Isolated Glycerol Kinase Deficiency

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Classifications

ICIMD (Inherited Metabolic Disorders)

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Mappings

MONDO

MONDO:0018459 isolated glycerol kinase deficiency

MONDO:0018459 is the exact disease concept for the isolated (nonsyndromic) form and carries the Orphanet ORPHA:408 equivalence used by the IEMbase WP-007 seed row.

MONDO:0010613 inborn glycerol kinase deficiency Not Yet Curated

MONDO:0010613 is the parent concept that carries the OMIM:307030 cross-reference cited by the WP-007 seed row. It is deliberately recorded as a broad match rather than the primary anchor because it also subsumes the Xp21 contiguous-gene (complex) presentations, which this entry excludes.

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Inheritance

1

X-linked recessive HP:0001419

GK lies at Xp21.2. Clinically ascertained patients are hemizygous males; carrier females are unaffected.

X-linked recessive inheritance

Show evidence (1 reference)

PMID:39512433 SUPPORT Human Clinical

"Glycerol kinase deficiency (GKD) is an X-linked recessive disorder due to glycerol kinase (GK) gene mutations"

Establishes X-linked recessive inheritance and single-gene causation.

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Subtypes

2

Juvenile glycerol kinase deficiency MONDO:0017295

The symptomatic childhood presentation: episodic, catabolic-stress-triggered crises of vomiting with ketoacidosis, a tendency to hypoglycaemia, and disturbed consciousness, on a background of constant hyperglycerolaemia and glyceroluria. Crises typically remit after puberty.

Show evidence (1 reference)

PMID:9719371 SUPPORT Human Clinical

"Three patients had gastrointestinal symptoms with ketoacidosis or hypoglycaemia or both."

Documents the symptomatic childhood crisis phenotype in molecularly confirmed isolated GKD.

Adult glycerol kinase deficiency MONDO:0017296

A clinically silent form recognised incidentally, essentially always through a persistently and inexplicably raised triglyceride result that does not respond to lipid-lowering therapy and is not accompanied by lipaemic serum.

Show evidence (1 reference)

PMID:11032329 SUPPORT Human Clinical

"The clinical and biochemical phenotype of isolated GKD may vary from a life-threatening childhood metabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia."

Establishes the asymptomatic adult form defined by pseudohypertriglyceridaemia.

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Mechanistic Hypotheses

1

Age-dependent glycerol-as-gluconeogenic-substrate model

age_dependent_gluconeogenic_substrate_model CANONICAL

Evidence balance 3 support

Symptoms track how much the individual depends on glycerol as a gluconeogenic substrate rather than how much residual enzyme activity is present. Young children, whose fasting glucose production draws proportionally more on glycerol, decompensate under catabolic stress; the same individuals become tolerant after puberty despite an unchanged genotype and unchanged hyperglycerolaemia. This model accounts for the otherwise puzzling observation that genotype does not predict phenotype.

Show evidence (3 references)

PMID:15303806 SUPPORT Human Clinical

"The greater importance of glycerol as a gluconeogenetic substrate in children than in adults may explain the episodes in young patients with GKD, often elicited by catabolic stress."

States the age-dependent substrate-dependence model directly, from 20-year follow-up of two affected boys.

PMID:15303806 SUPPORT Human Clinical

"After puberty, the boys had no hypoglycaemic symptoms and now report no problems with their condition; thus, their phenotype has changed over time."

Provides the within-individual, genotype-invariant change in phenotype the model predicts.

PMID:11032329 SUPPORT Human Clinical

"The clinical variability in isolated GKD cannot be explained by biochemical or by molecular heterogeneity."

Excludes residual-activity and allele identity as the explanation for variable severity, which is what motivates a host-context model.

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Discussions and Knowledge Gaps

2

Are the childhood crises of isolated glycerol kinase deficiency caused by failure of glycerol-dependent gluconeogenesis, by a defect in ketolysis, or by both?

KNOWLEDGE GAP OPEN gap_gkd_gluconeogenesis_versus_ketolysis

Attached to

pathophysiology#Fasting and Catabolic-Stress Intolerance pathophysiology#Hyperketotic Hypoglycaemic Decompensation

The pathograph as curated routes the crisis through loss of glycerol as a gluconeogenic substrate, but the primary review of the disorder explicitly declines to settle that attribution and raises ketolysis as an alternative or additional contributor. The distinction matters for management: a gluconeogenic-substrate deficit is fully addressed by exogenous glucose, whereas a ketolytic defect would predict residual vulnerability despite adequate glucose supply. It also bears on why adults with unchanged hyperglycerolaemia still show pronounced ketonaemia on fasting while no longer becoming hypoglycaemic.

Proposed experiments

Paired glycerol and ketone tracer study across the pubertal transition

gkd_paired_tracer_gluconeogenesis_ketolysis

In hemizygous GK patients studied as children and again as adults, combine 13C3-glycerol infusion (already validated in this disorder) with a 13C-labelled beta-hydroxybutyrate infusion during a controlled fast. Measure glycerol-to-glucose conversion, whole-body glucose production, and ketone body oxidation rate. If gluconeogenic substrate loss alone explains the crises, ketone oxidation should be normal at both ages while glucose production falls only in childhood.

Show evidence (2 references)

PMID:11032329 SUPPORT Human Clinical

"Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further."

The review states the open question in its own words.

PMID:15303806 SUPPORT Human Clinical

"Tests performed in childhood documented pronounced sensitivity to fasting and physical exercise, whereas such tests at 23 and 31 y of age were essentially normal but with pronounced ketonaemia."

Shows the dissociation the gap is about — ketonaemia persists into adulthood after hypoglycaemic sensitivity has resolved.

MONDO places the infantile form of glycerol kinase deficiency (MONDO:0017294) under the parent term rather than under isolated GKD, while the juvenile and adult forms sit under the isolated term. Should this entry carry an infantile subtype?

INTERPRETATION RESOLVED interp_gkd_infantile_form_mondo_placement

Attached to

pathophysiology#Hyperketotic Hypoglycaemic Decompensation

MONDO:0017294 is a child of MONDO:0010613 (inborn glycerol kinase deficiency) but not of MONDO:0018459 (isolated glycerol kinase deficiency), and its definition explicitly folds in patients whose infantile presentation is due to complex GKD with adrenal hypoplasia congenita and/or Duchenne muscular dystrophy. Adding it as a subtype of this entry would import contiguous-gene disease into an entry that is scoped to the isolated form.

Resolution: Only the juvenile (MONDO:0017295) and adult (MONDO:0017296) forms are curated as subtypes. Severe infantile presentations of the isolated form are covered by the entry description and by the childhood crisis arm of the pathograph without borrowing a MONDO term whose scope is wider than this entry's.

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Pathophysiology

8

Glycerol Kinase Loss of Function

Mechanism confidence: Established

Hemizygous loss-of-function variants in GK (Xp21.2) — nonsense, frameshift, splice-site, missense and partial gene deletions — abolish or severely reduce glycerol kinase activity, which is measurable at under 10% of reference in patient fibroblasts. Because the gene is X-linked, essentially all clinically ascertained patients are hemizygous males and mothers are unaffected heterozygotes. No genotype-phenotype correlation has been established, so this node is modelled as a single functional lesion rather than an allele-graded one.

Hepatocyte CL:0000182

GK hgnc:4289

glycerol kinase activity GO:0004370 ⇓ LOSS OF FUNCTION

Downstream

Loss of Glycerol Entry into Gluconeogenesis and Glycerolipid Synthesis Phosphorylation of glycerol to glycerol-3-phosphate is the committed entry step; without it circulating glycerol cannot be routed into either pathway.

Hyperglycerolaemia and Glyceroluria Unphosphorylated glycerol accumulates in plasma and is excreted in urine.

Show evidence (3 references)

PMID:9719371 SUPPORT Human Clinical

"Isolated glycerol kinase deficiency (GKD) is an X linked recessive disorder."

Establishes the X-linked recessive single-gene trigger for the isolated form.

PMID:15303806 SUPPORT In Vitro

"The activity of glycerol kinase (GK) in fibroblasts was <10% of reference."

Quantifies the residual enzyme activity behind the functional lesion in molecularly confirmed patients.

PMID:9719371 SUPPORT Human Clinical

"So far, no genotype-phenotype correlation can be established in these GKD families."

Justifies modelling the lesion as one node rather than allele-stratified branches.

Loss of Glycerol Entry into Gluconeogenesis and Glycerolipid Synthesis

Mechanism confidence: Established

Glycerol-3-phosphate is the shared branch point at which glycerol either feeds the gluconeogenic and glycolytic pools or is acylated into triglycerides and phospholipids. Blocking its formation removes glycerol from both destinations at once. In vivo tracer studies show that affected men convert glycerol into neither glucose nor triglyceride, while a residual, order-of-magnitude-reduced conversion to lactate persists and has been attributed to homologous kinases encoded by other genes.

Hepatocyte CL:0000182

gluconeogenesis GO:0006094 ↓ DECREASED triglyceride biosynthetic process GO:0019432 ↓ DECREASED glycerol-3-phosphate metabolic process GO:0006072 ↓ DECREASED

Downstream

Fasting and Catabolic-Stress Intolerance Loss of one gluconeogenic substrate is silent while glucose supply is adequate; it becomes limiting when fasting, exercise or intercurrent illness raises the demand for endogenous glucose production.

Show evidence (2 references)

PMID:39512433 SUPPORT Human Clinical

"Men with GKD could not convert glycerol into glucose or triglycerides, which was preserved in the heterozygote carrier."

Direct in vivo demonstration that both downstream routes are lost.

PMID:39512433 SUPPORT Human Clinical

"Glycolytic metabolism of glycerol to lactate persisted in GKD, but it was reduced by a magnitude and, possibly, due to homologous glycerol kinases encoded by other genes."

Retained deliberately as a limit on the node: the block is not absolute for every downstream route, and the residual route is attributed to paralogous enzymes rather than to residual GK.

Hyperglycerolaemia and Glyceroluria

Mechanism confidence: Established

Glycerol that cannot be phosphorylated accumulates in the circulation and spills into the urine. This is the obligate, lifelong biochemical signature of the disorder and is present equally in symptomatic children and asymptomatic adults; it is not itself known to be injurious, and its clinical importance in the adult form is entirely as a measurement interferent.

glycerol catabolic process GO:0019563 ↓ DECREASED

Downstream

Pseudohypertriglyceridaemia on Lipase-Based Triglyceride Assay Routine analysers hydrolyse triglyceride and quantify the liberated glycerol, so a raised endogenous glycerol concentration is read directly as raised triglyceride.

Show evidence (2 references)

PMID:33212314 SUPPORT Human Clinical

"Glycerol kinase deficiency (GKD) is a rare genetic disorder characterized by hyperglycerolemia and glyceroluria, which could be misdiagnosed as a moderate to severe hypertriglyceridemia (HTG)."

Establishes hyperglycerolaemia and glyceroluria as the defining biochemical state and names its diagnostic consequence.

PMID:41047305 SUPPORT Human Clinical

"Hyperglycerolemia per se is not associated with premature ASCVD."

Supports the explicit statement in this node that the accumulating metabolite is not shown to be injurious, using long-term vascular follow-up rather than absence of evidence.

Fasting and Catabolic-Stress Intolerance

Mechanism confidence: Established

A compensated state is converted into a crisis by anything that raises the demand for endogenous glucose: intercurrent infection, prolonged fasting, vomiting, or strenuous exercise. This node conforms to the module's amplifier step by way of its energy-deficit arm only. The toxic-metabolite half of that module node is deliberately NOT asserted here: the metabolite that accumulates in this disease is glycerol, and no toxicity of glycerol has been demonstrated — long-term vascular follow-up of hyperglycerolaemic patients was negative, and adults with lifelong hyperglycerolaemia are asymptomatic.

Downstream

Hyperketotic Hypoglycaemic Decompensation Once endogenous glucose production cannot keep pace, blood glucose falls and ketogenesis is driven hard, producing the ketoacidotic biochemical picture.

Show evidence (2 references)

PMID:11032329 SUPPORT Human Clinical

"At least 7 of these patients had a metabolic crisis during a catabolic condition."

Establishes catabolic stress as the recurrent precipitant across the reported isolated-GKD literature.

PMID:15303806 SUPPORT Human Clinical

"Tests performed in childhood documented pronounced sensitivity to fasting and physical exercise, whereas such tests at 23 and 31 y of age were essentially normal but with pronounced ketonaemia."

Provocation testing demonstrates the fasting- and exercise-dependence of the intolerance.

Hyperketotic Hypoglycaemic Decompensation

Mechanism confidence: Established

The acute crisis: hypoglycaemia with marked ketosis and metabolic acidosis, typically with vomiting. Compared with the organic acidaemias and urea-cycle disorders that anchor the shared decompensation module, the biochemical pattern here is the hypoglycaemia-and-ketoacidosis one rather than the hyperammonaemic one, and it is confined to childhood.

glucose homeostasis GO:0042593 ⚠ ABNORMAL ketone body biosynthetic process GO:0046951 ↑ INCREASED

Downstream

Encephalopathic Crisis Hypoglycaemia and acidosis produce the neurological face of the crisis — lethargy, disturbed consciousness, and in some patients convulsions.

Show evidence (2 references)

PMID:11032329 SUPPORT Human Clinical

"Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further."

Establishes the hypoglycaemia-plus-hyperketonaemia pattern and, in the same sentence, marks the upstream attribution as unresolved.

PMID:9719371 SUPPORT Human Clinical

"Three patients had gastrointestinal symptoms with ketoacidosis or hypoglycaemia or both."

Documents the decompensated biochemical state in individually described patients.

Encephalopathic Crisis

Mechanism confidence: Provisional

The Reye-like clinical presentation of the childhood crisis: vomiting, lethargy progressing to disturbed consciousness, and seizures. Seizures are not always tied to a documented catabolic state — one reported patient had recurrent convulsions as the sole acute manifestation — so the link between the biochemical crisis and every neurological event is not one-to-one.

Show evidence (2 references)

PMID:9719371 SUPPORT Human Clinical

"One patient had recurrent convulsions as the only acute sign, without evidence that it was correlated with a catabolic state."

Retained as the explicit limit on this node: a neurological event was observed without the upstream catabolic trigger being demonstrable.

PMID:11032329 SUPPORT Human Clinical

"Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis."

Supports treating the crisis as an outcome-determining, recognition-dependent event.

Pseudohypertriglyceridaemia on Lipase-Based Triglyceride Assay

Mechanism confidence: Established

An analytical artefact, not a lipid disorder. Enzymatic triglyceride assays liberate glycerol with a lipase and measure it as a proxy for triglyceride; in hyperglycerolaemia the pre-existing endogenous glycerol is counted as though it were triglyceride-derived. Orthogonal NMR measurement in the same patients returns normal triglycerides and, in the same comparison, shows that lipase-based assays simultaneously under-report LDL cholesterol. The serum is characteristically not lipaemic, which is the bedside clue that the number is wrong.

Downstream

Misdiagnosis as Primary Hypertriglyceridaemia and Ineffective Lipid-Lowering Treatment A spuriously high triglyceride result in an otherwise well adult is acted on as though it were dyslipidaemia.

Show evidence (2 references)

PMID:39512433 SUPPORT Human Clinical

"Compared to NMR, lipase-based assays overreported triglycerides"

Establishes the direction of the assay-dependent discrepancy against an orthogonal method.

PMID:40741920 SUPPORT Human Clinical

"In all cases, elevated triglyceride levels were unresponsive to therapy, and serum samples lacked lipemic appearance."

Supports both discriminating features — therapy-resistance and non-lipaemic serum.

Misdiagnosis as Primary Hypertriglyceridaemia and Ineffective Lipid-Lowering Treatment

Mechanism confidence: Established

The dominant morbidity of the adult form is iatrogenic and informational rather than metabolic: years of hypolipidaemic drug exposure, dietary restriction and cardiovascular alarm directed at a laboratory number that no treatment can move. One reported patient was treated for 13 years before the correct diagnosis was made. The counterfactual is well documented — once the diagnosis is made, lipid-lowering treatment is stopped without adverse consequence.

Show evidence (2 references)

PMID:35292548 SUPPORT Human Clinical

"In this report, a case of a 50-year-old Nepalese male is presented with an apparent hypertriglyceridaemia refractory to various hypolipidaemic drugs for the last 13 years until a correct diagnosis of his condition was made."

Documents the duration and futility of treatment directed at the artefact in an individual patient.

PMID:33212314 SUPPORT Human Clinical

"GKD cases reported a history of high TG levels resistant to lipid-lowering therapy."

Generalises the therapy-resistant pattern beyond single case reports.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Digestive 1

Vomiting HP:0002013

Temporal: RECURRENT

Show evidence (1 reference)

PMID:9719371 SUPPORT Human Clinical

"Three patients had gastrointestinal symptoms with ketoacidosis or hypoglycaemia or both."

Supports gastrointestinal symptoms as part of the crisis presentation.

Metabolism 3

Elevated circulating glycerol OBLIGATE Elevated circulating glycerol concentration HP:0040302

Show evidence (1 reference)

PMID:9719371 SUPPORT Human Clinical

"All patients had hyperglycerolaemia and glyceroluria."

Supports both the association and the OBLIGATE band: every one of the eight molecularly confirmed hemizygotes studied, symptomatic and asymptomatic alike, had it.

Hypoglycemia HP:0001943

Temporal: RECURRENT

Show evidence (1 reference)

PMID:9719371 SUPPORT Human Clinical

"Fasting tests in two symptomatic patients of family 1 showed hyperketotic states, together with a tendency to hypoglycaemia."

Documents hypoglycaemia under controlled fasting provocation.

Episodic ketoacidosis HP:0005974

Show evidence (1 reference)

PMID:9719371 SUPPORT Human Clinical

"Three patients had gastrointestinal symptoms with ketoacidosis or hypoglycaemia or both."

Documents ketoacidosis as part of the episodic crisis phenotype.

Nervous System 1

Seizure HP:0001250

Show evidence (1 reference)

PMID:9719371 SUPPORT Human Clinical

"One patient had recurrent convulsions as the only acute sign, without evidence that it was correlated with a catabolic state."

Documents convulsions in isolated GKD while recording that the trigger was not established.

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Genetic Associations

1

Hemizygous GK loss-of-function variants

Gene: GK hgnc:4289 relationship_type: CAUSATIVE

X-linked recessive

Show evidence (2 references)

PMID:40741920 SUPPORT Human Clinical

"Two siblings with isolated GKD presented with persistent, asymptomatic hypertriglyceridemia, confirmed by glyceroluria and genetic testing revealing a hemizygous c.213_214delAT (p.Cys72Ter) mutation."

Documents a hemizygous truncating GK allele in molecularly confirmed isolated GKD.

PMID:15303806 SUPPORT Human Clinical

"Two maternal male cousins in one of the families were hemizygotes without symptoms."

Documents asymptomatic hemizygotes within an affected family, supporting the absence of genotype-phenotype correlation.

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Medical Actions

2

Frequent Feeding, Glucose Access and Avoidance of Strenuous Exercise

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Management of the symptomatic childhood form is entirely preventive: keep the child out of the catabolic state that unmasks the missing gluconeogenic substrate. Frequent meals, ready access to glucose, and avoidance of strenuous sport were sufficient for a good long-term outcome in two boys followed for around 20 years, whose crises then ceased after puberty.

Mechanism Target:

BYPASSES Fasting and Catabolic-Stress Intolerance — Supplying exogenous glucose and shortening fasting intervals removes the demand for glycerol-derived gluconeogenesis rather than correcting the enzyme defect.

Show evidence (1 reference)

PMID:15303806 SUPPORT Human Clinical

"With meals at frequent intervals, access to glucose and avoidance of strenuous sports, the prognosis is good for a normal adult life of a young child with isolated GKD and symptoms of hypoglycaemia."

States the intervention and its outcome in the same sentence, in patients followed for two decades.

Show evidence (1 reference)

PMID:15303806 SUPPORT Human Clinical

"With meals at frequent intervals, access to glucose and avoidance of strenuous sports, the prognosis is good for a normal adult life of a young child with isolated GKD and symptoms of hypoglycaemia."

Primary evidence for the preventive regimen and for the favourable prognosis under it.

Withdrawal of Lipid-Lowering Therapy After Diagnosis

In the adult form the therapeutic act is subtractive. Once the raised triglyceride is recognised as glycerol, hypolipidaemic drugs directed at it can be stopped; in a paediatric series all three patients had lipid-lowering treatment discontinued after diagnosis without adverse outcome, and a long-followed hyperglycerolaemic cohort showed no premature atherosclerotic cardiovascular disease attributable to the condition itself. A published clinical suspicion score exists specifically to spare these patients unwarranted treatment. Ordinary cardiovascular risk factors still require routine monitoring.

Mechanism Target:

INHIBITS Misdiagnosis as Primary Hypertriglyceridaemia and Ineffective Lipid-Lowering Treatment — Stopping the drug removes the iatrogenic arm of the disease; nothing is done to the underlying enzyme defect or to the hyperglycerolaemia.

Show evidence (1 reference)

PMID:40741920 SUPPORT Human Clinical

"Lipid-lowering treatments were discontinued following diagnosis, with no adverse outcomes."

Documents the deprescribing step and its safety in molecularly confirmed patients.

Show evidence (2 references)

PMID:33212314 SUPPORT Human Clinical

"The proposed score would have a broad utility in clinical practice to avoid unwarranted lipid lowering treatment in GKD patients."

States avoidance of unwarranted lipid-lowering treatment as the explicit clinical goal.

PMID:41047305 SUPPORT Human Clinical

"The confirmation of hyperglycerolemia can help the clinician reassure the patient concerning his CV risk, as no further assessment is required other than common CV risk factors monitoring, including body weight increase and insulin resistance that may appear over the life course."

Supports withdrawal plus ordinary risk-factor monitoring, and bounds the claim: routine cardiovascular risk factors still need following.

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Biochemical Markers

5

Plasma glycerol (Increased)

Pathograph Readouts

Readout Of Hyperglycerolaemia and Glyceroluria

A raised plasma glycerol is the direct measurement of the accumulation node and is what distinguishes this disorder from true hypertriglyceridaemia.

Show evidence (1 reference)

PMID:41047305 SUPPORT Human Clinical

"Over 314,268 lipid profiles, 11.8% had hypertriglyceridemia, of whom 13 patients had biological hyperglycerolemia."

Quantifies detection of raised plasma glycerol in a large real-world lipid-clinic denominator.

Urinary glycerol (Increased)

Pathograph Readouts

Readout Of Hyperglycerolaemia and Glyceroluria

Urinary spillover of unphosphorylated glycerol measures the same accumulation node non-invasively.

Show evidence (1 reference)

PMID:40741920 SUPPORT Human Clinical

"Urinary glycerol analysis and the absence of serum lipemia are key diagnostic clues."

Establishes urinary glycerol as the confirmatory biochemical marker.

Serum triglyceride measured by lipase-based enzymatic assay (Increased)

Pathograph Readouts

Readout Of Pseudohypertriglyceridaemia on Lipase-Based Triglyceride Assay

The elevation is method-dependent; a normal NMR triglyceride in the same sample identifies the result as an artefact rather than a lipid abnormality.

Show evidence (1 reference)

PMID:39512433 SUPPORT Human Clinical

"Compared to NMR, lipase-based assays overreported triglycerides"

Establishes the direction of the assay-dependent discrepancy.

Serum total cholesterol (Decreased)

Show evidence (1 reference)

PMID:39512433 SUPPORT Human Clinical

"men with GKD (n = 5) had significantly lower total cholesterol levels"

Within-family comparison showing the lipid profile is not that of hypertriglyceridaemia.

Fibroblast glycerol kinase activity (Decreased)

Pathograph Readouts

Readout Of Glycerol Kinase Loss of Function

Enzymatic confirmation of the trigger lesion in patient-derived cells.

Show evidence (1 reference)

PMID:15303806 SUPPORT In Vitro

"The activity of glycerol kinase (GK) in fibroblasts was <10% of reference."

Direct enzymatic confirmation of the deficiency in patient cells.

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Diagnosis

3

Measurement of plasma and urinary glycerol

Direct measurement of glycerol resolves the question that the lipid panel cannot. It is indicated specifically in persistent hypertriglyceridaemia that does not respond to treatment, particularly when the serum is not lipaemic.

diagnostic procedure NCIT:C18020

Markers: Plasma glycerol; urinary glycerol

Results: Raised plasma glycerol with glyceroluria supports glycerol kinase deficiency.

Show evidence (2 references)

PMID:40741920 SUPPORT Human Clinical

"Urinary glycerol analysis and the absence of serum lipemia are key diagnostic clues."

Establishes the confirmatory analyte and the accompanying bedside sign.

PMID:41047305 SUPPORT Human Clinical

"Its screening should be considered only in patients with persistent hypertriglyceridemia unresponsive to treatment."

Defines the clinical trigger for testing rather than leaving the indication open.

Orthogonal (NMR) lipid measurement

Re-measuring the lipid profile by a method that does not use glycerol as a proxy separates artefact from disease. In affected men, NMR returns normal triglycerides and higher LDL cholesterol than the lipase-based assay reported.

diagnostic procedure NCIT:C18020

Markers: Serum triglyceride and LDL cholesterol by NMR versus lipase-based assay

Results: Normal NMR triglyceride alongside a high lipase-based triglyceride indicates pseudohypertriglyceridaemia.

Show evidence (1 reference)

PMID:39512433 SUPPORT Human Clinical

"Compared to NMR, lipase-based assays overreported triglycerides"

Demonstrates the method-dependent discrepancy that establishes the artefact.

GK sequencing

Molecular confirmation identifies the hemizygous GK variant, distinguishes the isolated form from an Xp21 contiguous-gene deletion, and enables carrier testing in the maternal line.

genetic testing NCIT:C15709

Markers: Hemizygous pathogenic GK variant

Results: A hemizygous loss-of-function GK variant confirms isolated glycerol kinase deficiency.

Show evidence (2 references)

PMID:40741920 SUPPORT Human Clinical

"Two siblings with isolated GKD presented with persistent, asymptomatic hypertriglyceridemia, confirmed by glyceroluria and genetic testing revealing a hemizygous c.213_214delAT (p.Cys72Ter) mutation."

Documents molecular confirmation of the isolated form by GK genotyping.

PMID:34743506 SUPPORT Human Clinical

"Genetic examinations in both patients revealed a deletion on Xp21 chromosome including complete deletion of NR0B1 and GK genes."

Shows what molecular testing must exclude — the contiguous-gene deletion that defines the complex form.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

The true population prevalence is unknown and is generally regarded as underestimated, because the disorder is usually silent in adults and is found only when someone thinks to measure glycerol. A 2020 systematic review of the isolated form assembled 39 previously published subjects from 15 articles. Population denominators are not directly comparable to these literature counts, so no numeric rate is asserted.

Show evidence (2 references)

PMID:41047305 SUPPORT Human Clinical

"Hyperglycerolemia is a rare X-linked inborn error of metabolism whose prevalence is currently unknown."

Directly supports classifying occurrence qualitatively rather than asserting a rate.

PMID:33212314 SUPPORT Human Clinical

"The systematic review retrieved a total of 15 articles involving 39 subjects with GKD."

Gives the literature-case scale that underlies the ULTRA_RARE band.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Isolated Glycerol Kinase Deficiency:

Complex glycerol kinase deficiency (Xp21 contiguous gene deletion syndrome) Not Yet Curated MONDO:0010399

Overlapping Features A deletion at Xp21 that removes GK together with neighbouring genes — NR0B1 (adrenal hypoplasia congenita), DMD (Duchenne muscular dystrophy) and sometimes IL1RAPL1 (intellectual disability). It shares the hyperglycerolaemia but is a different disease: the danger comes from the adrenal insufficiency, not from the glycerol.

Distinguishing Features

Salt-wasting adrenal crisis in infancy, usually the first and most dangerous manifestation
Raised creatine kinase and a Duchenne muscular dystrophy phenotype
Intellectual disability when the deletion extends to IL1RAPL1
A multigene Xp21 deletion on microarray or MLPA rather than an intragenic GK variant

Show evidence (2 references)

PMID:23739620 SUPPORT Human Clinical

"It is caused by partial deletion of Xp21, which includes the genes responsible for glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy and intellectual disability."

Defines the contiguous-gene entity that must be separated from isolated GKD.

PMID:23739620 SUPPORT Human Clinical

"Usually the first and most severe are the signs of adrenal hypoplasia, which, if not cured, may lead to death in a short time."

Establishes why the distinction is urgent rather than taxonomic.

Primary hypertriglyceridaemia

Overlapping Features The condition patients with the adult form are almost always labelled with first. True hypertriglyceridaemia gives lipaemic serum, responds at least partly to lipid-lowering therapy, and is not accompanied by glyceroluria.

Distinguishing Features

Non-lipaemic serum despite a high reported triglyceride
Complete resistance to hypolipidaemic drugs over years of treatment
Normal triglyceride when measured by NMR rather than a lipase-based assay
Raised plasma and urinary glycerol

Show evidence (1 reference)

PMID:35292548 SUPPORT Human Clinical

"High triglyceride in a serum sample with no apparent visible lipaemia is a confusing laboratory condition."

Names the discriminating bedside observation that separates the two.

{ }

Source YAML

click to show

name: Isolated Glycerol Kinase Deficiency
category: Mendelian
creation_date: "2026-08-19T12:00:00Z"
synonyms:
- Isolated GKD
- Hyperglycerolemia
- Nonsyndromic glycerol kinase deficiency
- GK-related glycerol kinase deficiency
- Isolated inborn glycerol kinase deficiency
description: >-
  Isolated glycerol kinase deficiency is an X-linked recessive inborn error of
  glycerol metabolism caused by hemizygous loss-of-function variants in GK
  (Xp21.2). Glycerol kinase phosphorylates glycerol to glycerol-3-phosphate, the
  committed step through which circulating glycerol enters gluconeogenesis and
  glycerolipid synthesis; when the enzyme is absent, glycerol accumulates in
  plasma and urine and is no longer available as a fuel or a lipid backbone.
  The disorder has two faces that are easy to mistake for two different
  diseases. In infancy and childhood, when glycerol is a proportionally more
  important gluconeogenic substrate, fasting or an intercurrent catabolic stress
  can precipitate a Reye-like crisis of vomiting, hyperketotic hypoglycaemia,
  acidosis and impaired consciousness. In adults the same genotype is typically
  asymptomatic and is discovered only because the hyperglycerolaemia defeats the
  routine lipid panel: lipase-based triglyceride assays quantify glycerol as a
  proxy for triglyceride, so affected men are reported as having severe
  hypertriglyceridaemia that no lipid-lowering drug will correct. This
  pseudohypertriglyceridaemia is an analytical artefact, not lipid disease —
  NMR-based measurement shows normal triglycerides, total cholesterol is if
  anything lower than in relatives, and a long-followed cohort developed no
  premature atherosclerotic cardiovascular disease. Recognising the artefact is
  therefore itself a therapeutic act, because the main iatrogenic harm in the
  adult form is years of ineffective hypolipidaemic treatment. This entry covers
  the isolated form only; complex glycerol kinase deficiency, in which the GK
  locus is lost as part of an Xp21 contiguous-gene deletion together with NR0B1
  (adrenal hypoplasia congenita) and/or DMD, is a mechanistically distinct
  entity and is curated here as a differential diagnosis.
disease_term:
  preferred_term: isolated glycerol kinase deficiency
  term:
    id: MONDO:0018459
    label: isolated glycerol kinase deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018459
      label: isolated glycerol kinase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0018459 is the exact disease concept for the isolated (nonsyndromic)
      form and carries the Orphanet ORPHA:408 equivalence used by the IEMbase
      WP-007 seed row.
  - term:
      id: MONDO:0010613
      label: inborn glycerol kinase deficiency
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0010613 is the parent concept that carries the OMIM:307030
      cross-reference cited by the WP-007 seed row. It is deliberately recorded
      as a broad match rather than the primary anchor because it also subsumes
      the Xp21 contiguous-gene (complex) presentations, which this entry
      excludes.
classifications:
  icimd_category:
  - classification_value: gluconeogenesis
    notes: >-
      IEMbase/ICIMD places GK-related isolated glycerol kinase deficiency under
      disorders of gluconeogenesis within disorders of carbohydrate metabolism
      (WP-007 package, classification code 3.2.01.01), alongside FBP1 and
      pyruvate carboxylase deficiency.
parents:
- Inborn Error of Metabolism
has_subtypes:
- name: Juvenile GKD
  display_name: Juvenile glycerol kinase deficiency
  subtype_term:
    preferred_term: glycerol kinase deficiency, juvenile form
    term:
      id: MONDO:0017295
      label: glycerol kinase deficiency, juvenile form
  description: >-
    The symptomatic childhood presentation: episodic, catabolic-stress-triggered
    crises of vomiting with ketoacidosis, a tendency to hypoglycaemia, and
    disturbed consciousness, on a background of constant hyperglycerolaemia and
    glyceroluria. Crises typically remit after puberty.
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had gastrointestinal symptoms with ketoacidosis or
      hypoglycaemia or both.
    explanation: Documents the symptomatic childhood crisis phenotype in molecularly confirmed isolated GKD.
- name: Adult GKD
  display_name: Adult glycerol kinase deficiency
  subtype_term:
    preferred_term: glycerol kinase deficiency, adult form
    term:
      id: MONDO:0017296
      label: glycerol kinase deficiency, adult form
  description: >-
    A clinically silent form recognised incidentally, essentially always through
    a persistently and inexplicably raised triglyceride result that does not
    respond to lipid-lowering therapy and is not accompanied by lipaemic serum.
  evidence:
  - reference: PMID:11032329
    reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical and biochemical phenotype of isolated GKD may vary from a
      life-threatening childhood metabolic crisis to asymptomatic adult
      'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia.
    explanation: Establishes the asymptomatic adult form defined by pseudohypertriglyceridaemia.
mechanistic_hypotheses:
- hypothesis_group_id: age_dependent_gluconeogenic_substrate_model
  hypothesis_label: Age-dependent glycerol-as-gluconeogenic-substrate model
  status: CANONICAL
  description: >-
    Symptoms track how much the individual depends on glycerol as a
    gluconeogenic substrate rather than how much residual enzyme activity is
    present. Young children, whose fasting glucose production draws
    proportionally more on glycerol, decompensate under catabolic stress; the
    same individuals become tolerant after puberty despite an unchanged
    genotype and unchanged hyperglycerolaemia. This model accounts for the
    otherwise puzzling observation that genotype does not predict phenotype.
  evidence:
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The greater importance of glycerol as a gluconeogenetic substrate in
      children than in adults may explain the episodes in young patients with
      GKD, often elicited by catabolic stress.
    explanation: States the age-dependent substrate-dependence model directly, from 20-year follow-up of two affected boys.
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After puberty, the boys had no hypoglycaemic symptoms and now report no
      problems with their condition; thus, their phenotype has changed over
      time.
    explanation: Provides the within-individual, genotype-invariant change in phenotype the model predicts.
  - reference: PMID:11032329
    reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical variability in isolated GKD cannot be explained by
      biochemical or by molecular heterogeneity.
    explanation: >-
      Excludes residual-activity and allele identity as the explanation for
      variable severity, which is what motivates a host-context model.
pathophysiology:
- name: Glycerol Kinase Loss of Function
  description: >-
    Hemizygous loss-of-function variants in GK (Xp21.2) — nonsense, frameshift,
    splice-site, missense and partial gene deletions — abolish or severely
    reduce glycerol kinase activity, which is measurable at under 10% of
    reference in patient fibroblasts. Because the gene is X-linked, essentially
    all clinically ascertained patients are hemizygous males and mothers are
    unaffected heterozygotes. No genotype-phenotype correlation has been
    established, so this node is modelled as a single functional lesion rather
    than an allele-graded one.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  conforms_to: "metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism"
  genes:
  - preferred_term: GK
    term:
      id: hgnc:4289
      label: GK
  molecular_functions:
  - preferred_term: glycerol kinase activity
    term:
      id: GO:0004370
      label: glycerol kinase activity
    modifier: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated glycerol kinase deficiency (GKD) is an X linked recessive
      disorder.
    explanation: Establishes the X-linked recessive single-gene trigger for the isolated form.
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The activity of glycerol kinase (GK) in fibroblasts was <10% of reference.
    explanation: Quantifies the residual enzyme activity behind the functional lesion in molecularly confirmed patients.
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, no genotype-phenotype correlation can be established in these GKD
      families.
    explanation: Justifies modelling the lesion as one node rather than allele-stratified branches.
  downstream:
  - target: Loss of Glycerol Entry into Gluconeogenesis and Glycerolipid Synthesis
    causal_link_type: DIRECT
    description: >-
      Phosphorylation of glycerol to glycerol-3-phosphate is the committed entry
      step; without it circulating glycerol cannot be routed into either
      pathway.
    evidence:
    - reference: PMID:39512433
      reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Men with GKD could not convert glycerol into glucose or triglycerides,
        which was preserved in the heterozygote carrier.
      explanation: >-
        Isotope-tracer infusion in affected men demonstrates the blocked entry
        into both gluconeogenesis and triglyceride synthesis in vivo, with the
        carrier as an internal control.
  - target: Hyperglycerolaemia and Glyceroluria
    causal_link_type: DIRECT
    description: >-
      Unphosphorylated glycerol accumulates in plasma and is excreted in urine.
    evidence:
    - reference: PMID:9719371
      reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had hyperglycerolaemia and glyceroluria.
      explanation: Establishes the obligate biochemical consequence in every affected individual studied.
- name: Loss of Glycerol Entry into Gluconeogenesis and Glycerolipid Synthesis
  description: >-
    Glycerol-3-phosphate is the shared branch point at which glycerol either
    feeds the gluconeogenic and glycolytic pools or is acylated into
    triglycerides and phospholipids. Blocking its formation removes glycerol
    from both destinations at once. In vivo tracer studies show that affected
    men convert glycerol into neither glucose nor triglyceride, while a
    residual, order-of-magnitude-reduced conversion to lactate persists and has
    been attributed to homologous kinases encoded by other genes.
  role: amplifier
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  - preferred_term: triglyceride biosynthetic process
    term:
      id: GO:0019432
      label: triglyceride biosynthetic process
    modifier: DECREASED
  - preferred_term: glycerol-3-phosphate metabolic process
    term:
      id: GO:0006072
      label: glycerol-3-phosphate metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Men with GKD could not convert glycerol into glucose or triglycerides,
      which was preserved in the heterozygote carrier.
    explanation: Direct in vivo demonstration that both downstream routes are lost.
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glycolytic metabolism of glycerol to lactate persisted in GKD, but it was
      reduced by a magnitude and, possibly, due to homologous glycerol kinases
      encoded by other genes.
    explanation: >-
      Retained deliberately as a limit on the node: the block is not absolute
      for every downstream route, and the residual route is attributed to
      paralogous enzymes rather than to residual GK.
  downstream:
  - target: Fasting and Catabolic-Stress Intolerance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of one gluconeogenic substrate is silent while glucose supply is
      adequate; it becomes limiting when fasting, exercise or intercurrent
      illness raises the demand for endogenous glucose production.
    evidence:
    - reference: PMID:15303806
      reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Tests performed in childhood documented pronounced sensitivity to
        fasting and physical exercise, whereas such tests at 23 and 31 y of age
        were essentially normal but with pronounced ketonaemia.
      explanation: Formal fasting and exercise provocation ties the metabolic block to demand-dependent intolerance.
- name: Hyperglycerolaemia and Glyceroluria
  description: >-
    Glycerol that cannot be phosphorylated accumulates in the circulation and
    spills into the urine. This is the obligate, lifelong biochemical signature
    of the disorder and is present equally in symptomatic children and
    asymptomatic adults; it is not itself known to be injurious, and its
    clinical importance in the adult form is entirely as a measurement
    interferent.
  role: effector
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: glycerol catabolic process
    term:
      id: GO:0019563
      label: glycerol catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:33212314
    reference_title: "Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glycerol kinase deficiency (GKD) is a rare genetic disorder characterized
      by hyperglycerolemia and glyceroluria, which could be misdiagnosed as a
      moderate to severe hypertriglyceridemia (HTG).
    explanation: Establishes hyperglycerolaemia and glyceroluria as the defining biochemical state and names its diagnostic consequence.
  - reference: PMID:41047305
    reference_title: Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperglycerolemia per se is not associated with premature ASCVD.
    explanation: >-
      Supports the explicit statement in this node that the accumulating
      metabolite is not shown to be injurious, using long-term vascular
      follow-up rather than absence of evidence.
  downstream:
  - target: Pseudohypertriglyceridaemia on Lipase-Based Triglyceride Assay
    causal_link_type: DIRECT
    description: >-
      Routine analysers hydrolyse triglyceride and quantify the liberated
      glycerol, so a raised endogenous glycerol concentration is read directly
      as raised triglyceride.
    evidence:
    - reference: PMID:35292548
      reference_title: Pseudo-hypertriglyceridaemia in glycerol kinase deficiency misdiagnosed and treated as true hypertriglyceridaemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Glycerol is increased in glycerol kinase deficiency, therefore
        biochemical analysers that measure glycerol to estimate triglyceride
        report high triglyceride values.
      explanation: States the analytical mechanism of the artefact explicitly.
- name: Fasting and Catabolic-Stress Intolerance
  description: >-
    A compensated state is converted into a crisis by anything that raises the
    demand for endogenous glucose: intercurrent infection, prolonged fasting,
    vomiting, or strenuous exercise. This node conforms to the module's
    amplifier step by way of its energy-deficit arm only. The toxic-metabolite
    half of that module node is deliberately NOT asserted here: the metabolite
    that accumulates in this disease is glycerol, and no toxicity of glycerol
    has been demonstrated — long-term vascular follow-up of hyperglycerolaemic
    patients was negative, and adults with lifelong hyperglycerolaemia are
    asymptomatic.
  role: amplifier
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  conforms_to: "metabolic_intoxication_decompensation#Toxic Metabolite Accumulation and Energy Deficit"
  notes: >-
    Left without a biological_processes binding. This node is ORGANISM-scale —
    it is about whole-body tolerance of a catabolic state — and the nearest GO
    term, GO:0009267 "cellular response to starvation", is a cellular-scale
    process, so binding it would misstate the scale of the claim. The node is
    already anchored by its resolving conforms_to and needs no term.
  evidence:
  - reference: PMID:11032329
    reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At least 7 of these patients had a metabolic crisis during a catabolic
      condition.
    explanation: Establishes catabolic stress as the recurrent precipitant across the reported isolated-GKD literature.
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tests performed in childhood documented pronounced sensitivity to fasting
      and physical exercise, whereas such tests at 23 and 31 y of age were
      essentially normal but with pronounced ketonaemia.
    explanation: Provocation testing demonstrates the fasting- and exercise-dependence of the intolerance.
  downstream:
  - target: Hyperketotic Hypoglycaemic Decompensation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Once endogenous glucose production cannot keep pace, blood glucose falls
      and ketogenesis is driven hard, producing the ketoacidotic biochemical
      picture.
    evidence:
    - reference: PMID:9719371
      reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Fasting tests in two symptomatic patients of family 1 showed
        hyperketotic states, together with a tendency to hypoglycaemia.
      explanation: Fasting provocation directly links the intolerance to the hyperketotic hypoglycaemic state.
- name: Hyperketotic Hypoglycaemic Decompensation
  description: >-
    The acute crisis: hypoglycaemia with marked ketosis and metabolic acidosis,
    typically with vomiting. Compared with the organic acidaemias and urea-cycle
    disorders that anchor the shared decompensation module, the biochemical
    pattern here is the hypoglycaemia-and-ketoacidosis one rather than the
    hyperammonaemic one, and it is confined to childhood.
  role: central_effector
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  biological_processes:
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  - preferred_term: ketone body biosynthetic process
    term:
      id: GO:0046951
      label: ketone body biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:11032329
    reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated GKD patients showed a tendency towards hypoglycaemia with
      hyperketonaemia; whether the clinical symptoms of GKD are caused by
      dysfunction of gluconeogenesis and/or ketolysis needs to be investigated
      further.
    explanation: >-
      Establishes the hypoglycaemia-plus-hyperketonaemia pattern and, in the
      same sentence, marks the upstream attribution as unresolved.
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had gastrointestinal symptoms with ketoacidosis or
      hypoglycaemia or both.
    explanation: Documents the decompensated biochemical state in individually described patients.
  downstream:
  - target: Encephalopathic Crisis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hypoglycaemia and acidosis produce the neurological face of the crisis —
      lethargy, disturbed consciousness, and in some patients convulsions.
    evidence:
    - reference: PMID:11032329
      reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The clinical and biochemical phenotype of isolated GKD may vary from a
        life-threatening childhood metabolic crisis to asymptomatic adult
        'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia.
      explanation: Establishes that the childhood decompensation can be life-threatening rather than purely biochemical.
- name: Encephalopathic Crisis
  description: >-
    The Reye-like clinical presentation of the childhood crisis: vomiting,
    lethargy progressing to disturbed consciousness, and seizures. Seizures are
    not always tied to a documented catabolic state — one reported patient had
    recurrent convulsions as the sole acute manifestation — so the link between
    the biochemical crisis and every neurological event is not one-to-one.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had recurrent convulsions as the only acute sign, without
      evidence that it was correlated with a catabolic state.
    explanation: >-
      Retained as the explicit limit on this node: a neurological event was
      observed without the upstream catabolic trigger being demonstrable.
  - reference: PMID:11032329
    reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since the outcome of the crisis in GKD is highly dependent on the
      physicians' knowledge of the disease, we devised an algorithmic approach
      to the diagnosis.
    explanation: Supports treating the crisis as an outcome-determining, recognition-dependent event.
- name: Pseudohypertriglyceridaemia on Lipase-Based Triglyceride Assay
  description: >-
    An analytical artefact, not a lipid disorder. Enzymatic triglyceride assays
    liberate glycerol with a lipase and measure it as a proxy for triglyceride;
    in hyperglycerolaemia the pre-existing endogenous glycerol is counted as
    though it were triglyceride-derived. Orthogonal NMR measurement in the same
    patients returns normal triglycerides and, in the same comparison, shows
    that lipase-based assays simultaneously under-report LDL cholesterol. The
    serum is characteristically not lipaemic, which is the bedside clue that the
    number is wrong.
  role: consequence
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to NMR, lipase-based assays overreported triglycerides
    explanation: Establishes the direction of the assay-dependent discrepancy against an orthogonal method.
  - reference: PMID:40741920
    reference_title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all cases, elevated triglyceride levels were unresponsive to therapy,
      and serum samples lacked lipemic appearance.
    explanation: Supports both discriminating features — therapy-resistance and non-lipaemic serum.
  downstream:
  - target: Misdiagnosis as Primary Hypertriglyceridaemia and Ineffective Lipid-Lowering Treatment
    causal_link_type: DIRECT
    description: >-
      A spuriously high triglyceride result in an otherwise well adult is acted
      on as though it were dyslipidaemia.
    evidence:
    - reference: PMID:35292548
      reference_title: Pseudo-hypertriglyceridaemia in glycerol kinase deficiency misdiagnosed and treated as true hypertriglyceridaemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinicians are often unaware of this laboratory condition; as a result,
        patients are subjected to aggressive hypolipidaemic drugs and lifestyle
        changes, and these measures turn ineffective to lower triglyceride
        levels.
      explanation: States the causal chain from unrecognised artefact to ineffective treatment.
- name: Misdiagnosis as Primary Hypertriglyceridaemia and Ineffective Lipid-Lowering Treatment
  description: >-
    The dominant morbidity of the adult form is iatrogenic and informational
    rather than metabolic: years of hypolipidaemic drug exposure, dietary
    restriction and cardiovascular alarm directed at a laboratory number that no
    treatment can move. One reported patient was treated for 13 years before the
    correct diagnosis was made. The counterfactual is well documented — once the
    diagnosis is made, lipid-lowering treatment is stopped without adverse
    consequence.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:35292548
    reference_title: Pseudo-hypertriglyceridaemia in glycerol kinase deficiency misdiagnosed and treated as true hypertriglyceridaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this report, a case of a 50-year-old Nepalese male is presented with an
      apparent hypertriglyceridaemia refractory to various hypolipidaemic drugs
      for the last 13 years until a correct diagnosis of his condition was made.
    explanation: Documents the duration and futility of treatment directed at the artefact in an individual patient.
  - reference: PMID:33212314
    reference_title: "Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GKD cases reported a history of high TG levels resistant to lipid-lowering
      therapy.
    explanation: Generalises the therapy-resistant pattern beyond single case reports.
phenotypes:
- category: Biochemical
  name: Elevated circulating glycerol
  description: >-
    Raised plasma glycerol with corresponding urinary excretion is present in
    every affected individual, symptomatic or not, and is the direct biochemical
    read-out of the enzyme block.
  phenotype_term:
    preferred_term: Elevated circulating glycerol concentration
    term:
      id: HP:0040302
      label: Elevated circulating glycerol concentration
  frequency: OBLIGATE
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had hyperglycerolaemia and glyceroluria.
    explanation: >-
      Supports both the association and the OBLIGATE band: every one of the
      eight molecularly confirmed hemizygotes studied, symptomatic and
      asymptomatic alike, had it.
- category: Metabolic
  name: Hypoglycemia
  description: >-
    A tendency to hypoglycaemia during fasting or catabolic stress in childhood,
    demonstrable on formal fasting provocation and remitting after puberty.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
    temporality: RECURRENT
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fasting tests in two symptomatic patients of family 1 showed hyperketotic
      states, together with a tendency to hypoglycaemia.
    explanation: Documents hypoglycaemia under controlled fasting provocation.
- category: Metabolic
  name: Episodic ketoacidosis
  description: >-
    Ketoacidosis accompanying the childhood crises, with marked ketonaemia
    persisting on fasting provocation even in adults who no longer become
    hypoglycaemic.
  phenotype_term:
    preferred_term: Episodic ketoacidosis
    term:
      id: HP:0005974
      label: Episodic ketoacidosis
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had gastrointestinal symptoms with ketoacidosis or
      hypoglycaemia or both.
    explanation: Documents ketoacidosis as part of the episodic crisis phenotype.
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Gastrointestinal symptoms, characteristically episodic vomiting, are the
    usual presenting complaint of a crisis.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: RECURRENT
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had gastrointestinal symptoms with ketoacidosis or
      hypoglycaemia or both.
    explanation: Supports gastrointestinal symptoms as part of the crisis presentation.
- category: Neurological
  name: Seizure
  description: >-
    Convulsions occur during or, in at least one reported patient, independently
    of a documented catabolic crisis.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:9719371
    reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had recurrent convulsions as the only acute sign, without
      evidence that it was correlated with a catabolic state.
    explanation: Documents convulsions in isolated GKD while recording that the trigger was not established.
biochemical:
- name: Plasma glycerol
  presence: Increased
  notes: >-
    The diagnostic analyte. In one dyslipidaemia referral centre, systematic
    glycerol measurement in hypertriglyceridaemic sera identified 13
    hyperglycerolaemic patients out of 314,268 lipid profiles screened.
  readouts:
  - target: Hyperglycerolaemia and Glyceroluria
    relationship: READOUT_OF
    interpretation: >-
      A raised plasma glycerol is the direct measurement of the accumulation
      node and is what distinguishes this disorder from true
      hypertriglyceridaemia.
  evidence:
  - reference: PMID:41047305
    reference_title: Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over 314,268 lipid profiles, 11.8% had hypertriglyceridemia, of whom 13
      patients had biological hyperglycerolemia.
    explanation: Quantifies detection of raised plasma glycerol in a large real-world lipid-clinic denominator.
- name: Urinary glycerol
  presence: Increased
  notes: >-
    Glyceroluria is a practical confirmatory test and, together with the absence
    of serum lipaemia, is described as a key diagnostic clue.
  readouts:
  - target: Hyperglycerolaemia and Glyceroluria
    relationship: READOUT_OF
    interpretation: Urinary spillover of unphosphorylated glycerol measures the same accumulation node non-invasively.
  evidence:
  - reference: PMID:40741920
    reference_title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary glycerol analysis and the absence of serum lipemia are key
      diagnostic clues.
    explanation: Establishes urinary glycerol as the confirmatory biochemical marker.
- name: Serum triglyceride measured by lipase-based enzymatic assay
  presence: Increased
  notes: >-
    Spuriously raised. This marker is recorded because it is what brings
    patients to attention, not because triglyceride is genuinely elevated —
    orthogonal NMR measurement in the same individuals is normal.
  readouts:
  - target: Pseudohypertriglyceridaemia on Lipase-Based Triglyceride Assay
    relationship: READOUT_OF
    interpretation: >-
      The elevation is method-dependent; a normal NMR triglyceride in the same
      sample identifies the result as an artefact rather than a lipid
      abnormality.
  evidence:
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to NMR, lipase-based assays overreported triglycerides
    explanation: Establishes the direction of the assay-dependent discrepancy.
- name: Serum total cholesterol
  presence: Decreased
  notes: >-
    Affected men had lower total cholesterol than their unaffected relatives —
    the opposite direction to the lipid disorder they are mistaken for.
  evidence:
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      men with GKD (n = 5) had significantly lower total cholesterol levels
    explanation: Within-family comparison showing the lipid profile is not that of hypertriglyceridaemia.
- name: Fibroblast glycerol kinase activity
  presence: Decreased
  readouts:
  - target: Glycerol Kinase Loss of Function
    relationship: READOUT_OF
    interpretation: Enzymatic confirmation of the trigger lesion in patient-derived cells.
  evidence:
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The activity of glycerol kinase (GK) in fibroblasts was <10% of reference.
    explanation: Direct enzymatic confirmation of the deficiency in patient cells.
genetic:
- name: Hemizygous GK loss-of-function variants
  gene_term:
    preferred_term: GK
    term:
      id: hgnc:4289
      label: GK
  relationship_type: CAUSATIVE
  inheritance:
  - name: X-linked recessive
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
    evidence:
    - reference: PMID:9719371
      reference_title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Isolated glycerol kinase deficiency (GKD) is an X linked recessive
        disorder.
      explanation: Explicitly establishes X-linked recessive inheritance for the isolated form.
  features: >-
    Reported alleles span the full loss-of-function spectrum — nonsense and
    frameshift (for example c.213_214delAT, p.Cys72Ter), splice-site, missense,
    and single- or multi-exon deletions. Mothers are unaffected heterozygotes;
    asymptomatic hemizygous male relatives are regularly found on family
    testing, which is one reason genotype does not predict phenotype.
  evidence:
  - reference: PMID:40741920
    reference_title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings with isolated GKD presented with persistent, asymptomatic
      hypertriglyceridemia, confirmed by glyceroluria and genetic testing
      revealing a hemizygous c.213_214delAT (p.Cys72Ter) mutation.
    explanation: Documents a hemizygous truncating GK allele in molecularly confirmed isolated GKD.
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two maternal male cousins in one of the families were hemizygotes without
      symptoms.
    explanation: Documents asymptomatic hemizygotes within an affected family, supporting the absence of genotype-phenotype correlation.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    GK lies at Xp21.2. Clinically ascertained patients are hemizygous males;
    carrier females are unaffected.
  evidence:
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glycerol kinase deficiency (GKD) is an X-linked recessive disorder due to
      glycerol kinase (GK) gene mutations
    explanation: Establishes X-linked recessive inheritance and single-gene causation.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The true population prevalence is unknown and is generally regarded as
    underestimated, because the disorder is usually silent in adults and is
    found only when someone thinks to measure glycerol. A 2020 systematic review
    of the isolated form assembled 39 previously published subjects from 15
    articles. Population denominators are not directly comparable to these
    literature counts, so no numeric rate is asserted.
  evidence:
  - reference: PMID:41047305
    reference_title: Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperglycerolemia is a rare X-linked inborn error of metabolism whose
      prevalence is currently unknown.
    explanation: Directly supports classifying occurrence qualitatively rather than asserting a rate.
  - reference: PMID:33212314
    reference_title: "Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The systematic review retrieved a total of 15 articles involving 39
      subjects with GKD.
    explanation: Gives the literature-case scale that underlies the ULTRA_RARE band.
diagnosis:
- name: Measurement of plasma and urinary glycerol
  description: >-
    Direct measurement of glycerol resolves the question that the lipid panel
    cannot. It is indicated specifically in persistent hypertriglyceridaemia
    that does not respond to treatment, particularly when the serum is not
    lipaemic.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  markers: Plasma glycerol; urinary glycerol
  results: Raised plasma glycerol with glyceroluria supports glycerol kinase deficiency.
  evidence:
  - reference: PMID:40741920
    reference_title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary glycerol analysis and the absence of serum lipemia are key
      diagnostic clues.
    explanation: Establishes the confirmatory analyte and the accompanying bedside sign.
  - reference: PMID:41047305
    reference_title: Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Its screening should be considered only in patients with persistent
      hypertriglyceridemia unresponsive to treatment.
    explanation: Defines the clinical trigger for testing rather than leaving the indication open.
- name: Orthogonal (NMR) lipid measurement
  description: >-
    Re-measuring the lipid profile by a method that does not use glycerol as a
    proxy separates artefact from disease. In affected men, NMR returns normal
    triglycerides and higher LDL cholesterol than the lipase-based assay
    reported.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  markers: Serum triglyceride and LDL cholesterol by NMR versus lipase-based assay
  results: Normal NMR triglyceride alongside a high lipase-based triglyceride indicates pseudohypertriglyceridaemia.
  evidence:
  - reference: PMID:39512433
    reference_title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to NMR, lipase-based assays overreported triglycerides
    explanation: Demonstrates the method-dependent discrepancy that establishes the artefact.
- name: GK sequencing
  description: >-
    Molecular confirmation identifies the hemizygous GK variant, distinguishes
    the isolated form from an Xp21 contiguous-gene deletion, and enables carrier
    testing in the maternal line.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  markers: Hemizygous pathogenic GK variant
  results: A hemizygous loss-of-function GK variant confirms isolated glycerol kinase deficiency.
  evidence:
  - reference: PMID:40741920
    reference_title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings with isolated GKD presented with persistent, asymptomatic
      hypertriglyceridemia, confirmed by glyceroluria and genetic testing
      revealing a hemizygous c.213_214delAT (p.Cys72Ter) mutation.
    explanation: Documents molecular confirmation of the isolated form by GK genotyping.
  - reference: PMID:34743506
    reference_title: Complex glycerol kinase deficiency - long-term follow-up of two patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic examinations in both patients revealed a deletion on Xp21
      chromosome including complete deletion of NR0B1 and GK genes.
    explanation: Shows what molecular testing must exclude — the contiguous-gene deletion that defines the complex form.
treatments:
- name: Frequent Feeding, Glucose Access and Avoidance of Strenuous Exercise
  description: >-
    Management of the symptomatic childhood form is entirely preventive: keep
    the child out of the catabolic state that unmasks the missing gluconeogenic
    substrate. Frequent meals, ready access to glucose, and avoidance of
    strenuous sport were sufficient for a good long-term outcome in two boys
    followed for around 20 years, whose crises then ceased after puberty.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Fasting and Catabolic-Stress Intolerance
    treatment_effect: BYPASSES
    description: >-
      Supplying exogenous glucose and shortening fasting intervals removes the
      demand for glycerol-derived gluconeogenesis rather than correcting the
      enzyme defect.
    evidence:
    - reference: PMID:15303806
      reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        With meals at frequent intervals, access to glucose and avoidance of
        strenuous sports, the prognosis is good for a normal adult life of a
        young child with isolated GKD and symptoms of hypoglycaemia.
      explanation: States the intervention and its outcome in the same sentence, in patients followed for two decades.
  evidence:
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With meals at frequent intervals, access to glucose and avoidance of
      strenuous sports, the prognosis is good for a normal adult life of a young
      child with isolated GKD and symptoms of hypoglycaemia.
    explanation: Primary evidence for the preventive regimen and for the favourable prognosis under it.
- name: Withdrawal of Lipid-Lowering Therapy After Diagnosis
  description: >-
    In the adult form the therapeutic act is subtractive. Once the raised
    triglyceride is recognised as glycerol, hypolipidaemic drugs directed at it
    can be stopped; in a paediatric series all three patients had lipid-lowering
    treatment discontinued after diagnosis without adverse outcome, and a
    long-followed hyperglycerolaemic cohort showed no premature atherosclerotic
    cardiovascular disease attributable to the condition itself. A published
    clinical suspicion score exists specifically to spare these patients
    unwarranted treatment. Ordinary cardiovascular risk factors still require
    routine monitoring.
  treatment_term:
    preferred_term: withdrawal of unwarranted lipid-lowering pharmacotherapy
  target_mechanisms:
  - target: Misdiagnosis as Primary Hypertriglyceridaemia and Ineffective Lipid-Lowering Treatment
    treatment_effect: INHIBITS
    description: >-
      Stopping the drug removes the iatrogenic arm of the disease; nothing is
      done to the underlying enzyme defect or to the hyperglycerolaemia.
    evidence:
    - reference: PMID:40741920
      reference_title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lipid-lowering treatments were discontinued following diagnosis, with no
        adverse outcomes.
      explanation: Documents the deprescribing step and its safety in molecularly confirmed patients.
  evidence:
  - reference: PMID:33212314
    reference_title: "Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proposed score would have a broad utility in clinical practice to
      avoid unwarranted lipid lowering treatment in GKD patients.
    explanation: States avoidance of unwarranted lipid-lowering treatment as the explicit clinical goal.
  - reference: PMID:41047305
    reference_title: Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The confirmation of hyperglycerolemia can help the clinician reassure the
      patient concerning his CV risk, as no further assessment is required other
      than common CV risk factors monitoring, including body weight increase and
      insulin resistance that may appear over the life course.
    explanation: >-
      Supports withdrawal plus ordinary risk-factor monitoring, and bounds the
      claim: routine cardiovascular risk factors still need following.
differential_diagnoses:
- name: Complex glycerol kinase deficiency (Xp21 contiguous gene deletion syndrome)
  disease_term:
    preferred_term: chromosome Xp21 deletion syndrome
    term:
      id: MONDO:0010399
      label: chromosome Xp21 deletion syndrome
  description: >-
    A deletion at Xp21 that removes GK together with neighbouring genes —
    NR0B1 (adrenal hypoplasia congenita), DMD (Duchenne muscular dystrophy) and
    sometimes IL1RAPL1 (intellectual disability). It shares the
    hyperglycerolaemia but is a different disease: the danger comes from the
    adrenal insufficiency, not from the glycerol.
  distinguishing_features:
  - Salt-wasting adrenal crisis in infancy, usually the first and most dangerous manifestation
  - Raised creatine kinase and a Duchenne muscular dystrophy phenotype
  - Intellectual disability when the deletion extends to IL1RAPL1
  - A multigene Xp21 deletion on microarray or MLPA rather than an intragenic GK variant
  evidence:
  - reference: PMID:23739620
    reference_title: "Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by partial deletion of Xp21, which includes the genes
      responsible for glycerol kinase deficiency, congenital adrenal hypoplasia,
      Duchenne muscular dystrophy and intellectual disability.
    explanation: Defines the contiguous-gene entity that must be separated from isolated GKD.
  - reference: PMID:23739620
    reference_title: "Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Usually the first and most severe are the signs of adrenal hypoplasia,
      which, if not cured, may lead to death in a short time.
    explanation: Establishes why the distinction is urgent rather than taxonomic.
- name: Primary hypertriglyceridaemia
  description: >-
    The condition patients with the adult form are almost always labelled with
    first. True hypertriglyceridaemia gives lipaemic serum, responds at least
    partly to lipid-lowering therapy, and is not accompanied by glyceroluria.
  distinguishing_features:
  - Non-lipaemic serum despite a high reported triglyceride
  - Complete resistance to hypolipidaemic drugs over years of treatment
  - Normal triglyceride when measured by NMR rather than a lipase-based assay
  - Raised plasma and urinary glycerol
  evidence:
  - reference: PMID:35292548
    reference_title: Pseudo-hypertriglyceridaemia in glycerol kinase deficiency misdiagnosed and treated as true hypertriglyceridaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High triglyceride in a serum sample with no apparent visible lipaemia is a
      confusing laboratory condition.
    explanation: Names the discriminating bedside observation that separates the two.
datasets: []
discussions:
- discussion_id: gap_gkd_gluconeogenesis_versus_ketolysis
  prompt: >-
    Are the childhood crises of isolated glycerol kinase deficiency caused by
    failure of glycerol-dependent gluconeogenesis, by a defect in ketolysis, or
    by both?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Fasting and Catabolic-Stress Intolerance
  - pathophysiology#Hyperketotic Hypoglycaemic Decompensation
  rationale: >-
    The pathograph as curated routes the crisis through loss of glycerol as a
    gluconeogenic substrate, but the primary review of the disorder explicitly
    declines to settle that attribution and raises ketolysis as an alternative
    or additional contributor. The distinction matters for management: a
    gluconeogenic-substrate deficit is fully addressed by exogenous glucose,
    whereas a ketolytic defect would predict residual vulnerability despite
    adequate glucose supply. It also bears on why adults with unchanged
    hyperglycerolaemia still show pronounced ketonaemia on fasting while no
    longer becoming hypoglycaemic.
  evidence:
  - reference: PMID:11032329
    reference_title: "Isolated and contiguous glycerol kinase gene disorders: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated GKD patients showed a tendency towards hypoglycaemia with
      hyperketonaemia; whether the clinical symptoms of GKD are caused by
      dysfunction of gluconeogenesis and/or ketolysis needs to be investigated
      further.
    explanation: The review states the open question in its own words.
  - reference: PMID:15303806
    reference_title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tests performed in childhood documented pronounced sensitivity to fasting
      and physical exercise, whereas such tests at 23 and 31 y of age were
      essentially normal but with pronounced ketonaemia.
    explanation: >-
      Shows the dissociation the gap is about — ketonaemia persists into
      adulthood after hypoglycaemic sensitivity has resolved.
  proposed_experiments:
  - experiment_id: gkd_paired_tracer_gluconeogenesis_ketolysis
    name: Paired glycerol and ketone tracer study across the pubertal transition
    description: >-
      In hemizygous GK patients studied as children and again as adults, combine
      13C3-glycerol infusion (already validated in this disorder) with a
      13C-labelled beta-hydroxybutyrate infusion during a controlled fast.
      Measure glycerol-to-glucose conversion, whole-body glucose production, and
      ketone body oxidation rate. If gluconeogenic substrate loss alone explains
      the crises, ketone oxidation should be normal at both ages while glucose
      production falls only in childhood.
- discussion_id: interp_gkd_infantile_form_mondo_placement
  prompt: >-
    MONDO places the infantile form of glycerol kinase deficiency
    (MONDO:0017294) under the parent term rather than under isolated GKD, while
    the juvenile and adult forms sit under the isolated term. Should this entry
    carry an infantile subtype?
  kind: INTERPRETATION
  status: RESOLVED
  attaches_to:
  - pathophysiology#Hyperketotic Hypoglycaemic Decompensation
  rationale: >-
    MONDO:0017294 is a child of MONDO:0010613 (inborn glycerol kinase
    deficiency) but not of MONDO:0018459 (isolated glycerol kinase deficiency),
    and its definition explicitly folds in patients whose infantile presentation
    is due to complex GKD with adrenal hypoplasia congenita and/or Duchenne
    muscular dystrophy. Adding it as a subtype of this entry would import
    contiguous-gene disease into an entry that is scoped to the isolated form.
  resolution_note: >-
    Only the juvenile (MONDO:0017295) and adult (MONDO:0017296) forms are
    curated as subtypes. Severe infantile presentations of the isolated form are
    covered by the entry description and by the childhood crisis arm of the
    pathograph without borrowing a MONDO term whose scope is wider than this
    entry's.
references:
- reference: PMID:11032329
  title: "Isolated and contiguous glycerol kinase gene disorders: a review."
- reference: PMID:9719371
  title: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.
- reference: PMID:15303806
  title: "Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis."
- reference: PMID:33212314
  title: "Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score."
- reference: PMID:39512433
  title: In vivo glycerol metabolism in patients with glycerol kinase deficiency.
- reference: PMID:35292548
  title: Pseudo-hypertriglyceridaemia in glycerol kinase deficiency misdiagnosed and treated as true hypertriglyceridaemia.
- reference: PMID:40741920
  title: "Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases."
- reference: PMID:41047305
  title: Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.
- reference: PMID:23739620
  title: "Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion)."
- reference: PMID:34743506
  title: Complex glycerol kinase deficiency - long-term follow-up of two patients.
review_notes: >-
  Identity was checked before curating, against the WP-007 seed row (3.2.01.01,
  GK, OMIM:307030, ORPHA:408). MONDO:0018459 carries the ORPHA:408 equivalence
  and is the exact concept for the isolated form; OMIM:307030 sits on the parent
  MONDO:0010613, which also subsumes the contiguous-gene presentations, so the
  parent is recorded as a broadMatch rather than used as the anchor. GK was
  confirmed as hgnc:4289 at Xp21.2. Complex GKD is curated as a differential
  diagnosis, not a subtype, because its causal lesion is a multigene deletion
  rather than a GK defect.
  Two deliberate omissions. Hypertriglyceridemia (HP:0002155) is NOT curated as
  a phenotype even though every clinical report mentions it, because in this
  disorder it is a property of the assay rather than of the patient: NMR
  measurement in the same individuals is normal and total cholesterol is lower
  than in relatives. It is instead recorded as a biochemical marker whose notes
  say it is spurious, and the artefact and its iatrogenic consequence are
  modelled as explicit pathograph nodes. Second, no frequency band is asserted
  for any phenotype except the obligate hyperglycerolaemia, because the
  published series are small and largely ascertained through lipid clinics,
  which biases the symptomatic fraction downwards; the sources support the
  associations but not the bands.
  Module conformance is claimed on three nodes of
  metabolic_intoxication_decompensation and deliberately withheld from the
  encephalopathy node, whose mechanism in that module is ammonia-driven
  astrocytic injury that this disorder does not have. The amplifier conformance
  is qualified in the node description: only the energy-deficit arm applies, as
  glycerol has not been shown to be toxic and long-term vascular follow-up of
  hyperglycerolaemic patients was negative.
  All ten references were fetched with `just fetch-reference`; no cache file was
  written by hand. Snippets were taken from the abstract text of each cached
  record, and quotations containing statistical parentheses were shortened to
  the plain-text clause so that matching does not depend on typographic
  characters. Three cited papers are review types (PMID:11032329, PMID:23739620,
  PMID:33212314) and their evidence items are nonetheless typed HUMAN_CLINICAL:
  each aggregates human patient data, which is what evidence_source grades, and
  OTHER is reserved for evidence that fits none of the named categories, such as
  expert consensus without data. The two items quoting the cultured-fibroblast
  enzyme assay from PMID:15303806 are typed IN_VITRO, since that paper is
  mixed-source — a 20-year clinical follow-up plus a cell-based assay — and each
  item carries the single source type of the measurement it quotes. No
  deep-research provider was used for this entry; it was curated directly from
  PubMed-retrieved abstracts.

📚

References & Deep Research

References

10

PMID:11032329

Isolated and contiguous glycerol kinase gene disorders: a review.

No top-level findings curated for this source.

PMID:9719371

Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.

No top-level findings curated for this source.

PMID:15303806

Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis.

No top-level findings curated for this source.

PMID:33212314

Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score.

No top-level findings curated for this source.

PMID:39512433

In vivo glycerol metabolism in patients with glycerol kinase deficiency.

No top-level findings curated for this source.

PMID:35292548

Pseudo-hypertriglyceridaemia in glycerol kinase deficiency misdiagnosed and treated as true hypertriglyceridaemia.

No top-level findings curated for this source.

PMID:40741920

Pseudohypertriglyceridemia as a clue: clinical and genetic spectrum of glycerol kinase deficiency in three pediatric cases.

No top-level findings curated for this source.

PMID:41047305

Cardiometabolic risk in pseudohypertriglyceridemia resulting from hyperglycerolemia.

No top-level findings curated for this source.

PMID:23739620

Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion).

No top-level findings curated for this source.

PMID:34743506

Complex glycerol kinase deficiency - long-term follow-up of two patients.

No top-level findings curated for this source.

Isolated Glycerol Kinase Deficiency

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