Hereditary Deficiency of Beta-1,4-Mannosyltransferase (ALG1-CDG) is a Rare Violation of N-Glycosylation: Observation of Three Cases of the Disease in One Family
Introduction. ALG1-CDG (CDG-1k) is a rare disease from the group of isolated N-glycosylation defects type I. ALG1-CDG is caused by the deficiency of beta-1,4-mannosyltransferase activity, which results from mutations in the ALG1 gene. The article presents our own experience of diagnostics and clinical observation of three patients with this disease in the same family. Purpose. To reveal the etiology of hereditary disease in a family seeking help in connection with death of three children in their first year of life. Materials and methods. DNA samples from parents, a deceased child, and a healthy child were used for molecular genetic research. Next generation sequencing was performed for spouses. The presence of mutations in the ALG1 gene in children was confirmed by direct sequencing. Blood serum samples from a deceased child and a healthy child were used for isoelectric focusing of transferrin (IEFT). IEFT was performed as described by Wada and co-authors with some modifications. Results and discussion. Spouses applied for medical genetic counseling because of the birth of daughter with developmental disabilities, who died in 45 days after birth. The girl was born from the second full-term pregnancy, with body mass 3260 g, body length 51 cm, Apgar score 1/5 points. The condition of the child after birth was very poor: she suffered from hypoalbuminemia, edematous syndrome, seizures and multiple organ failure. Autopsy study revealed a congenital malformation of the central nervous system, cerebral edema, small focal post-hypoxic hemorrhages in the membranes of the brain and spinal cord, in the choroid plexuses and subependymal divisions of the brain substance, the sheaths of the spinal cord roots, resulting in hemosiderosis, ascites, swelling of the soft tissues of the head, face and lower extremities, bronchopneumonia, hemorrhagic syndrome with small focal hemorrhages in the lungs, kidneys and adrenal glands, hepatosplenomegaly, serous hepatitis, parenchymal protein dystrophy of the internal organs. Then two more children were born in the family. Both of them had similar clinical manifestations and died within the first year of life. New generation sequencing was performed in parents. The mutation p.Ser258Leu in the 7th exon of the ALG1 gene was found in the mother, and heterozygous p.Phe394Leu mutation in the 11th exon of the ALG1 gene was found in the father. These mutations are pathogenic, and they are described in patients with ALG1-CDG. The compound heterozygous carriage of these mutations was found in one of the deceased children. Abnormal profile of transferrin isoforms was detected during isoelectric focusing of transferrin of a serum sample obtained from this child. Conclusion. On the base of the results of the study, we made the conclusion that deceased children were compound heterozygous carriers of pathogenic mutations p.Ser258Leu and p.Phe394Leu in the ALG1 gene. The cause of death of these children was a hereditary disease from the group of isolated N-glycosylation defects ALG1-CDG (CDG-1k). Thus, we managed to diagnose three new cases of this extremely rare pathology in one family.