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J Inherit Metab Dis. 2016 Sep;39(5):689-695. doi: 10.1007/s10545-016-9956-7. Epub 2016 Jul 1.

Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.

Author information

1
Division of Metabolism, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy. carlo.dionisivici@opbg.net.
2
Pediatric Gastroenterology Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
3
Genetics and Rare Disease Research Division, Bambino Gesù Children's Hospital, Rome, Italy.
4
Division of Metabolism, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.
5
Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
6
The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
7
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
8
CINECA, SCAI-SuperComputing Applications and Innovation Department, Rome, Italy.
9
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
10
Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
11
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
12
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
13
Division of Pathology, Bambino Gesù Children's Hospital, Rome, Italy.
14
Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. yair.anikster@sheba.health.gov.il.
15
CINECA, SCAI-SuperComputing Applications and Innovation Department, Rome, Italy. yair.anikster@sheba.health.gov.il.

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.

PMID:
27368975
DOI:
10.1007/s10545-016-9956-7
[Indexed for MEDLINE]

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