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.

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

“…In addition, other forms of nephrotoxicity such as cisplatin-or glycerolinduced CKD are associated with abnormal Ggt1 and Gyk expression (74,75); in this study, we found that they also contributed to lipotoxicity. Hmgcs1, Phyh, and Gpd1 were, for the first time to our knowledge, found to be associated with nephrotoxicity, a finding that was also supported by previous reports that they were involved in cholesterol synthesis and steatosis (76)(77)(78). Moreover, these pathways or factors were reversed by troxerutin, suggesting a protective effect of troxerutin in reducing renal lipotoxicity.…”

Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature

“…And the persistent high level of DHEA‐S in the patient may due to his hepatic steatosis resulting in the increased 5β‐reductase activities (Westerbacka et al, ). GPD1 deficiency can lead to non‐alcoholic hepatic steatosis (NASH) (Dionisi‐Vici et al, ), which could be a risk factor for the development of an overt metabolic syndrome, such as type 2 diabetes and insulin resistance (Marchesini et al, ). Our patient was diagnosed with fatty liver and obesity, whereas the affected individuals described in previous reports had fatty liver with normal BMI.…”

“…More intriguingly, both of the patient's parents had an unsatisfactory height and his mother was overweight. Moreover, Dionisi‐Vici et al () reported a patient (patient B) that both of her parents had fatty liver. It seems that the GPD1 mutation carrier could have some lighter clinical features, which requires more clinical information from future report cases to confirm.…”

“…Subsequently, an affected female patient of Caucasian descent with a compound heterozygous consisting of a missense mutation (Arg229Gln) and a large deletion encompassing the GPD1 gene or part of its coding region was reported with the same characteristics (Joshi et al, ). More recently, Dionisi‐Vici et al () identified two novel variants (Arg269Gln and Cys214Arg) and a reported variant (c.361‐1G>C) in four patients with several clinical differences, including recurrent episodes of fasting hypoglycemia, intrahepatic cholestasis, and persistent hypertriglyceridemia.…”

A novel homozygous mutation in the glycerol-3-phosphate dehydrogenase 1 gene in a Chinese patient with transient infantile hypertriglyceridemia: a case report

“…reported biallelic mutations in GPD1 gene of a Chinese boy who presented with a different phenotype comprising obesity, insulin resistance, fatty liver, and short stature [ 4 ]. To date, only four reports have described 16 patients harboring homozygous or compound heterozygous mutations in the GPD1 gene [ 3 – 6 ]. Here, we describe a Han Chinese patient with a novel GPD1 homozygous mutation who presented with hepatomegaly, elevated transaminases, hypertriglyceridemia, and fatty liver in infancy.…”