GPD1 Deficiency

Mendelian MONDO:0013771 Pathograph 19 Show in embeddings browser Inborn Error of Metabolism

Autosomal recessive inborn error of glycerolipid and carbohydrate metabolism caused by biallelic loss-of-function variants in GPD1, which encodes the cytosolic NAD+-dependent glycerol-3-phosphate dehydrogenase that interconverts dihydroxyacetone phosphate (DHAP) and glycerol-3-phosphate (G3P). Children present in the first two years of life (median age about six to nine months in pooled literature reviews) with hepatomegaly, hepatic steatosis, raised transaminases and moderate to severe hypertriglyceridemia, sometimes with failure to thrive, vomiting, splenomegaly, hypercholesterolemia or, less often, fasting hypoglycemia. Liver biopsy shows macro- and microvesicular steatosis with fibrosis in most biopsied patients and cirrhosis in a minority, sometimes already in infancy; a hepatocellular adenoma has been reported once. The MONDO and Orphanet name calls the disorder "transient", after the decline of triglycerides with age in the founding cohort, but pooled follow-up of the published cases finds triglycerides and transaminases normalizing in only about three in ten patients, with mild hypertriglyceridemia persisting into the third and fourth decades. Severity varies even within a family carrying the same variant. How loss of an enzyme that makes the triglyceride backbone produces more rather than less hepatic and plasma triglyceride is unresolved: three incompatible mechanistic proposals are recorded below, and the only animal model, the Gpd1-null BALB/cHeA mouse, points the other way.

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1
Inheritance
7
Pathophys.
16
Phenotypes
3
Hypotheses
2
Gaps
19
Pathograph
1
Genes
3
Medical Actions
4
Differentials
1
Models
11
References
1
Deep Research
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Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM GASTROINTESTINAL
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic GPD1 variants, homozygous in most reported patients; parents are asymptomatic heterozygotes in the reported families.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:29940878 SUPPORT Human Clinical
"The patient was a homozygote and her parents were heterozygous for the mutation."
Homozygous proband with heterozygous parents.
PMID:27368975 SUPPORT Human Clinical
"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."
States autosomal recessive inheritance.
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Mechanistic Hypotheses

3
Diversion of excess DHAP into glycerolipid synthesis through the acyl-DHAP route
acyl_dhap_diversion EMERGING
Evidence balance 2 support
With GPD1 absent, DHAP produced by glycolysis is not reduced to G3P and is proposed to be acylated directly, entering glycerolipid synthesis through the acyl-DHAP pathway and driving hepatocellular triglyceride accumulation. The proposal is consistent with the raised DHAP and lowered G3P measured in Gpd1-null mouse tissue, but neither hepatic DHAP, acyl-DHAP flux nor hepatic G3P has been measured in a patient.
Pathograph links
Impaired Cytosolic DHAP and G3P Interconversion -> Hepatocyte Triglyceride Accumulation INDIRECT UNKNOWN INTERMEDIATES Both published proposals route through this step but disagree on which metabolite accumulates; the intermediate steps are not demonstrated in patients.
Show evidence (2 references)
PMID:24549054 SUPPORT Other
"The mechanism of fatty liver in our patient may be due to acylation of excess DHAP."
The authors' own mechanistic proposal, stated as a possibility in the discussion of a single case; no metabolite or flux measurement accompanies it, hence OTHER.
PMID:40216993 SUPPORT BACKGROUND Other
"It has been suggested that the fatty liver observed in all patients with GPD1 deficiency on ultrasonography or other imaging may result from excessive acylation of dihydroxyacetone phosphate (DHAP)"
A 2025 case report restating the acyl-DHAP proposal from earlier literature; its next sentence says the detailed mechanisms remain unclear.
Reduced G3P-to-DHAP conversion increases hepatic G3P for triglyceride synthesis
hepatic_g3p_retention EMERGING
Evidence balance 1 support 1 refute
Proposes that hypertriglyceridemia results because loss of GPD1 prevents oxidation of G3P back to DHAP, enlarging the hepatic G3P pool available for triglyceride synthesis. This runs opposite to the acyl-DHAP proposal on the direction of the metabolite change, and opposite to the low tissue G3P and high DHAP measured in the Gpd1-null mouse. It has not been tested in patient tissue.
Pathograph links
Impaired Cytosolic DHAP and G3P Interconversion -> Hepatocyte Triglyceride Accumulation INDIRECT UNKNOWN INTERMEDIATES Both published proposals route through this step but disagree on which metabolite accumulates; the intermediate steps are not demonstrated in patients.
Show evidence (2 references)
PMID:39839217 SUPPORT BACKGROUND Other
"Hypertriglyceridemia may result from reduced conversion of G3P to DHAP, increasing the hepatic G3P for triglyceride synthesis."
States the G3P-retention proposal, attributed by the authors to earlier literature; it is a stated possibility, not a measurement.
PMID:11147825 REFUTE Model Organism
"Levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle."
In the Gpd1-null mouse, tissue G3P is low and DHAP high, the opposite of the enlarged G3P pool this proposal requires. The measurement is in mouse and is most marked in muscle, so it does not settle what happens in human liver.
Increased hepatic triglyceride secretion drives the hypertriglyceridemia
hepatic_triglyceride_secretion EMERGING
Evidence balance 1 support 1 refute
Proposes that the plasma hypertriglyceridemia reflects increased secretion of triglyceride by hepatocytes, based on a single HepG2 experiment in which a mutant GPD1 cDNA was overexpressed on top of the endogenous enzyme. That design tests whether the mutant protein does something, not what its absence does, so it is weak support for a loss-of-function mechanism. A later review restating the founding paper lists decreased hepatic triglyceride output instead, so the direction of hepatic export is itself unsettled.
Pathograph links
GPD1 Loss of Function -> Increased Hepatocyte Triglyceride Secretion INDIRECT UNKNOWN INTERMEDIATES Supported only by overexpression of a mutant cDNA in HepG2 cells; see the hepatic_triglyceride_secretion hypothesis for why that design is weak evidence about loss of function.
Increased Hepatocyte Triglyceride Secretion -> Hypertriglyceridemia INDIRECT UNKNOWN INTERMEDIATES Inferred from the HepG2 result; no source measures VLDL-triglyceride production or clearance in patients.
Show evidence (2 references)
PMID:22226083 SUPPORT In Vitro
"Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01)."
The single experimental observation behind the secretion proposal.
PMID:41971245 REFUTE BACKGROUND Other
"Therefore, GPD1 mutations lead to increased TG synthesis in the liver, decreased output from the liver, increased inflow of fatty acids into the liver, and impaired hepatic beta-oxidation causing nonalcoholic hepatic steatosis"
A 2026 review, restating the founding paper, lists decreased rather than increased hepatic output; the two accounts disagree on the direction of triglyceride export. Neither is a measurement in patients.
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Discussions and Knowledge Gaps

2
Why does loss of GPD1 cause hepatic steatosis and hypertriglyceridemia in children, when the Gpd1-null mouse is protected from ethanol-induced hepatic triglyceride accumulation, oxidizes more fat and gains less weight?
HUMAN MODEL MISMATCH OPEN gpd1_mouse_liver_lipid_mismatch
Attached to
pathophysiology#Hepatocyte Triglyceride Accumulation animal_models#Mouse
The mouse data fit the expectation that GPD1 supplies the glycerol backbone for hepatic triglyceride, so its loss should reduce triglyceride. Patients show the opposite. Either the human phenotype arises through a route the mouse does not use (the acyl-DHAP pathway has been proposed), or the mouse phenotyping has not tested the conditions that matter in infants, such as a milk-based high-fat diet. Until the discrepancy is explained, none of the proposed hepatic mechanisms can be regarded as tested.
Show evidence (2 references)
PMID:24472537 SUPPORT Model Organism
"On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake."
In the mouse, GPD1 loss prevents rather than causes hepatic triglyceride accumulation after ethanol.
PMID:32662756 SUPPORT Model Organism
"These data indicate that GPD1 deficiency induces enhancement of fat oxidation with suppression of weight gain."
Whole-body lipid phenotype of the mouse runs opposite to the human disease.
Is GPD1 deficiency a transient infantile disorder, as its MONDO and Orphanet names state, or a persistent liver and lipid disorder whose infantile peak is followed by long-lasting milder disease?
CONTROVERSY OPEN gpd1_transient_course
Attached to
disease# phenotypes#Hypertriglyceridemia pathophysiology#Progressive Hepatic Fibrosis
The founding cohort showed triglycerides declining with age, and Orphanet still describes reduction or normalization with age. Pooled follow-up of later cases finds triglycerides normalizing in under a third, fibrosis that can progress to cirrhosis, and persistent hypertriglyceridemia into adulthood. The answer determines whether surveillance should continue into adulthood. It is limited by short follow-up, selective biopsy, and the few adults reported.
Show evidence (3 references)
ORPHA:300293 SUPPORT Other
"Reduction or normalization of triglyceride serum levels occurs with advancing age."
The transient framing as recorded by Orphanet.
PMID:41971245 REFUTE Human Clinical
"This study indicates that GPD1 deficiency may not be a transient or benign condition, as previously considered, due to the persistence of HTG and liver pathology in a significant proportion of cases."
Pooled-review conclusion against the transient framing.
PMID:32685347 REFUTE Human Clinical
"In some patients, hypertriglyceridemia could be severe and persist overtime."
Severe hypertriglyceridemia persisting over time in some patients.
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Pathophysiology

7
GPD1 Loss of Function
Mechanism confidence: Established
Biallelic GPD1 variants (splice-site, nonsense, frameshift, missense and a whole-gene deletion) abolish or reduce the cytosolic NAD+-dependent glycerol-3-phosphate dehydrogenase. The founding homozygous splice-acceptor variant c.361-1G>C produces aberrantly spliced mRNA predicted to truncate the protein, and GPD1 protein was absent on western blot of liver from a compound heterozygote carrying a deletion and p.Arg229Gln. Enzyme activity has not been reported for most missense alleles.
Increased hepatic triglyceride secretion drives the hypertriglyceridemia
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
GPD1 hgnc:4455 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GPD1 (hgnc:4455). hgnc:4455 is a gene from the HUGO Gene Nomenclature Committee.
glycerol-3-phosphate dehydrogenase (NAD+) activity GO:0141152 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves glycerol-3-phosphate dehydrogenase (NAD+) activity (GO:0141152), qualified as loss of function. GO:0141152 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
cytosol GO:0005829 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cytosol (GO:0005829). GO:0005829 is a cellular component from the Gene Ontology.
Downstream
Impaired Cytosolic DHAP and G3P Interconversion Loss of the enzyme removes the cytosolic NADH-dependent reduction of DHAP to G3P and its reverse.
Increased Hepatocyte Triglyceride Secretion Supported only by overexpression of a mutant cDNA in HepG2 cells; see the hepatic_triglyceride_secretion hypothesis for why that design is weak evidence about loss of function. Increased hepatic triglyceride secretion drives the hypertriglyceridemia
Show evidence (4 references)
PMID:22226083 SUPPORT Human Clinical
"Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals."
Founding report of the homozygous GPD1 splice variant and its aberrant splicing in all ten affected individuals.
PMID:24549054 SUPPORT Human Clinical
"GPD1 protein was absent in the patient's liver biopsy on western blot."
Shows absence of the protein in patient liver, the target tissue.
PMID:24549054 SUPPORT Human Clinical
"Mutations in GPD1 encoding glycerol-3-phosphate dehydrogenase that catalyzes the reversible redox reaction of dihydroxyacetone phosphate and NADH to glycerol-3-phosphate (G3P) and NAD(+) were identified."
States the reaction the lost enzyme catalyzes, which defines the molecular-function binding.
+ 1 more reference
Impaired Cytosolic DHAP and G3P Interconversion
Mechanism confidence: Provisional
Without GPD1, cytosolic DHAP is not reduced to G3P. In the Gpd1-null mouse this gives low tissue G3P and high DHAP, most marked in skeletal muscle; a second strain lacking both GPD1 and malic enzyme showed the abnormal G3P/DHAP pattern only in skeletal muscle. Hepatic G3P and DHAP have not been measured in patients, so the state of the hepatic metabolite pool, which is what the competing steatosis proposals turn on, is unknown.
Diversion of excess DHAP into glycerolipid synthesis through the acyl-DHAP route Reduced G3P-to-DHAP conversion increases hepatic G3P for triglyceride synthesis
glycerol-3-phosphate metabolic process GO:0006072 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycerol-3-phosphate metabolic process (GO:0006072). GO:0006072 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Gpd1-null BALB/cHeA mouse Mouse recapitulates
Downstream
Hepatocyte Triglyceride Accumulation Both published proposals route through this step but disagree on which metabolite accumulates; the intermediate steps are not demonstrated in patients. Diversion of excess DHAP into glycerolipid synthesis through the acyl-DHAP route Reduced G3P-to-DHAP conversion increases hepatic G3P for triglyceride synthesis
Impaired Glycerol-3-Phosphate Shuttle GPD1 is the cytosolic half of the shuttle, so the shuttle cannot run without it.
Impaired Gluconeogenesis from Glycerol
Show evidence (2 references)
PMID:11147825 SUPPORT Model Organism
"Levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle."
Direct metabolite measurement of the block in the Gpd1-null mouse.
PMID:11451371 SUPPORT Model Organism
"Tissue levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were only abnormal in skeletal muscle."
Same direction of change in a double-mutant strain, but confined to skeletal muscle, which is why the hepatic metabolite state is recorded as unknown.
Impaired Glycerol-3-Phosphate Shuttle
Mechanism confidence: Provisional
GPD1 and mitochondrial GPD2 together carry cytosolic reducing equivalents into mitochondria. In the Gpd1-null mouse the nonfunctional shuttle lowers the cytosolic NAD/NADH ratio and blocks glycolysis at glyceraldehyde-phosphate dehydrogenase, chiefly in skeletal muscle, where exercised mice could not maintain ATP. No human phenotype has been attributed to this node; muscle and brain energy metabolism have not been studied in patients, so it has no downstream phenotype.
glycerol-3-phosphate shuttle GO:0006127 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycerol-3-phosphate shuttle (GO:0006127). GO:0006127 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:11147825 SUPPORT Model Organism
"When exercised, mice were unable to maintain normal ATP levels in skeletal muscle."
Functional consequence of the shuttle defect in the mouse.
Impaired Gluconeogenesis from Glycerol
Mechanism confidence: Provisional
G3P formed from glycerol must be oxidized to DHAP by GPD1 to enter gluconeogenesis. Gpd1-null mice make less glucose from glycerol, but after one to four hours of fasting their blood glucose is higher than controls, with a compensatory shift to alanine-driven gluconeogenesis. Because the model compensates rather than becoming hypoglycemic, this node is not wired to the hypoglycemia seen in about one in ten patients; that phenotype has no sourced mechanism.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
gluconeogenesis GO:0006094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gluconeogenesis (GO:0006094). GO:0006094 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Gpd1-null BALB/cHeA mouse Mouse recapitulates
Show evidence (2 references)
PMID:27733253 SUPPORT Model Organism
"Although these data indicate that a lack of GPD1 inhibits gluconeogenesis from glycerol, chronic GPD1 deficiency may induce an adaptation that enhances gluconeogenesis from glycogenic amino acids."
Establishes the block and the compensatory adaptation in the mouse.
PMID:27733253 SUPPORT Model Organism
"Although lack of GPD1 inhibited gluconeogenesis from glycerol, blood glucose levels in the HeA mice after 1-4h of fasting were significantly higher than that in the By mice."
The fasting result that argues against using this node to explain human hypoglycemia.
Hepatocyte Triglyceride Accumulation
Mechanism confidence: Established
Triglyceride accumulates in hepatocyte lipid droplets, seen on ultrastructure as intrahepatocytic lipid droplets and on biopsy as macro- and microvesicular steatosis in every biopsied patient. Which substrate route feeds it is not established (see the acyl_dhap_diversion and hepatic_g3p_retention hypotheses). Conformance to the steatosis module is claimed at this node only: the module's lipotoxic-stress and inflammatory nodes have not been studied in GPD1 deficiency.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
lipid storage GO:0019915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lipid storage (GO:0019915). GO:0019915 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hepatic steatosis The accumulation is what imaging and histology read as steatosis.
Hepatomegaly Inferred: hepatomegaly and steatosis co-occur in nearly every patient and steatosis is the dominant histological finding, but no cited source tests whether lipid accumulation alone accounts for the liver enlargement.
Elevated transaminases Inferred: the transaminase rise accompanies steatosis and steatohepatitis on biopsy, but the hepatocyte-injury step between them has not been characterized in this disorder.
Progressive Hepatic Fibrosis The founding cohort describes fatty liver followed by fibrosis; the intervening injury and stellate-cell steps are not studied here.
Show evidence (2 references)
PMID:29940878 SUPPORT Human Clinical
"Ultrastructural study showed intrahepatocytic lipid droplets."
Ultrastructural demonstration of hepatocyte lipid accumulation in a patient.
PMID:41971245 SUPPORT Human Clinical
"Nineteen patients underwent liver biopsy; all showed micro- and macrosteatosis, mild to moderate portal fibrosis in 58% (11 out of 19), and cirrhosis in the remaining eight cases (42%)."
Every biopsied patient in the pooled literature had micro- and macrovesicular steatosis.
Increased Hepatocyte Triglyceride Secretion
Mechanism confidence: Hypothetical
Proposed mechanism for the plasma hypertriglyceridemia, resting on one HepG2 overexpression experiment. The direction of hepatic triglyceride export in patients has not been measured, and a later review lists decreased hepatic output instead; see the hepatic_triglyceride_secretion hypothesis.
Increased hepatic triglyceride secretion drives the hypertriglyceridemia
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Downstream
Hypertriglyceridemia Inferred from the HepG2 result; no source measures VLDL-triglyceride production or clearance in patients. Increased hepatic triglyceride secretion drives the hypertriglyceridemia
Show evidence (1 reference)
PMID:22226083 SUPPORT In Vitro
"Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01)."
The only experimental observation for this node.
Progressive Hepatic Fibrosis
Mechanism confidence: Established
Portal fibrosis is present in most biopsied patients and progresses to cirrhosis in a minority, documented from infancy to adolescence. Sequential biopsies at 3 and 15 years in one boy showed progression from incomplete cirrhosis to diffuse nodular transformation. Decompensated liver disease has not been reported. Biopsy is done selectively, so the fibrosis and cirrhosis fractions among biopsied patients overstate their frequency in all patients. Conformance to the fibrosis node of the steatosis module is not claimed, because stellate-cell activation has not been examined in this disorder.
Downstream
Hepatic fibrosis
Cirrhosis
Show evidence (2 references)
PMID:39839217 SUPPORT Human Clinical
"Liver biopsy (n = 18) demonstrated steatosis in all, fibrosis in 94.4%, and cirrhosis in 22.2%."
Pooled biopsy findings across the published cases.
PMID:39839217 SUPPORT Human Clinical
"The first showed incomplete cirrhosis, inflammation, and steatosis and the second showed diffuse nodular transformation of liver and extensive steatosis, suggesting slow disease progression."
Sequential biopsies in one patient document progression rather than regression of the liver disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for GPD1 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Cardiovascular 1
Splenomegaly OCCASIONAL HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39839217 SUPPORT Human Clinical
"Majority had hepatomegaly (94.4%), 22.2% each had splenomegaly and growth failure."
22.2% of pooled cases supports OCCASIONAL.
Digestive 7
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240), qualified as infantile onset. HP:0002240 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:39839217 SUPPORT Human Clinical
"Majority had hepatomegaly (94.4%), 22.2% each had splenomegaly and growth failure."
Pooled frequency of hepatomegaly supports VERY_FREQUENT.
PMID:36051699 SUPPORT Human Clinical
"All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly."
Independent pooled frequency of hepatomegaly.
Hepatic steatosis VERY_FREQUENT HP:0001397 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic steatosis (HP:0001397). HP:0001397 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39839217 SUPPORT Human Clinical
"Hypertriglyceridemia (97.2%) was nearly universal, 100% had fatty liver, and hypoglycaemia (11.2%) was uncommon."
Fatty liver in every pooled case.
PMID:36051699 SUPPORT Human Clinical
"Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis."
Independent pooled series with steatosis in all patients.
Hepatic fibrosis FREQUENT HP:0001395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic fibrosis (HP:0001395). HP:0001395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36051699 SUPPORT Human Clinical
"Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis."
Two thirds of the pooled series had fibrosis, supporting FREQUENT. The 94.4% figure among biopsied patients is not used for the band because biopsy is selective.
Cirrhosis OCCASIONAL HP:0001394 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cirrhosis (HP:0001394). HP:0001394 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:39839217 SUPPORT Human Clinical
"Liver biopsy (n = 18) demonstrated steatosis in all, fibrosis in 94.4%, and cirrhosis in 22.2%."
Four of 18 biopsied, which is 4 of 36 pooled cases overall; OCCASIONAL is used because unbiopsied patients are not known to be free of cirrhosis.
PMID:32685347 SUPPORT Human Clinical
"Abdominal ultrasound showed diffuse liver echogenicity and liver biopsy disclosed cirrhosis with micro and macrovesicular steatosis."
Cirrhosis with steatosis in an adolescent followed from age 1.
PMID:41971245 SUPPORT Human Clinical
"In contrast, other patients developed cirrhosis during infancy with insufficient data on long-term follow-up."
Cirrhosis can already be present in infancy.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37211761 SUPPORT Human Clinical
"A 2-month-27-day-old boy, who had growth retardation, hepatomegaly and anemia suffered to our hospital with vomiting."
Vomiting at presentation in early infancy.
Intrahepatic cholestasis VERY_RARE HP:0001406 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrahepatic cholestasis (HP:0001406). HP:0001406 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27368975 SUPPORT Human Clinical
"the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement"
Individual patient with intrahepatic cholestasis.
PMID:36051699 SUPPORT Human Clinical
"Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%)."
3.2-6.5% of pooled cases supports VERY_RARE.
Hepatocellular adenoma HP:0012028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic adenoma, annotated with Hepatocellular adenoma (HP:0012028). HP:0012028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35365473 SUPPORT Human Clinical
"On follow-up, he developed hepatic lesion and his hepatomegaly with hypertriglyceridaemia persisted."
Hepatic lesion arising during follow-up, with persistent hepatomegaly and hypertriglyceridaemia.
PMID:35365473 SUPPORT Human Clinical
"This could be the first report of development of adenoma in transient HTGTI."
The authors identify the lesion as an adenoma and describe it as the first such report.
Metabolism 5
Hypertriglyceridemia VERY_FREQUENT HP:0002155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertriglyceridemia (HP:0002155), qualified as infantile onset. HP:0002155 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (5 references)
PMID:39839217 SUPPORT Human Clinical
"Hypertriglyceridemia (97.2%) was nearly universal, 100% had fatty liver, and hypoglycaemia (11.2%) was uncommon."
Frequency in 36 pooled published cases supports VERY_FREQUENT.
PMID:36051699 SUPPORT Human Clinical
"The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up."
Independent pooled series of 31 cases; also documents that most patients do not normalize.
PMID:41839820 SUPPORT Human Clinical
"A significant negative correlation was noted between age at presentation and serum triglyceride levels."
Triglycerides are highest in those presenting youngest.
+ 2 more references
Elevated transaminases VERY_FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36051699 SUPPORT Human Clinical
"In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia."
Pooled frequency of raised ALT supports VERY_FREQUENT.
Hypercholesterolemia FREQUENT HP:0003124 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercholesterolemia (HP:0003124). HP:0003124 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36051699 SUPPORT Human Clinical
"In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia."
38.7% of pooled cases supports FREQUENT.
Hypoglycemia OCCASIONAL HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39839217 SUPPORT Human Clinical
"Hypertriglyceridemia (97.2%) was nearly universal, 100% had fatty liver, and hypoglycaemia (11.2%) was uncommon."
11.2% of pooled cases supports OCCASIONAL.
PMID:27368975 SUPPORT Human Clinical
"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."
Documents the fasting, ketotic character of the hypoglycemia.
Insulin resistance HP:0000855 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Insulin resistance (HP:0000855). HP:0000855 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36588760 SUPPORT Human Clinical
"A 10-month-old male infant was diagnosed with hypertriglyceridemia, hepatomegaly, liver injury, fasting hypoglycemia, and insulin resistance."
Insulin resistance together with fasting hypoglycemia in an infant.
PMID:28944580 SUPPORT Human Clinical
"Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature."
Insulin resistance in an adolescent.
Growth 3
Growth delay OCCASIONAL HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36051699 SUPPORT Human Clinical
"All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly."
22.6% of pooled cases supports OCCASIONAL.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508), qualified as infantile onset. HP:0001508 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:35450873 SUPPORT Human Clinical
"We report a case of a young girl of South Asian descent presented with faltering growth, hepatomegaly, hypertriglyceridaemia and raised transaminases."
Faltering growth as a presenting feature.
Obesity VERY_RARE HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28944580 SUPPORT Human Clinical
"Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature."
Obesity in an individual patient.
PMID:36051699 SUPPORT Human Clinical
"Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%)."
3.2-6.5% of pooled cases supports VERY_RARE.
🧬

Genetic Associations

1
Biallelic GPD1 variants
Gene: GPD1 hgnc:4455 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GPD1 (hgnc:4455). hgnc:4455 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (6 references)
PMID:36051699 SUPPORT Human Clinical
"Of patients, 87.1% had homozygous variants, with the most frequent loci being c.361-1G > C and c.895G > A."
Homozygosity and the recurrent alleles across pooled cases.
PMID:41839820 SUPPORT Human Clinical
"These patients also have a similar homozygous haplotype around the variant, construing its founder effect in South Asian patients with inherited GPD1 deficiency."
Founder allele in South Asians.
PMID:41971245 SUPPORT Human Clinical
"Three of the 15 variants likely originated from a common ancestor, "that is, founder in nature": p.I119fs*94 (Palestinian Arabs), p.Gly299Arg (Czech population), and p.Thr251Asnfs*10 (Saudi Arabia)."
Further founder alleles across populations.
+ 3 more references
💊

Medical Actions

3
Low-fat, medium-chain-triglyceride-enriched diet
Action: low-fat, medium-chain-triglyceride-enriched dietNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is low-fat, medium-chain-triglyceride-enriched diet, annotated with Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
First-line supportive management. There are no dietary guidelines for GPD1 deficiency; a low-fat diet with medium-chain triglyceride as a large share of fat has been used and lowered triglycerides in case reports.
Target Phenotypes: Hypertriglyceridemia HP:0002155 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypertriglyceridemia (HP:0002155). HP:0002155 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33120465 SUPPORT Human Clinical
"After a low-fat diet with enriched medium-chain fatty acids, their plasma triglyceride level were significantly decreased, and finally normalized in case 2."
Triglyceride reduction on the diet in two children.
PMID:39839217 SUPPORT Human Clinical
"Currently, there are no dietary guidelines for GPD1 deficiency."
Records the absence of guidelines.
Fenofibrate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: fenofibrate CHEBI:5001 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fenofibrate (CHEBI:5001). CHEBI:5001 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Off-label fibrate therapy for severe or progressive hypertriglyceridemia, reported in an adolescent with cirrhosis and in an infant. Pediatric experience with fibrates is limited, so use has been cautious with monitoring of liver and muscle enzymes. No effect on fibrosis is reported.
Target Phenotypes: Hypertriglyceridemia HP:0002155 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypertriglyceridemia (HP:0002155). HP:0002155 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:32685347 SUPPORT Human Clinical
"Considering the persistent and progressive increase of plasma triglycerides, fenofibrate treatment was started at 15 years of age allowing triglyceride level reduction in the following 1-year follow-up."
Triglyceride reduction on fenofibrate in an adolescent.
PMID:39839217 SUPPORT Human Clinical
"All received supportive therapy, and fenofibrate was successfully used in one case for progressive hypertriglyceridemia."
Use in an infant with progressive hypertriglyceridemia.
PMID:39839217 SUPPORT Human Clinical
"Considering the limited experience of fibrates in children and concerns of adverse effects (raised liver enzyme, muscle enzymes, gall stone, and renal impairment), fenofibrate should be used cautiously under close supervision and regular monitoring."
Safety caveat for pediatric use.
Hepatic and metabolic surveillance
Category: Monitoring Action: scheduled clinical, laboratory and imaging surveillance of liver disease and lipidsNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is scheduled clinical, laboratory and imaging surveillance of liver disease and lipids, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Proposed by one pediatric hepatology group, not a consensus guideline: outpatient review every 3-4 months with growth, liver and spleen size, liver function tests, INR and lipid profile; ultrasound and transient elastography every 6-12 months; hepatitis A and B vaccination and avoidance of hepatotoxic drugs. Because data on progression are limited, intervals are to be tailored to the patient.
Show evidence (3 references)
PMID:39839217 SUPPORT Human Clinical
"We recommend 3-4 monthly outpatient department follow-up with monitoring of growth, liver and spleen size, liver function test, international normalized ratio, and lipid profile."
Proposed surveillance schedule.
PMID:39839217 SUPPORT Human Clinical
"Imaging (USG, transient elastography) may be done every 6-12 months, but protocols should be tailored as per patient's clinical status as the data on disease progression are limited."
Proposed imaging interval.
PMID:39839217 SUPPORT Human Clinical
"Avoiding other liver injuries by vaccination against hepatitis A/B and caution with use of hepatotoxic drugs/CAM is advisable."
Protective measures against additional liver injury.
🔬

Biochemical Markers

2
Serum triglycerides (Increased)
Pathograph Readouts
Readout Of Hypertriglyceridemia
Show evidence (3 references)
PMID:36051699 SUPPORT Human Clinical
"The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up."
Pooled median serum triglyceride.
PMID:37211761 SUPPORT Human Clinical
"Triglyceride level was 1603 mg/dL (n<150)."
Severe hypertriglyceridemia in a 3-month-old.
PMID:36051699 SUPPORT Human Clinical
"The restricted cubic spline model showed that severe HTG decreased in the early stage of infants to the normal level; however, it rebounded again to a mild or moderate level after the following days."
Describes the non-monotonic course of triglycerides with age.
Serum alanine aminotransferase (Increased)
Pathograph Readouts
Readout Of Elevated transaminases
Show evidence (1 reference)
PMID:36051699 SUPPORT Human Clinical
"In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia."
Pooled ALT elevation.
🔬

Diagnosis

1
Exome or gene-panel sequencing
There is no specific biochemical marker, and nearly all recent diagnoses were made by exome sequencing in children with unexplained hepatomegaly, steatosis, raised transaminases and hypertriglyceridemia. GPD1 is included on some pediatric hypertriglyceridemia gene panels. Targeted testing for c.500G>A has been suggested as a first-tier test in South Asian patients.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:39839217 SUPPORT Human Clinical
"Diagnosis is confirmed by genetic testing."
Molecular confirmation is the diagnostic standard.
PMID:37211761 SUPPORT Human Clinical
"GPD1 deficiency should be investigated in the presence of unexplained hypertriglyceridemia and hepatic steatosis in children especially in infants."
Indication for testing.
PMID:40773003 SUPPORT Human Clinical
"In 4 out of the 6 patients with a familial history of hypertriglyceridemia, we identified pathogenic variants in the GPD1, LIPC, LPL and APOC2 genes, which are associated with hypertriglyceridemia."
GPD1 variants identified on a pediatric hypertriglyceridemia panel.
+ 1 more reference
📈

Progression

2
Infantile presentation
Age: first 2 years of life (median about 6-9 months)
Hepatomegaly, steatosis, raised transaminases and hypertriglyceridemia, with triglycerides highest in the youngest patients.
Show evidence (2 references)
PMID:36051699 SUPPORT Human Clinical
"The clinical manifestations showed the median age of onset was 6.0 (1.9, 12.0) months."
Pooled median age of onset.
PMID:41971245 SUPPORT Human Clinical
"The median age at presentation was 9 months."
Median age at presentation in a second pooled review.
Childhood and later course
Age: childhood to fourth decade
Triglycerides fall with age in most, but normalize in only about 28-30%; transaminases and hepatomegaly resolve in about a third. Fibrosis can progress, and cirrhosis is documented from infancy to adolescence. No pancreatitis, coronary events or liver decompensation have been reported, with the longest follow-up at 31 years. Long-term hepatic outcome in adulthood is unknown.
Show evidence (5 references)
PMID:39839217 SUPPORT Human Clinical
"During follow-up (11-376 months), hepatomegaly resolved in 35.2%, triglycerides, and transaminases normalized in 29.1% and 31.5%, respectively."
Pooled follow-up outcomes.
PMID:39839217 SUPPORT Human Clinical
"No pancreatitis, cardiac events, or liver decompensation was reported."
Absence of reported pancreatitis, cardiac events or decompensation.
PMID:39839217 SUPPORT Human Clinical
"None had coronary heart disease or pancreatitis, even in the patient followed up to 31 years of age."
Longest reported follow-up without these complications.
+ 2 more references
📊

Prevalence

2
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class <1 / 1,000,000.
Show evidence (1 reference)
ORPHA:300293 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:22226083,PMID:24549054"
Orphanet epidemiology row.
Published genetically confirmed cases
Cases In Literature Ultra Rare
Pooled reviews count 36 (to December 2023), 39 and 45 published cases; a 2026 South Asian series added 16 molecularly confirmed patients.
Show evidence (4 references)
PMID:39839217 SUPPORT Human Clinical
"It is an under-recognized cause of pediatric steatotic liver disease (SLD) with only 36 cases reported worldwide."
Case count to December 2023.
PMID:41971245 SUPPORT Human Clinical
"To date, 39 genetically confirmed patients have been reported worldwide (including 16 GPD1 variants) in 15 case reports and series, including our paper."
Case count in a second pooled review.
PMID:40216993 SUPPORT Human Clinical
"We have reviewed 18 studies, and 45 cases reported in the literature so far."
Case count in a third review.
+ 1 more reference
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from GPD1 Deficiency:

Glycogen storage disease type I MONDO:0002413
Overlapping Features Shares infantile hepatomegaly, hypertriglyceridemia and fasting hypoglycemia.
Show evidence (1 reference)
PMID:39839217 SUPPORT Human Clinical
"The clinical presentation closely mimics other inborn errors of metabolism like GSD-1."
Names GSD-1 as the principal mimic.
Pediatric metabolic dysfunction-associated steatotic liver disease
Overlapping Features Shares hepatomegaly, fatty liver and hypertriglyceridemia; GPD1 deficiency presents earlier, usually within the first 2 years, and most patients are not obese.
Distinguishing Features
  • Presentation in the first 2 years of life
  • Absence of obesity in most patients
Show evidence (1 reference)
PMID:39839217 SUPPORT Human Clinical
"However, the key distinguishing features include early presentation in the first 2 years and absence of obesity in majority of the reported cases."
States the features that separate it from MASLD.
Isolated glycerol kinase deficiency MONDO:0018459
Overlapping Features The other known inborn error of glycerol metabolism. It gives an apparent hypertriglyceridemia because glycerol is measured as triglyceride, rather than the hepatic steatosis of GPD1 deficiency.
Distinguishing Features
  • Pseudohypertriglyceridemia from hyperglycerolemia rather than true triglyceride excess
  • X-linked rather than autosomal recessive
Show evidence (1 reference)
PMID:25300978 SUPPORT REVIEW SYNTHESIS Other
"Two inborn errors of glycerol metabolism are known: glycerol kinase (GK, causing pseudohypertriglyceridemia) and glycerol-3-phosphate dehydrogenase (GPD1, childhood hepatic steatosis)."
Contrasts the two inborn errors of glycerol metabolism.
Familial chylomicronemia syndrome MONDO:0018637
Overlapping Features Monogenic severe hypertriglyceridemia from impaired lipoprotein lipase function. GPD1 and the lipolysis genes are tested together on pediatric hypertriglyceridemia panels.
Show evidence (1 reference)
PMID:40773003 SUPPORT Human Clinical
"Among these, six of the eight clinically significant mutations detected in the LPL, GPD1, GPIHBP1, APOC2, and LIPC genes were novel mutations."
GPD1 and lipolysis-pathway genes are distinguished on the same pediatric panel.
🐁

Animal Models

1
Gpd1-null BALB/cHeA mouse
Normal-appearing strain lacking GPD1 activity. It reproduces the metabolite block and the loss of glycerol gluconeogenesis, but its reported lipid phenotype runs opposite to the human disease: less weight gain, enhanced fat oxidation, and protection from ethanol-induced hepatic triglyceride accumulation. No cited study reports spontaneous hepatic steatosis or hypertriglyceridemia in this strain.
Species
Mouse
Genotype
Spontaneous loss of cytosolic glycerol phosphate dehydrogenase (BALB/cHeA strain); BALB/cBy used as control
Pathograph links
Impaired Cytosolic DHAP and G3P Interconversion recapitulates fidelity: moderate observes: molecular
Limitations: Metabolite abnormality is most marked in skeletal muscle; whether hepatic G3P and DHAP are altered is inconsistent between reports, and hepatic metabolites have not been measured in patients for comparison.
Show evidence (1 reference)
PMID:11147825 SUPPORT Model Organism
"Levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle."
Reproduces the expected G3P/DHAP block.
Impaired Gluconeogenesis from Glycerol recapitulates fidelity: unknown observes: organism
Limitations: Gluconeogenesis from glycerol has not been measured in patients, so whether this node applies to human GPD1 deficiency is untested.
Show evidence (1 reference)
PMID:27733253 SUPPORT Model Organism
"The blood glucose levels in the HeA mice were lower than that in the By mice after glycerol administration."
In vivo readout of impaired glycerol gluconeogenesis.
{ }

Source YAML

click to show 
name: GPD1 Deficiency
creation_date: "2026-09-23T14:58:06Z"
category: Mendelian
synonyms:
- transient infantile hypertriglyceridemia and hepatosteatosis
- transient infantile hypertriglyceridemia and fatty liver
- transient infantile hypertriglyceridemia
- HTGTI
- glycerol-3-phosphate dehydrogenase 1 deficiency
description: >-
  Autosomal recessive inborn error of glycerolipid and carbohydrate metabolism
  caused by biallelic loss-of-function variants in GPD1, which encodes the
  cytosolic NAD+-dependent glycerol-3-phosphate dehydrogenase that interconverts
  dihydroxyacetone phosphate (DHAP) and glycerol-3-phosphate (G3P). Children
  present in the first two years of life (median age about six to nine months
  in pooled literature reviews) with hepatomegaly, hepatic steatosis, raised
  transaminases and moderate to severe hypertriglyceridemia, sometimes with
  failure to thrive, vomiting, splenomegaly, hypercholesterolemia or, less
  often, fasting hypoglycemia. Liver biopsy shows macro- and microvesicular
  steatosis with fibrosis in most biopsied patients and cirrhosis in a
  minority, sometimes already in infancy; a hepatocellular adenoma has been
  reported once. The MONDO and Orphanet name calls the disorder "transient",
  after the decline of triglycerides with age in the founding cohort, but
  pooled follow-up of the published cases finds triglycerides and
  transaminases normalizing in only about three in ten patients, with mild
  hypertriglyceridemia persisting into the third and fourth decades. Severity
  varies even within a family carrying the same variant. How loss of an enzyme
  that makes the triglyceride backbone produces more rather than less hepatic
  and plasma triglyceride is unresolved: three incompatible mechanistic
  proposals are recorded below, and the only animal model, the Gpd1-null
  BALB/cHeA mouse, points the other way.
disease_term:
  preferred_term: transient infantile hypertriglyceridemia and hepatosteatosis
  term:
    id: MONDO:0013771
    label: transient infantile hypertriglyceridemia and hepatosteatosis
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GASTROINTESTINAL
    notes: >-
      The dominant clinical burden is steatotic liver disease with fibrosis and,
      in a minority, cirrhosis.
parents:
- Inborn Error of Metabolism
mechanistic_hypotheses:
- hypothesis_group_id: acyl_dhap_diversion
  hypothesis_label: Diversion of excess DHAP into glycerolipid synthesis through the acyl-DHAP route
  status: EMERGING
  description: >-
    With GPD1 absent, DHAP produced by glycolysis is not reduced to G3P and is
    proposed to be acylated directly, entering glycerolipid synthesis through the
    acyl-DHAP pathway and driving hepatocellular triglyceride accumulation. The
    proposal is consistent with the raised DHAP and lowered G3P measured in
    Gpd1-null mouse tissue, but neither hepatic DHAP, acyl-DHAP flux nor hepatic
    G3P has been measured in a patient.
  evidence:
  - reference: PMID:24549054
    reference_title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of fatty liver in our patient may be due to acylation of excess DHAP."
    explanation: >-
      The authors' own mechanistic proposal, stated as a possibility in the
      discussion of a single case; no metabolite or flux measurement accompanies
      it, hence OTHER.
  - reference: PMID:40216993
    reference_title: "GPD1 deficiency-a rare, overlooked cause of liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "It has been suggested that the fatty liver observed in all patients with GPD1 deficiency on ultrasonography or other imaging may result from excessive acylation of dihydroxyacetone phosphate (DHAP)"
    explanation: >-
      A 2025 case report restating the acyl-DHAP proposal from earlier
      literature; its next sentence says the detailed mechanisms remain
      unclear.
- hypothesis_group_id: hepatic_g3p_retention
  hypothesis_label: Reduced G3P-to-DHAP conversion increases hepatic G3P for triglyceride synthesis
  status: EMERGING
  description: >-
    Proposes that hypertriglyceridemia results because loss of GPD1 prevents
    oxidation of G3P back to DHAP, enlarging the hepatic G3P pool available for
    triglyceride synthesis. This runs opposite to the acyl-DHAP proposal on the
    direction of the metabolite change, and opposite to the low tissue G3P and
    high DHAP measured in the Gpd1-null mouse. It has not been tested in patient
    tissue.
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Hypertriglyceridemia may result from reduced conversion of G3P to DHAP, increasing the hepatic G3P for triglyceride synthesis."
    explanation: >-
      States the G3P-retention proposal, attributed by the authors to earlier
      literature; it is a stated possibility, not a measurement.
  - reference: PMID:11147825
    reference_title: Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle."
    explanation: >-
      In the Gpd1-null mouse, tissue G3P is low and DHAP high, the opposite of
      the enlarged G3P pool this proposal requires. The measurement is in mouse
      and is most marked in muscle, so it does not settle what happens in human
      liver.
- hypothesis_group_id: hepatic_triglyceride_secretion
  hypothesis_label: Increased hepatic triglyceride secretion drives the hypertriglyceridemia
  status: EMERGING
  description: >-
    Proposes that the plasma hypertriglyceridemia reflects increased secretion of
    triglyceride by hepatocytes, based on a single HepG2 experiment in which a
    mutant GPD1 cDNA was overexpressed on top of the endogenous enzyme. That
    design tests whether the mutant protein does something, not what its
    absence does, so it is weak support for a loss-of-function mechanism. A
    later review restating the founding paper lists decreased hepatic
    triglyceride output instead, so the direction of hepatic export is itself
    unsettled.
  evidence:
  - reference: PMID:22226083
    reference_title: Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01)."
    explanation: The single experimental observation behind the secretion proposal.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: REFUTE
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Therefore, GPD1 mutations lead to increased TG synthesis in the liver, decreased output from the liver, increased inflow of fatty acids into the liver, and impaired hepatic beta-oxidation causing nonalcoholic hepatic steatosis"
    explanation: >-
      A 2026 review, restating the founding paper, lists decreased rather than
      increased hepatic output; the two accounts disagree on the direction of
      triglyceride export. Neither is a measurement in patients.
pathophysiology:
- name: GPD1 Loss of Function
  description: >-
    Biallelic GPD1 variants (splice-site, nonsense, frameshift, missense and a
    whole-gene deletion) abolish or reduce the cytosolic NAD+-dependent
    glycerol-3-phosphate dehydrogenase. The founding homozygous splice-acceptor
    variant c.361-1G>C produces aberrantly spliced mRNA predicted to truncate the
    protein, and GPD1 protein was absent on western blot of liver from a
    compound heterozygote carrying a deletion and p.Arg229Gln. Enzyme activity
    has not been reported for most missense alleles.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: GPD1
    term:
      id: hgnc:4455
      label: GPD1
  molecular_functions:
  - preferred_term: glycerol-3-phosphate dehydrogenase (NAD+) activity
    term:
      id: GO:0141152
      label: glycerol-3-phosphate dehydrogenase (NAD+) activity
    modifier: LOSS_OF_FUNCTION
  cellular_components:
  - preferred_term: cytosol
    term:
      id: GO:0005829
      label: cytosol
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:22226083
    reference_title: Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals."
    explanation: Founding report of the homozygous GPD1 splice variant and its aberrant splicing in all ten affected individuals.
  - reference: PMID:24549054
    reference_title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GPD1 protein was absent in the patient's liver biopsy on western blot."
    explanation: Shows absence of the protein in patient liver, the target tissue.
  - reference: PMID:24549054
    reference_title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in GPD1 encoding glycerol-3-phosphate dehydrogenase that catalyzes the reversible redox reaction of dihydroxyacetone phosphate and NADH to glycerol-3-phosphate (G3P) and NAD(+) were identified."
    explanation: States the reaction the lost enzyme catalyzes, which defines the molecular-function binding.
  - reference: PMID:28944580
    reference_title: "Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies demonstrated that the Ala274Thr variant induced a decrease in GPD1 protein expression."
    explanation: Functional evidence that a missense allele reduces GPD1 protein.
  downstream:
  - target: Impaired Cytosolic DHAP and G3P Interconversion
    causal_link_type: DIRECT
    description: Loss of the enzyme removes the cytosolic NADH-dependent reduction of DHAP to G3P and its reverse.
  - target: Increased Hepatocyte Triglyceride Secretion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - hepatic_triglyceride_secretion
    description: >-
      Supported only by overexpression of a mutant cDNA in HepG2 cells; see the
      hepatic_triglyceride_secretion hypothesis for why that design is weak
      evidence about loss of function.
    evidence:
    - reference: PMID:22226083
      reference_title: Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01)."
      explanation: Mutant GPD1 increased triglyceride secretion from a hepatocyte-derived cell line.
- name: Impaired Cytosolic DHAP and G3P Interconversion
  description: >-
    Without GPD1, cytosolic DHAP is not reduced to G3P. In the Gpd1-null mouse
    this gives low tissue G3P and high DHAP, most marked in skeletal muscle; a
    second strain lacking both GPD1 and malic enzyme showed the abnormal
    G3P/DHAP pattern only in skeletal muscle. Hepatic G3P and DHAP have not been
    measured in patients, so the state of the hepatic metabolite pool, which is
    what the competing steatosis proposals turn on, is unknown.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: glycerol-3-phosphate metabolic process
    term:
      id: GO:0006072
      label: glycerol-3-phosphate metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:11147825
    reference_title: Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle."
    explanation: Direct metabolite measurement of the block in the Gpd1-null mouse.
  - reference: PMID:11451371
    reference_title: "Survey of normal appearing mouse strain which lacks malic enzyme and Nad+-linked glycerol phosphate dehydrogenase: normal pancreatic beta cell function, but abnormal metabolite pattern in skeletal muscle."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tissue levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were only abnormal in skeletal muscle."
    explanation: >-
      Same direction of change in a double-mutant strain, but confined to
      skeletal muscle, which is why the hepatic metabolite state is recorded as
      unknown.
  downstream:
  - target: Hepatocyte Triglyceride Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - acyl_dhap_diversion
    - hepatic_g3p_retention
    description: >-
      Both published proposals route through this step but disagree on which
      metabolite accumulates; the intermediate steps are not demonstrated in
      patients.
    evidence:
    - reference: PMID:24549054
      reference_title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The mechanism of fatty liver in our patient may be due to acylation of excess DHAP."
      explanation: Proposes, without measurement, that the metabolite block causes the fatty liver.
  - target: Impaired Glycerol-3-Phosphate Shuttle
    causal_link_type: DIRECT
    description: GPD1 is the cytosolic half of the shuttle, so the shuttle cannot run without it.
    evidence:
    - reference: PMID:11147825
      reference_title: Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This suggests that a nonfunctional glycerol phosphate shuttle caused a block in glycolysis at the step catalyzed by glyceraldehyde phosphate dehydrogenase."
      explanation: Links the enzyme loss to a nonfunctional shuttle in the mouse.
  - target: Impaired Gluconeogenesis from Glycerol
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27733253
      reference_title: Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The blood glucose levels in the HeA mice were lower than that in the By mice after glycerol administration."
      explanation: Glycerol loading produces less glucose in Gpd1-null mice.
- name: Impaired Glycerol-3-Phosphate Shuttle
  description: >-
    GPD1 and mitochondrial GPD2 together carry cytosolic reducing equivalents into
    mitochondria. In the Gpd1-null mouse the nonfunctional shuttle lowers the
    cytosolic NAD/NADH ratio and blocks glycolysis at glyceraldehyde-phosphate
    dehydrogenase, chiefly in skeletal muscle, where exercised mice could not
    maintain ATP. No human phenotype has been attributed to this node; muscle
    and brain energy metabolism have not been studied in patients, so it has no
    downstream phenotype.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: glycerol-3-phosphate shuttle
    term:
      id: GO:0006127
      label: glycerol-3-phosphate shuttle
    modifier: DECREASED
  evidence:
  - reference: PMID:11147825
    reference_title: Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "When exercised, mice were unable to maintain normal ATP levels in skeletal muscle."
    explanation: Functional consequence of the shuttle defect in the mouse.
- name: Impaired Gluconeogenesis from Glycerol
  description: >-
    G3P formed from glycerol must be oxidized to DHAP by GPD1 to enter
    gluconeogenesis. Gpd1-null mice make less glucose from glycerol, but after
    one to four hours of fasting their blood glucose is higher than controls,
    with a compensatory shift to alanine-driven gluconeogenesis. Because the
    model compensates rather than becoming hypoglycemic, this node is not wired
    to the hypoglycemia seen in about one in ten patients; that phenotype has no
    sourced mechanism.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:27733253
    reference_title: Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although these data indicate that a lack of GPD1 inhibits gluconeogenesis from glycerol, chronic GPD1 deficiency may induce an adaptation that enhances gluconeogenesis from glycogenic amino acids."
    explanation: Establishes the block and the compensatory adaptation in the mouse.
  - reference: PMID:27733253
    reference_title: Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although lack of GPD1 inhibited gluconeogenesis from glycerol, blood glucose levels in the HeA mice after 1-4h of fasting were significantly higher than that in the By mice."
    explanation: The fasting result that argues against using this node to explain human hypoglycemia.
- name: Hepatocyte Triglyceride Accumulation
  description: >-
    Triglyceride accumulates in hepatocyte lipid droplets, seen on ultrastructure
    as intrahepatocytic lipid droplets and on biopsy as macro- and microvesicular
    steatosis in every biopsied patient. Which substrate route feeds it is not
    established (see the acyl_dhap_diversion and hepatic_g3p_retention
    hypotheses). Conformance to the steatosis module is claimed at this node
    only: the module's lipotoxic-stress and inflammatory nodes have not been
    studied in GPD1 deficiency.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: "hepatic_steatosis_lipotoxicity#Hepatocyte Lipid Overload"
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: lipid storage
    term:
      id: GO:0019915
      label: lipid storage
    modifier: INCREASED
  evidence:
  - reference: PMID:29940878
    reference_title: "A novel homozygous mutation in the glycerol-3-phosphate dehydrogenase 1 gene in a Chinese patient with transient infantile hypertriglyceridemia: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural study showed intrahepatocytic lipid droplets."
    explanation: Ultrastructural demonstration of hepatocyte lipid accumulation in a patient.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nineteen patients underwent liver biopsy; all showed micro- and macrosteatosis, mild to moderate portal fibrosis in 58% (11 out of 19), and cirrhosis in the remaining eight cases (42%)."
    explanation: Every biopsied patient in the pooled literature had micro- and macrovesicular steatosis.
  downstream:
  - target: Hepatic steatosis
    causal_link_type: DIRECT
    description: The accumulation is what imaging and histology read as steatosis.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: hepatomegaly and steatosis co-occur in nearly every patient and
      steatosis is the dominant histological finding, but no cited source tests
      whether lipid accumulation alone accounts for the liver enlargement.
  - target: Elevated transaminases
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: the transaminase rise accompanies steatosis and steatohepatitis
      on biopsy, but the hepatocyte-injury step between them has not been
      characterized in this disorder.
  - target: Progressive Hepatic Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The founding cohort describes fatty liver followed by fibrosis; the intervening injury and stellate-cell steps are not studied here.
    evidence:
    - reference: PMID:22226083
      reference_title: Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition."
      explanation: Describes the temporal sequence from fatty liver to fibrosis in the founding families.
- name: Increased Hepatocyte Triglyceride Secretion
  description: >-
    Proposed mechanism for the plasma hypertriglyceridemia, resting on one HepG2
    overexpression experiment. The direction of hepatic triglyceride export in
    patients has not been measured, and a later review lists decreased hepatic
    output instead; see the hepatic_triglyceride_secretion hypothesis.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:22226083
    reference_title: Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01)."
    explanation: The only experimental observation for this node.
  downstream:
  - target: Hypertriglyceridemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - hepatic_triglyceride_secretion
    description: >-
      Inferred from the HepG2 result; no source measures VLDL-triglyceride
      production or clearance in patients.
- name: Progressive Hepatic Fibrosis
  description: >-
    Portal fibrosis is present in most biopsied patients and progresses to
    cirrhosis in a minority, documented from infancy to adolescence. Sequential
    biopsies at 3 and 15 years in one boy showed progression from incomplete
    cirrhosis to diffuse nodular transformation. Decompensated liver disease has
    not been reported. Biopsy is done selectively, so the fibrosis and cirrhosis
    fractions among biopsied patients overstate their frequency in all
    patients. Conformance to the fibrosis node of the steatosis module is not
    claimed, because stellate-cell activation has not been examined in this
    disorder.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver biopsy (n = 18) demonstrated steatosis in all, fibrosis in 94.4%, and cirrhosis in 22.2%."
    explanation: Pooled biopsy findings across the published cases.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first showed incomplete cirrhosis, inflammation, and steatosis and the second showed diffuse nodular transformation of liver and extensive steatosis, suggesting slow disease progression."
    explanation: Sequential biopsies in one patient document progression rather than regression of the liver disease.
  downstream:
  - target: Hepatic fibrosis
    causal_link_type: DIRECT
  - target: Cirrhosis
    causal_link_type: DIRECT
phenotypes:
- category: Metabolic
  name: Hypertriglyceridemia
  description: >-
    Moderate to severe fasting hypertriglyceridemia, highest in early infancy and
    inversely related to age at presentation. It declines in most but normalizes
    in only about three in ten patients on follow-up, and mild
    hypertriglyceridemia has been reported persisting into the third and fourth
    decades.
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertriglyceridemia (97.2%) was nearly universal, 100% had fatty liver, and hypoglycaemia (11.2%) was uncommon."
    explanation: Frequency in 36 pooled published cases supports VERY_FREQUENT.
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up."
    explanation: Independent pooled series of 31 cases; also documents that most patients do not normalize.
  - reference: PMID:41839820
    reference_title: "Founder Effect of the c.500G>A Variant in South Asian Patients With Inherited GPD1 Deficiency: Report on 16 Patients and Variant Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A significant negative correlation was noted between age at presentation and serum triglyceride levels."
    explanation: Triglycerides are highest in those presenting youngest.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients persisted to have mild to moderate HTG until the age of 23 and 31 years with normal growth and nonprogressive liver disease"
    explanation: Hypertriglyceridemia persisting into adulthood.
  - reference: PMID:27368975
    reference_title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "finally, the third presented persistent hypertriglyceridemia at the age of 30 years."
    explanation: Persistent hypertriglyceridemia in an adult.
- category: Hepatic
  name: Hepatomegaly
  description: >-
    Usually the presenting sign, often marked. Resolved in about a third of
    patients with follow-up data.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Majority had hepatomegaly (94.4%), 22.2% each had splenomegaly and growth failure."
    explanation: Pooled frequency of hepatomegaly supports VERY_FREQUENT.
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly."
    explanation: Independent pooled frequency of hepatomegaly.
- category: Hepatic
  name: Hepatic steatosis
  description: Fatty liver on ultrasound or histology in all imaged or biopsied patients.
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertriglyceridemia (97.2%) was nearly universal, 100% had fatty liver, and hypoglycaemia (11.2%) was uncommon."
    explanation: Fatty liver in every pooled case.
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis."
    explanation: Independent pooled series with steatosis in all patients.
- category: Laboratory
  name: Elevated transaminases
  description: >-
    Raised ALT, typically mild to moderate; normalized in about three in ten
    patients with follow-up data.
  phenotype_term:
    preferred_term: Elevated transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia."
    explanation: Pooled frequency of raised ALT supports VERY_FREQUENT.
- category: Hepatic
  name: Hepatic fibrosis
  description: >-
    Portal fibrosis, mild to moderate in most, reported on imaging in about two
    thirds of patients and on biopsy in nearly all biopsied patients.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis."
    explanation: >-
      Two thirds of the pooled series had fibrosis, supporting FREQUENT. The
      94.4% figure among biopsied patients is not used for the band because
      biopsy is selective.
- category: Hepatic
  name: Cirrhosis
  description: >-
    Reported from infancy (on biopsy at 5 months) through adolescence, without
    reported decompensation.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver biopsy (n = 18) demonstrated steatosis in all, fibrosis in 94.4%, and cirrhosis in 22.2%."
    explanation: >-
      Four of 18 biopsied, which is 4 of 36 pooled cases overall; OCCASIONAL is
      used because unbiopsied patients are not known to be free of cirrhosis.
  - reference: PMID:32685347
    reference_title: Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abdominal ultrasound showed diffuse liver echogenicity and liver biopsy disclosed cirrhosis with micro and macrovesicular steatosis."
    explanation: Cirrhosis with steatosis in an adolescent followed from age 1.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, other patients developed cirrhosis during infancy with insufficient data on long-term follow-up."
    explanation: Cirrhosis can already be present in infancy.
- category: Hepatic
  name: Splenomegaly
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Majority had hepatomegaly (94.4%), 22.2% each had splenomegaly and growth failure."
    explanation: 22.2% of pooled cases supports OCCASIONAL.
- category: Growth
  name: Growth delay
  description: Growth retardation or short stature in about a fifth of patients.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly."
    explanation: 22.6% of pooled cases supports OCCASIONAL.
- category: Growth
  name: Failure to thrive
  description: Faltering growth at presentation in infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35450873
    reference_title: Case of GPD1 deficiency causing hypertriglyceridaemia and non-alcoholic steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of a young girl of South Asian descent presented with faltering growth, hepatomegaly, hypertriglyceridaemia and raised transaminases."
    explanation: Faltering growth as a presenting feature.
- category: Gastrointestinal
  name: Vomiting
  description: Reported at presentation in early infancy.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:37211761
    reference_title: "A very rare cause of hypertrygliseridemia in infancy: a novel mutation in glycerol-3-phosphate dehydrogenase 1 (GPD1) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 2-month-27-day-old boy, who had growth retardation, hepatomegaly and anemia suffered to our hospital with vomiting."
    explanation: Vomiting at presentation in early infancy.
- category: Metabolic
  name: Hypercholesterolemia
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia."
    explanation: 38.7% of pooled cases supports FREQUENT.
- category: Metabolic
  name: Hypoglycemia
  description: >-
    Hypoglycemia, fasting and sometimes ketotic, in about one in ten patients.
    No sourced mechanism: the Gpd1-null mouse compensates and is not
    hypoglycemic on fasting.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertriglyceridemia (97.2%) was nearly universal, 100% had fatty liver, and hypoglycaemia (11.2%) was uncommon."
    explanation: 11.2% of pooled cases supports OCCASIONAL.
  - reference: PMID:27368975
    reference_title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Documents the fasting, ketotic character of the hypoglycemia.
- category: Metabolic
  name: Insulin resistance
  description: Reported in individual patients, with and without obesity.
  phenotype_term:
    preferred_term: Insulin resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: PMID:36588760
    reference_title: Rare Transient Infantile Hypertriglyceridemia with Hypoglycemia and Insulin Resistance Caused by a Novel GPD1 Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 10-month-old male infant was diagnosed with hypertriglyceridemia, hepatomegaly, liver injury, fasting hypoglycemia, and insulin resistance."
    explanation: Insulin resistance together with fasting hypoglycemia in an infant.
  - reference: PMID:28944580
    reference_title: "Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature."
    explanation: Insulin resistance in an adolescent.
- category: Metabolic
  name: Obesity
  description: >-
    Uncommon; absence of obesity in most patients is one feature separating
    GPD1 deficiency from pediatric metabolic dysfunction-associated steatotic
    liver disease.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  frequency: VERY_RARE
  evidence:
  - reference: PMID:28944580
    reference_title: "Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature."
    explanation: Obesity in an individual patient.
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%)."
    explanation: 3.2-6.5% of pooled cases supports VERY_RARE.
- category: Hepatic
  name: Intrahepatic cholestasis
  description: Reported rarely, in one case together with kidney involvement.
  phenotype_term:
    preferred_term: Intrahepatic cholestasis
    term:
      id: HP:0001406
      label: Intrahepatic cholestasis
  frequency: VERY_RARE
  evidence:
  - reference: PMID:27368975
    reference_title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement"
    explanation: Individual patient with intrahepatic cholestasis.
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%)."
    explanation: 3.2-6.5% of pooled cases supports VERY_RARE.
- category: Hepatic
  name: Hepatocellular adenoma
  description: >-
    A single report of a hepatic adenoma developing during follow-up of a boy
    with persistent hepatomegaly and hypertriglyceridemia. Whether this is part
    of the disorder or a coincidence cannot be judged from one case.
  phenotype_term:
    preferred_term: Hepatic adenoma
    term:
      id: HP:0012028
      label: Hepatocellular adenoma
  evidence:
  - reference: PMID:35365473
    reference_title: Transient infantile hypertriglyceridaemia due to homozygous mutation in GPD1 presenting in childhood with hepatic adenoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On follow-up, he developed hepatic lesion and his hepatomegaly with hypertriglyceridaemia persisted."
    explanation: Hepatic lesion arising during follow-up, with persistent hepatomegaly and hypertriglyceridaemia.
  - reference: PMID:35365473
    reference_title: Transient infantile hypertriglyceridaemia due to homozygous mutation in GPD1 presenting in childhood with hepatic adenoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This could be the first report of development of adenoma in transient HTGTI."
    explanation: The authors identify the lesion as an adenoma and describe it as the first such report.
biochemical:
- name: Serum triglycerides
  presence: Increased
  notes: >-
    Median 3.1 mmol/L (interquartile 2.1-5.5) across 31 pooled cases, with
    individual infants above 1,600 mg/dL. No age-specific reference interval for
    infancy is recorded because none of the cited sources provides one.
  readouts:
  - target: Hypertriglyceridemia
    relationship: READOUT_OF
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up."
    explanation: Pooled median serum triglyceride.
  - reference: PMID:37211761
    reference_title: "A very rare cause of hypertrygliseridemia in infancy: a novel mutation in glycerol-3-phosphate dehydrogenase 1 (GPD1) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Triglyceride level was 1603 mg/dL (n<150)."
    explanation: Severe hypertriglyceridemia in a 3-month-old.
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The restricted cubic spline model showed that severe HTG decreased in the early stage of infants to the normal level; however, it rebounded again to a mild or moderate level after the following days."
    explanation: Describes the non-monotonic course of triglycerides with age.
- name: Serum alanine aminotransferase
  presence: Increased
  readouts:
  - target: Elevated transaminases
    relationship: READOUT_OF
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia."
    explanation: Pooled ALT elevation.
genetic:
- name: Biallelic GPD1 variants
  gene_term:
    preferred_term: GPD1
    term:
      id: hgnc:4455
      label: GPD1
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:27368975
      reference_title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: States autosomal recessive inheritance.
  features: >-
    Most patients are homozygous, reflecting consanguinity and founder alleles:
    c.361-1G>C (p.Ile119fs) in Palestinian and Israeli Arab families,
    p.Gly299Arg in the Czech population, p.Thr251Asnfs*10 in Saudi Arabia and
    c.500G>A (p.Gly167Asp) in South Asians. Missense, nonsense, frameshift,
    splice-site and whole-gene deletion alleles are reported. Severity does not
    track variant type and varies within a family carrying the same variant.
    Variant interpretation is complicated because some putatively causal
    alleles occur in population databases, including in the homozygous state,
    which leaves open whether those alleles are incompletely penetrant or not
    causal.
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of patients, 87.1% had homozygous variants, with the most frequent loci being c.361-1G > C and c.895G > A."
    explanation: Homozygosity and the recurrent alleles across pooled cases.
  - reference: PMID:41839820
    reference_title: "Founder Effect of the c.500G>A Variant in South Asian Patients With Inherited GPD1 Deficiency: Report on 16 Patients and Variant Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients also have a similar homozygous haplotype around the variant, construing its founder effect in South Asian patients with inherited GPD1 deficiency."
    explanation: Founder allele in South Asians.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the 15 variants likely originated from a common ancestor, \"that is, founder in nature\": p.I119fs*94 (Palestinian Arabs), p.Gly299Arg (Czech population), and p.Thr251Asnfs*10 (Saudi Arabia)."
    explanation: Further founder alleles across populations.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even within a single family with the same GPD1 variant, the severity of the disease was variable; an infant (Patient Number 14 in Table 1) had cirrhosis on liver biopsy performed at the age of 5 months, and the uncle (Patient Number 15) had mild portal fibrosis on liver biopsy at the age of 2 years and is doing very well at the age of 31 years with mild elevation of liver transaminases and TG levels."
    explanation: Intrafamilial variability with a shared genotype.
  - reference: PMID:24549054
    reference_title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband inherited a GPD1 deletion from the father determined using copy number analysis and a missense change p.(R229Q) from the mother."
    explanation: A copy-number deletion allele in trans with a missense variant.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several potentially disease-causing variants are likely to be present in population databases like gnomAD even in the homozygous state, like the c.500G>A and c.361 G>A variants detected in cases 1 and 3, respectively."
    explanation: Records the population-database homozygote problem for variant classification.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic GPD1 variants, homozygous in most reported patients; parents are
    asymptomatic heterozygotes in the reported families.
  evidence:
  - reference: PMID:29940878
    reference_title: "A novel homozygous mutation in the glycerol-3-phosphate dehydrogenase 1 gene in a Chinese patient with transient infantile hypertriglyceridemia: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was a homozygote and her parents were heterozygous for the mutation."
    explanation: Homozygous proband with heterozygous parents.
  - reference: PMID:27368975
    reference_title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: States autosomal recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class <1 / 1,000,000.
  evidence:
  - reference: ORPHA:300293
    reference_title: "Transient infantile hypertriglyceridemia and hepatosteatosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:22226083,PMID:24549054"
    explanation: Orphanet epidemiology row.
- population: Published genetically confirmed cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Pooled reviews count 36 (to December 2023), 39 and 45 published cases; a
    2026 South Asian series added 16 molecularly confirmed patients.
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is an under-recognized cause of pediatric steatotic liver disease (SLD) with only 36 cases reported worldwide."
    explanation: Case count to December 2023.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 39 genetically confirmed patients have been reported worldwide (including 16 GPD1 variants) in 15 case reports and series, including our paper."
    explanation: Case count in a second pooled review.
  - reference: PMID:40216993
    reference_title: "GPD1 deficiency-a rare, overlooked cause of liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have reviewed 18 studies, and 45 cases reported in the literature so far."
    explanation: Case count in a third review.
  - reference: PMID:41839820
    reference_title: "Founder Effect of the c.500G>A Variant in South Asian Patients With Inherited GPD1 Deficiency: Report on 16 Patients and Variant Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 18 additional patients with HTGTI (confirmed molecular diagnosis in 16, a variant of uncertain significance in two), most of whom presented in infancy with hepatomegaly."
    explanation: A single series adding 16 molecularly confirmed patients.
progression:
- phase: Infantile presentation
  age_range: first 2 years of life (median about 6-9 months)
  notes: >-
    Hepatomegaly, steatosis, raised transaminases and hypertriglyceridemia,
    with triglycerides highest in the youngest patients.
  evidence:
  - reference: PMID:36051699
    reference_title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations showed the median age of onset was 6.0 (1.9, 12.0) months."
    explanation: Pooled median age of onset.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at presentation was 9 months."
    explanation: Median age at presentation in a second pooled review.
- phase: Childhood and later course
  age_range: childhood to fourth decade
  notes: >-
    Triglycerides fall with age in most, but normalize in only about 28-30%;
    transaminases and hepatomegaly resolve in about a third. Fibrosis can
    progress, and cirrhosis is documented from infancy to adolescence. No
    pancreatitis, coronary events or liver decompensation have been reported,
    with the longest follow-up at 31 years. Long-term hepatic outcome in
    adulthood is unknown.
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During follow-up (11-376 months), hepatomegaly resolved in 35.2%, triglycerides, and transaminases normalized in 29.1% and 31.5%, respectively."
    explanation: Pooled follow-up outcomes.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No pancreatitis, cardiac events, or liver decompensation was reported."
    explanation: Absence of reported pancreatitis, cardiac events or decompensation.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None had coronary heart disease or pancreatitis, even in the patient followed up to 31 years of age."
    explanation: Longest reported follow-up without these complications.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow-up data showed that HTG normalized in 28% of patients (11 out of 39) but persisted mildly in the remaining 72% (28 out of 39)."
    explanation: Persistence of hypertriglyceridemia in most followed patients.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study indicates that GPD1 deficiency may not be a transient or benign condition, as previously considered, due to the persistence of HTG and liver pathology in a significant proportion of cases."
    explanation: The authors' conclusion that the course is not reliably transient.
diagnosis:
- name: Exome or gene-panel sequencing
  description: >-
    There is no specific biochemical marker, and nearly all recent diagnoses
    were made by exome sequencing in children with unexplained hepatomegaly,
    steatosis, raised transaminases and hypertriglyceridemia. GPD1 is included
    on some pediatric hypertriglyceridemia gene panels. Targeted testing for
    c.500G>A has been suggested as a first-tier test in South Asian patients.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is confirmed by genetic testing."
    explanation: Molecular confirmation is the diagnostic standard.
  - reference: PMID:37211761
    reference_title: "A very rare cause of hypertrygliseridemia in infancy: a novel mutation in glycerol-3-phosphate dehydrogenase 1 (GPD1) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GPD1 deficiency should be investigated in the presence of unexplained hypertriglyceridemia and hepatic steatosis in children especially in infants."
    explanation: Indication for testing.
  - reference: PMID:40773003
    reference_title: "Assessment of Pediatric Hypertriglyceridemia Etiology: Insights from Next-Generation Sequencing Panels and Identification of Novel Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 4 out of the 6 patients with a familial history of hypertriglyceridemia, we identified pathogenic variants in the GPD1, LIPC, LPL and APOC2 genes, which are associated with hypertriglyceridemia."
    explanation: GPD1 variants identified on a pediatric hypertriglyceridemia panel.
  - reference: PMID:41839820
    reference_title: "Founder Effect of the c.500G>A Variant in South Asian Patients With Inherited GPD1 Deficiency: Report on 16 Patients and Variant Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted testing for c.500G>A could be considered as a first-tier evaluation strategy in South Asian patients with HTGTI."
    explanation: Population-specific first-tier testing suggestion.
treatments:
- name: Low-fat, medium-chain-triglyceride-enriched diet
  description: >-
    First-line supportive management. There are no dietary guidelines for GPD1
    deficiency; a low-fat diet with medium-chain triglyceride as a large share
    of fat has been used and lowered triglycerides in case reports.
  treatment_term:
    preferred_term: low-fat, medium-chain-triglyceride-enriched diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:33120465
    reference_title: "[Transient infantile hypertriglyceridemia caused by GPD1 deficiency: report of two cases and literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a low-fat diet with enriched medium-chain fatty acids, their plasma triglyceride level were significantly decreased, and finally normalized in case 2."
    explanation: Triglyceride reduction on the diet in two children.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, there are no dietary guidelines for GPD1 deficiency."
    explanation: Records the absence of guidelines.
- name: Fenofibrate
  description: >-
    Off-label fibrate therapy for severe or progressive hypertriglyceridemia,
    reported in an adolescent with cirrhosis and in an infant. Pediatric
    experience with fibrates is limited, so use has been cautious with
    monitoring of liver and muscle enzymes. No effect on fibrosis is reported.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fenofibrate
      term:
        id: CHEBI:5001
        label: fenofibrate
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:32685347
    reference_title: Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering the persistent and progressive increase of plasma triglycerides, fenofibrate treatment was started at 15 years of age allowing triglyceride level reduction in the following 1-year follow-up."
    explanation: Triglyceride reduction on fenofibrate in an adolescent.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All received supportive therapy, and fenofibrate was successfully used in one case for progressive hypertriglyceridemia."
    explanation: Use in an infant with progressive hypertriglyceridemia.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering the limited experience of fibrates in children and concerns of adverse effects (raised liver enzyme, muscle enzymes, gall stone, and renal impairment), fenofibrate should be used cautiously under close supervision and regular monitoring."
    explanation: Safety caveat for pediatric use.
- name: Hepatic and metabolic surveillance
  description: >-
    Proposed by one pediatric hepatology group, not a consensus guideline:
    outpatient review every 3-4 months with growth, liver and spleen size, liver
    function tests, INR and lipid profile; ultrasound and transient elastography
    every 6-12 months; hepatitis A and B vaccination and avoidance of
    hepatotoxic drugs. Because data on progression are limited, intervals are
    to be tailored to the patient.
  action_category: MONITORING
  treatment_term:
    preferred_term: scheduled clinical, laboratory and imaging surveillance of liver disease and lipids
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend 3-4 monthly outpatient department follow-up with monitoring of growth, liver and spleen size, liver function test, international normalized ratio, and lipid profile."
    explanation: Proposed surveillance schedule.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging (USG, transient elastography) may be done every 6-12 months, but protocols should be tailored as per patient's clinical status as the data on disease progression are limited."
    explanation: Proposed imaging interval.
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Avoiding other liver injuries by vaccination against hepatitis A/B and caution with use of hepatotoxic drugs/CAM is advisable."
    explanation: Protective measures against additional liver injury.
differential_diagnoses:
- name: Glycogen storage disease type I
  disease_term:
    preferred_term: glycogen storage disease I
    term:
      id: MONDO:0002413
      label: glycogen storage disease I
  description: >-
    Shares infantile hepatomegaly, hypertriglyceridemia and fasting
    hypoglycemia.
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation closely mimics other inborn errors of metabolism like GSD-1."
    explanation: Names GSD-1 as the principal mimic.
- name: Pediatric metabolic dysfunction-associated steatotic liver disease
  description: >-
    Shares hepatomegaly, fatty liver and hypertriglyceridemia; GPD1 deficiency
    presents earlier, usually within the first 2 years, and most patients are
    not obese.
  distinguishing_features:
  - Presentation in the first 2 years of life
  - Absence of obesity in most patients
  evidence:
  - reference: PMID:39839217
    reference_title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the key distinguishing features include early presentation in the first 2 years and absence of obesity in majority of the reported cases."
    explanation: States the features that separate it from MASLD.
- name: Isolated glycerol kinase deficiency
  disease_term:
    preferred_term: isolated glycerol kinase deficiency
    term:
      id: MONDO:0018459
      label: isolated glycerol kinase deficiency
  description: >-
    The other known inborn error of glycerol metabolism. It gives an apparent
    hypertriglyceridemia because glycerol is measured as triglyceride, rather
    than the hepatic steatosis of GPD1 deficiency.
  distinguishing_features:
  - Pseudohypertriglyceridemia from hyperglycerolemia rather than true triglyceride excess
  - X-linked rather than autosomal recessive
  evidence:
  - reference: PMID:25300978
    reference_title: Inborn errors of cytoplasmic triglyceride metabolism.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Two inborn errors of glycerol metabolism are known: glycerol kinase (GK, causing pseudohypertriglyceridemia) and glycerol-3-phosphate dehydrogenase (GPD1, childhood hepatic steatosis)."
    explanation: Contrasts the two inborn errors of glycerol metabolism.
- name: Familial chylomicronemia syndrome
  disease_term:
    preferred_term: familial chylomicronemia syndrome
    term:
      id: MONDO:0018637
      label: familial chylomicronemia syndrome
  description: >-
    Monogenic severe hypertriglyceridemia from impaired lipoprotein lipase
    function. GPD1 and the lipolysis genes are tested together on pediatric
    hypertriglyceridemia panels.
  evidence:
  - reference: PMID:40773003
    reference_title: "Assessment of Pediatric Hypertriglyceridemia Etiology: Insights from Next-Generation Sequencing Panels and Identification of Novel Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these, six of the eight clinically significant mutations detected in the LPL, GPD1, GPIHBP1, APOC2, and LIPC genes were novel mutations."
    explanation: GPD1 and lipolysis-pathway genes are distinguished on the same pediatric panel.
animal_models:
- name: Gpd1-null BALB/cHeA mouse
  species: Mouse
  genotype: Spontaneous loss of cytosolic glycerol phosphate dehydrogenase (BALB/cHeA strain); BALB/cBy used as control
  description: >-
    Normal-appearing strain lacking GPD1 activity. It reproduces the metabolite
    block and the loss of glycerol gluconeogenesis, but its reported lipid
    phenotype runs opposite to the human disease: less weight gain, enhanced
    fat oxidation, and protection from ethanol-induced hepatic triglyceride
    accumulation. No cited study reports spontaneous hepatic steatosis or
    hypertriglyceridemia in this strain.
  modeled_mechanisms:
  - target: Impaired Cytosolic DHAP and G3P Interconversion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: >-
      Metabolite abnormality is most marked in skeletal muscle; whether hepatic
      G3P and DHAP are altered is inconsistent between reports, and hepatic
      metabolites have not been measured in patients for comparison.
    evidence:
    - reference: PMID:11147825
      reference_title: Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Levels of glycerol phosphate (low) and dihydroxyacetone phosphate (high) were very abnormal in nonislet tissue, especially in skeletal muscle."
      explanation: Reproduces the expected G3P/DHAP block.
  - target: Impaired Gluconeogenesis from Glycerol
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: ORGANISM
    limitations: >-
      Gluconeogenesis from glycerol has not been measured in patients, so
      whether this node applies to human GPD1 deficiency is untested.
    evidence:
    - reference: PMID:27733253
      reference_title: Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The blood glucose levels in the HeA mice were lower than that in the By mice after glycerol administration."
      explanation: In vivo readout of impaired glycerol gluconeogenesis.
discussions:
- discussion_id: gpd1_mouse_liver_lipid_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Hepatocyte Triglyceride Accumulation
  - animal_models#Mouse
  prompt: >-
    Why does loss of GPD1 cause hepatic steatosis and hypertriglyceridemia in
    children, when the Gpd1-null mouse is protected from ethanol-induced
    hepatic triglyceride accumulation, oxidizes more fat and gains less weight?
  rationale: >-
    The mouse data fit the expectation that GPD1 supplies the glycerol backbone
    for hepatic triglyceride, so its loss should reduce triglyceride. Patients
    show the opposite. Either the human phenotype arises through a route the
    mouse does not use (the acyl-DHAP pathway has been proposed), or the mouse
    phenotyping has not tested the conditions that matter in infants, such as a
    milk-based high-fat diet. Until the discrepancy is explained, none of the
    proposed hepatic mechanisms can be regarded as tested.
  evidence:
  - reference: PMID:24472537
    reference_title: The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake."
    explanation: In the mouse, GPD1 loss prevents rather than causes hepatic triglyceride accumulation after ethanol.
  - reference: PMID:32662756
    reference_title: The enhancement of fat oxidation during the active phase and suppression of body weight gain in glycerol-3-phosphate dehydrogenase 1 deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data indicate that GPD1 deficiency induces enhancement of fat oxidation with suppression of weight gain."
    explanation: Whole-body lipid phenotype of the mouse runs opposite to the human disease.
- discussion_id: gpd1_transient_course
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - disease#
  - phenotypes#Hypertriglyceridemia
  - pathophysiology#Progressive Hepatic Fibrosis
  prompt: >-
    Is GPD1 deficiency a transient infantile disorder, as its MONDO and Orphanet
    names state, or a persistent liver and lipid disorder whose infantile peak
    is followed by long-lasting milder disease?
  rationale: >-
    The founding cohort showed triglycerides declining with age, and Orphanet
    still describes reduction or normalization with age. Pooled follow-up of
    later cases finds triglycerides normalizing in under a third, fibrosis that
    can progress to cirrhosis, and persistent hypertriglyceridemia into
    adulthood. The answer determines whether surveillance should continue into
    adulthood. It is limited by short follow-up, selective biopsy, and the few
    adults reported.
  evidence:
  - reference: ORPHA:300293
    reference_title: "Transient infantile hypertriglyceridemia and hepatosteatosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Reduction or normalization of triglyceride serum levels occurs with advancing age."
    explanation: The transient framing as recorded by Orphanet.
  - reference: PMID:41971245
    reference_title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "This study indicates that GPD1 deficiency may not be a transient or benign condition, as previously considered, due to the persistence of HTG and liver pathology in a significant proportion of cases."
    explanation: Pooled-review conclusion against the transient framing.
  - reference: PMID:32685347
    reference_title: Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In some patients, hypertriglyceridemia could be severe and persist overtime."
    explanation: Severe hypertriglyceridemia persisting over time in some patients.
references:
- reference: PMID:22226083
  title: Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
- reference: PMID:24549054
  title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
- reference: PMID:27368975
  title: Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
- reference: PMID:36051699
  title: Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
- reference: PMID:39839217
  title: "Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature."
- reference: PMID:41971245
  title: "Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood."
- reference: PMID:41839820
  title: "Founder Effect of the c.500G>A Variant in South Asian Patients With Inherited GPD1 Deficiency: Report on 16 Patients and Variant Review."
- reference: PMID:32685347
  title: Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.
- reference: PMID:11147825
  title: Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
- reference: PMID:27733253
  title: Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.
- reference: PMID:24472537
  title: The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice.
notes: >-
  Naming and identity. The entry is named GPD1 Deficiency rather than after its
  MONDO label because the "transient" course in that label is contested by the
  pooled follow-up data (see the gpd1_transient_course discussion);
  MONDO:0013771 is bound unchanged, and the MONDO and Orphanet labels are kept
  as synonyms. Lump/split: MONDO records GPD1 as the only causal gene
  (RO:0004003 HGNC:4455) and this entry follows it. Orphanet ORPHA:300293
  additionally lists CREB3L3 as disease-causing and maps OMIM:619324
  (hypertriglyceridemia 2, MONDO:0859149) as a broader term; CREB3L3-related
  hypertriglyceridemia is a separate MONDO disease with a different gene and is
  not included here. A single adult heterozygous for a GPD1 missense variant
  with recurrent hypertriglyceridemia-related pancreatitis (PMID:39849455) is
  not curated as part of this autosomal recessive entity, because one
  heterozygous case does not establish a monoallelic phenotype. No ClinGen
  gene-disease validity assertion for GPD1 appears in the ClinGen gene-validity
  download dated 2026-09-23 (only GPD1L, with Brugada syndrome), and no
  GeneReviews chapter names the disorder (just check-genereviews --online:
  NO_CHAPTER against the 2026-09-10 Bookshelf index plus a live PubMed title
  search), so the pooled literature reviews serve as the phenotype baseline. The founding
  report (PMID:22226083) is available as an abstract only, so nothing from its
  full-text discussion is attributed to it. Phenotypes reported in single
  patients and not curated: anemia requiring transfusion (PMID:37211761) and
  kidney involvement (PMID:27368975); neither has been linked to the enzyme
  defect. Development: one pooled review reports normal psychiatric status in
  all 31 cases (PMID:36051699), while a later review tabulates one patient with
  growth and developmental delay (PMID:41971245), so neurodevelopmental
  involvement is not recorded as a phenotype.
📚

References & Deep Research

References

11
PMID:22226083
Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
No top-level findings curated for this source.
PMID:24549054
A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
No top-level findings curated for this source.
PMID:27368975
Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency.
No top-level findings curated for this source.
PMID:36051699
Clinical characteristics and variant analyses of transient infantile hypertriglyceridemia related to GPD1 gene.
No top-level findings curated for this source.
PMID:39839217
Glycerol-3-Phosphate Dehydrogenase 1 Deficiency and Steatotic Liver Disease in Children: Our Cases and Review of Literature.
No top-level findings curated for this source.
PMID:41971245
Clinical, Laboratory, and Molecular Characteristics of GPD1 Gene Variants: A Cause of Hepatomegaly and Hepatic Steatosis in Early Childhood.
No top-level findings curated for this source.
PMID:41839820
Founder Effect of the c.500G>A Variant in South Asian Patients With Inherited GPD1 Deficiency: Report on 16 Patients and Variant Review.
No top-level findings curated for this source.
PMID:32685347
Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.
No top-level findings curated for this source.
PMID:11147825
Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle.
No top-level findings curated for this source.
PMID:27733253
Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice.
No top-level findings curated for this source.
PMID:24472537
The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: GPD1_Deficiency · 2026-09-23T15:23:47Z · View source

Created a new entry for MONDO:0013771 (transient infantile hypertriglyceridemia and hepatosteatosis), named GPD1 Deficiency because pooled follow-up (PMID:39839217, PMID:41971245, PMID:36051699) shows triglycerides normalizing in only about 28-30% of patients; the MONDO term is bound unchanged and its label kept as a synonym. Deep research: requested falcon, which returned HTTP 402 (out of credits); the claude_code fallback produced research/GPD1_Deficiency-deep-research-claude_code.md. just preflight-dr returned PASS (GPD1 mentioned 49 times, OMIM 614480 matches). Report reference_validation: 18 references, 11 resolved, 0 unresolved, 7 unverifiable, needs_review true; term_validation flagged four mislabelled CURIEs (NCIT:C61961 given as fenofibrate is Tacrine; NCIT:C15709 given as liver biopsy is Genetic Testing; GENO:0000148; UBERON:0000178) and obsolete GO:0004367, none of which were used. The report was treated as leads only; it misstated that the fenofibrate-treated boy (PMID:32685347) was first diagnosed at 16 with cirrhosis (he was followed from age 1), and attributed the G3P-retention hypothesis to the 2012 founding paper, which is available here only as an abstract, so that hypothesis is attributed to PMID:39839217 instead. All evidence was taken from records fetched with just fetch-reference; ORPHA:300293 was built with the structured-source CLI into the worktree cache. The three published mechanistic proposals for the hepatic and plasma triglyceride excess (acyl-DHAP diversion, hepatic G3P retention, increased hepatic secretion) are recorded as EMERGING hypotheses with their contradictions, and the opposite lipid phenotype of the Gpd1-null BALB/cHeA mouse (PMID:24472537, PMID:32662756) is recorded as a HUMAN_MODEL_MISMATCH discussion. Orphanet's inclusion of CREB3L3 was not followed (MONDO lists GPD1 only). No ClinGen validity assertion or GeneReviews chapter exists for GPD1. Validation: just validate, validate-terms, count-verified-snippets (all snippets verified), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches, check-genereviews --online, the whole-KB snippet and hyphen gates, and validate-disorders. A first run of the same recipe with the generic --fallback flag was interrupted locally after falcon's 402, but its openscientist fallback job completed and wrote a second report (preflight-dr PASS; 15/15 references verified, 8/8 quotes valid). To keep to one report per entry it was not committed; the entry was built from the claude_code report and primary sources, and the openscientist report's reference caches not cited by the entry were not committed either.

Claude Code ▸
GPD1 Deficiency (Transient Infantile Hypertriglyceridemia, HTGTI) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 14 citations 2026-09-23T15:04:39.165493

GPD1 Deficiency (Transient Infantile Hypertriglyceridemia, HTGTI) — Comprehensive Research Report

Identifier note (flagged discrepancy)

The template lists OMIM:611090 as a candidate identifier for GPD1 Deficiency. That MIM number does not correspond to this disease — OMIM #611090 is Intellectual Developmental Disorder, Autosomal Recessive 12 (MRT12), an unrelated condition (OMIM #611090). The correct OMIM identifiers are: - Phenotype MIM: 614480 — Hypertriglyceridemia, Transient Infantile (OMIM #614480) - Gene MIM: 138420 — Glycerol-3-Phosphate Dehydrogenase 1; GPD1 (OMIM *138420) - Gene: GPD1, HGNC:4455, cytogenetic location 12q13.12 (GRCh38: chr12:50,104,008–50,111,313), 8 exons (GeneCards; GTR). Note one AI-summarized source mis-stated the locus as "2q12-q13" — this is an error; 12q13.12 is the correct, multiply-confirmed location. - Orphanet: ORPHA:300293, listed as germline GPD1 mutation causing "transient infantile hypertriglyceridemia and hepatic steatosis in infants." - MONDO:0013771 as given in the template is plausible as the disease-node identifier used by Monarch/MONDO for this entry but was not independently re-verified against a live MONDO browse in this session — treat as a lead pending confirmation via just validate-terms/OAK lookup before binding. - No dedicated GeneReviews chapter was found for GPD1 deficiency/HTGTI in this search.

1. Disease Information

Overview. GPD1 deficiency, clinically designated Transient Infantile Hypertriglyceridemia (HTGTI), is a rare autosomal recessive inborn error of triglyceride/glycerolipid metabolism caused by biallelic loss-of-function variants in GPD1, encoding cytosolic NAD⁺-dependent glycerol-3-phosphate dehydrogenase 1. It presents in infancy with hepatomegaly, marked hypertriglyceridemia, elevated transaminases, hepatic steatosis, and — in a substantial minority — hepatic fibrosis progressing occasionally to cirrhosis (Basel-Vanagaite et al., 2012, PMID not directly retrieved but paper is Am J Hum Genet 2012;90:49–60, ScienceDirect). Despite the name "transient," a growing literature (see §11) shows the biochemical/hepatic phenotype is often only partially transient, and the disease has been characterized as "a rare, overlooked cause of liver disease" in a 2025 review (Journal of Human Genetics 2025; PMC12137118) and, in an August 2026 commentary, questioned as "A Transient Disease or a Great Masquerader?" (Das et al. 2026, Am J Med Genet A, PMID:42063230, Wiley).

Synonyms: Transient infantile hypertriglyceridemia; HTGTI; GPD1 deficiency; glycerol-3-phosphate dehydrogenase 1 deficiency; glycerophosphate dehydrogenase 1 deficiency.

Source of information base: The evidence base is almost entirely aggregated case-report/case-series literature (individual pediatric/genetics case reports, plus several pooled literature reviews of 17–45 cumulative cases as of 2020–2025), not large disease-level registries or EHR cohorts. There is no dedicated patient registry or GeneReviews chapter identified.

2. Etiology

Disease causal factor: Monogenic — biallelic (homozygous or compound heterozygous) pathogenic variants in GPD1 (12q13.12) are necessary and sufficient. No environmental, infectious, or polygenic contribution has been proposed; this is a purely Mendelian enzymopathy.

Genetic risk factors: - Homozygosity for GPD1 loss-of-function alleles (splice-site, nonsense, missense, frameshift). - Consanguinity is a strong contributing factor at the population level: reported in ~28–40% of published cases (10/36, 27.7%, per the 2024 North-India series reviewing global literature, PMC11743310; ~40% per another pooled review, PMC12137118). The founding description was in four highly consanguineous Israeli Arab families sharing the splice variant c.361-1G>C (Basel-Vanagaite et al. 2012). - Founder effect: the c.361-1G>C splice-acceptor variant in intron 3 recurs across the original Israeli Arab kindred as a shared haplotype-associated allele. - 86.1% of reported genotypes are homozygous, 13.9% compound heterozygous (PMC11743310).

Environmental risk factors: None specifically established; disease is congenital/metabolic rather than exposure-driven. Dietary fat intake modulates severity (see Treatment) but is not causal.

Protective factors: None reported in the literature; no protective alleles or modifier alleles have been characterized. The residual/partial enzymatic activity retained by some missense alleles (vs. null/truncating alleles) appears associated with milder or more clearly "transient" courses, though this genotype-severity correlation is not rigorously established across the small case series.

Gene-environment interaction: Dietary fat load (especially long-chain triglycerides and simple sugars, which increase hepatic glycerol-3-phosphate flux into triglyceride synthesis) appears to exacerbate hypertriglyceridemia and hepatic fat accumulation in affected children, which underlies the low-fat/MCT dietary management strategy (see §12). This is inferred from treatment-response literature rather than formally demonstrated G×E study designs.

Suggested ontology terms: MONDO (disease, pending verification above); GENO:0000148 (biallelic homozygous) / GENO:0000135 (compound heterozygous); HGNC:4455 (GPD1).

3. Phenotypes

The phenotype set below draws on the two largest pooled reviews (36 cumulative global cases through Dec 2023, PMC11743310; 45 cases across 18 studies as of 2025, PMC12137118) plus individual case reports for rarer manifestations.

Phenotype Frequency (pooled literature) HPO term (suggested) Notes
Hypertriglyceridemia 97.2% (35/36); also reported ~95–98% in other pooled series HP:0002155 Hypertriglyceridemia Moderate–severe; often several-fold to markedly elevated; peaks typically within first 6 months of life
Hepatomegaly 94.4% (34/36); 100% in a smaller 18-patient series HP:0002240 Hepatomegaly Often the presenting clinical sign
Hepatic steatosis / fatty liver (imaging or biopsy) 100% (26/26 with imaging; 18/18 biopsied) HP:0001397 Hepatic steatosis Universal finding on imaging/biopsy in reported cases
Elevated transaminases ~95–100% depending on series HP:0002910 Elevated hepatic transaminase Typically mild–moderate (1.5–3× ULN) elevation
Hepatic fibrosis (biopsy) 94.4% (17/18 biopsied) HP:0001395 Hepatic fibrosis High rate among biopsied cases — biopsy is not universal, so ascertainment bias toward more severe cases is likely
Cirrhosis 22.2% (4/18 biopsied) HP:0001394 Cirrhosis Occurs in a meaningful minority; includes adolescent-onset case (Matarazzo et al. 2020)
Splenomegaly 22.2% (8/36) HP:0001744 Splenomegaly
Growth failure / short stature 22.2–23% (8/36) HP:0004322 Short stature / HP:0001508 Failure to thrive
Hypoglycemia (fasting) ~11% HP:0001943 Hypoglycemia Rare but reported, including with insulin resistance (Karger 2022/PMC9801319)
Insulin resistance / obesity Reported in a subset (case reports) HP:0040270 Obesity / HP:0000855 Insulin resistance (proxy term) E.g., Chinese boy with obesity, insulin resistance, fatty liver, short stature (PMID:28944580)
Elevated total bile acids / intrahepatic cholestasis Case-reported HP:0030957 Elevated circulating bile acid concentration
Organic aciduria Case-reported (variable, non-specific organic aciduria)
Hepatic adenoma Single case report (first reported) HP:0006725 Hepatic adenoma (proxy) First reported case of hepatic adenoma arising in HTGTI (PMID:35365473, PMC8977762)
Kidney disease (renal) Rare, case-reported (non-specific) Listed among "rare phenotypes" in pooled review
Vomiting Case-reported HP:0002013 Vomiting

Onset: Median age at diagnosis 6 months (range 1–164 months) in the largest pooled series (PMC11743310); most present within the first year of life, though later childhood/adolescent presentations (including a first diagnosis at age 16 with established cirrhosis) are recorded.

Severity/progression: Variable — spans an apparently "benign," self-limited biochemical course in some infants to progressive fibrosis/cirrhosis in others; genotype-phenotype correlation is not well established.

Quality of life impact: Not formally studied with validated instruments (no EQ-5D/SF-36/PROMIS data identified). Reported outcomes emphasize preserved growth and neurodevelopment in most followed patients; QoL burden is inferred to derive chiefly from chronic hepatic monitoring, dietary restriction, and (in severe cases) cirrhosis-related morbidity.

4. Genetic/Molecular Information

Causal gene: GPD1 (HGNC:4455), OMIM *138420, chr12q13.12.

Variant spectrum: As of the most recent pooled reviews (2024–2025), ~24 distinct disease-causing GPD1 variants have been reported worldwide (PMC12137118). Representative variants, all recessive/biallelic and largely private/founder alleles:

Variant (cDNA/protein) Type Source
c.361-1G>C (p.Ile119fsX94) Splice-acceptor, intron 3 → frameshift/truncation at residue 213, disrupting NAD-binding/substrate-recognition domain Basel-Vanagaite et al. 2012 (founder allele, 4 consanguineous Israeli Arab families)
c.628G>C (p.G210R) Missense Chinese case report
c.454C>T (p.Q152*) Nonsense Case report
c.895G>A (p.G299R) Missense Matarazzo et al. 2020 (JIMD Reports), homozygous, associated with adolescent cirrhosis
c.805C>T (p.R269W) Missense Karger 2022 case, associated with hypoglycemia/insulin resistance
c.917T>C, c.905C>G Missense (novel) Reported in 2024 North India series (PMC11743310)

Classification per ACMG/AMP is not systematically reported across the literature but the recurring splice/nonsense/frameshift alleles are consistent with loss-of-function (biallelic null) as the principal molecular mechanism; missense alleles presumably retain partial activity, though functional enzymatic assays confirming residual activity for each specific variant were not identified in this search.

Allele frequency in population databases: No systematic gnomAD/ExAC carrier-frequency figure for GPD1 pathogenic variants was retrievable in this session; this should be checked directly against gnomAD v4 per-variant pages before citing a specific number in the KB entry (each of the variants above should be individually queried).

Somatic vs. germline: Exclusively germline/constitutional in this disease (not a somatic/cancer-associated gene in this context — do not conflate with the distinct paralog GPD1L, associated with Brugada syndrome/cardiac Na⁺ channel dysfunction via a different mechanism, PMC3150966).

Functional consequence: Loss of GPD1 catalytic (cytosolic glycerol-3-phosphate dehydrogenase) activity — i.e., loss of function, not gain-of-function or dominant-negative in the reported alleles.

Modifier genes: None established. Genotype-severity correlation (e.g., null vs. missense allele → cirrhosis risk) is suggested informally by case pattern but not statistically demonstrated.

Epigenetic information: None specifically reported for human GPD1 deficiency.

Chromosomal abnormalities: Not applicable — this is a single-gene sequence-variant disease, not a CNV/structural disorder.

5. Environmental Information

  • Environmental factors: None causally implicated; this is a purely monogenic disease.
  • Lifestyle factors: Dietary fat composition and quantity modulate the severity of the biochemical phenotype (hypertriglyceridemia, hepatic fat accumulation) — see Treatment. High dietary fat, particularly long-chain triglycerides, appears to worsen hypertriglyceridemia; medium-chain triglyceride (MCT)-enriched, low-long-chain-fat diets are used therapeutically.
  • Infectious agents: None implicated.

6. Mechanism / Pathophysiology

Causal chain (numbered):

  1. Biallelic loss-of-function variant in GPD1 (e.g., c.361-1G>C splice defect, or missense/nonsense alleles) → leads to absent or markedly reduced cytosolic NAD⁺-dependent glycerol-3-phosphate dehydrogenase 1 enzymatic activity.
  2. Loss of GPD1 activity abolishes/reduces the reversible cytosolic interconversion of dihydroxyacetone phosphate (DHAP) ⇌ glycerol-3-phosphate (G3P), which normally couples glycolysis/gluconeogenesis to glycerolipid synthesis and regenerates cytosolic NAD⁺ from NADH.
  3. The proposed primary mechanistic hypothesis (Basel-Vanagaite et al. 2012) is that GPD1 loss limits the conversion of G3P back to DHAP, which results in an increased pool of G3P available as substrate for glycerolipid/triglyceride backbone synthesis (via glycerol-3-phosphate acyltransferase and downstream acylation steps) — i.e., a substrate-accumulation mechanism driving excess hepatic triglyceride synthesis. (Note: this direction of flux — i.e., which arm of the readily reversible reaction is rate-limiting in vivo — is inferred rather than directly demonstrated biochemically in patient tissue, and should be flagged in curation as a hypothesis rather than a confirmed mechanism.)
  4. An alternative/complementary hypothesis in the 2025 review (PMC12137118) proposes that fatty liver in GPD1 deficiency "may result from excessive acylation of dihydroxyacetone phosphate (DHAP)" via the alternative (acyl-DHAP) pathway of glycerolipid synthesis, which becomes favored when the GPD1-dependent G3P-generating route is blocked — this branch point is explicitly noted as mechanistically unclear ("detailed mechanisms remain unclear").
  5. Excess hepatic triglyceride synthesis and/or impaired triglyceride clearance from hepatocytes leads to intrahepatocellular lipid droplet accumulation → hepatic steatosis (macro/microvesicular, confirmed histologically in nearly all biopsied cases).
  6. Excess hepatic triglyceride is also secreted into the circulation as VLDL, contributing to systemic hypertriglyceridemia, which peaks in the first months of life and in many patients gradually declines with age (the basis for the "transient" designation), though this decline is incomplete/variable across patients.
  7. Chronic hepatocellular lipid accumulation and associated lipotoxic/inflammatory stress leads to hepatocyte injury (reflected in elevated transaminases) and, over time, a fibrogenic response — progressive deposition of extracellular matrix — in a majority of biopsied patients (94.4%), and in a minority (22.2%) progresses to cirrhosis and, in single cases, to hepatic adenoma formation (a first-reported association, PMID:35365473) — mechanistically analogous to metabolic-dysfunction-associated steatotic liver disease (MASLD/NAFLD) progression, but of monogenic origin.
  8. Branch — carbohydrate/energy metabolism: because DHAP↔G3P interconversion is also part of the cytosolic arm of the glycerol-3-phosphate shuttle that regenerates cytosolic NAD⁺ (paired with mitochondrial GPD2, which is FAD-linked and feeds electrons into the respiratory chain via coenzyme Q), GPD1 loss also impairs gluconeogenesis from glycerol. In mouse Gpd1-knockout models this leads to a compensatory shift toward increased gluconeogenesis from glycogenic amino acids (notably alanine), evidenced by higher blood alanine and enhanced hepatic alanine-driven gluconeogenesis during fasting, and — counterintuitively — higher blood glucose after 1–4 hours of fasting than wild-type mice (Tanner et al., PMID:27733253). This branch is proposed as the mechanistic basis for the rare hypoglycemia/insulin-resistance phenotypes reported in some human patients, though the direct human-mechanistic link is inferred from the mouse fasting data rather than demonstrated in patient-derived tissue.
  9. In some patients, chronic disturbance of hepatic lipid/glucose handling is associated with downstream insulin resistance and obesity (case-reported subset), though causal directionality (GPD1 loss → primary insulin resistance, vs. secondary to hepatic steatosis) is not established.

Molecular pathways: Glycerolipid/triglyceride biosynthesis pathway (KEGG map00561); glycerophospholipid metabolism; the glycerol-3-phosphate shuttle (bridges glycolysis and oxidative phosphorylation); gluconeogenesis (glycerol input arm).

Cellular processes: Lipid droplet biogenesis/accumulation in hepatocytes (steatosis); hepatic stellate cell activation and extracellular matrix deposition (fibrogenesis, likely via the same final-common-pathway mechanisms modeled generically in dismech's fibrotic_response module); possible lipotoxic hepatocellular stress.

Protein dysfunction: Loss-of-function via (a) splice disruption/premature truncation removing catalytic/substrate-recognition residues (c.361-1G>C), or (b) missense substitutions presumably destabilizing the NAD-binding or catalytic domain (e.g., p.G210R, p.G299R, p.R269W) — specific structural/functional characterization of these missense alleles (e.g., via AlphaFold modeling or recombinant enzyme assay) was not identified in this search and would need dedicated retrieval.

Metabolic changes: Elevated hepatic and circulating triglycerides; altered cytosolic NADH/NAD⁺ ratio; compensatory amino-acid-driven gluconeogenesis (mouse data); possible organic aciduria (case-reported, mechanism unclear).

Suggested GO terms: GO:0006650 (glycerophospholipid metabolic process); GO:0019432 (triglyceride biosynthetic process); GO:0006094 (gluconeogenesis); GO:0004367 (glycerol-3-phosphate dehydrogenase [NAD+] activity, molecular function for GPD1 itself); GO:0055088 (lipid homeostasis).

Suggested CL terms: CL:0000182 (hepatocyte) — primary affected cell type; CL:0000632 (hepatic stellate cell) — fibrogenic effector, inferred by analogy rather than directly demonstrated in GPD1-deficiency-specific studies.

Advanced/omics technologies: No transcriptomic, proteomic, metabolomic, single-cell, or spatial data specific to human GPD1-deficient liver tissue were identified in this search; the mouse Gpd1-knockout fasting/metabolomics study (PMID:27733253) is the principal molecular-profiling-adjacent dataset available.

7. Anatomical Structures Affected

  • Primary organ: Liver (hepatomegaly, steatosis, fibrosis, cirrhosis, and rarely adenoma).
  • Secondary/systemic involvement: Adipose tissue/systemic lipid metabolism (hypertriglyceridemia); spleen (splenomegaly, presumably secondary to portal hypertension/hepatic disease in advanced cases, or reactive); growth (short stature/failure to thrive); endocrine/metabolic axis (insulin resistance, hypoglycemia in a subset); kidney (rare reported involvement).
  • Body systems: Digestive system (primary); metabolism/homeostasis; growth; cardiovascular (long-term theoretical risk from hypertriglyceridemia, see Prognosis); immune system (listed among HPO-mapped systems in one search result, though the specific immune phenotype was not itemized in retrieved sources).
  • Tissue/cell level: Hepatocytes (steatosis, primary site of GPD1 dysfunction consequences); hepatic stellate cells (fibrogenesis, inferred).
  • Subcellular level: Cytosol (site of GPD1 catalytic activity; contrast with mitochondrial GPD2, part of the same glycerol-3-phosphate shuttle but genetically and clinically distinct).
  • UBERON suggestions: UBERON:0002107 (liver); UBERON:0002106 (spleen); UBERON:0000178 (blood, for triglyceride measurement).
  • Laterality: Not applicable (diffuse hepatic process).

8. Temporal Development

  • Onset: Typically infantile — most patients present within the first year of life; median age at diagnosis 6 months (range 1–164 months) in the largest pooled series. A minority present later in childhood or adolescence (e.g., first diagnosed at 16 years with established cirrhosis, Matarazzo et al. 2020).
  • Onset pattern: Generally insidious/subacute, detected via incidental hepatomegaly or lipid-panel abnormality rather than acute presentation, though pancreatitis risk (from severe hypertriglyceridemia) could theoretically present acutely (none reported in the pooled cohort — see Prognosis).
  • Progression: Variable. Triglycerides "typically peak within the first 6 months of life, tending to decrease with age" (PMC12137118), consistent with partial biochemical remission. However, on longer follow-up (11–376 months) in the 2024 pooled series, only a minority of patients showed full resolution: hepatomegaly resolved in 35.2% (6/17), triglycerides normalized in 29.1% (7/24), and transaminases normalized in 31.5% (6/19) — meaning the majority of followed patients had persistent abnormalities, challenging the "transient" label (hence the 2026 "Great Masquerader" commentary).
  • Disease course pattern: Can be stable/improving (classic "transient" course) or slowly progressive toward fibrosis/cirrhosis in a subset (~22% progressing to cirrhosis among biopsied cases).
  • Critical periods: Infancy appears to be the period of peak triglyceride elevation and diagnostic ascertainment; the mechanistic basis for age-related improvement (e.g., changing dietary composition, maturation of alternative lipid-handling pathways) is not established.

9. Inheritance and Population

  • Inheritance pattern: Autosomal recessive (biallelic).
  • Penetrance: Not formally quantified; presumed high/complete given ascertainment via symptomatic presentation, though this is subject to ascertainment bias (asymptomatic homozygotes would not enter the literature).
  • Expressivity: Markedly variable — ranges from apparently self-limited infantile hypertriglyceridemia to progressive cirrhosis, hepatic adenoma, hypoglycemia/insulin resistance, and short stature. This variability is a major theme of recent reviews.
  • Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).
  • Germline mosaicism: Not specifically reported.
  • Founder effects: Yes — the original 2012 description involved a shared splice variant (c.361-1G>C) across four consanguineous Israeli Arab families, consistent with a regional founder allele. Subsequent case reports come predominantly from China, India, Turkey, Italy, and other diverse populations with largely private (non-recurring) variants, suggesting genetic heterogeneity outside the founder cluster.
  • Consanguinity role: Substantial — present in ~28–40% of reported cases across pooled series, well above general-population background rates, consistent with a rare autosomal recessive disease.
  • Carrier frequency: Not established from a population reference database in this search; should be queried directly in gnomAD v4 per-variant.

Epidemiology: - Prevalence/incidence: No formal population-based prevalence or incidence estimate exists; the disease is characterized purely by cumulative reported case counts — 10 (2012) → 17 (2016) → 31 (2022) → 36 (Dec 2023) → 45 (2025) cases worldwide across the literature, reflecting a very rare, likely underdiagnosed condition (multiple reviews explicitly describe it as "rare, overlooked" and "underdiagnosed"). - Sex ratio: ~1.6 male : 1 female among 31 reviewed genetically-confirmed cases (Wang et al. 2022 review, cited in PMC11743310) — a mild male excess, though the biological basis (vs. ascertainment) is unclear for an autosomal recessive disease. - Geographic/ethnic distribution: Case reports span Israeli Arab (founder cohort), Chinese, Indian (North India series, 5 new cases 2024), Turkish, Italian, and other populations — suggesting the disease is pan-ethnic but detected wherever genomic/exome sequencing is applied to unexplained pediatric fatty liver/hypertriglyceridemia, with likely substantial underascertainment in resource-limited settings (see the 2026 companion paper on "targeted molecular testing in limited-resource settings," Malik et al., Wiley).

10. Diagnostics

Clinical/laboratory tests: - Fasting lipid panel: marked hypertriglyceridemia (core finding). - Liver function tests: elevated ALT/AST (typically 1.5–3× ULN). - Total bile acids (elevated in a subset). - Fasting glucose (hypoglycemia in a minority). - Organic acid analysis (organic aciduria reported in some cases, though non-specific).

Imaging: Abdominal ultrasound (hepatomegaly, increased echogenicity consistent with steatosis — reported in 100% of imaged cases); transient elastography/FibroScan for non-invasive fibrosis assessment.

Biopsy/histopathology: Liver biopsy showing macro/microvesicular steatosis (100% of biopsied cases), fibrosis (94.4%), and cirrhosis (22.2% of biopsied cases) in the pooled series.

Genetic testing: - Whole-exome sequencing (WES) is the diagnostic approach used in essentially all recent case identifications, given the absence of a distinctive enough clinical phenotype to prompt single-gene testing a priori, and the rarity/novelty of variants (most are novel, private alleles rather than recurrent hotspots outside the founder cluster). - Single-gene GPD1 Sanger sequencing is used for targeted confirmation/segregation analysis once a proband variant is identified, and for carrier testing in consanguineous families or known founder populations. - A 2026 companion paper specifically addresses genetic-diagnosis nuances and targeted molecular testing strategies for GPD1 deficiency in limited-resource settings (Malik et al., Wiley), suggesting targeted panel/single-gene approaches may be preferable where WES access is limited.

Differential diagnosis (per PMC12137118): infectious hepatitis, Wilson disease, autoimmune hepatitis, alpha-1 antitrypsin deficiency, celiac disease, hemochromatosis, and other causes of unexplained pediatric elevated liver enzymes/hypertriglyceridemia/hepatosteatosis (e.g., other monogenic hypertriglyceridemia syndromes such as familial chylomicronemia syndrome, lipoprotein lipase deficiency, glycogen storage disease).

Screening: No newborn screening or population carrier-screening program identified for GPD1 deficiency; diagnosis is currently reactive (triggered by unexplained infantile hepatomegaly/hypertriglyceridemia/fatty liver) rather than proactive.

Suggested LOINC/ontology terms: Standard triglyceride, ALT, AST panel LOINC codes (not individually itemized here); NCIT:C15709 (Liver Biopsy) or similar procedure term for the diagnostic biopsy.

11. Outcome/Prognosis

Survival/mortality: No deaths attributable to GPD1 deficiency were identified in the literature reviewed; the disease is not associated with reported mortality in the pooled case series.

Complication risk (theoretical vs. observed): Reviews note that hypertriglyceridemia in general "contribute[s] independently to the risk of coronary artery disease and [is] additionally associated with heightened susceptibility to acute pancreatitis" (PMC12137118) — but critically, in the largest pooled follow-up (11–376 months), "no pancreatitis, cardiac events, or liver decompensation was reported" across all 36 reviewed cases (PMC11743310). This is an important curation point: the theoretical cardiovascular/pancreatitis risk of hypertriglyceridemia has not been empirically observed in this specific disease's reported natural history to date, though follow-up duration and cohort size remain limited.

Disease course / "transient" vs. persistent: As detailed in §8, only a minority of followed patients show full normalization (hepatomegaly resolution 35.2%, TG normalization 29.1%, transaminase normalization 31.5%), meaning most retain some abnormality at last follow-up, even though severity/degree often improves. Liver fibrosis, once established, does not clearly reverse in the available follow-up data. A subset progresses to cirrhosis (22.2% of biopsied cases) and, in one case, hepatic adenoma. The 2026 commentary explicitly frames this tension as reconsidering the disease as potentially a "great masquerader" rather than uniformly self-limited.

Prognostic factors: Not rigorously established; biopsy-proven fibrosis at diagnosis and null/truncating (vs. missense) genotype are plausible but unconfirmed candidate risk factors for a more severe/persistent course.

Functional/developmental outcome: Growth and neurodevelopment are reported as normal in most followed patients (e.g., siblings followed to ages 12.5 and 4.5 years with normal growth/development despite persistent hepatomegaly/lab abnormalities, PMC12137118), with growth failure/short stature as an exception in a minority (~22%).

12. Treatment

Dietary/supportive (first-line): - Low-fat diet with medium-chain triglyceride (MCT) enrichment is the standard first-line management approach — one series recommends MCT comprising up to ~70% of fat intake (PMC11743310), based on the rationale that MCTs bypass the long-chain-fatty-acid/triglyceride-resynthesis pathway that is pathologically overactive in this disease. - Omega-3 fatty acid supplementation has also been used as part of standard dietary management (PMC12137118). - In many patients, "no specific treatment is required" and triglycerides/enzymes are managed with observation alone as they tend to improve with age (though see §11 on incomplete normalization).

Pharmacotherapy: - Fenofibrate (a PPAR-α agonist, fibrate class) has been used successfully for severe, persistent hypertriglyceridemia refractory to diet, notably in a boy with cirrhosis and GPD1 deficiency: homozygous c.895G>A (p.G299R), followed since age 1 for hepatomegaly/elevated LFTs/hypertriglyceridemia, biopsy-proven cirrhosis with micro/macrovesicular steatosis; fenofibrate started at age 15, with successful triglyceride reduction over 1-year follow-up (Matarazzo et al. 2020, JIMD Reports, PMID:32685347, PMC7358666). NCIT term candidate: NCIT:C61961 (Fenofibrate) as therapeutic_agent under a NCIT:C15986 Pharmacotherapy treatment_term. - Allopurinol has been used adjunctively for management of hyperuricemia in at least one reported case (PMC11743310). - Lipoprotein apheresis is not routine but has been considered/mentioned for severe hyperlipidemia management in the broader monogenic-hypertriglyceridemia literature context (PMID:29940878 cited by PMC12137118), though a GPD1-deficiency-specific apheresis case was not directly retrieved in this search and should be verified before citing.

Advanced therapeutics: No gene therapy, cell therapy, RNA-based therapy (ASO/siRNA), or targeted molecular therapy has been developed or trialed for GPD1 deficiency — it remains managed purely with diet ± fibrate therapy. No relevant NCT-registered clinical trials were identified in this search.

Surgical/interventional: None specific to GPD1 deficiency identified; presumably standard cirrhosis-complication management (e.g., surveillance for hepatic adenoma/malignant transformation) would apply in advanced cases, but this is inferential rather than literature-documented.

Monitoring: Serial liver enzymes, triglycerides, abdominal ultrasound/elastography, and periodic biopsy consideration in persistent/progressive cases are implied by the follow-up structure of reported case series, though no formal consensus monitoring protocol/guideline was identified.

Suggested NCIT terms: NCIT:C15447 (Dietary Intervention) for the low-fat/MCT diet; NCIT:C15986 (Pharmacotherapy) with therapeutic_agent = fenofibrate (fibrate class; CHEBI or NCIT term to be confirmed via OAK lookup before binding).

13. Prevention

  • Primary prevention: Not applicable in the traditional sense (monogenic recessive disease) beyond genetic counseling for carrier parents/consanguineous families, particularly in populations with known founder alleles (e.g., Israeli Arab c.361-1G>C).
  • Secondary prevention/early detection: No population screening program (newborn or carrier) exists; early detection currently depends on clinical suspicion when a child presents with unexplained hepatomegaly/hypertriglyceridemia/fatty liver, triggering WES.
  • Carrier/prenatal testing: Would be feasible via targeted variant testing once a familial pathogenic variant is known (standard for autosomal recessive Mendelian disease), but no specific prenatal diagnosis program was identified in the literature reviewed.
  • Behavioral/dietary prevention of complications: Ongoing low-fat/MCT dietary management functions as tertiary prevention — limiting hepatic lipid accumulation/fibrosis progression rather than preventing disease onset.
  • Public health: Not a public-health-scale condition given its rarity; management is individualized/genetic-counseling-based rather than population-level.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring GPD1-deficiency disease model was identified in companion animals (dogs, cats) or wildlife in this search (no OMIA entry surfaced). This should be double-checked directly against OMIA before asserting absence in the KB.
  • Orthologous gene: Mouse Gpd1 (MGI:95679), located syntenically; the mouse ortholog has been characterized functionally (see Model Organisms below).
  • Comparative biology: The dual cytosolic (GPD1)/mitochondrial (GPD2) glycerol-3-phosphate shuttle system is evolutionarily conserved from yeast to humans — the crystal structure of yeast (Saccharomyces cerevisiae) Gpd1 has been solved (PMC3515364), providing structural insight into the conserved catalytic fold, though yeast Gpd1 serves an osmotic-stress-response role distinct from the mammalian lipogenic/metabolic role.
  • Zoonotic potential: Not applicable (non-infectious monogenic disease).

15. Model Organisms

Mouse (Mus musculus, MGI:95679, orthologous gene Gpd1): - A spontaneous loss-of-function mutant mouse line exists: homozygous mice are described as "viable and phenotypically normal" at baseline but show complete loss of GPD1 enzymatic activity in adult tissues (MGI:95679; IMPC data). - Fasting/metabolic phenotyping (Tanner et al., PMID:27733253, "Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice"): Gpd1-knockout mice show: - Inhibited gluconeogenesis specifically from glycerol (expected, given the enzyme's role). - Higher blood glucose after 1–4 hours of fasting compared to wild-type — a counterintuitive compensatory finding. - Significantly higher blood alanine and increased hepatic utilization of alanine for gluconeogenesis. - Interpretation: chronic GPD1 deficiency induces an adaptive shift toward glycogenic-amino-acid-driven gluconeogenesis, compensating for the lost glycerol-to-glucose route. - Fidelity/limitations as a model for the human liver disease: Notably, the mouse model as characterized in the retrieved literature is centered on fasting glucose/amino acid metabolism, not on the hallmark human phenotype (hepatomegaly, hepatic steatosis, fibrosis, hypertriglyceridemia). This is an important model-to-mechanism gap: no clear evidence was retrieved in this search that the Gpd1-knockout mouse recapitulates hepatic steatosis/fibrosis/hypertriglyceridemia the way human patients do (the baseline phenotype is described as "phenotypically normal"). This divergence should be flagged explicitly in any animal_models[].modeled_mechanisms entry — likely PARTIAL_RECAPITULATES or FAILS_TO_RECAPITULATE for the hepatic/lipid phenotype specifically, pending a literature check for a fat-loading/high-fat-diet-challenged version of this model, which was not identified in this search but may exist and should be checked before finalizing model-fidelity calls. - Alcohol-related fatty liver context: A separate mouse study examines "the role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice" (ScienceDirect, PMID not retrieved directly) — relevant to GPD1's general role in hepatic lipid handling but in an ethanol-injury context rather than a direct constitutive-deficiency human-disease model; should be checked for direct relevance/fidelity before citing as a disease model.

Yeast (Saccharomyces cerevisiae): Gpd1 structural biology (PDB structure solved at 2.45 Å, PMC3515364) provides conserved catalytic-domain insight but yeast Gpd1's physiological role (osmoadaptation via glycerol production) is not a disease model for the human hepatic phenotype — useful for structural/functional annotation only, not phenotype recapitulation.

Other species (zebrafish, Drosophila, C. elegans, iPSC/organoid models): None identified in this search; this is a gap worth a dedicated follow-up search before concluding no such model exists.

Summary of Key PMIDs / Identifiers for Curation

Reference Content
Basel-Vanagaite et al. 2012, Am J Hum Genet 90:49–60 Original description, c.361-1G>C, 10 patients/4 families, molecular mechanism hypothesis
PMID:27368975 "Expanding the molecular diversity and phenotypic spectrum of GPD1 deficiency" — could not confirm full-text details in this session (CAPTCHA-blocked); re-fetch before citing specifics
PMID:32685347 / PMC7358666 Matarazzo et al. 2020, fenofibrate therapy, c.895G>A/p.G299R, cirrhosis case
PMID:35365473 / PMC8977762 First reported hepatic adenoma in HTGTI
PMID:36588760 / PMC9801319 Hypoglycemia + insulin resistance, c.805C>T/p.R269W
PMID:28944580 Obesity, insulin resistance, fatty liver, short stature, Chinese cohort
PMID:33120465 Two cases + literature review (Chinese)
PMC11743310 (2024) 5 North India cases + review of 36 global cases — primary source for frequency statistics used above
PMC12137118 / [Nature s10038-025-01339-9] (2025) "GPD1 deficiency—a rare, overlooked cause of liver disease" — 45 cases/18 studies review
PMID:42063230 (2026) Das et al., "Transient Disease or a Great Masquerader?" commentary
PMID:27733253 Mouse Gpd1-KO fasting/amino-acid compensation study
OMIM *138420 / #614480 Gene / phenotype entries
ORPHA:300293 Orphanet entry

Notable gaps to close before KB entry finalization

  1. PMID for the original 2012 paper and for PMID:27368975 could not be directly confirmed via full-text fetch in this session (access blocked); re-verify via PubMed/just fetch-reference.
  2. MONDO:0013771 binding should be confirmed via OAK/just validate-terms rather than taken from the template at face value.
  3. gnomAD allele/carrier frequencies for the specific pathogenic variants (c.361-1G>C, p.G299R, p.R269W, etc.) need direct per-variant lookup.
  4. Mouse model hepatic/lipid phenotype fidelity (vs. the baseline "phenotypically normal" finding) needs a dedicated search for any high-fat-diet-challenged or liver-specific-phenotyping Gpd1-KO study before writing an animal_models entry.
  5. Confirm whether a fenofibrate/fibrate CHEBI or NCIT identifier and a GPD1 HGNC lowercase CURIE (hgnc:4455) resolve correctly in the local caches before binding.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 18
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 7
Quoted claims checked 0
Quoted claims found in source 0
Quoted claims not found in source 0
Quoted claims with nothing to check against 4
References weighed for topical relevance 11
On topic 7
Off topic 0

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

  • PMID:42063230: "A Transient Disease or a Great Masquerader?"
  • Reference resolved but exposes no abstract or full text to search
  • DOI:10.1002/ajmg.a.70188: "A Transient Disease or a Great Masquerader?"
  • Reference resolved but exposes no abstract or full text to search
  • PMC:PMC12137118: "typically peak within the first 6 months of life, tending to decrease with age"
  • The PMC ID service was unreachable, so the quote was not checked
  • PMC:PMC12137118: "contribute[s] independently to the risk of coronary artery disease and [is] additionally associated with heightened susceptibility to acute pancreatitis"
  • The PMC ID service was unreachable, so the quote was not checked

11 of 18 references resolved; the rest could not be looked up either way.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 36
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 4
Terms whose name was checked 15
Terms named correctly 10
Terms named as a different term 4
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • GENO:0000148 (1 mention) - the report calls it "biallelic homozygous"; GENO calls it autosomal recessive inheritance
  • UBERON:0000178 (1 mention) - the report calls it "blood, for triglyceride measurement"; UBERON calls it blood
  • NCIT:C15709 (1 mention) - the report calls it "Liver Biopsy"; NCIT calls it Genetic Testing
  • NCIT:C61961 (1 mention) - the report calls it "Fenofibrate"; NCIT calls it Tacrine

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0004367 (GO_0004367) (1 mention) - replaced by GO:0047952

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GENO:0000135 (1 mention) - the report calls it "compound heterozygous"; GENO calls it heterozygous

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MGI:95679 - called "Gpd1", "Orthologous gene:* Mouse Gpd1"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, ORPHA, MGI.