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

J Inherit Metab Dis. 2022 Nov;45(6):1106-1117. doi: 10.1002/jimd.12556. Epub 2022 Sep 26.


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.

Keywords: POI; S135L variant; acute symptoms; galactosemia; long-term outcomes; neurocognitive outcomes; speech delay.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Female
  • Galactose
  • Galactosemias* / diagnosis
  • Galactosemias* / genetics
  • Homozygote
  • Humans
  • Infant, Newborn
  • UTP-Hexose-1-Phosphate Uridylyltransferase / genetics


  • Galactose
  • UTP-Hexose-1-Phosphate Uridylyltransferase
  • GALT protein, human