Glycerol kinase deficiency

Glycerol kinase deficiency is a rare X-linked inborn error of metabolism in which glycerol released from fat cannot be converted to glycerol-3-phosphate, so glycerol accumulates in blood and urine and is falsely measured as triglyceride by routine laboratory assays.

The isolated form may cause only hyperglycerolaemia and pseudohypertriglyceridaemia in adults, whereas contiguous deletion of neighbouring genes on Xp21 produces a severe infantile syndrome with adrenal hypoplasia, muscular dystrophy and developmental delay.

Terminology and classification

• The standard names are glycerol kinase deficiency and isolated glycerol kinase deficiency, and hyperglycerolaemia and hyperglyceroluria describe the biochemical phenotype rather than separate diseases.
• Pseudohypertriglyceridaemia is the misleading laboratory label given to the elevated triglyceride result produced when glycerol is oxidised in glycerol kinase-based triglyceride assays.
• Isolated glycerol kinase deficiency is Orphanet ORPHA:408, complex glycerol kinase deficiency is ORPHA:308993 and the Xp21 contiguous deletion syndrome is ORPHA:261476.
• ICD-10 uses E74.8 for the isolated form and Q99.8 for the contiguous deletion, while ICD-11 assigns 5C51.1 to isolated glycerol kinase deficiency.
• Other identifiers are OMIM 307030 for isolated deficiency, OMIM 300679 for the Xp21 deletion syndrome, MONDO:0018459, MedGen 82803, UMLS C0268418 and Wikidata Q5572555.
• Three clinical forms are traditionally described, namely infantile, juvenile and adult, although they form a continuum determined by the extent of the deletion and by residual enzyme activity.

History

• Glycerol kinase deficiency was recognised in the late 1970s when children with hyperglycerolaemia and glyceroluria were described, and McCabe and colleagues characterised the enzyme defect in cultured fibroblasts in 1982.^[1]
• In 1985 cytogenetic and molecular studies showed that glycerol kinase deficiency could result from a deletion of the Xp21 region, linking the enzyme defect to neighbouring Duchenne muscular dystrophy and adrenal hypoplasia.
• Francke and colleagues demonstrated in 1987 that congenital adrenal hypoplasia, myopathy and glycerol kinase deficiency could occur together through molecular deletions, defining the contiguous gene syndrome model.^[2]
• The GK gene was cloned in the early 1990s, and mutation analysis in 1996 showed that isolated deficiency can be clinically silent or cause severe psychomotor retardation, bone dysplasia and seizures.^[3]
• A mouse model created in 1997 reproduced growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death, supporting a direct metabolic role for the enzyme.^[4]
• A 2020 systematic review of adult cases compiled 39 patients from 15 articles, and a 2025 report described a severe neonatal Xp21 deletion with adrenal crisis and neuromuscular involvement.^[5]

Epidemiology

• No population prevalence has been measured, and Orphanet records prevalence as unknown for both isolated and complex forms.
• Isolated glycerol kinase deficiency is rare and the 2020 systematic review found only 39 published subjects, many of them adults investigated for apparent hypertriglyceridaemia.
• Complex glycerol kinase deficiency is more frequently reported than the isolated form, with more than 100 cases of the Xp21 contiguous deletion described, because the adrenal and muscle phenotypes prompt genetic testing.
• Because inheritance is X-linked recessive, affected individuals are almost all male, and heterozygous females usually have normal glycerol metabolism although skewed X-inactivation may produce mild biochemical changes.
• Adult cases are probably underdiagnosed because hyperglycerolaemia is asymptomatic and is mistaken for true hypertriglyceridaemia that fails to respond to statins.
• The disorder occurs worldwide without a recognised founder population, and reported families are too few to estimate regional differences.
• A 2024 review of glycerol metabolism estimated the population prevalence at approximately one in a million, consistent with the small number of published isolated cases.
• A French-Canadian population screen of 1,056 people identified five males with hyperglycerolaemia and 18 affected males among their relatives, showing that mild adult cases can be detected in founder populations.

Pathophysiology

• Glycerol kinase catalyses the adenosine triphosphate-dependent phosphorylation of glycerol to glycerol-3-phosphate, the first step that allows glycerol to enter glycolysis or gluconeogenesis.
• Glycerol is released continuously by adipose tissue lipolysis, so enzyme deficiency causes accumulation in plasma and excretion in urine, where it acts as an osmotically active solute.
• In the absence of phosphorylation, glycerol cannot be used for hepatic gluconeogenesis, which becomes critical during fasting or illness and can cause hypoglycaemia and metabolic acidosis.
• Most clinical chemistry analysers measure triglycerides by a glycerol kinase-coupled reaction, so an excess of glycerol is reported as triglyceride and produces pseudohypertriglyceridaemia that is resistant to lipid-lowering drugs.
• Complex deficiency arises from a contiguous deletion that removes GK together with DMD, NR0B1 and sometimes IL1RAPL1, producing combined glycerol kinase deficiency, Duchenne dystrophy, adrenal hypoplasia and intellectual disability.
• Residual enzyme activity explains part of the phenotypic variability, and splice-site and missense variants with residual activity tend to produce the mild adult form.^[6]

Clinical features

• Infantile complex deficiency presents in the newborn period with adrenal crisis, hypoglycaemia, vomiting, dehydration, hypotonia and sometimes seizures, and it can be fatal without steroid replacement.
• Boys with Xp21 deletions may also show delayed motor milestones, calf pseudohypertrophy, elevated creatine kinase and a dystrophic muscle biopsy consistent with Duchenne muscular dystrophy.
• Juvenile deficiency causes recurrent episodes of vomiting, abdominal pain, lethargy, metabolic acidosis and hypoglycaemia during fasting or intercurrent infection, with growth retardation and bone dysplasia in some.
• The adult form is usually asymptomatic and discovered when a routine lipid panel reports high triglycerides that do not respond to diet or statins, with normal cholesterol and normal apolipoprotein B.
• Glyceroluria may cause no symptoms, although large osmotic loads can produce polyuria, and some adults report fatigue or exercise intolerance of uncertain relation to the enzyme defect.
• Complex cases may additionally show adrenal insufficiency with hyperpigmentation, salt wasting, intellectual disability, behavioural problems and, in later childhood, scoliosis or contractures.

Diagnosis

• The diagnosis requires direct measurement of glycerol in plasma or urine by gas chromatography-mass spectrometry or a specific enzymatic method, because routine triglyceride assays cannot distinguish glycerol from triglyceride.
• A striking discrepancy between a high triglyceride result and normal cholesterol, normal apolipoprotein B, normal lipoprotein electrophoresis and absent chylomicronaemia suggests pseudohypertriglyceridaemia.
• GK sequencing with deletion and duplication analysis confirms the diagnosis, and MLPA or chromosomal microarray is needed when a contiguous Xp21 deletion is suspected.
• Boys with the complex form need adrenal evaluation with morning cortisol, adrenocorticotropic hormone, renin and electrolytes, plus creatine kinase and cardiac assessment for dystrophinopathy.
• Newborns with unexplained hypoglycaemia, salt wasting, ambiguous adrenal function or a family history of Duchenne dystrophy should be tested for an Xp21 deletion even before glycerol results are available.
• The differential diagnosis includes familial hypertriglyceridaemia, lipoprotein lipase deficiency, adrenal hypoplasia congenita, Duchenne muscular dystrophy, organic acidaemias and disorders of gluconeogenesis.

Management

• No enzyme replacement or gene therapy is available, so management targets the metabolic consequences, particularly hypoglycaemia during fasting and adrenal insufficiency in complex cases.
• Patients should avoid prolonged fasting, carry a written emergency plan and receive intravenous glucose early during vomiting or febrile illness to prevent hypoglycaemia and acidosis.
• Adrenal insufficiency is treated with hydrocortisone for glucocorticoid replacement and fludrocortisone for mineralocorticoid replacement, with dose increases during stress and education on emergency injectable hydrocortisone.
• Hyperglycerolaemia itself does not require treatment, and lipid-lowering drugs should not be prescribed for pseudohypertriglyceridaemia because the reported triglyceride is not a true lipid risk factor.
• Growth, development, cardiac function in dystrophinopathy and bone health should be monitored in complex cases by a multidisciplinary team including endocrinology, neurology and cardiology.
• Genetic counselling explains the X-linked recessive inheritance, offers carrier testing to mothers and at-risk female relatives and discusses prenatal or newborn testing for subsequent pregnancies.
• Adrenal insufficiency requires stress-dose hydrocortisone during febrile illness, vomiting or surgery, together with an emergency card and injectable hydrocortisone, because unrecognised adrenal crisis can be fatal.
• In complex Xp21 deletions, cardiac surveillance for dystrophinopathy cardiomyopathy should begin in childhood and continue into adulthood, and respiratory function should be monitored as muscle weakness progresses.

Research and controversies

• The 2020 diagnostic score was developed to help lipidologists separate glycerol kinase deficiency from true hypertriglyceridaemia and avoid unnecessary treatment, but it has not been validated prospectively.^[5]
• Why some adults with absent enzyme activity remain asymptomatic while others have episodic metabolic crises is unexplained, and modifying genes or environmental stress are plausible contributors.
• Recognition of pseudohypertriglyceridaemia is a public health issue because mislabelled patients may receive statins, fibrates or even apheresis for a condition that carries no atherosclerotic risk.
• Newborn screening programmes do not currently include glycerol kinase deficiency, and whether dried blood spot glycerol measurement would be cost-effective is unknown.
• Xp21 deletion size correlates imperfectly with phenotype, and reports of discordant monozygotic twins and siblings suggest additional epigenetic or environmental influences.
• Long-term adult outcome data are scarce, and prospective cohorts are needed to define the risk of metabolic decompensation, renal effects of chronic glyceroluria and optimal follow-up intervals.