics, Oakland Medical Center, Kaiser Permanente, Oakland, California, USA
Search for more papers by this authorBrandi Nichols
Department of Clinical Nutrition, Arkansas Children's Hospital, Little Rock, Arkansas, USA
Search for more papers by this authorWladimir Bocca Vieira de Rezende Pinto
Division of Neuromuscular Diseases, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
Search for more papers by this authorJúlio César Rocha
Nutrition & Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
Reference Centre of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
Center for Health Technology and Services Research (CINTESIS), NOVA Medical School, Lisbon, Portugal, Lisbon, Portugal
Search for more papers by this authorM. Estela Rubio-Gozalbo
Department of Pediatrics, Department of Clinical Genetics, GROW-School for Oncology and Reproduction, European Reference Network for Hereditary Metabolic Disorders (MetabERN) member and United for Metabolic Diseases Member, Maastricht University Medical Centre, Maastricht, The Netherlands
Search for more papers by this authorMichael Saad-Naguib
Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
Search for more papers by this authorSabine Scholl-Buergi
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorSarah Searcy
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
Search for more papers by this authorPaulo Victor Sgobbi de Souza
Division of Neuromuscular Diseases, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
Search for more papers by this authorAngela Wittenauer
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Search for more papers by this authorCorresponding Author
Judith L. Fridovich-Keil
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Correspondence
Judith L. Fridovich-Keil, Department of Human Genetics, Emory University School of Medicine, Room 325.2 Whitehead Building, 615 Michael St, Atlanta, GA 30322, USA.
Email: [email protected]
Search for more papers by this authorAbstract
Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.
CONFLICT OF INTEREST
Quinton S. Katler, Karolina M. Stepien, Nathan Paull, Sneh Patel, Michael Adams, Mehmet Cihan Cihan Balci, Gerard T. Berry, Annet M. Bosch, Angela DeLaO, Didem Demirbas, Julianna Edman, Melanie Goff, Stephanie Hacker, Ina Knerr, Kristen Lancaster, Hong Li, Bryce A. Mendelsohn, Brandi Nichols, Wladimir Bocca Vieira de Rezende Pinto, Júlio César Rocha, M. Estela Rubio-Gozalbo, Michael Saad-Naguib, Sabine Scholl-Buergi, Sarah Searcy, Paulo Victor Sgobbi de Souza, Angela Wittenauer, and Judith L. Fridovich-Keil all declare that they have no conflict of interest with this work. Can Ficicioglu declares the following potential conflicts of interest: consulting fees from Horizon, Takeda, Travere, Swedish Orphan, and Sanofi, and honoraria from Sanofi and Horizon.
Open Research
DATA AVAILABILITY STATEMENT
All data for this article are included in Supplemental Tables.
Supporting Information
| Filename | Description |
|---|---|
| jimd12556-sup-0001-TablesS1.docxWord 2007 document , 63.9 KB | TABLE S1 Detection of galactosemia among S135L/S135L (n = 12), S135L/G (n = 25), and GALT-null (n = 105) participants TABLE S2 Adverse speech outcomes among participants with S135L–GALT as a function of early galactose exposure and presence of acute symptoms. Participants <24 months old at the time of study, or missing relevant information, were excluded TABLE S3 Adverse cognitive outcomes among participants with S135L–GALT as a function of early galactose exposure and presence of acute symptoms. Participants <24 months old at the time of study, or missing relevant information, were excluded TABLE S4 Adverse motor outcomes among participants with S135L–GALT as a function of early galactose exposure and presence of acute symptoms. Participants missing relevant information were excluded TABLE S5 Evidence of adverse ovarian outcomes among participants with S135L–GALT as a function of early galactose exposure and presence of acute symptoms. All male participants, and girls or women missing relevant information, were excluded TABLE S6 All S135L/S135L participants in this study. Participants unable to be scored for a given outcome due to age or sex are listed as “N/A”; missing information is listed as “UNK.” Shaded rows represent participants switched to low galactose formula within the first week of life TABLE S7 All S135L/G participants in this study. Participants unable to be scored for a given outcome due to age or sex are listed as “N/A”; missing information is listed as “UNK.” Shaded rows represent participants switched to low galactose formula within the first week of life |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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