Phosphoglycerate Kinase 1 Deficiency

Mendelian MONDO:0010392 Pathograph 24 Show in embeddings browser disorder of glycolysis disorder of glycogen metabolism

Phosphoglycerate kinase 1 deficiency is an X-linked recessive glycolytic disorder caused by hemizygous pathogenic variants in PGK1. PGK1 catalyzes the first ATP-generating step of glycolysis, the transfer of phosphate from 1,3-bisphosphoglycerate to ADP, and is expressed in all somatic tissues. Affected males show variable combinations of three tissue syndromes, and rarely all three: chronic nonspherocytic hemolytic anemia; a metabolic myopathy with exercise intolerance, cramps and exertional rhabdomyolysis with myoglobinuria; and central nervous system involvement including intellectual disability, seizures, stroke-like and encephalopathic episodes, retinal dystrophy and early-onset levodopa-responsive parkinsonism. Most pathogenic variants reduce the kinetic stability of the enzyme as well as, to different degrees, its catalytic efficiency, and complete loss-of-function alleles have not been observed. Which tissue is affected is not fully explained by the molecular properties of the mutant enzyme, although lower residual glycolytic capacity is associated with multisystem disease. Red cells accumulate 2,3-bisphosphoglycerate, which right-shifts the oxygen-hemoglobin dissociation curve and partly offsets the anemia. Some heterozygous women are affected, through reduced red-cell activity or, in one reported mother, parkinsonism. There is no disease-specific therapy; management is supportive (transfusion, levodopa for parkinsonism, avoidance of strenuous exercise), and hematopoietic cell transplantation has been attempted in a few children.

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Classifications

ICIMD (Inherited Metabolic Disorders)

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Mappings

MONDO

MONDO:0010392 glycogen storage disease due to phosphoglycerate kinase 1 deficiency

MONDO:0010392 is the PGK1-specific disease concept; its definition names the hemolytic, myopathic and central nervous system combinations curated here, and its synonyms include "phosphoglycerate kinase 1 deficiency, X-linked recessive" and "PGK deficiency".

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Inheritance

X-linked recessive HP:0001419

Hemizygous males are affected. Heterozygous women are usually unaffected but can show reduced red-cell activity and hemolytic anemia, and one heterozygous mother developed early-onset parkinsonism, which the authors attribute to skewed X inactivation.

X-linked recessive inheritance

Show evidence (2 references)

PMID:6938182 SUPPORT Human Clinical

"They had moderate haemolytic anaemia, considerable reduction of red cell PGK activity (19% and 35% of normal, respectively)"

Manifesting heterozygous women with reduced activity and hemolysis.

PMID:28649613 SUPPORT Human Clinical

"Here, we report a boy with PGK-1 deficiency and his mother, a carrier of a heterozygous mutation in PGK-1, both of whom presented with early-onset parkinsonism."

Parkinsonism in a heterozygous mother.

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Mechanistic Hypotheses

Residual glycolytic capacity determines tissue involvement

pgk1_residual_glycolytic_capacity_model EMERGING

Evidence balance 1 support 1 refute

The degree to which glycolytic flux is lost, set by the combined effect of a variant on catalytic efficiency and on protein stability, determines which tissues fail. In a case series, the lowest residual activity accompanied multisystem disease and the smallest ischemic lactate rise. The model does not account for every genotype: some variants with mild molecular defects produce broad phenotypes, and one recurrent variant has produced both isolated myopathy and myopathy with parkinsonism.

Pathograph links

Reduced Glycolytic ATP Generation -> Skeletal Muscle Glycolytic Failure During Exertion DIRECT During intense or ischemic exercise, muscle cannot raise glycolytic flux, so lactate output and ATP supply fall short of demand.

Reduced Glycolytic ATP Generation -> Neuronal Energy Failure INDIRECT UNKNOWN INTERMEDIATES Reduced glycolytic ATP generation in the central nervous system is the proposed basis of the neurological syndrome, supported by an invertebrate model; the human neural lesion has not been measured directly.

Neuronal Energy Failure -> Seizure INDIRECT UNKNOWN INTERMEDIATES Neuronal energy failure is proposed to underlie seizures, by analogy with the seizure phenotype of the PGK-mutant fly.

Neuronal Energy Failure -> Intellectual disability INDIRECT UNKNOWN INTERMEDIATES Developmental neural energy failure is the proposed basis of intellectual disability; the intermediate steps are not characterized.

Neuronal Energy Failure -> Nigrostriatal Dopaminergic Dysfunction INDIRECT UNKNOWN INTERMEDIATES Glycolytic energy failure is proposed to make nigrostriatal dopaminergic neurons especially vulnerable; why this population is affected is unknown.

Show evidence (2 references)

PMID:30111548 SUPPORT Human Clinical

"Lower glycolytic capacity in PGK1 deficiency seems to result in multisystem involvement and increased susceptibility to exertional rhabdomyolysis."

Human exercise physiology relates lower residual glycolytic capacity to multisystem rather than purely myopathic disease.

PMID:22348148 REFUTE In Vitro

"However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme."

The largest recombinant-enzyme study finds that molecular properties alone do not predict the tissue pattern, so the model is incomplete.

2,3-bisphosphoglycerate excess as the proximate cause of hemolysis

pgk1_2_3_bpg_hemolysis_model ALTERNATIVE

Evidence balance 1 support

Rather than ATP shortfall alone, hemolysis may follow from intracellular acidification and inhibition of other glycolytic enzymes by the raised erythrocyte 2,3-bisphosphoglycerate concentration. This is offered as a suggestion in the source rather than a demonstrated mechanism.

Pathograph links

Erythrocyte 2,3-Bisphosphoglycerate Accumulation -> Premature Destruction of Energy-Depleted Erythrocytes DIRECT 2,3-bisphosphoglycerate excess may contribute to hemolysis through intracellular acidification and inhibition of glycolytic enzymes.

Show evidence (1 reference)

PMID:22348148 SUPPORT In Vitro

"that the true cause of the hemolysis is better ascribable to an increase of acidity or inhibition of several glycolytic enzymes (such as hexokinase, phosphofructo kinase, and pyruvate kinase) as a consequence of an increased intracellular concentration of 2,3-BPG"

States the alternative hemolysis mechanism, in explicitly conjectural language.

Discussions and Knowledge Gaps

Why do variants in a ubiquitously expressed enzyme produce hemolysis alone, myopathy alone, or central nervous system disease in different patients, and why does the same variant (p.Thr378Pro) cause isolated myopathy in one man and myopathy with parkinsonism in another?

KNOWLEDGE GAP OPEN gap_pgk1_tissue_selectivity

Attached to

pathophysiology#Reduced Glycolytic ATP Generation pathophysiology#Neuronal Energy Failure mechanistic_hypotheses#pgk1_residual_glycolytic_capacity_model

Molecular stability and catalytic data correlate with tissue pattern for some variant classes but not others, and the authors of the largest study point to environmental, genetic and epigenetic modifiers. A co-inherited NUBPL disruption worsened one PGK1 phenotype, which shows that modifiers exist. Resolving this decides whether a patient's neurological prognosis can be predicted from genotype.

Show evidence (3 references)

PMID:17222195 SUPPORT REVIEW SYNTHESIS Human Clinical

"The reason for different clinical manifestations of mutations of the same gene remains unknown."

States the gap directly.

PMID:22348148 SUPPORT In Vitro

"Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes."

Names candidate modifier classes.

PMID:25814383 SUPPORT Human Clinical

"Nevertheless, its co-inheritance presumably exacerbates PGK1-deficient phenotype, most likely due to a synergistic interaction of the affected genes both involved in cell energy supply."

A worked example of a genetic modifier of severity.

Do heterozygous PGK1 variants increase susceptibility to early-onset or sporadic Parkinson disease, given parkinsonism in one heterozygous mother with normal red-cell activity and the location of PGK1 within the PARK12 linkage interval?

OPEN QUESTION OPEN gap_pgk1_heterozygote_parkinson_susceptibility

Attached to

pathophysiology#Nigrostriatal Dopaminergic Dysfunction

The evidence is one pedigree and a linkage-region coincidence. Sequencing PGK1 in early-onset Parkinson disease cohorts, as both reporting groups propose, would settle it.

Show evidence (2 references)

PMID:28649613 SUPPORT Human Clinical

"Interestingly, PGK-1 is located within the confirmed susceptibility locus for PD known as PARK12."

States the linkage coincidence underlying the question.

PMID:20151463 SUPPORT Human Clinical

"it may be worthwhile to sequence the PGK1 gene in a cohort of idiopathic juvenile PD cases"

Proposes the cohort study that would answer the question.

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Pathophysiology

PGK1 Enzyme Instability and Catalytic Deficiency

Mechanism confidence: Established

Hemizygous PGK1 variants in males reduce phosphoglycerate kinase activity, most often by lowering the kinetic stability of the enzyme so that it denatures quickly at body temperature, and to a variable extent by impairing catalysis. Residual activity is retained in every reported patient; complete loss-of-function alleles have not been observed, which suggests that some PGK1 function is needed for male viability.

PGK1 hgnc:8896

Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

phosphoglycerate kinase activity GO:0004618 ↓ DECREASED

Downstream

Reduced Glycolytic ATP Generation PGK1 catalyzes the first ATP-yielding step of glycolysis, so loss of its activity reduces glycolytic ATP production.

Show evidence (4 references)

PMID:30887539 SUPPORT Human Clinical

"Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder caused by mutations in the PGK1 gene."

Establishes PGK1 as the causal gene and X-linked transmission.

PMID:22348148 SUPPORT In Vitro

"Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients."

Recombinant characterization of 16 disease variants shows that instability and catalytic impairment together account for the low enzyme activity.

PMID:23336698 SUPPORT In Vitro

"Kinetic analysis of differential scanning calorimetry profiles shows that the disease-causing mutations decrease PGK1 kinetic stability from ~5-fold (E252A) to ~100000-fold (L89P) compared to that of wild-type PGK1, and in some cases, mutant enzymes are denatured on a time scale of a few minutes..."

Quantifies the kinetic destabilization of disease variants.

+ 1 more reference

Reduced Glycolytic ATP Generation

Mechanism confidence: Established

Reduced PGK1 activity lowers flux through the lower half of glycolysis and the ATP it yields. Tissues differ in how much this matters: mature erythrocytes have no mitochondria and depend on glycolysis entirely, skeletal muscle depends on it during brief intense or ischemic exertion, and neurons may fail to replace unstable enzyme fast enough. How severe the loss of flux is in a given patient is associated with which tissues are affected.

Residual glycolytic capacity determines tissue involvement

glycolytic process GO:0006096 ↓ DECREASED

Downstream

Erythrocyte ATP Depletion Erythrocytes have no alternative ATP source, so the glycolytic block lowers red-cell ATP.

Erythrocyte 2,3-Bisphosphoglycerate Accumulation The glycolytic block raises the upstream intermediate 2,3-bisphosphoglycerate in erythrocytes.

Skeletal Muscle Glycolytic Failure During Exertion During intense or ischemic exercise, muscle cannot raise glycolytic flux, so lactate output and ATP supply fall short of demand.

Neuronal Energy Failure Reduced glycolytic ATP generation in the central nervous system is the proposed basis of the neurological syndrome, supported by an invertebrate model; the human neural lesion has not been measured directly.

Show evidence (2 references)

PMID:22348148 SUPPORT In Vitro

"Thus, an increased degradation rate of such variants leads to a decreased PGK1 content which primarily accounts for the enzyme deficiency and in turn for a reduced ATP production."

Links variant instability to reduced enzyme content and reduced ATP production.

PMID:30111548 SUPPORT Human Clinical

"This case series study of PGK1 deficiency suggests that the level of impaired glycolysis in PGK deficiency is a major determinant of phenotype."

Human data place impaired glycolysis at the center of the phenotype.

Erythrocyte ATP Depletion

Mechanism confidence: Established

In affected red cells, ATP falls substantially. The ATP shortfall compromises the energy-dependent maintenance of the red cell, which is then cleared early. Erythrocyte disease is reported mainly with variants that are unstable but only mildly impaired catalytically.

erythrocyte CL:0000232

Downstream

Premature Destruction of Energy-Depleted Erythrocytes ATP-depleted red cells are removed from the circulation early.

Show evidence (2 references)

PMID:6938182 SUPPORT Human Clinical

"Red cell ATP levels were substantially decreased in both subjects."

Direct measurement of red-cell ATP depletion in affected males.

PMID:20151463 SUPPORT Human Clinical

"Anaerobic glycolysis is the only source of energy in mature erythrocytes due to their lack of mitochondria, and hemolytic anemia is the common presentation of glycogenoses that affect red blood cells."

States why the erythrocyte is especially exposed to a glycolytic block.

Erythrocyte 2,3-Bisphosphoglycerate Accumulation

Mechanism confidence: Established

In affected red cells, 2,3-bisphosphoglycerate rises to more than twice normal. The elevated concentration shifts the oxygen-hemoglobin dissociation curve and may contribute to hemolysis by intracellular acidification and inhibition of other glycolytic enzymes.

2,3-bisphosphoglycerate excess as the proximate cause of hemolysis

erythrocyte CL:0000232

Downstream

Rightward Shift of the Oxygen-Hemoglobin Dissociation Curve Raised 2,3-bisphosphoglycerate lowers hemoglobin oxygen affinity.

Premature Destruction of Energy-Depleted Erythrocytes 2,3-bisphosphoglycerate excess may contribute to hemolysis through intracellular acidification and inhibition of glycolytic enzymes.

Show evidence (1 reference)

PMID:6938182 SUPPORT Human Clinical

"However, they had more than double the normal level of 2,3-diphosphoglycerate (2,3-DPG) in their red cells"

Direct measurement of 2,3-bisphosphoglycerate accumulation.

Rightward Shift of the Oxygen-Hemoglobin Dissociation Curve

Mechanism confidence: Established

The 2,3-bisphosphoglycerate excess lowers hemoglobin oxygen affinity, so oxygen is released to tissues at higher tension. Outside hemolytic crises this offsets much of the loss of oxygen-carrying capacity from the anemia.

Show evidence (1 reference)

PMID:6938182 SUPPORT Human Clinical

"This shift in the curve was sufficient to permit oxygen delivery to most body tissues, including the brain, at better tensions than normal, except during a haemolytic crisis."

Shows the compensatory effect of the right shift on oxygen delivery.

Premature Destruction of Energy-Depleted Erythrocytes

Mechanism confidence: Established

Energy-depleted erythrocytes have a shortened lifespan. Hemolysis is chronic and compensated in most affected males, with crises that are often triggered by febrile infection.

erythrocyte CL:0000232

erythrocyte clearance GO:0034102 ↑ INCREASED

Downstream

Nonspherocytic hemolytic anemia Shortened red-cell survival produces chronic nonspherocytic hemolytic anemia.

Show evidence (2 references)

PMID:6938182 SUPPORT Human Clinical

"Both had moderate haemolytic anaemia complicated by the occurrence of haemolytic crises."

Documents chronic hemolysis with superimposed crises in affected males.

PMID:28801086 SUPPORT Human Clinical

"hemolytic crisis with rhabdomyolysis triggered by febrile viral infections"

Reports infection as the trigger of hemolytic crisis.

Skeletal Muscle Glycolytic Failure During Exertion

Mechanism confidence: Established

During brief intense or ischemic exercise, skeletal muscle with low PGK1 activity cannot raise glycolytic flux. Lactate output on forearm testing is blunted, while ammonia rises normally, and the energy shortfall precipitates cramps, myalgia and fiber breakdown. Most reported myopathy-only variants impair both stability and catalysis.

skeletal muscle fiber CL:0008002

glycolytic process in skeletal muscle GO:0006096 ↓ DECREASED

Downstream

Exertional Rhabdomyolysis An energy deficit in exercising muscle leads to fiber breakdown and release of myoglobin and creatine kinase.

Exercise intolerance Inability to raise glycolytic flux limits brief intense exertion.

Exercise-induced muscle cramps Cramps and contracture-like pain accompany exertion in energy-depleted muscle.

Show evidence (3 references)

PMID:35527021 SUPPORT Human Clinical

"A semi-ischemic forearm exercise test evoked only a modest or sub-normal lactate increase (Figure B), while NH3 showed a normal increase."

Functional evidence of a muscle glycolytic block with preserved ammonia response.

PMID:30111548 SUPPORT Human Clinical

"Enzyme levels of PGK were 4% to 9% of normal in red cells and 5% to10% in muscle in pure myopathy patients and 2.6% in both muscle and red cells in the 2 patients with multisystem involvement."

Documents the low muscle enzyme activity underlying the myopathy.

PMID:22348148 SUPPORT In Vitro

"Conversely, the myopathy without hemolytic or neurological symptoms is observed in some patients with variants heavily affected in both catalytic properties and protein stability"

Relates the myopathic presentation to variants with combined catalytic and stability defects.

Exertional Rhabdomyolysis

Mechanism confidence: Established

Recurrent exercise-induced breakdown of skeletal muscle with myoglobinuria is the defining event of the myopathic form and can also be provoked by febrile illness. It occurs in isolated myopathy and in multisystem disease, in which lower glycolytic capacity is associated with greater susceptibility.

Downstream

Rhabdomyolysis Muscle fiber breakdown is the clinical rhabdomyolysis.

Myoglobinuria Released myoglobin is excreted in the urine.

Elevated circulating creatine kinase activity Damaged muscle fibers release creatine kinase into the circulation.

Show evidence (2 references)

PMID:19157875 SUPPORT Human Clinical

"We describe an 18-year-old man with muscle cramps and recurrent exertional myoglobinuria, without hemolytic anemia or brain dysfunction."

Clinical description of exertional myoglobinuria as an isolated presentation.

PMID:30111548 SUPPORT Human Clinical

"One multisystem-affected patient developed frank myoglobinuria after the short exercise test."

Exercise testing directly provoked myoglobinuria in a patient with low residual activity.

Neuronal Energy Failure

Mechanism confidence: Hypothetical

The neurological syndrome is attributed to inadequate glycolytic ATP supply in the central nervous system, possibly because neural tissue does not replace the unstable enzyme quickly enough. This is supported by a Drosophila PGK mutant with reduced brain ATP, seizures and a later loss of synaptic transmission. Brain ATP has not been measured in patients, and neurological disease is associated with unstable variants that are only mildly impaired catalytically.

Residual glycolytic capacity determines tissue involvement

neuron CL:0000540

Downstream

Seizure Neuronal energy failure is proposed to underlie seizures, by analogy with the seizure phenotype of the PGK-mutant fly.

Intellectual disability Developmental neural energy failure is the proposed basis of intellectual disability; the intermediate steps are not characterized.

Nigrostriatal Dopaminergic Dysfunction Glycolytic energy failure is proposed to make nigrostriatal dopaminergic neurons especially vulnerable; why this population is affected is unknown.

Show evidence (3 references)

PMID:22348148 SUPPORT In Vitro

"As for the neurological dysfunctions, the tissue presumably does not promptly supply new enzyme to replace the damaged fraction, leading to a depletion of ATP."

Proposes neural ATP depletion from failure to replace unstable enzyme; the wording is conjectural, which is why the node is HYPOTHETICAL.

PMID:15140922 SUPPORT INDIRECT Model Organism

"Consistent with altered ATP generation in nubian animals, brain extracts show a threefold reduction in resting ATP levels compared with controls."

A PGK mutant fly shows reduced brain ATP, the proposed lesion of this node.

PMID:15140922 SUPPORT INDIRECT Model Organism

"Disruption of ATP generation in nubian animals is accompanied by temperature-dependent defects in neuronal activity, with initial seizure activity, followed by an activity-dependent loss of synaptic transmission."

Links reduced PGK-dependent ATP generation to seizures and synaptic failure in a model organism.

Nigrostriatal Dopaminergic Dysfunction

Mechanism confidence: Provisional

Affected males with early-onset parkinsonism show severe bilateral loss of putaminal dopamine transporter binding without structural lesions, and respond to levodopa. Parkinsonism has been reported both with and without hemolysis, and in one heterozygous mother, whose reduced activity in the substantia nigra the authors attribute to skewed X inactivation.

dopaminergic neuron CL:0000700

Downstream

Parkinsonism Loss of presynaptic nigrostriatal dopaminergic function produces levodopa-responsive parkinsonism.

Show evidence (3 references)

PMID:30975619 SUPPORT Human Clinical

"99mTc-TRODAT-1 SPECT showed severe bilateral reduced putaminal uptake in the three patients."

Dopamine transporter imaging shows presynaptic nigrostriatal deficit in affected males.

PMID:30975619 SUPPORT Human Clinical

"None of the patients had structural lesions that could explain either pre- or postsynaptic dopaminergic dysfunction."

Excludes a structural explanation for the dopaminergic deficit.

PMID:28649613 SUPPORT Human Clinical

"Therefore, selective enzymatic deficiency in the substantia nigra is possible in heterozygous carriers even when erythrocytes exhibit normal enzymatic activity, as observed in the present case."

Proposes a nigra-specific enzyme deficit to explain parkinsonism in a heterozygous mother with normal red-cell activity.

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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

Blood 1

Nonspherocytic hemolytic anemia HP:0001930

Temporal: CHRONIC

Show evidence (2 references)

PMID:17222195 SUPPORT REVIEW SYNTHESIS Human Clinical

"Phosphoglycerate kinase (PGK) deficiency is one of the relatively uncommon causes of hereditary non-spherocytic haemolytic anaemia (HNSHA)."

Places PGK deficiency among the causes of hereditary nonspherocytic hemolytic anemia.

PMID:16740138 SUPPORT Human Clinical

"In a white American family, two sons presented with haemolytic anaemia, seizures, and developmental delay."

Reports hemolytic anemia with neurological involvement in affected brothers.

Cardiovascular 1

Stroke-like episode HP:0002401

Show evidence (1 reference)

PMID:30975619 SUPPORT Human Clinical

"All patients initially presented with infantile-onset encephalopathic and stroke-like episodes, haemolytic anaemia and epilepsy."

Stroke-like and encephalopathic episodes in three affected males.

Eye 1

Retinal dystrophy HP:0000556

Show evidence (2 references)

PMID:26396085 SUPPORT Human Clinical

"Visual electrophysiology results identified retinal involvement involving both rod and cone dysfunction."

Electrophysiological evidence of retinal dystrophy.

PMID:16740138 SUPPORT Human Clinical

"in the proband, hemiplegic migraines, retinal dystrophy and muscle fatigue"

Retinal dystrophy in a patient with the recurrent p.Asp164Val variant.

Genitourinary 1

Myoglobinuria HP:0002913

Temporal: RECURRENT

Show evidence (1 reference)

PMID:19157875 SUPPORT Human Clinical

"We describe an 18-year-old man with muscle cramps and recurrent exertional myoglobinuria, without hemolytic anemia or brain dysfunction."

Recurrent exertional myoglobinuria.

Metabolism 1

Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:40026287 SUPPORT Human Clinical

"presented with acute respiratory distress, elevated creatine kinase, anemia, and progressive encephalopathy"

Elevated creatine kinase at presentation.

Musculoskeletal 2

Rhabdomyolysis HP:0003201

Temporal: RECURRENT

Show evidence (2 references)

PMID:30887539 SUPPORT Human Clinical

"Case 2 was a 71-year-old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation."

Recurrent exertional rhabdomyolysis in a genetically confirmed patient.

PMID:26883264 SUPPORT Human Clinical

"We report two brothers with mild intellectual deficiency, exercise intolerance, rhabdomyolysis, seizures and no hemolysis."

Rhabdomyolysis with central nervous system involvement and no hemolysis.

Exercise-induced muscle cramps HP:0003710

Show evidence (1 reference)

PMID:22348148 SUPPORT REVIEW SYNTHESIS Human Clinical

"Mental retardation, behavioral abnormalities, seizures or strokes represent the main neurological alterations, whereas cramps and myoglobinuria characterize the myopathic forms."

Summarizes cramps as characteristic of the myopathic form across reported patients.

Nervous System 8

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:17222195 SUPPORT REVIEW SYNTHESIS Human Clinical

"Mutations of this gene may cause chronic haemolysis with or without mental retardation and they may cause myopathies, often with episodes of myoglobinuria, or a combination of these clinical manifestations."

Summarizes intellectual disability as a recurrent feature across reported families.

Seizure HP:0001250

Show evidence (1 reference)

PMID:16740138 SUPPORT Human Clinical

"In a white American family, two sons presented with haemolytic anaemia, seizures, and developmental delay."

Seizures in affected brothers.

Encephalopathy HP:0001298

Show evidence (1 reference)

PMID:40026287 SUPPORT Human Clinical

"presented with acute respiratory distress, elevated creatine kinase, anemia, and progressive encephalopathy"

Progressive encephalopathy at presentation.

Parkinsonism HP:0001300

Show evidence (2 references)

PMID:30975619 SUPPORT Human Clinical

"Two patients had an early-onset and one juvenile-onset levodopa responsive Parkinsonism with motor fluctuations."

Early-onset levodopa-responsive parkinsonism in affected males.

PMID:20151463 SUPPORT Human Clinical

"A 25-year-old man with exertional myoglobinuria had no evidence of hemolytic anemia, but he had severe parkinsonism that was responsive to levodopa."

Parkinsonism in the myopathic form without hemolysis.

Hemiplegic migraine HP:0002076

Show evidence (1 reference)

PMID:16740138 SUPPORT Human Clinical

"in the proband, hemiplegic migraines, retinal dystrophy and muscle fatigue"

Hemiplegic migraine in a single proband.

Leukodystrophy HP:0002415

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:28801086 SUPPORT Human Clinical

"Brain magnetic resonance (MR) imaging revealed leukodystrophy in the periventricular white matter, posterior limbs of the internal capsule, dorsal pons, and middle cerebellar peduncles."

Imaging evidence of leukodystrophy.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:28801086 SUPPORT Human Clinical

"confirmed the presence of pyramidal tract signs, increased muscle tone, and generalized dystonia"

Generalized dystonia on examination.

Sensorimotor neuropathy HP:0007141

Show evidence (1 reference)

PMID:30887539 SUPPORT Human Clinical

"demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT-like disorder"

Peripheral nerve involvement in PGK deficiency.

Constitutional 1

Exercise intolerance HP:0003546

Show evidence (1 reference)

PMID:30570712 SUPPORT Human Clinical

"a personal history of childhood-onset metabolic myopathy that involves episodes of muscle pain, stiffness after activity, exercise intolerance, and myoglobinuria after exertion"

Exercise intolerance as part of childhood-onset metabolic myopathy.

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Genetic Associations

PGK1

Gene: PGK1 hgnc:8896 relationship_type: CAUSATIVE

X-linked recessive

Show evidence (3 references)

PMID:16740138 SUPPORT Human Clinical

"Haplotype analysis of the c. 91A --> T mutation indicated that this was a recurrent mutation."

Establishes p.Asp164Val as a recurrent rather than founder allele.

PMID:30570712 SUPPORT Human Clinical

"This is the first deletion reported in the PGK1 gene and is the first pathogenic variant involving the 3'UTR polyadenylation site of this gene."

Documents a noncoding structural variant reducing PGK1 transcript.

PMID:20151463 SUPPORT Human Clinical

"molecular analysis of the PGK1 gene identified the p.T378P mutation that was recently reported in a patient with isolated myopathy"

The same variant gives isolated myopathy in one patient and myopathy with parkinsonism in another.

💊

Medical Actions

Red Cell Transfusion

Action: red blood cell transfusion Ontology label: Blood Transfusion NCIT:C15192

Platform: Other

Transfusion for symptomatic anemia and hemolytic crises. One report describes subjective improvement with serial transfusion in advanced disease; there is no recommended disease-specific treatment.

Mechanism Target:

BYPASSES Nonspherocytic hemolytic anemia — Replaces erythrocytes lost to hemolysis without correcting the enzyme defect.

Show evidence (2 references)

PMID:30951021 SUPPORT Human Clinical

"we initiated serial blood transfusions and report significant subjective improvement in the patient's physical condition"

Single-patient report of subjective benefit from serial transfusion.

PMID:30951021 SUPPORT Human Clinical

"There is no recommended treatment for PGK deficiency."

Records the absence of disease-specific therapy.

Levodopa

Action: Pharmacotherapy NCIT:C15986

Agent: levodopa CHEBI:15765

Platform: Small molecule

Levodopa improves parkinsonism in affected males, with motor fluctuations. Psychosis at high doses has required an antipsychotic to allow levodopa to be continued.

Mechanism Target:

BYPASSES Nigrostriatal Dopaminergic Dysfunction — Restores striatal dopamine without addressing the cause of the dopaminergic deficit.

Show evidence (2 references)

PMID:30713856 SUPPORT Human Clinical

"Here, we show that their parkinsonism was responsive to levodopa."

Levodopa response in two patients with p.Thr378Pro.

PMID:30713856 SUPPORT Human Clinical

"The psychosis was not responsive to quetiapine at 100 mg/day, but improved when l-dopa was discontinued and quetiapine was maintained."

Records the dose-limiting psychiatric adverse effect.

Hematopoietic Cell Transplantation

Action: allogeneic bone marrow transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Allogeneic bone marrow transplantation has been tried in a few children, partly in the hope of preventing neurological disease. In one boy transplanted at 9 months, hemolytic crises did not recur, but encephalopathic episodes and a later retinal dystrophy did. Whether it changes neurological outcome is not established.

Mechanism Target:

RESTORES Erythrocyte ATP Depletion — Donor-derived erythrocytes carry normal PGK1.

Show evidence (2 references)

PMID:24970202 SUPPORT REVIEW SYNTHESIS Human Clinical

"Recently, an allogeneic bone marrow transplant for hPGK1 deficiency has been attempted to arrest neurological manifestations development"

Records the use and intended purpose of transplantation.

PMID:26396085 SUPPORT Human Clinical

"He had two episodes of encephalopathy following the transplant but no acute episode of haemolysis."

After transplantation, hemolysis did not recur but neurological events did.

Splenectomy

Action: splenectomy Ontology label: Splenectomy NCIT:C15328

Platform: Surgery

Splenectomy has helped some patients but does not stop hemolysis.

Mechanism Target:

INHIBITS Premature Destruction of Energy-Depleted Erythrocytes — Removes a site of red-cell clearance; the defect itself persists.

Show evidence (1 reference)

PMID:24970202 SUPPORT REVIEW SYNTHESIS Human Clinical

"Splenectomy has a favorable outcome in some cases, but does not correct the hemolytic process"

Partial benefit without correction of hemolysis.

Ketogenic Diet

Action: ketogenic diet Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Tried in one adolescent to supply ATP independently of the PGK step; it was stopped after two weeks because hemolysis emerged.

Show evidence (1 reference)

PMID:28801086 REFUTE Human Clinical

"The diet was not tolerated owing to the unexpected emergence of hemolysis."

The one reported trial failed through hemolysis, arguing against this approach.

🔬

Biochemical Markers

Erythrocyte phosphoglycerate kinase activity (Decreased)

Show evidence (1 reference)

PMID:16740138 SUPPORT Human Clinical

"The diagnosis of PGK deficiency was made based on the remarkably low (<5% of normal) erythrocyte PGK enzyme activity level"

Red-cell enzyme activity is the diagnostic assay.

Erythrocyte 2,3-bisphosphoglycerate (Increased)

Show evidence (1 reference)

PMID:6938182 SUPPORT Human Clinical

"However, they had more than double the normal level of 2,3-diphosphoglycerate (2,3-DPG) in their red cells"

More than twofold red-cell 2,3-bisphosphoglycerate.

Lactate response to ischemic forearm exercise (Decreased)

Show evidence (1 reference)

PMID:30111548 SUPPORT Human Clinical

"Patients with pure myopathy had greater increases in lactate with ischemic exercise (2-3 mmol/L) vs the 2 multisystem-affected patients (<1 mmol/L)."

The ischemic lactate rise is blunted, and lowest in multisystem disease.

📊

Prevalence

Worldwide

Cases In Literature Ultra Rare

Twenty-six families had been described by 2007; later reports add a small number. No population-based estimate exists.

Show evidence (2 references)

PMID:17222195 SUPPORT REVIEW SYNTHESIS Human Clinical

"Twenty-six families have been described and in 20 of these the mutations are known."

Literature case count.

PMID:30887539 SUPPORT Human Clinical

"This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum"

A national survey found only three French patients.

{ }

Source YAML

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name: Phosphoglycerate Kinase 1 Deficiency
category: Mendelian
creation_date: "2026-10-01T00:00:00Z"
synonyms:
- PGK deficiency
- PGK1 deficiency
- Phosphoglycerate kinase deficiency
- Phosphoglycerate kinase 1 deficiency, X-linked recessive
- Glycogen storage disease due to phosphoglycerate kinase 1 deficiency
- GSD due to phosphoglycerate kinase 1 deficiency
- PGK1 glycogen storage disease
description: >-
  Phosphoglycerate kinase 1 deficiency is an X-linked recessive glycolytic
  disorder caused by hemizygous pathogenic variants in PGK1. PGK1 catalyzes the
  first ATP-generating step of glycolysis, the transfer of phosphate from
  1,3-bisphosphoglycerate to ADP, and is expressed in all somatic tissues.
  Affected males show variable combinations of three tissue syndromes, and rarely
  all three: chronic nonspherocytic hemolytic anemia; a metabolic myopathy with
  exercise intolerance, cramps and exertional rhabdomyolysis with myoglobinuria;
  and central nervous system involvement including intellectual disability,
  seizures, stroke-like and encephalopathic episodes, retinal dystrophy and
  early-onset levodopa-responsive parkinsonism. Most pathogenic variants reduce
  the kinetic stability of the enzyme as well as, to different degrees, its
  catalytic efficiency, and complete loss-of-function alleles have not been
  observed. Which tissue is affected is not fully explained by the molecular
  properties of the mutant enzyme, although lower residual glycolytic capacity
  is associated with multisystem disease. Red cells accumulate
  2,3-bisphosphoglycerate, which right-shifts the oxygen-hemoglobin
  dissociation curve and partly offsets the anemia. Some heterozygous women
  are affected, through reduced red-cell activity or, in one reported mother,
  parkinsonism. There is no disease-specific therapy; management is supportive
  (transfusion, levodopa for parkinsonism, avoidance of strenuous exercise), and
  hematopoietic cell transplantation has been attempted in a few children.
disease_term:
  preferred_term: phosphoglycerate kinase 1 deficiency
  term:
    id: MONDO:0010392
    label: glycogen storage disease due to phosphoglycerate kinase 1 deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010392
      label: glycogen storage disease due to phosphoglycerate kinase 1 deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0010392 is the PGK1-specific disease concept; its definition names
      the hemolytic, myopathic and central nervous system combinations curated
      here, and its synonyms include "phosphoglycerate kinase 1 deficiency,
      X-linked recessive" and "PGK deficiency".
classifications:
  icimd_category:
  - classification_value: glycolysis
    notes: >-
      IEMbase/ICIMD places PGK1-related phosphoglycerate kinase deficiency under
      disorders of glycolysis within disorders of carbohydrate metabolism
      (WP-007 package, classification code 3.3.1.01).
parents:
- disorder of glycolysis
- disorder of glycogen metabolism
mechanistic_hypotheses:
- hypothesis_group_id: pgk1_residual_glycolytic_capacity_model
  hypothesis_label: Residual glycolytic capacity determines tissue involvement
  status: EMERGING
  description: >-
    The degree to which glycolytic flux is lost, set by the combined effect of
    a variant on catalytic efficiency and on protein stability, determines
    which tissues fail. In a case series, the lowest residual activity
    accompanied multisystem disease and the smallest ischemic lactate rise. The
    model does not account for every genotype: some variants with mild
    molecular defects produce broad phenotypes, and one recurrent variant has
    produced both isolated myopathy and myopathy with parkinsonism.
  evidence:
  - reference: PMID:30111548
    reference_title: Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower glycolytic capacity in PGK1 deficiency seems to result in
      multisystem involvement and increased susceptibility to exertional
      rhabdomyolysis.
    explanation: >-
      Human exercise physiology relates lower residual glycolytic capacity to
      multisystem rather than purely myopathic disease.
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      However, the clinical symptoms can not be understood only on the bases of
      molecular properties of the mutant enzyme.
    explanation: >-
      The largest recombinant-enzyme study finds that molecular properties
      alone do not predict the tissue pattern, so the model is incomplete.
- hypothesis_group_id: pgk1_2_3_bpg_hemolysis_model
  hypothesis_label: 2,3-bisphosphoglycerate excess as the proximate cause of hemolysis
  status: ALTERNATIVE
  description: >-
    Rather than ATP shortfall alone, hemolysis may follow from intracellular
    acidification and inhibition of other glycolytic enzymes by the raised
    erythrocyte 2,3-bisphosphoglycerate concentration. This is offered as a
    suggestion in the source rather than a demonstrated mechanism.
  evidence:
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      that the true cause of the hemolysis is better ascribable to an increase of acidity or
      inhibition of several glycolytic enzymes (such as hexokinase,
      phosphofructo kinase, and pyruvate kinase) as a consequence of an increased
      intracellular concentration of 2,3-BPG
    explanation: >-
      States the alternative hemolysis mechanism, in explicitly conjectural
      language.
pathophysiology:
- name: PGK1 Enzyme Instability and Catalytic Deficiency
  description: >-
    Hemizygous PGK1 variants in males reduce phosphoglycerate kinase activity,
    most often by lowering the kinetic stability of the enzyme so that it
    denatures quickly at body temperature, and to a variable extent by impairing
    catalysis. Residual activity is retained in every reported patient;
    complete loss-of-function alleles have not been observed, which suggests
    that some PGK1 function is needed for male viability.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  genes:
  - preferred_term: PGK1
    term:
      id: hgnc:8896
      label: PGK1
  molecular_functions:
  - preferred_term: phosphoglycerate kinase activity
    term:
      id: GO:0004618
      label: phosphoglycerate kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:30887539
    reference_title: "Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic
      disorder caused by mutations in the PGK1 gene.
    explanation: Establishes PGK1 as the causal gene and X-linked transmission.
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Most mutations heavily affect thermal stability and to a different extent
      catalytic efficiency, in line with the remarkably low PGK activity
      clinically observed in the patients.
    explanation: >-
      Recombinant characterization of 16 disease variants shows that instability
      and catalytic impairment together account for the low enzyme activity.
  - reference: PMID:23336698
    reference_title: Structural and energetic basis of protein kinetic destabilization in human phosphoglycerate kinase 1 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Kinetic analysis of differential scanning calorimetry profiles shows that
      the disease-causing mutations decrease PGK1 kinetic stability from ~5-fold
      (E252A) to ~100000-fold (L89P) compared to that of wild-type PGK1, and in
      some cases, mutant enzymes are denatured on a time scale of a few minutes
      at physiological temperature.
    explanation: Quantifies the kinetic destabilization of disease variants.
  - reference: PMID:30570712
    reference_title: A Hemizygous Deletion Within the PGK1 Gene in Males with PGK1 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete loss-of-function variants have not been reported in this gene,
      indicating that residual enzyme function is critical for viability in
      males.
    explanation: Supports modelling the trigger as a partial rather than complete loss of function.
  downstream:
  - target: Reduced Glycolytic ATP Generation
    causal_link_type: DIRECT
    description: >-
      PGK1 catalyzes the first ATP-yielding step of glycolysis, so loss of its
      activity reduces glycolytic ATP production.
- name: Reduced Glycolytic ATP Generation
  description: >-
    Reduced PGK1 activity lowers flux through the lower half of glycolysis and
    the ATP it yields. Tissues differ in how much this matters: mature
    erythrocytes have no mitochondria and depend on glycolysis entirely,
    skeletal muscle depends on it during brief intense or ischemic exertion,
    and neurons may fail to replace unstable enzyme fast enough. How severe the
    loss of flux is in a given patient is associated with which tissues are
    affected.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: ATP
    term:
      id: CHEBI:15422
      label: ATP
    modifier: DECREASED
  evidence:
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, an increased degradation rate of such variants leads to a decreased
      PGK1 content which primarily accounts for the enzyme deficiency and in
      turn for a reduced ATP production.
    explanation: Links variant instability to reduced enzyme content and reduced ATP production.
  - reference: PMID:30111548
    reference_title: Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case series study of PGK1 deficiency suggests that the level of
      impaired glycolysis in PGK deficiency is a major determinant of phenotype.
    explanation: Human data place impaired glycolysis at the center of the phenotype.
  downstream:
  - target: Erythrocyte ATP Depletion
    causal_link_type: DIRECT
    description: >-
      Erythrocytes have no alternative ATP source, so the glycolytic block
      lowers red-cell ATP.
  - target: Erythrocyte 2,3-Bisphosphoglycerate Accumulation
    causal_link_type: DIRECT
    description: >-
      The glycolytic block raises the upstream intermediate
      2,3-bisphosphoglycerate in erythrocytes.
  - target: Skeletal Muscle Glycolytic Failure During Exertion
    causal_link_type: DIRECT
    description: >-
      During intense or ischemic exercise, muscle cannot raise glycolytic flux,
      so lactate output and ATP supply fall short of demand.
    hypothesis_groups:
    - pgk1_residual_glycolytic_capacity_model
  - target: Neuronal Energy Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced glycolytic ATP generation in the central nervous system is the
      proposed basis of the neurological syndrome, supported by an invertebrate
      model; the human neural lesion has not been measured directly.
    hypothesis_groups:
    - pgk1_residual_glycolytic_capacity_model
- name: Erythrocyte ATP Depletion
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Reduced Erythrocyte Integrity"
  description: >-
    In affected red cells, ATP falls substantially. The ATP shortfall compromises
    the energy-dependent maintenance of the red cell, which is then cleared early.
    Erythrocyte disease is reported mainly with variants that are unstable but
    only mildly impaired catalytically.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  chemical_entities:
  - preferred_term: ATP
    term:
      id: CHEBI:15422
      label: ATP
    modifier: DECREASED
  evidence:
  - reference: PMID:6938182
    reference_title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Red cell ATP levels were substantially decreased in both subjects.
    explanation: Direct measurement of red-cell ATP depletion in affected males.
  - reference: PMID:20151463
    reference_title: Myopathy and parkinsonism in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anaerobic glycolysis is the only source of energy in mature erythrocytes
      due to their lack of mitochondria, and hemolytic anemia is the common
      presentation of glycogenoses that affect red blood cells.
    explanation: States why the erythrocyte is especially exposed to a glycolytic block.
  downstream:
  - target: Premature Destruction of Energy-Depleted Erythrocytes
    causal_link_type: DIRECT
    description: >-
      ATP-depleted red cells are removed from the circulation early.
- name: Erythrocyte 2,3-Bisphosphoglycerate Accumulation
  description: >-
    In affected red cells, 2,3-bisphosphoglycerate rises to more than twice normal.
    The elevated concentration shifts the oxygen-hemoglobin dissociation curve
    and may contribute to hemolysis by intracellular acidification and inhibition
    of other glycolytic enzymes.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  chemical_entities:
  - preferred_term: 2,3-bisphosphoglycerate
    term:
      id: CHEBI:17720
      label: 2,3-bisphospho-D-glyceric acid
    modifier: INCREASED
  evidence:
  - reference: PMID:6938182
    reference_title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, they had more than double the normal level of
      2,3-diphosphoglycerate (2,3-DPG) in their red cells
    explanation: Direct measurement of 2,3-bisphosphoglycerate accumulation.
  downstream:
  - target: Rightward Shift of the Oxygen-Hemoglobin Dissociation Curve
    causal_link_type: DIRECT
    description: >-
      Raised 2,3-bisphosphoglycerate lowers hemoglobin oxygen affinity.
  - target: Premature Destruction of Energy-Depleted Erythrocytes
    causal_link_type: DIRECT
    description: >-
      2,3-bisphosphoglycerate excess may contribute to hemolysis through
      intracellular acidification and inhibition of glycolytic enzymes.
    hypothesis_groups:
    - pgk1_2_3_bpg_hemolysis_model
- name: Rightward Shift of the Oxygen-Hemoglobin Dissociation Curve
  description: >-
    The 2,3-bisphosphoglycerate excess lowers hemoglobin oxygen affinity, so
    oxygen is released to tissues at higher tension. Outside hemolytic crises
    this offsets much of the loss of oxygen-carrying capacity from the anemia.
  role: compensation
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:6938182
    reference_title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This shift in the curve was sufficient to permit oxygen delivery to most
      body tissues, including the brain, at better tensions than normal, except
      during a haemolytic crisis.
    explanation: Shows the compensatory effect of the right shift on oxygen delivery.
- name: Premature Destruction of Energy-Depleted Erythrocytes
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  description: >-
    Energy-depleted erythrocytes have a shortened lifespan. Hemolysis is chronic
    and compensated in most affected males, with crises that are often
    triggered by febrile infection.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: erythrocyte clearance
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  evidence:
  - reference: PMID:6938182
    reference_title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both had moderate haemolytic anaemia complicated by the occurrence of
      haemolytic crises.
    explanation: Documents chronic hemolysis with superimposed crises in affected males.
  - reference: PMID:28801086
    reference_title: Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hemolytic crisis with rhabdomyolysis triggered by febrile viral infections
    explanation: Reports infection as the trigger of hemolytic crisis.
  downstream:
  - target: Nonspherocytic hemolytic anemia
    causal_link_type: DIRECT
    description: >-
      Shortened red-cell survival produces chronic nonspherocytic hemolytic
      anemia.
- name: Skeletal Muscle Glycolytic Failure During Exertion
  description: >-
    During brief intense or ischemic exercise, skeletal muscle with low PGK1
    activity cannot raise glycolytic flux. Lactate output on forearm testing is
    blunted, while ammonia rises normally, and the energy shortfall precipitates
    cramps, myalgia and fiber breakdown. Most reported myopathy-only variants
    impair both stability and catalysis.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: glycolytic process in skeletal muscle
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: DECREASED
  evidence:
  - reference: PMID:35527021
    reference_title: "A Mild Clinical Phenotype with Myopathic and Hemolytic Forms of Phosphoglycerate Kinase Deficiency (PGK Osaka): A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A semi-ischemic forearm exercise test evoked only a modest or sub-normal
      lactate increase (Figure B), while NH3 showed a normal increase.
    explanation: Functional evidence of a muscle glycolytic block with preserved ammonia response.
  - reference: PMID:30111548
    reference_title: Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Enzyme levels of PGK were 4% to 9% of normal in red cells and 5% to10% in
      muscle in pure myopathy patients and 2.6% in both muscle and red cells in
      the 2 patients with multisystem involvement.
    explanation: Documents the low muscle enzyme activity underlying the myopathy.
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Conversely, the myopathy without hemolytic or neurological symptoms is
      observed in some patients with variants heavily affected in both catalytic
      properties and protein stability
    explanation: Relates the myopathic presentation to variants with combined catalytic and stability defects.
  downstream:
  - target: Exertional Rhabdomyolysis
    causal_link_type: DIRECT
    description: >-
      An energy deficit in exercising muscle leads to fiber breakdown and
      release of myoglobin and creatine kinase.
  - target: Exercise intolerance
    causal_link_type: DIRECT
    description: >-
      Inability to raise glycolytic flux limits brief intense exertion.
  - target: Exercise-induced muscle cramps
    causal_link_type: DIRECT
    description: >-
      Cramps and contracture-like pain accompany exertion in energy-depleted
      muscle.
- name: Exertional Rhabdomyolysis
  description: >-
    Recurrent exercise-induced breakdown of skeletal muscle with myoglobinuria
    is the defining event of the myopathic form and can also be provoked by
    febrile illness. It occurs in isolated myopathy and in multisystem disease,
    in which lower glycolytic capacity is associated with greater
    susceptibility.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:19157875
    reference_title: "Myopathic form of phosphoglycerate kinase (PGK) deficiency: a new case and pathogenic considerations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe an 18-year-old man with muscle cramps and recurrent exertional
      myoglobinuria, without hemolytic anemia or brain dysfunction.
    explanation: Clinical description of exertional myoglobinuria as an isolated presentation.
  - reference: PMID:30111548
    reference_title: Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One multisystem-affected patient developed frank myoglobinuria after the
      short exercise test.
    explanation: Exercise testing directly provoked myoglobinuria in a patient with low residual activity.
  downstream:
  - target: Rhabdomyolysis
    causal_link_type: DIRECT
    description: Muscle fiber breakdown is the clinical rhabdomyolysis.
  - target: Myoglobinuria
    causal_link_type: DIRECT
    description: Released myoglobin is excreted in the urine.
  - target: Elevated circulating creatine kinase activity
    causal_link_type: DIRECT
    description: Damaged muscle fibers release creatine kinase into the circulation.
- name: Neuronal Energy Failure
  description: >-
    The neurological syndrome is attributed to inadequate glycolytic ATP supply
    in the central nervous system, possibly because neural tissue does not
    replace the unstable enzyme quickly enough. This is supported by a
    Drosophila PGK mutant with reduced brain ATP, seizures and a later loss of
    synaptic transmission. Brain ATP has not been measured in patients, and
    neurological disease is associated with unstable variants that are only
    mildly impaired catalytically.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  chemical_entities:
  - preferred_term: ATP
    term:
      id: CHEBI:15422
      label: ATP
    modifier: DECREASED
  evidence:
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      As for the neurological dysfunctions, the tissue presumably does not
      promptly supply new enzyme to replace the damaged fraction, leading to a
      depletion of ATP.
    explanation: >-
      Proposes neural ATP depletion from failure to replace unstable enzyme;
      the wording is conjectural, which is why the node is HYPOTHETICAL.
  - reference: PMID:15140922
    reference_title: A Drosophila temperature-sensitive seizure mutant in phosphoglycerate kinase disrupts ATP generation and alters synaptic function.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with altered ATP generation in nubian animals, brain extracts
      show a threefold reduction in resting ATP levels compared with controls.
    explanation: A PGK mutant fly shows reduced brain ATP, the proposed lesion of this node.
  - reference: PMID:15140922
    reference_title: A Drosophila temperature-sensitive seizure mutant in phosphoglycerate kinase disrupts ATP generation and alters synaptic function.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Disruption of ATP generation in nubian animals is accompanied by
      temperature-dependent defects in neuronal activity, with initial seizure
      activity, followed by an activity-dependent loss of synaptic transmission.
    explanation: Links reduced PGK-dependent ATP generation to seizures and synaptic failure in a model organism.
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neuronal energy failure is proposed to underlie seizures, by analogy with
      the seizure phenotype of the PGK-mutant fly.
    hypothesis_groups:
    - pgk1_residual_glycolytic_capacity_model
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Developmental neural energy failure is the proposed basis of intellectual
      disability; the intermediate steps are not characterized.
    hypothesis_groups:
    - pgk1_residual_glycolytic_capacity_model
  - target: Nigrostriatal Dopaminergic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Glycolytic energy failure is proposed to make nigrostriatal dopaminergic
      neurons especially vulnerable; why this population is affected is unknown.
    hypothesis_groups:
    - pgk1_residual_glycolytic_capacity_model
- name: Nigrostriatal Dopaminergic Dysfunction
  conforms_to: "parkinsonism_dopaminergic_degeneration#Nigrostriatal Dopaminergic Neurodegeneration"
  description: >-
    Affected males with early-onset parkinsonism show severe bilateral loss of
    putaminal dopamine transporter binding without structural lesions, and
    respond to levodopa. Parkinsonism has been reported both with and without
    hemolysis, and in one heterozygous mother, whose reduced activity in the
    substantia nigra the authors attribute to skewed X inactivation.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  evidence:
  - reference: PMID:30975619
    reference_title: Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      99mTc-TRODAT-1 SPECT showed severe bilateral reduced putaminal uptake in
      the three patients.
    explanation: Dopamine transporter imaging shows presynaptic nigrostriatal deficit in affected males.
  - reference: PMID:30975619
    reference_title: Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the patients had structural lesions that could explain either
      pre- or postsynaptic dopaminergic dysfunction.
    explanation: Excludes a structural explanation for the dopaminergic deficit.
  - reference: PMID:28649613
    reference_title: "Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, selective enzymatic deficiency in the substantia nigra is
      possible in heterozygous carriers even when erythrocytes exhibit normal
      enzymatic activity, as observed in the present case.
    explanation: >-
      Proposes a nigra-specific enzyme deficit to explain parkinsonism in a
      heterozygous mother with normal red-cell activity.
  downstream:
  - target: Parkinsonism
    causal_link_type: DIRECT
    description: >-
      Loss of presynaptic nigrostriatal dopaminergic function produces
      levodopa-responsive parkinsonism.
phenotypes:
- name: Nonspherocytic hemolytic anemia
  category: Hematologic
  description: >-
    Chronic nonspherocytic hemolytic anemia, mild to severe, with hemolytic
    crises. It is the commonest presentation, alone or with central nervous
    system involvement, and is absent in the purely myopathic form.
  phenotype_term:
    preferred_term: Nonspherocytic hemolytic anemia
    term:
      id: HP:0001930
      label: Nonspherocytic hemolytic anemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:17222195
    reference_title: PGK deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Phosphoglycerate kinase (PGK) deficiency is one of the relatively uncommon
      causes of hereditary non-spherocytic haemolytic anaemia (HNSHA).
    explanation: Places PGK deficiency among the causes of hereditary nonspherocytic hemolytic anemia.
  - reference: PMID:16740138
    reference_title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a white American family, two sons presented with haemolytic anaemia,
      seizures, and developmental delay.
    explanation: Reports hemolytic anemia with neurological involvement in affected brothers.
- name: Rhabdomyolysis
  category: Musculoskeletal
  description: >-
    Recurrent rhabdomyolysis, usually after exertion and sometimes with febrile
    illness, is the main feature of the myopathic form.
  phenotype_term:
    preferred_term: Exertional rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
    temporality: RECURRENT
  evidence:
  - reference: PMID:30887539
    reference_title: "Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Case 2 was a 71-year-old patient with recurrent exertional rhabdomyolysis,
      and a c.943G > A PGK1 hemizygous mutation.
    explanation: Recurrent exertional rhabdomyolysis in a genetically confirmed patient.
  - reference: PMID:26883264
    reference_title: "Recurrent episodes of myoglobinuria, mental retardation and seizures but no hemolysis in two brothers with phosphoglycerate kinase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two brothers with mild intellectual deficiency, exercise
      intolerance, rhabdomyolysis, seizures and no hemolysis.
    explanation: Rhabdomyolysis with central nervous system involvement and no hemolysis.
- name: Myoglobinuria
  category: Musculoskeletal
  description: Episodic myoglobinuria accompanies exertional rhabdomyolysis.
  phenotype_term:
    preferred_term: Exercise-induced myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
    temporality: RECURRENT
  evidence:
  - reference: PMID:19157875
    reference_title: "Myopathic form of phosphoglycerate kinase (PGK) deficiency: a new case and pathogenic considerations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe an 18-year-old man with muscle cramps and recurrent exertional
      myoglobinuria, without hemolytic anemia or brain dysfunction.
    explanation: Recurrent exertional myoglobinuria.
- name: Exercise intolerance
  category: Musculoskeletal
  description: Exercise intolerance limited to brief, intense or ischemic effort.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:30570712
    reference_title: A Hemizygous Deletion Within the PGK1 Gene in Males with PGK1 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a personal history of childhood-onset metabolic myopathy that involves
      episodes of muscle pain, stiffness after activity, exercise intolerance,
      and myoglobinuria after exertion
    explanation: Exercise intolerance as part of childhood-onset metabolic myopathy.
- name: Exercise-induced muscle cramps
  category: Musculoskeletal
  description: Cramps and myalgia with exertion.
  phenotype_term:
    preferred_term: Exercise-induced muscle cramps
    term:
      id: HP:0003710
      label: Exercise-induced muscle cramps
  evidence:
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mental retardation, behavioral abnormalities, seizures or strokes
      represent the main neurological alterations, whereas cramps and
      myoglobinuria characterize the myopathic forms.
    explanation: Summarizes cramps as characteristic of the myopathic form across reported patients.
- name: Elevated circulating creatine kinase activity
  category: Laboratory
  description: Creatine kinase rises during episodes of muscle breakdown.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:40026287
    reference_title: First Report of Phosphoglycerate Kinase Deficiency in a Dinè Child With Review of Current Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with acute respiratory distress, elevated creatine kinase,
      anemia, and progressive encephalopathy
    explanation: Elevated creatine kinase at presentation.
- name: Intellectual disability
  category: Neurological
  description: Intellectual disability or developmental delay, the commonest central nervous system feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:17222195
    reference_title: PGK deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mutations of this gene may cause chronic haemolysis with or without mental
      retardation and they may cause myopathies, often with episodes of
      myoglobinuria, or a combination of these clinical manifestations.
    explanation: Summarizes intellectual disability as a recurrent feature across reported families.
- name: Seizure
  category: Neurological
  description: Seizures, in some patients as epilepsy.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:16740138
    reference_title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a white American family, two sons presented with haemolytic anaemia,
      seizures, and developmental delay.
    explanation: Seizures in affected brothers.
- name: Stroke-like episode
  category: Neurological
  description: >-
    Infantile-onset encephalopathic and stroke-like episodes, reported with the
    recurrent p.Asp164Val variant.
  phenotype_term:
    preferred_term: Stroke-like episode
    term:
      id: HP:0002401
      label: Stroke-like episode
  evidence:
  - reference: PMID:30975619
    reference_title: Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients initially presented with infantile-onset encephalopathic and
      stroke-like episodes, haemolytic anaemia and epilepsy.
    explanation: Stroke-like and encephalopathic episodes in three affected males.
- name: Encephalopathy
  category: Neurological
  description: Acute or progressive encephalopathy, including after hematopoietic cell transplantation.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:40026287
    reference_title: First Report of Phosphoglycerate Kinase Deficiency in a Dinè Child With Review of Current Literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with acute respiratory distress, elevated creatine kinase,
      anemia, and progressive encephalopathy
    explanation: Progressive encephalopathy at presentation.
- name: Parkinsonism
  category: Neurological
  description: >-
    Early-onset or juvenile parkinsonism that responds to levodopa, with motor
    fluctuations; reported with and without hemolysis.
  phenotype_term:
    preferred_term: Early-onset parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:30975619
    reference_title: Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients had an early-onset and one juvenile-onset levodopa
      responsive Parkinsonism with motor fluctuations.
    explanation: Early-onset levodopa-responsive parkinsonism in affected males.
  - reference: PMID:20151463
    reference_title: Myopathy and parkinsonism in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 25-year-old man with exertional myoglobinuria had no evidence of
      hemolytic anemia, but he had severe parkinsonism that was responsive to
      levodopa.
    explanation: Parkinsonism in the myopathic form without hemolysis.
- name: Retinal dystrophy
  category: Ophthalmologic
  description: >-
    Retinal dystrophy with rod and cone dysfunction and a normal visual evoked
    potential. The mechanism is unknown, so the phenotype is not linked to a
    pathophysiology node.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:26396085
    reference_title: "A negative waveform in the scotopic response in a patient with phosphoglycerate kinase deficiency: a visual electrophysiology report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual electrophysiology results identified retinal involvement involving
      both rod and cone dysfunction.
    explanation: Electrophysiological evidence of retinal dystrophy.
  - reference: PMID:16740138
    reference_title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the proband, hemiplegic migraines, retinal dystrophy and muscle fatigue
    explanation: Retinal dystrophy in a patient with the recurrent p.Asp164Val variant.
- name: Hemiplegic migraine
  category: Neurological
  description: Hemiplegic migraine reported in one patient.
  phenotype_term:
    preferred_term: Hemiplegic migraine
    term:
      id: HP:0002076
      label: Migraine
  evidence:
  - reference: PMID:16740138
    reference_title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the proband, hemiplegic migraines, retinal dystrophy and muscle fatigue
    explanation: Hemiplegic migraine in a single proband.
- name: Leukodystrophy
  category: Neurological
  description: >-
    Slowly progressive leukodystrophy with pyramidal signs and dystonia,
    reported in one adolescent. A single case; the mechanism is not known.
  phenotype_term:
    preferred_term: Progressive leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28801086
    reference_title: Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance (MR) imaging revealed leukodystrophy in the
      periventricular white matter, posterior limbs of the internal capsule,
      dorsal pons, and middle cerebellar peduncles.
    explanation: Imaging evidence of leukodystrophy.
- name: Dystonia
  category: Neurological
  description: Generalized dystonia, reported with leukodystrophy in one patient.
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:28801086
    reference_title: Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      confirmed the presence of pyramidal tract signs, increased muscle tone,
      and generalized dystonia
    explanation: Generalized dystonia on examination.
- name: Sensorimotor neuropathy
  category: Neurological
  description: >-
    Severe chronic axonal sensorimotor polyneuropathy resembling
    Charcot-Marie-Tooth disease, reported in one patient.
  phenotype_term:
    preferred_term: Axonal sensorimotor polyneuropathy
    term:
      id: HP:0007141
      label: Sensorimotor neuropathy
  evidence:
  - reference: PMID:30887539
    reference_title: "Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      demonstrates for the first time that PGK deficiency may affect the
      peripheral nervous system and present as a CMT-like disorder
    explanation: Peripheral nerve involvement in PGK deficiency.
biochemical:
- name: Erythrocyte phosphoglycerate kinase activity
  presence: Decreased
  notes: >-
    Usually below 10% of normal in affected males; myopathy-only patients may
    retain somewhat more activity than multisystem-affected patients.
  evidence:
  - reference: PMID:16740138
    reference_title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of PGK deficiency was made based on the remarkably low (<5%
      of normal) erythrocyte PGK enzyme activity level
    explanation: Red-cell enzyme activity is the diagnostic assay.
- name: Erythrocyte 2,3-bisphosphoglycerate
  presence: Increased
  evidence:
  - reference: PMID:6938182
    reference_title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, they had more than double the normal level of
      2,3-diphosphoglycerate (2,3-DPG) in their red cells
    explanation: More than twofold red-cell 2,3-bisphosphoglycerate.
- name: Lactate response to ischemic forearm exercise
  presence: Decreased
  notes: Ammonia rises normally, which distinguishes a glycolytic block from myoadenylate deaminase deficiency.
  evidence:
  - reference: PMID:30111548
    reference_title: Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with pure myopathy had greater increases in lactate with
      ischemic exercise (2-3 mmol/L) vs the 2 multisystem-affected patients (<1
      mmol/L).
    explanation: The ischemic lactate rise is blunted, and lowest in multisystem disease.
genetic:
- name: PGK1
  gene_term:
    preferred_term: PGK1
    term:
      id: hgnc:8896
      label: PGK1
  relationship_type: CAUSATIVE
  inheritance:
  - name: X-linked recessive
    evidence:
    - reference: PMID:30887539
      reference_title: "Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic
        disorder caused by mutations in the PGK1 gene.
      explanation: X-linked PGK1 causation.
  features: >-
    Mostly missense variants, with splice-site, in-frame deletion and one
    3' UTR polyadenylation-site deletion also reported. The recurrent
    c.491A>T (p.Asp164Val; PGK Amiens/New York) arose independently in
    several families and is associated with hemolysis, epilepsy and
    parkinsonism. p.Thr378Pro has been reported both as isolated myopathy and
    as myopathy with parkinsonism.
  evidence:
  - reference: PMID:16740138
    reference_title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Haplotype analysis of the c. 91A --> T mutation indicated that this was a
      recurrent mutation.
    explanation: Establishes p.Asp164Val as a recurrent rather than founder allele.
  - reference: PMID:30570712
    reference_title: A Hemizygous Deletion Within the PGK1 Gene in Males with PGK1 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first deletion reported in the PGK1 gene and is the first
      pathogenic variant involving the 3'UTR polyadenylation site of this gene.
    explanation: Documents a noncoding structural variant reducing PGK1 transcript.
  - reference: PMID:20151463
    reference_title: Myopathy and parkinsonism in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      molecular analysis of the PGK1 gene identified the p.T378P mutation that
      was recently reported in a patient with isolated myopathy
    explanation: The same variant gives isolated myopathy in one patient and myopathy with parkinsonism in another.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Hemizygous males are affected. Heterozygous women are usually unaffected
    but can show reduced red-cell activity and hemolytic anemia, and one
    heterozygous mother developed early-onset parkinsonism, which the authors
    attribute to skewed X inactivation.
  evidence:
  - reference: PMID:6938182
    reference_title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They had moderate haemolytic anaemia, considerable reduction of red cell
      PGK activity (19% and 35% of normal, respectively)
    explanation: Manifesting heterozygous women with reduced activity and hemolysis.
  - reference: PMID:28649613
    reference_title: "Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a boy with PGK-1 deficiency and his mother, a carrier of a
      heterozygous mutation in PGK-1, both of whom presented with early-onset
      parkinsonism.
    explanation: Parkinsonism in a heterozygous mother.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twenty-six families had been described by 2007; later reports add a small
    number. No population-based estimate exists.
  evidence:
  - reference: PMID:17222195
    reference_title: PGK deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Twenty-six families have been described and in 20 of these the mutations
      are known.
    explanation: Literature case count.
  - reference: PMID:30887539
    reference_title: "Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study confirms that PGK deficiency is an extremely rare disorder with
      a wide phenotypic spectrum
    explanation: A national survey found only three French patients.
treatments:
- name: Red Cell Transfusion
  description: >-
    Transfusion for symptomatic anemia and hemolytic crises. One report
    describes subjective improvement with serial transfusion in advanced
    disease; there is no recommended disease-specific treatment.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Nonspherocytic hemolytic anemia
    treatment_effect: BYPASSES
    description: Replaces erythrocytes lost to hemolysis without correcting the enzyme defect.
  evidence:
  - reference: PMID:30951021
    reference_title: "Therapeutic Benefit of Blood Transfusion in a Patient With Novel PGK1 Mutation (c.461T>C [p.L154P])."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we initiated serial blood transfusions and report significant subjective
      improvement in the patient's physical condition
    explanation: Single-patient report of subjective benefit from serial transfusion.
  - reference: PMID:30951021
    reference_title: "Therapeutic Benefit of Blood Transfusion in a Patient With Novel PGK1 Mutation (c.461T>C [p.L154P])."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There is no recommended treatment for PGK deficiency.
    explanation: Records the absence of disease-specific therapy.
- name: Levodopa
  description: >-
    Levodopa improves parkinsonism in affected males, with motor fluctuations.
    Psychosis at high doses has required an antipsychotic to allow levodopa to
    be continued.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_mechanisms:
  - target: Nigrostriatal Dopaminergic Dysfunction
    treatment_effect: BYPASSES
    description: Restores striatal dopamine without addressing the cause of the dopaminergic deficit.
  evidence:
  - reference: PMID:30713856
    reference_title: Levodopa Responsive Parkinsonism in Two Patients With Phosphoglycerate Kinase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we show that their parkinsonism was responsive to levodopa.
    explanation: Levodopa response in two patients with p.Thr378Pro.
  - reference: PMID:30713856
    reference_title: Levodopa Responsive Parkinsonism in Two Patients With Phosphoglycerate Kinase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The psychosis was not responsive to quetiapine at 100 mg/day, but improved
      when l-dopa was discontinued and quetiapine was maintained.
    explanation: Records the dose-limiting psychiatric adverse effect.
- name: Hematopoietic Cell Transplantation
  description: >-
    Allogeneic bone marrow transplantation has been tried in a few children,
    partly in the hope of preventing neurological disease. In one boy
    transplanted at 9 months, hemolytic crises did not recur, but encephalopathic
    episodes and a later retinal dystrophy did. Whether it changes neurological
    outcome is not established.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic bone marrow transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Erythrocyte ATP Depletion
    treatment_effect: RESTORES
    description: Donor-derived erythrocytes carry normal PGK1.
  evidence:
  - reference: PMID:24970202
    reference_title: "Protein Stability, Folding and Misfolding in Human PGK1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Recently, an allogeneic bone marrow transplant for hPGK1 deficiency has
      been attempted to arrest neurological manifestations development
    explanation: Records the use and intended purpose of transplantation.
  - reference: PMID:26396085
    reference_title: "A negative waveform in the scotopic response in a patient with phosphoglycerate kinase deficiency: a visual electrophysiology report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had two episodes of encephalopathy following the transplant but no
      acute episode of haemolysis.
    explanation: After transplantation, hemolysis did not recur but neurological events did.
- name: Splenectomy
  description: Splenectomy has helped some patients but does not stop hemolysis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Premature Destruction of Energy-Depleted Erythrocytes
    treatment_effect: INHIBITS
    description: Removes a site of red-cell clearance; the defect itself persists.
  evidence:
  - reference: PMID:24970202
    reference_title: "Protein Stability, Folding and Misfolding in Human PGK1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Splenectomy has a favorable outcome in some cases, but does not correct
      the hemolytic process
    explanation: Partial benefit without correction of hemolysis.
- name: Ketogenic Diet
  description: >-
    Tried in one adolescent to supply ATP independently of the PGK step; it was
    stopped after two weeks because hemolysis emerged.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: ketogenic diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:28801086
    reference_title: Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diet was not tolerated owing to the unexpected emergence of
      hemolysis.
    explanation: The one reported trial failed through hemolysis, arguing against this approach.
discussions:
- discussion_id: gap_pgk1_tissue_selectivity
  prompt: >-
    Why do variants in a ubiquitously expressed enzyme produce hemolysis alone,
    myopathy alone, or central nervous system disease in different patients,
    and why does the same variant (p.Thr378Pro) cause isolated myopathy in one
    man and myopathy with parkinsonism in another?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Glycolytic ATP Generation
  - pathophysiology#Neuronal Energy Failure
  - mechanistic_hypotheses#pgk1_residual_glycolytic_capacity_model
  rationale: >-
    Molecular stability and catalytic data correlate with tissue pattern for
    some variant classes but not others, and the authors of the largest study
    point to environmental, genetic and epigenetic modifiers. A co-inherited
    NUBPL disruption worsened one PGK1 phenotype, which shows that modifiers
    exist. Resolving this decides whether a patient's neurological prognosis
    can be predicted from genotype.
  evidence:
  - reference: PMID:17222195
    reference_title: PGK deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The reason for different clinical manifestations of mutations of the same
      gene remains unknown.
    explanation: States the gap directly.
  - reference: PMID:22348148
    reference_title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Different (environmental, metabolic, genetic and/or epigenetic)
      intervening factors can contribute toward the expression of PGK deficient
      clinical phenotypes.
    explanation: Names candidate modifier classes.
  - reference: PMID:25814383
    reference_title: "Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, its co-inheritance presumably exacerbates PGK1-deficient
      phenotype, most likely due to a synergistic interaction of the affected
      genes both involved in cell energy supply.
    explanation: A worked example of a genetic modifier of severity.
- discussion_id: gap_pgk1_heterozygote_parkinson_susceptibility
  prompt: >-
    Do heterozygous PGK1 variants increase susceptibility to early-onset or
    sporadic Parkinson disease, given parkinsonism in one heterozygous mother
    with normal red-cell activity and the location of PGK1 within the PARK12
    linkage interval?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Nigrostriatal Dopaminergic Dysfunction
  rationale: >-
    The evidence is one pedigree and a linkage-region coincidence. Sequencing
    PGK1 in early-onset Parkinson disease cohorts, as both reporting groups
    propose, would settle it.
  evidence:
  - reference: PMID:28649613
    reference_title: "Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, PGK-1 is located within the confirmed susceptibility locus
      for PD known as PARK12.
    explanation: States the linkage coincidence underlying the question.
  - reference: PMID:20151463
    reference_title: Myopathy and parkinsonism in phosphoglycerate kinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it may be worthwhile to sequence the PGK1 gene in a cohort of idiopathic
      juvenile PD cases
    explanation: Proposes the cohort study that would answer the question.
references:
- reference: PMID:17222195
  title: PGK deficiency.
- reference: PMID:30887539
  title: "Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study."
- reference: PMID:30111548
  title: Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
- reference: PMID:22348148
  title: Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
- reference: PMID:23336698
  title: Structural and energetic basis of protein kinetic destabilization in human phosphoglycerate kinase 1 deficiency.
- reference: PMID:24970202
  title: "Protein Stability, Folding and Misfolding in Human PGK1 Deficiency."
- reference: PMID:30975619
  title: Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.
- reference: PMID:30713856
  title: Levodopa Responsive Parkinsonism in Two Patients With Phosphoglycerate Kinase Deficiency.
- reference: PMID:20151463
  title: Myopathy and parkinsonism in phosphoglycerate kinase deficiency.
- reference: PMID:28649613
  title: "Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism?"
- reference: PMID:30951021
  title: "Therapeutic Benefit of Blood Transfusion in a Patient With Novel PGK1 Mutation (c.461T>C [p.L154P])."
- reference: PMID:28801086
  title: Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.
- reference: PMID:26396085
  title: "A negative waveform in the scotopic response in a patient with phosphoglycerate kinase deficiency: a visual electrophysiology report."
- reference: PMID:19157875
  title: "Myopathic form of phosphoglycerate kinase (PGK) deficiency: a new case and pathogenic considerations."
- reference: PMID:25814383
  title: "Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene."
- reference: PMID:30570712
  title: A Hemizygous Deletion Within the PGK1 Gene in Males with PGK1 Deficiency.
- reference: PMID:16740138
  title: The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA.
- reference: PMID:6938182
  title: "Erythrocyte phosphoglycerate kinase deficiency: enzymatic and oxygen binding studies."
- reference: PMID:15140922
  title: A Drosophila temperature-sensitive seizure mutant in phosphoglycerate kinase disrupts ATP generation and alters synaptic function.
- reference: PMID:40026287
  title: First Report of Phosphoglycerate Kinase Deficiency in a Dinè Child With Review of Current Literature.
- reference: PMID:26883264
  title: "Recurrent episodes of myoglobinuria, mental retardation and seizures but no hemolysis in two brothers with phosphoglycerate kinase deficiency."
- reference: PMID:35527021
  title: "A Mild Clinical Phenotype with Myopathic and Hemolytic Forms of Phosphoglycerate Kinase Deficiency (PGK Osaka): A Case Report and Literature Review."

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