Two Lithuanian Cases of Classical Galactosemia with a Literature Review: A Novel GALT Gene Mutation Identified

Galactosemia is a rare autosomal recessive genetic disorder that causes impaired metabolism of the carbohydrate galactose. This leads to severe liver and kidney insufficiency, central nervous system damage and long-term complications in newborns. We present two clinical cases of classical galactosemia diagnosed at the Lithuanian University of Health Sciences (LUHS) Kaunas Clinics hospital and we compare these cases in terms of clinical symptoms and genetic variation in the GALT gene. The main clinical symptoms were jaundice and hepatomegaly, significant weight loss, and lethargy. The clinical presentation of the disease in Patient 1 was more severe than that in Patient 2 due to liver failure and E. coli-induced sepsis. A novel, likely pathogenic GALT variant NM_000155.4:c.305T>C (p.Leu102Pro) was identified and we believe it could be responsible for a more severe course of the disease, although further study is needed to confirm this. It is very important to suspect and diagnose galactosemia as early in its course as possible, and introduce lactose-free formula into the patient’s diet. Wide-scale newborn screening and genetic testing are particularly crucial for the early detection of the disease.

Microcephaly-capillary malformation syndrome: the newly reported cases

Microcephaly-capillary malformation syndrome (MICCAP: OMIM 614261) is a severe monogenic disorder inherited in an autosomal recessive manner caused by mutations in the STAMBP gene. There are less than 20 published cases of the syndrome to date. The paper reports three new cases of rare MICCAP syndrome. The cause of the disorder was confirmed in three affected individuals from two unrelated families by pedigree analysis, biochemical analysis, RFLP analysis and automated Sanger sequencing. The two brothers were homozygous for the potentially pathogenic STAMBP gene variant c.188A>G (p.Tyr63Cys). Clinical phenotype of the girl from the second family resulted from the combination of two genetic disorders: galactosemia caused by the compound heterozygosity for the pathogenic GALT gene variants (c.563A>G and c.855G>T), and MICCAP caused by the STAMBP gene variants (c.204-5c>g and с.668_669delCA), one of which originated de novo. The prevalence of microcephaly-capillary malformation syndrome in Russia is evaluated, it is one per 120,000 people (CI: 1/356 724–1/62 691). The carrier frequency is one per 173 people. The target STAMBP gene analysis makes the genetic confirmation of the MICCAP syndrome quicklier. When determining the tactics of diagnosis and therapy in each particular case, the possibility of combination of two rare genetic disorders in one patient should be considered.

Novel Mutation in GALT Gene in Galactosemia Patient with Group B Streptococcus Meningitis and Acute Liver Failure

Classic galactosemia is an autosomal recessive disorder caused by the deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) involved in galactose metabolism. Bacterial infections are a known cause of early morbidity and mortality in children with classic galactosemia. The most common agent is Escherichia coli, but in rare situations, other bacteria are incriminated. We report a case of a three-week-old female patient with galactosemia, who presented with Group B Streptococcus (GBS) meningitis/sepsis. She received treatment with antibiotics, supportive therapy, and erythrocyte transfusion, but after a short period of improvement, she presented acute liver failure with suspicion of an inborn error of metabolism. Rapid nuclear magnetic resonance (NMR) spectroscopy from urine showed highly elevated values of galactose and galactitol. Under intensive treatment for acute liver failure and with a lactose-free diet, her clinical features and laboratory parameters improved considerably. Genetic testing confirmed compound heterozygous status for GALT mutations: c.563 A>G [p.Q188R] and c. 910 C>T, the last mutation being a novel mutation in GALT gene. In countries without an extensive newborn screening program, a high index of suspicion is necessary for early diagnosis and treatment of galactosemia.

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

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.