AAV ‐mediated expression of galactose‐1‐phosphate uridyltransferase corrects defects of galactose metabolism in Classic Galactosemia patient fibroblasts

2021 ◽  
Author(s):  
Megan L. Brophy ◽  
John C. Stansfield ◽  
Youngwook Ahn ◽  
Seng H. Cheng ◽  
John E. Murphy ◽  
...  
Keyword(s):  
Galactose Metabolism ◽  
Classic Galactosemia

scholarly journals Current and Future Treatments for Classic Galactosemia

2021 ◽  
Vol 11 (2) ◽  
pp. 75 ◽  
Author(s):  
Britt Delnoy ◽  
Ana I. Coelho ◽  
Maria Estela Rubio-Gozalbo
Keyword(s):  
Standard Of Care ◽  
Type I ◽  
Therapeutic Approaches ◽  
Restricted Diet ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Classic Galactosemia ◽  
Pathogenic Factors ◽  
Future Treatments ◽  
Novel Therapeutic

Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.

scholarly journals Galactose-1-Phosphate Uridyltransferase Activities in Different Genotypes: A Retrospective Analysis of 927 Samples

2018 ◽  
Vol 3 (2) ◽  
pp. 222-230 ◽  
Author(s):  
Tatiana Yuzyuk ◽  
Andrew R Wilson ◽  
Rong Mao ◽  
Marzia Pasquali
Keyword(s):  
Dietary Intervention ◽  
Finite Mixture Models ◽  
Gene Analysis ◽  
Molecular Testing ◽  
Reference Ranges ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Classic Galactosemia ◽  
Galt Gene ◽  
Life Threatening

Abstract Background Classic galactosemia is an inherited disorder of galactose metabolism caused by the impaired activity of galactose-1-phosphate uridyltransferase (GALT). Untreated galactosemia is life-threatening; however, early dietary intervention prevents mortality and reduces morbidity associated with this disease. The diagnosis of galactosemia includes the measurement of GALT activity in red blood cells (RBC) and GALT gene analysis. In this study, we evaluate GALT activity in different genotypes using the results of combined biochemical and molecular testing in 927 samples. Methods GALT activity in RBC was measured by LC-MS/MS. The analysis of the GALT gene was performed by targeted gene analysis and/or full gene sequencing. Samples were assigned based on the presence of pathogenic (G) or Duarte 2 (D) variants, or their absence (Neg), to G/G, D/G, G/Neg, D/D, D/Neg, and Neg/Neg genotypes. Finite mixture models were applied to investigate distributions of GALT activities in these genotypes. The reference ranges were determined using the central 95% of values of GALT activities. Results The ranges of GALT activity in G/G, D/G, G/Neg, D/D, D/Neg, and Neg/Neg genotypes are 0.0 to 0.7 μmol·h−1 gHb−1, 3.1 to 7.8 μmol·h−1 gHb−1, 6.5 to 16.2 μmol·h−1 gHb−1, 6.4 to 16.5 μmol·h−1 gHb−1, 12.0 to 24.0 μmol·h−1 gHb−1, and 19.4 to 33.4 μmol·h−1 gHb−1, respectively. Conclusions The GALT activity ranges established in this study are in agreement with the expected impact of the genotype on the enzymatic activity. Molecular findings should be interpreted in view of biochemical results to confirm genotype–phenotype correlation.

scholarly journals Fluorinated Galactoses Inhibit Galactose-1-Phosphate Uridyltransferase and Metabolically Induce Galactosemia-like Phenotypes in HEK-293 Cells

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 607 ◽  
Author(s):  
Verena Janes ◽  
Simona Grabany ◽  
Julien Delbrouck ◽  
Stephane P. Vincent ◽  
Johannes Gottschalk ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
Surface Expression ◽  
Hek293 Cells ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Hek 293 ◽  
Classic Galactosemia ◽  
Developmental Impairment ◽  
The Unfolded Protein Response ◽  
Metabolic Induction

Genetic defects of human galactose-1-phosphate uridyltransferase (hGALT) and the partial loss of enzyme function result in an altered galactose metabolism with serious long-term developmental impairment of organs in classic galactosemia patients. In search for cellular pathomechanisms induced by the stressor galactose, we looked for ways to induce metabolically a galactosemia-like phenotype by hGALT inhibition in HEK293 cells. In kinetic studies, we provide evidence for 2-fluorinated galactose-1-phosphate (F-Gal-1-P) to competitively inhibit recombinant hGALT with a KI of 0.9 mM. Contrasting with hepatic cells, no alterations of N-glycoprofiles in MIG (metabolic induction of galactosemia)-HEK293 cells were revealed for an inducible secretory netrin-1 probe by MALDI-MS. Differential fluorescence-activated cell sorting demonstrated reduced surface expression of N-glycosylated CD109, EGFR, DPP4, and rhMUC1. Membrane raft proteomes exhibited dramatic alterations pointing to an affection of the unfolded protein response, and of targeted protein traffick. Most prominent, a negative regulation of oxidative stress was revealed presumably as a response to a NADPH pool depletion during reduction of Gal/F-Gal. Cellular perturbations induced by fluorinated galactoses in normal epithelial cells resemble proteomic changes revealed for galactosemic fibroblasts. In conclusion, the metabolic induction of galactosemia-like phenotypes in healthy epithelial/neuronal cells could support studies on the molecular pathomechanisms in classic galactosemia, in particular under conditions of low galactose stress and residual GALT activity.

Molecular basis and clinical presentation of classic galactosemia in a Croatian population

2018 ◽  
Vol 31 (1) ◽  
pp. 71-75 ◽  
Author(s):  
Danijela Petković Ramadža ◽  
Vladimir Sarnavka ◽  
Jurica Vuković ◽  
Ksenija Fumić ◽  
Vjekoslav Krželj ◽  
...  
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Dietary Treatment ◽  
Autosomal Recessive Disorder ◽  
Neurological Complications ◽  
Galactose Metabolism ◽  
Classic Galactosemia ◽  
Number Of Patients ◽  
Direct Sequence Analysis ◽  
Single Allele

AbstractBackground:Classic galactosemia is an autosomal recessive disorder of galactose metabolism caused by severely decreased activity of galactose-1-phosphate uridylyltransferase (GALT) due to pathogenic mutations in theGALTgene. To date more than 330 mutations have been described, with p.Q188R and p.K285N being the most common in Caucasian populations. Although acute manifestations can be fully avoided by a galactose-restricted diet, chronic complications, such as neurological ones, cannot be prevented in a significant number of patients despite compliance with the dietary treatment.Methods:A cohort of 16 galactosemic Croatian patients, including one pair of siblings, was studied. Molecular characterization was performed by direct sequence analysis of theGALTgene.Results:Sixteen patients were analyzed and only four different mutations were detected. As expected, p.Q188R and p.K285N were common, accounting for 40% and 37% of unrelated alleles, respectively. The third mutation accounting for 20% of mutant alleles was p.R123X causing a premature stop codon, is thus considered to be severe, which is in accordance with the phenotype presented by the homozygous patient described here. The fourth mutation p.E271D was found in a single allele. More than half of our patients manifested some chronic neurological complications.Conclusions:This is the first report on mutational and phenotypic spectra of classic galactosemia in Croatia that expands the knowledge on the mutational map of theGALTgene across Europe and reveals the genetic homogeneity of the Croatian population.

scholarly journals Puberty and fertility in classic galactosemia

2021 ◽  
Author(s):  
Isabelle Flechtner ◽  
Magali Viaud ◽  
Dulanjalee Kariyawasam ◽  
Marie Perrissin-Fabert ◽  
Maud Bidet ◽  
...  
Keyword(s):  
Age Groups ◽  
Dietary Treatment ◽  
Oocyte Donation ◽  
Primary Objective ◽  
Breast Development ◽  
Normal Range ◽  
Galactose Metabolism ◽  
Birth Prevalence ◽  
Classic Galactosemia ◽  
Pelvic Morphology

Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30 000-60 000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotrop axis, and pelvic morphology by ultrasound The secondary objective was to determine predictive factors for potent pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years [5-52 years]) and 47 males (median age, 19 years [3-45 years]), were analyzed. Among the 45 females older than 11 years old, mean age for breast development first stage was 12 years; spontaneous menarche occurred in 25 females at a mean age of 14.6 years. After puberty, 60% of females had irregular menstrual cycles and 50% experienced amenorrhea at a median age of 30 years [15;42]. All age-groups confounded, FSH was above normal range for 65% of the patients, anti-Müllerian hormone and inhibin B were below the normal range according to age, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had tried to conceive. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.

scholarly journals A galactose‐1‐phosphate uridylyltransferase‐null rat model of classic galactosemia mimics relevant patient outcomes and reveals tissue‐specific and longitudinal differences in galactose metabolism

2019 ◽  
Vol 43 (3) ◽  
pp. 518-528 ◽  
Author(s):  
Shauna A. Rasmussen ◽  
Jennifer M. I. Daenzer ◽  
Jessica A. MacWilliams ◽  
S. Taylor Head ◽  
Martine B. Williams ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Rat Model ◽  
Galactose Metabolism ◽  
Tissue Specific ◽  
Classic Galactosemia

scholarly journals The yeast protein Ubx4p contributes to mitochondrial respiration and lithium–galactose–mediated activation of the unfolded protein response

2020 ◽  
Vol 295 (12) ◽  
pp. 3773-3782
Author(s):  
Evandro A. De-Souza ◽  
Felipe S. A. Pimentel ◽  
Ana Luiza F. V. De-Queiroz ◽  
Henrique Camara ◽  
Mikaella L. Felix-Formiga ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Oxygen Consumption ◽  
Unfolded Protein Response ◽  
Mitochondrial Respiration ◽  
Galactose Metabolism ◽  
Classic Galactosemia ◽  
Unfolded Protein ◽  
Yeast Strains ◽  
The Unfolded Protein Response ◽  
Protein Response

In the presence of galactose, lithium ions activate the unfolded protein response (UPR) by inhibiting phosphoglucomutase activity and causing the accumulation of galactose-related metabolites, including galactose-1-phosphate. These metabolites also accumulate in humans who have the disease classic galactosemia. Here, we demonstrate that Saccharomyces cerevisiae yeast strains harboring a deletion of UBX4, a gene encoding a partner of Cdc48p in the endoplasmic reticulum–associated degradation (ERAD) pathway, exhibit delayed UPR activation after lithium and galactose exposure because the deletion decreases galactose-1-phosphate levels. The delay in UPR activation did not occur in yeast strains in which key ERAD or proteasomal pathway genes had been disrupted, indicating that the ubx4Δ phenotype is ERAD-independent. We also observed that the ubx4Δ strain displays decreased oxygen consumption. The inhibition of mitochondrial respiration was sufficient to diminish galactose-1-phosphate levels and, consequently, affects UPR activation. Finally, we show that the deletion of the AMP-activated protein kinase ortholog–encoding gene SNF1 can restore the oxygen consumption rate in ubx4Δ strain, thereby reestablishing galactose metabolism, UPR activation, and cellular adaption to lithium–galactose challenge. Our results indicate a role for Ubx4p in yeast mitochondrial function and highlight that mitochondrial and endoplasmic reticulum functions are intertwined through galactose metabolism. These findings also shed new light on the mechanisms of lithium action and on the pathophysiology of galactosemia.

scholarly journals Classical galactosemia in a Thai infant: case report and review of the literature

2017 ◽  
Vol 9 (1) ◽  
pp. 95-100 ◽  
Author(s):  
Thitima Ngoenmak ◽  
Julintorn Somran ◽  
Chutima Phuaksaman ◽  
Jaruwat Khunrat
Keyword(s):  
Breast Feeding ◽  
English Language ◽  
Early Recognition ◽  
Gas Chromatography Mass Spectrometry ◽  
Galactose Metabolism ◽  
Classical Galactosemia ◽  
Classic Galactosemia ◽  
Hepatocellular Damage ◽  
High Level

Abstract Background Classic galactosemia is an inherited disorder of galactose metabolism that is caused by a deficiency of galactose-1-phosphate uridyl transferase (GALT). As in other Asians, the prevalence of galactosemia in Thai people is very low. An accumulation of its toxic metabolites leads to acute neonatal toxicity and long-term complications. Objective To present the fourth known published case of classical galactosemia in a Thai infant and review the English language literature. Method A 4-month-old boy who was born into a Thai family with no history of consanguinity developed persistent jaundice, hepatosplenomegaly, and lethargy, since introduction to breast-feeding. Result Urine gas chromatography-mass spectrometry demonstrated a high level of galactose, galactitol, and galactonate. Liver biopsy confirmed severe hepatocellular damage and fibrosis. Breast-feeding was immediately replaced by a lactose-free diet and soy milk. His clinical features and subsequent laboratory measurements improved. Developmental delays and defects on speech presented at the last followed up. Conclusion Long-term complications are diet-independent and inevitable. However early recognition and immediate withdraw of galactose from the diet can prevent serious morbidity and mortality.

Gonadal function and ovarian galactose metabolism in classic galactosemia

1989 ◽  
Vol 121 (6) ◽  
pp. 866
Author(s):  
Francine Ratner Kaufman ◽  
Yan Kang Xu ◽  
Won G. Ng ◽  
Paul D. Silva ◽  
Rogerio A. Lobo ◽  
...  
Keyword(s):  
Gonadal Function ◽  
Galactose Metabolism ◽  
Classic Galactosemia

Gonadal function and ovarian galactose metabolism in classic galactosemia

1989 ◽  
Vol 120 (2) ◽  
pp. 129-133 ◽  
Author(s):  
Francine Ratner Kaufman ◽  
Yan Kang Xu ◽  
Won G. Ng ◽  
Paul D. Silva ◽  
Rogerio A. Lobo ◽  
...  
Keyword(s):  
Ovarian Tissue ◽  
Fibrous Tissue ◽  
Insoluble Fraction ◽  
Histologic Examination ◽  
Hypergonadotropic Hypogonadism ◽  
Galactose Metabolism ◽  
Tissue Slices ◽  
Steroid Secretion ◽  
Classic Galactosemia ◽  
Ovarian Stroma

Abstract. Evaluation of ovarian steroid secretion, histologic examination of ovarian tissue, and incubation studies with radiolabelled galactose in ovarian tissue slices were performed in a 21-year-old woman with galactosemia and incipient ovarian failure. After exogenous gonadotropin administration in an attempt to achieve fertility, there was no evidence of ovulation by ultrasound; estrogen and androgen production were deficient indicating ovarian unresponsiveness. Histologic examination of the ovary revealed that the ovarian stroma had an increase in fibrous tissue and that a few hyalinized atretic follicles were present with no intermediate or evolving Graffian follicles. After incubation with galactose-l-14C, there was absence of labelled CO2 production and only labelled galactose-l-phosphate was identified as compared to controls in which several labelled intermediates could be seen. The incorporation of galactose into the TCA-insoluble fraction was drastically reduced in the patient compared to controls, suggesting that there may be a deficiency of ovarian galactose-containing glycolipids, glycoproteins and mucopolysaccharides in the galactosemic ovary. Deficiency in the production of galactose containing compounds, or galactose-phosphate accumulation or both, may lead to the development of hypergonadotropic hypogonadism seen in women with galactosemia.

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