A multinational study of acute and long‐term outcomes of Type 1 galactosemia patients who carry the S135L (c.404C > T) variant of GALT

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...

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Published in:	Journal of inherited metabolic disease Vol. 45; no. 6; pp. 1106 - 1117
Main Authors:	Katler, Quinton S., Stepien, Karolina M., Paull, Nathan, Patel, Sneh, Adams, Michael, Balci, Mehmet Cihan, Berry, Gerard T., Bosch, Annet M., DeLaO, Angela, Demirbas, Didem, Edman, Julianna, Ficicioglu, Can, Goff, Melanie, Hacker, Stephanie, Knerr, Ina, Lancaster, Kristen, Li, Hong, Mendelsohn, Bryce A., Nichols, Brandi, Rezende Pinto, Wladimir Bocca Vieira, Rocha, Júlio César, Rubio‐Gozalbo, M. Estela, Saad‐Naguib, Michael, Scholl‐Buergi, Sabine, Searcy, Sarah, Souza, Paulo Victor Sgobbi, Wittenauer, Angela, Fridovich‐Keil, Judith L.
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-11-2022 Blackwell Publishing Ltd
Subjects:	acute symptoms Alleles Cognition Dietary restrictions Female Galactose Galactosemia Galactosemias - diagnosis Galactosemias - genetics Homozygote Homozygotes Humans Infant, Newborn long‐term outcomes Medical screening Menarche neurocognitive outcomes POI S135L variant speech delay UTP-Hexose-1-Phosphate Uridylyltransferase - genetics S135L variant neurocognitive outcomes galactosemia speech delay POI long-term outcomes acute symptoms
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Nathan Paull participated in data gathering and manuscript editing Julianna Edman participated in data gathering and manuscript editing Júlio César Rocha participated in data gathering and manuscript editing Mehmet Cihan Balci participated in data gathering and manuscript editing Brandi Nichols participated in data gathering and manuscript editing Sneh Patel participated in data analysis and manuscript editing Judith L. Fridovich-Keil initiated the project and participated in study design, data gathering, data analysis, manuscript writing, and manuscript editing Karolina M. Stepien participated in study design, data gathering, and manuscript editing Ina Knerr participated in data gathering and manuscript editing Quinton Katler participated in study design, data gathering, data analysis, manuscript writing, and manuscript editing Sabine Scholl-Buergi participated in data gathering and manuscript editing Gerard T. Berry participated in data gathering and analysis and manuscript editing Paulo Victor Sgobbi de Souza participated in data gathering and manuscript editing Can Ficicioglu participated in data gathering and manuscript editing Didem Demirbas participated in data gathering and manuscript editing Stephanie Hacker participated in data gathering and manuscript editing Sarah Searcy participated in data gathering and manuscript editing Annet M. Bosch participated in data gathering and manuscript editing M Estela Rubio-Gozalbo participated in data gathering and manuscript editing Author contributions Angela Wittenauer participated in data gathering and manuscript editing Melanie Goff participated in data gathering and manuscript editing Wladimir Bocca Vieira de Rezende Pinto participated in data gathering and manuscript editing Michael Saad-Naguib participated in data gathering and manuscript editing Michael Adams participated in data gathering and manuscript editing Kristen Lancaster participated in data gathering and manuscript editing Hong Li participated in data gathering and manuscript editing Bryce A. Mendelsohn participated in data gathering and manuscript editing Angela De La O participated in data gathering and manuscript editing
ISSN:	0141-8955 1573-2665
DOI:	10.1002/jimd.12556