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

Abstract

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 longterm 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 evi-

Clinical and biochemical phenotypes, genotypes, and long-term outcomes of individuals with galactosemia type I from a single metabolic genetics center in Alberta

“…Katler et al reported that individuals who are homozygous or compound heterozygous for the p.Ser135Leu GALT variant exhibited initial presentations similar to classic galactosemia in the neonatal period. Their long-term complications were similar to classic galactosemia regarding cognitive and motor dysfunctions [ 42 ]. Welsink-Karssies et al reported tremors in two individuals with clinical variant galactosemia who were homozygous for the p.Ser135Leu GALT variant.…”

“…The clinical variant galactosemia is due to hypomorphic alleles in GALT resulting in a higher residual GALT activity (1–10% of normal) [ 1 ]. The p.Ser135Leu GALT variant is the most commonly reported hypomorphic GALT variant associated with the clinical variant galactosemia [ 1 , 42 ]. Katler et al reported that individuals who are homozygous or compound heterozygous for the p.Ser135Leu GALT variant exhibited initial presentations similar to classic galactosemia in the neonatal period.…”

“…Katler et al reported motor outcomes including hypotonia, spasticity, ataxia, intention tremors, gait instability, problems with fine and gross motor skills in individuals with galactosemia type I and with the p.Ser135Leu GALT variant (either homozygous or compound heterozygous). Motor abnormalities were reported in 40% of individuals with GALT-null, 28% of individuals with compound heterozygous p.Ser135Leu GALT variant, and 27% of the individuals with homozygous p.Ser135Leu GALT variant [ 42 ]. Adverse ovarian outcomes were reported in 25% of individuals with homozygous p.Ser135Leu GALT variant whereas it was reported in 98% of individuals with GALT- null variants [ 42 ].…”

“…Motor abnormalities were reported in 40% of individuals with GALT-null, 28% of individuals with compound heterozygous p.Ser135Leu GALT variant, and 27% of the individuals with homozygous p.Ser135Leu GALT variant [ 42 ]. Adverse ovarian outcomes were reported in 25% of individuals with homozygous p.Ser135Leu GALT variant whereas it was reported in 98% of individuals with GALT- null variants [ 42 ]. Welsink-Karssies et al reported additional hypomorphic GALT variants resulting in clinical variant galactosemia including p.Val128lle, p.Met219Lys, p.Arg201His and c.-96T>G [ 34 ].…”