title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
abstract: Transient infantile hypertriglyceridemia (HTGT1; OMIM #614480) is a rare autosomal recessive disorder, which manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis. This rare clinical entity is caused by inactivating mutations in the GPD1 gene, which encodes the cytosolic isoform of glycerol-3-phosphate dehydrogenase. Here we report on four patients from three unrelated families of diverse ethnic origins, who presented with hepatomegaly, liver steatosis, hypertriglyceridemia, with or without fasting ketotic hypoglycemia. Whole exome sequencing revealed the affected individuals to harbor deleterious biallelic mutations in the GPD1 gene, including the previously undescribed c.806G > A (p.Arg269Gln) and c.640T > C (p.Cys214Arg) mutations. The clinical features in three of our patients showed several differences compared to the original reports. One subject presented with recurrent episodes of fasting hypoglycemia along with hepatomegaly, hypetriglyceridemia, and elevated liver enzymes; the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement; finally, the third presented persistent hypertriglyceridemia at the age of 30 years. These findings expand the current knowledge of this rare disorder, both with regard to the phenotype and molecular basis. The enlarged phenotypic spectrum of glycerol-3-phosphate dehydrogenase 1 deficiency can mimic other inborn errors of metabolism with liver involvement and should alert clinicians to recognize this entity by considering GPD1 mutations in appropriate clinical settings.
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy. carlo.dionisivici@opbg.net.
authors.forename: Carlo
authors.identifier: 0000-0002-0007-3379
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: Pediatric Gastroenterology Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Shteyer
authors.affiliation: Genetics and Rare Disease Research Division, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Niceta
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rizzo
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Pode-Shakked
authors.affiliation: CINECA, SCAI-SuperComputing Applications and Innovation Department, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bruselles
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Semeraro
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Barel
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Kol
authors.affiliation: The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.|Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Haberman
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Avishai
authors.initials: A
authors.lastname: Lahad
authors.affiliation: Division of Pathology, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Diomedi-Camassei
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: CINECA, SCAI-SuperComputing Applications and Innovation Department, Rome, Italy.|Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: Genetics and Rare Disease Research Division, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. yair.anikster@sheba.health.gov.il.|CINECA, SCAI-SuperComputing Applications and Innovation Department, Rome, Italy. yair.anikster@sheba.health.gov.il.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005993:Glycerolphosphate Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D006529:Hepatomegaly / Q000235:genetics; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase