3-Phosphoglycerate Dehydrogenase Deficiency

Mendelian MONDO:0011152 Pathograph 30 Show in embeddings browser Metabolic Disease Inborn Error of Metabolism Neurometabolic disorder due to serine deficiency

3-Phosphoglycerate dehydrogenase deficiency is an autosomal recessive L-serine-biosynthesis disorder caused by biallelic pathogenic variants in PHGDH. Reduced activity of the first enzyme in the phosphorylated serine pathway causes low cerebrospinal-fluid L-serine and D-serine, variably low glycine in plasma and CSF, and usually low or borderline-low fasting plasma L-serine. PHGDH-related disease spans a classic infantile neurodevelopmental presentation, a milder juvenile presentation with absence seizures, a single reported adult neuropathy presentation, and the severe prenatal Neu-Laxova syndrome 1 spectrum. L-serine treatment most consistently improves seizures; developmental recovery is variable and appears strongly dependent on treatment timing. The human pathways linking serine deficiency to neurodevelopmental injury, hypomyelination, peripheral neuropathy, and prenatal multisystem malformations remain incompletely resolved.

Ask OpenScientist

Ask a research question about 3-Phosphoglycerate Dehydrogenase Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
6
Pathophys.
14
Phenotypes
1
Hypotheses
3
Gaps
30
Pathograph
1
Genes
5
Medical Actions
4
Subtypes
3
Differentials
1
Datasets
13
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
gly and ser
👪

Inheritance

1
Autosomal recessive inheritance with variable expressivity HP:0000007
Affected individuals carry biallelic germline PHGDH variants. Expressivity ranges from prenatal Neu-Laxova syndrome 1 to infantile, juvenile, and a reported adult presentation; clinical severity cannot currently be predicted reliably from routine biochemical measurements or variant position alone.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (3 references)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"is an autosomal recessive disorder caused by a defect in the synthesis of the amino acid L-serine."
Directly states the autosomal recessive inheritance of PHGDH deficiency.
PMID:25152457 SUPPORT Human Clinical
"Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families."
Establishes biallelic PHGDH variation in families with Neu-Laxova syndrome.
PMID:37347880 SUPPORT Other
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."
GeneReviews states the recurrence risks when both parents are known heterozygotes; these figures do not replace family-specific counseling.
◆

Subtypes

4
Infantile PHGDH deficiency
Classic severe neurodevelopmental presentation with congenital microcephaly, severe delay, variable seizures and spasticity, and possible hypomyelination.
Show evidence (1 reference)
PMID:28135894 SUPPORT Human Clinical
"6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency"
Supports the PHGDH-specific infantile subtype.
Juvenile-onset PHGDH deficiency
Milder presentation reported in two siblings with absence seizures, mild developmental delay, behavioral abnormalities, and no obligatory microcephaly or MRI abnormality.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"two siblings with juvenile onset of absence seizures and mild developmental delay"
Defines the juvenile subtype.
Reported adult PHGDH neuropathy presentation
Case-level presentation reported in one adult with axonal sensorimotor polyneuropathy, slight ataxia, congenital cataracts, and mild developmental impairment.
Show evidence (1 reference)
PMID:22393170 SUPPORT Human Clinical
"To describe a case of serine synthesis defect due to 3-phosphoglycerate dehydrogenase deficiency in an adult with prominent chronic polyneuropathy."
Supports an adult presentation but only from one case.
Neu-Laxova syndrome 1 MONDO:0009736
PHGDH-related Neu-Laxova syndrome 1 is the severe prenatal end of this exact disease. Neu-Laxova syndromes caused by PSAT1 or PSPH are genetically distinct and are not included in this subtype.
Show evidence (1 reference)
PMID:25152457 SUPPORT Human Clinical
"PHGDH missense mutations in three unrelated families of our cohort"
Establishes PHGDH-related NLS1 within the heterogeneous Neu-Laxova group.
◈

Mechanistic Hypotheses

1
Serine-derived CNS biosynthesis and signaling insufficiency
serine_derived_cns_insufficiency_model EMERGING Infantile Juvenile
Evidence balance 2 support
Low L-serine may impair phospholipid synthesis and reduce glycine and D-serine availability, contributing to hypomyelination, neurodevelopmental impairment, and seizures. The precursor relationships are established, but the phenotype-causing intermediates are incompletely demonstrated in patients.
Pathograph links
Low L-Serine and Downstream Metabolites -> Serine-Dependent CNS Biosynthetic and Signaling Insufficiency INDIRECT KNOWN INTERMEDIATES Candidate metabolic and signaling consequences may contribute to CNS disease, but their relative causal importance in patients is unresolved. Intermediates: Serine-derived phospholipid synthesis and glycine/D-serine availability.
Serine-Dependent CNS Biosynthetic and Signaling Insufficiency -> Infantile and Juvenile Neurologic Disease INDIRECT UNKNOWN INTERMEDIATES These candidate pathways may contribute to the established CNS phenotype, but required human intermediates remain unproven.
Show evidence (2 references)
PMID:29269105 SUPPORT Human Clinical
"The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine."
Supports a serine-to-phospholipid link in a mixed cohort, but not a causal link to neurologic manifestations.
PMID:31548413 SUPPORT Model Organism
"inhibition of astrocytic Phgdh suppressed the de novo synthesis of l-and d-serine and reduced the NMDAR synaptic potentials and long-term potentiation"
Provides model-system support for a PHGDH-dependent serine/NMDA-signaling pathway, not proof of the human disease mechanism.
?

Discussions and Knowledge Gaps

3
How reproducible, safe, dose-dependent, and timing-dependent are early postnatal and antenatal L-serine benefits in PHGDH deficiency?
KNOWLEDGE GAP OPEN gap_phgdh_treatment_timing_and_generalizability
Attached to
pathophysiology#Low L-Serine and Downstream Metabolites pathophysiology#Infantile and Juvenile Neurologic Disease
Seizure improvement is repeated across small cohorts, but developmental recovery is inconsistent. One antenatally treated fetus had improved head growth and an unremarkable 48-month outcome, which establishes precedent but not general efficacy or safety.
Proposed experiments
Prospective genotype- and treatment-timing registry
phgdh_prospective_treatment_registry
Enroll molecularly confirmed PHGDH cases before treatment and collect standardized dose, treatment-age, seizure, development, amino-acid, and longitudinal MRI outcomes, with a separately governed prenatal cohort.
Decision criterion
A reproducible dose/timing-response relationship across independent families with prospectively defined biochemical and clinical outcomes.
Would support
pathophysiology#Low L-Serine and Downstream Metabolites
Show evidence (2 references)
PMID:15610810 SUPPORT Human Clinical
"At birth, the girl's head circumference was normal, and at 48 months' follow-up, her psychomotor development has been unremarkable."
Defines the promising but unreplicated prenatal observation.
PMID:12118526 SUPPORT Human Clinical
"A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine."
Shows the limited and timing-associated developmental response that a prospective registry must resolve.
Which PHGDH variant, domain, or residual-activity features, if any, predict infantile, juvenile, adult, or Neu-Laxova syndrome 1 presentation?
KNOWLEDGE GAP OPEN gap_phgdh_genotype_residual_activity
Attached to
pathophysiology#PHGDH Enzyme Deficiency
Residual enzyme activity is hypothesized to influence severity, yet severe and mild presentations can have overlapping serine concentrations and fibroblast activity. No clinically reliable genotype-phenotype rule is established.
Proposed experiments
Standardized PHGDH variant-function and phenotype study
phgdh_variant_function_registry
Measure expression, stability, kinetics, and pathway flux for PHGDH variants under one protocol and link results to harmonized longitudinal clinical phenotypes and treatment exposure.
Decision criterion
Prespecified functional measurements predict subtype and severity in an independent validation cohort beyond treatment timing and family background.
Would support
pathophysiology#PHGDH Enzyme Deficiency
Show evidence (2 references)
PMID:32579715 SUPPORT Human Clinical
"We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability"
States the residual-activity model explicitly as a postulate requiring further functional study.
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"mild clinical phenotype could not be predicted from the biochemical or molecular analysis"
Shows why routine measurements cannot yet predict clinical severity.
Which serine-derived pathways produce central nervous system, peripheral nerve, eye/skin, and prenatal multisystem phenotypes in PHGDH deficiency?
KNOWLEDGE GAP OPEN gap_phgdh_tissue_selective_vulnerability
Attached to
pathophysiology#Serine-Dependent CNS Biosynthetic and Signaling Insufficiency pathophysiology#Adult Axonal Neuropathy Syndrome pathophysiology#Prenatal Neu-Laxova Multisystem Developmental Disruption
Human phospholipid profiles and an astrocytic PHGDH-dependent serine shuttle provide candidate mechanisms, but neither explains the full tissue and subtype spectrum or has been causally validated in human disease models.
Proposed experiments
Isogenic human tissue-selective serine-flux models
phgdh_isogenic_tissue_flux_models
Compare matched PHGDH-deficient and corrected neural progenitor, astrocyte-neuron, oligodendrocyte, peripheral-nerve, lens, and fetal developmental models using isotope-resolved serine, lipid, nucleotide, glycine, and D-serine flux with L-serine rescue.
Decision criterion
A tissue-specific deficit is reproduced across variants, corrected by isogenic repair, and rescued by pathway-specific supplementation in parallel with disease-relevant cellular readouts.
Would support
pathophysiology#Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
Show evidence (2 references)
PMID:29269105 SUPPORT Human Clinical
"low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin"
Supplies a human metabolic candidate requiring tissue-level causal testing.
PMID:31548413 SUPPORT Model Organism
"implicate both d-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism"
Supplies a model-system signaling candidate requiring translation to human PHGDH deficiency.
⚙

Pathophysiology

6
PHGDH Enzyme Deficiency
Biallelic PHGDH variants reduce 3-phosphoglycerate dehydrogenase activity, the first and rate-limiting step of the phosphorylated pathway of de novo L-serine biosynthesis.
PHGDH hgnc:8923 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PHGDH (hgnc:8923). hgnc:8923 is a gene from the HUGO Gene Nomenclature Committee.
L-serine biosynthetic process GO:0006564 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased L-serine biosynthetic process (GO:0006564). GO:0006564 is a biological process from the Gene Ontology. ↓ DECREASED
phosphoglycerate dehydrogenase activity GO:0004617 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphoglycerate dehydrogenase activity (GO:0004617). GO:0004617 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Low L-Serine and Downstream Metabolites Reduced PHGDH activity decreases de novo L-serine synthesis and can secondarily reduce glycine and D-serine.
Prenatal Neu-Laxova Multisystem Developmental Disruption Severe biallelic PHGDH dysfunction can produce Neu-Laxova syndrome 1, but the developmental intermediates are unresolved.
Show evidence (1 reference)
PMID:19235232 SUPPORT In Vitro
"Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations."
Patient fibroblast assays demonstrate reduced PHGDH activity from disease-associated missense variants.
Low L-Serine and Downstream Metabolites
PHGDH deficiency causes low L-serine in cerebrospinal fluid and usually low or borderline-low fasting plasma L-serine. Glycine and D-serine can also be reduced, but glycine may remain normal in milder PHGDH disease.
Serine-derived CNS biosynthesis and signaling insufficiency
Downstream
Serine-Dependent CNS Biosynthetic and Signaling Insufficiency Candidate metabolic and signaling consequences may contribute to CNS disease, but their relative causal importance in patients is unresolved. Serine-derived CNS biosynthesis and signaling insufficiency
Adult Axonal Neuropathy Syndrome Low serine is associated with the reported adult neuropathy presentation, but the nerve-injury mechanism is unknown.
Show evidence (2 references)
PMID:19235232 SUPPORT Human Clinical
"low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)"
Defines the central biochemical abnormality in PHGDH deficiency.
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"his plasma serine was at the lower end of the normal range"
Shows that plasma serine can be only borderline low in a mild PHGDH presentation.
Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
Human metabolomics and model-system data support altered serine-derived phospholipids and PHGDH-dependent NMDA-coagonist supply. Neither pathway has been shown to be the dominant cause of human microcephaly, hypomyelination, seizures, or developmental impairment.
Serine-derived CNS biosynthesis and signaling insufficiency
phospholipid metabolic process GO:0006644 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phospholipid metabolic process (GO:0006644). GO:0006644 is a biological process from the Gene Ontology. ↓ DECREASED ionotropic glutamate receptor signaling pathway GO:0035235 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ionotropic glutamate receptor signaling pathway (GO:0035235). GO:0035235 is a biological process from the Gene Ontology. ↓ DECREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Infantile and Juvenile Neurologic Disease These candidate pathways may contribute to the established CNS phenotype, but required human intermediates remain unproven. Serine-derived CNS biosynthesis and signaling insufficiency
Show evidence (2 references)
PMID:29269105 SUPPORT Human Clinical
"normalization of most of the low phospholipid compounds in the 4 children"
Shows treatment-responsive phospholipid abnormalities without proving that they mediate clinical disease.
PMID:31548413 SUPPORT Model Organism
"Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of l-serine from glucose."
Narrows PHGDH-dependent serine-shuttle evidence to an astrocyte-centered model system.
Infantile and Juvenile Neurologic Disease
PHGDH-specific reports establish infantile and juvenile neurologic presentations, while the molecular steps from serine deficiency to each manifestation remain incompletely resolved.
Downstream
Congenital microcephaly
Severe global developmental delay
Infantile seizures
Spastic tetraplegia
Cerebral hypomyelination
Juvenile absence seizures
Mild global developmental delay
Atypical behavior
Show evidence (2 references)
PMID:28135894 SUPPORT Human Clinical
"6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency"
Establishes the PHGDH-specific infantile clinical association.
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"very mild form of genetically confirmed 3-PGDH deficiency in two siblings"
Establishes the genetically confirmed juvenile presentation.
Adult Axonal Neuropathy Syndrome
One genetically confirmed adult case had chronic axonal sensorimotor polyneuropathy with slight cerebellar ataxia, congenital cataracts, and mild lifelong developmental impairment. This is a case-level association, not a well-characterized common subtype.
Downstream
Peripheral axonal neuropathy
Adult ataxia
Adult congenital cataracts
Show evidence (1 reference)
PMID:22393170 SUPPORT Human Clinical
"To describe a case of serine synthesis defect due to 3-phosphoglycerate dehydrogenase deficiency in an adult with prominent chronic polyneuropathy."
Defines the PHGDH-specific adult case report.
Prenatal Neu-Laxova Multisystem Developmental Disruption
Biallelic PHGDH variants cause Neu-Laxova syndrome 1, a severe prenatal multisystem phenotype. Neu-Laxova syndromes caused by PSAT1 or PSPH are separate genetic disorders and are differentials for this focal entry.
Downstream
Congenital microcephaly
Intrauterine growth retardation
Neu-Laxova congenital cataracts
Ichthyosis
Show evidence (1 reference)
PMID:25152457 SUPPORT Human Clinical
"NLS represents the severe end of serine-deficiency disorders"
Places PHGDH-related NLS1 at the severe end of the serine-deficiency spectrum.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 3-Phosphoglycerate Dehydrogenase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Eye 2
Neu-Laxova congenital cataracts Developmental cataract HP:0000519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental cataract (HP:0000519). HP:0000519 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37347880 SUPPORT Other
"microcephaly, congenital bilateral cataracts, characteristic dysmorphic features"
Supports congenital bilateral cataracts in NLS.
Adult congenital cataracts Developmental cataract HP:0000519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental cataract (HP:0000519). HP:0000519 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22393170 SUPPORT Human Clinical
"congenital cataracts"
Supports congenital cataracts in one adult.
Integument 1
Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37347880 SUPPORT Other
"limb anomalies, and collodion-like ichthyosis"
Supports the characteristic skin phenotype in NLS.
Nervous System 7
Severe global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28135894 SUPPORT Human Clinical
"infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype"
Supports severe developmental impairment in infantile disease.
Infantile seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as temporality recurrent. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:28135894 SUPPORT Human Clinical
"absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3"
Establishes variable seizure expression in the six-person infantile cohort.
Cerebral hypomyelination HP:0006808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral hypomyelination (HP:0006808). HP:0006808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11508546 SUPPORT Human Clinical
"Pre-treatment MRI demonstrated hypomyelination and profound white matter attenuation in all patients."
Documents the finding in all four individuals in the MRI series.
Juvenile absence seizures Generalized non-motor (absence) seizure HP:0002121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized non-motor (absence) seizure (HP:0002121), qualified as temporality recurrent. HP:0002121 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"two siblings with juvenile onset of absence seizures and mild developmental delay"
Supports absence seizures in both juvenile siblings.
Mild global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"two siblings with juvenile onset of absence seizures and mild developmental delay"
Supports the milder developmental phenotype.
Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"improvement of well-being and behaviour"
Supports a behavioral component but does not define a specific psychiatric phenotype.
Adult ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22393170 SUPPORT Human Clinical
"slight cerebellar ataxia"
Supports mild ataxia in the single adult case.
Growth 1
Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37347880 SUPPORT Other
"Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, microcephaly"
GeneReviews identifies severe fetal growth deficiency in NLS.
Other 3
Congenital microcephaly Primary microcephaly HP:0011451 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary microcephaly (HP:0011451). HP:0011451 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28135894 SUPPORT Human Clinical
"presented with psychomotor delay, growth failure, microcephaly, and spasticity"
Supports microcephaly in the PHGDH-specific infantile cohort.
PMID:37347880 SUPPORT Other
"severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts"
Supports microcephaly in the NLS feature bundle.
Spastic tetraplegia HP:0002510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic tetraplegia (HP:0002510). HP:0002510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"a severe spastic quadriplegia becomes evident during the first years of life"
Describes the classic infantile motor outcome in the PHGDH-specific review of prior cases.
Peripheral axonal neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22393170 SUPPORT Human Clinical
"chronic axonal sensorimotor polyneuropathy"
Supports this manifestation in a single adult.
🧬

Genetic Associations

1
PHGDH
Gene: PHGDH hgnc:8923 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PHGDH (hgnc:8923). hgnc:8923 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:19235232 SUPPORT Human Clinical
"We now describe five novel mutations in five patients with 3-PGDH deficiency; one frameshift mutation"
Establishes multiple PHGDH variant classes in affected individuals.
PMID:25152457 SUPPORT Human Clinical
"PHGDH missense mutations in three unrelated families of our cohort"
Extends the PHGDH association to Neu-Laxova syndrome 1.
💊

Medical Actions

5
L-Serine supplementation
Category: Therapeutic Action: amino acid supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is amino acid supplementation, annotated with Nutritional Supplementation (NCIT:C15425). NCIT:C15425 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Supplementation NCIT:C15425
Agent: L-serine CHEBI:17115 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-serine (CHEBI:17115). CHEBI:17115 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral L-serine bypasses the biosynthetic block and restores serine concentrations. Repeated small cohorts show the clearest benefit for seizure control and sometimes spasticity or well-being. Developmental improvement is inconsistent, especially after established injury; MRI improvement occurred in two of four treated individuals in one series.
Mechanism Target:
BYPASSES PHGDH Enzyme Deficiency — Exogenous L-serine supplies pathway product downstream of deficient PHGDH.
Show evidence (1 reference)
PMID:12118526 SUPPORT Human Clinical
"oral treatment with the deficient amino acids"
Supports substrate replacement as the treatment rationale but does not directly assay pathway flux.
RESTORES Low L-Serine and Downstream Metabolites — Supplementation normalizes plasma and CSF serine in treated patients.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"The values of CSF and plasma serine normalised during treatment."
Directly supports biochemical restoration in a juvenile patient.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology. Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Cerebral hypomyelination HP:0006808 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cerebral hypomyelination (HP:0006808). HP:0006808 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:12118526 SUPPORT Human Clinical
"A major reduction in seizure frequency occurred in all patients; two patients became free of seizures."
Reports seizure benefit in five treated patients; psychomotor progress occurred in only one, diagnosed early and treated at high dose.
PMID:28135894 SUPPORT Human Clinical
"The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2."
Supports seizure/spasticity response and limited developmental recovery in a PHGDH-specific cohort.
PMID:11508546 SUPPORT Human Clinical
"a significant increase in white matter volume was found and a progress of myelination in two patients"
Supports treatment-associated imaging improvement in two of four individuals.
+ 1 more reference
Adjunct glycine supplementation
Category: Therapeutic Action: amino acid supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is amino acid supplementation, annotated with Nutritional Supplementation (NCIT:C15425). NCIT:C15425 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Supplementation NCIT:C15425
Agent: glycine CHEBI:15428 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses glycine (CHEBI:15428). CHEBI:15428 is a therapeutic agent from Chemical Entities of Biological Interest.
Glycine has been added when high-dose L-serine did not control seizures. The evidence is limited to two siblings and should not be generalized as a universal requirement.
Mechanism Target:
RESTORES Low L-Serine and Downstream Metabolites — Adjunct glycine supplies one variably deficient downstream amino acid.
Show evidence (1 reference)
PMID:9708551 SUPPORT Human Clinical
"Addition of glycine 200 mg/kg/day resulted in complete disappearance of seizures."
Demonstrates clinical response in two siblings but does not separately quantify mechanism restoration.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9708551 SUPPORT Human Clinical
"L-Serine up to 500 mg/kg/day was not sufficient for seizure control. Addition of glycine 200 mg/kg/day resulted in complete disappearance of seizures."
Supports adjunct glycine after inadequate L-serine response in two siblings.
Maternal prenatal L-serine supplementation
Category: Therapeutic Action: amino acid supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is amino acid supplementation, annotated with Nutritional Supplementation (NCIT:C15425). NCIT:C15425 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Supplementation NCIT:C15425
Agent: L-serine CHEBI:17115 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-serine (CHEBI:17115). CHEBI:17115 is a therapeutic agent from Chemical Entities of Biological Interest.
Maternal L-serine was given after declining fetal head circumference in one affected pregnancy. Fetal head growth increased and development was reported as unremarkable at 48 months, but efficacy, safety, dose, and generalizability remain unestablished.
Mechanism Target:
RESTORES Low L-Serine and Downstream Metabolites — Maternal supplementation was intended to supply serine to the affected fetus.
Show evidence (1 reference)
PMID:15610810 SUPPORT Human Clinical
"L-serine was then given to the mother"
Documents the intervention but does not directly demonstrate fetal biochemical normalization.
Target Phenotypes: Primary microcephaly HP:0011451 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Primary microcephaly (HP:0011451). HP:0011451 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15610810 SUPPORT Human Clinical
"L-serine was then given to the mother, which resulted in an enlarged fetal head circumference to the 76th percentile at 31 weeks."
Supports the reported response in one fetus; no replication or comparator establishes general efficacy.
Longitudinal clinical surveillance
Category: Monitoring
Follow-up should be individualized across the broad PHGDH spectrum and monitor seizures, tone and contractures, development and behavior, growth and nutrition, feeding and constipation, respiratory and musculoskeletal issues, and family support needs. GeneReviews recommends dental evaluation every six months.
Show evidence (1 reference)
PMID:37347880 SUPPORT Other
"Surveillance: Monitor for seizures, changes in tone, contractures, developmental and educational needs, behavior issues, growth and nutrition, constipation and feeding issues, respiratory issues, musculoskeletal manifestations, and family needs at each visit. Dental evaluation every six months."
GeneReviews gives the multisystem surveillance domains and dental interval for serine deficiency disorders.
Seizure-trigger avoidance counseling
Category: Counseling / Informational
Families should receive anticipatory counseling and illness planning around recognized seizure triggers, including infection and physical or emotional stress.
Show evidence (1 reference)
PMID:37347880 SUPPORT Other
"Agents/circumstances to avoid: Known triggers of seizure activity (e.g., infection, physical stress, emotional stress)."
GeneReviews identifies clinically relevant seizure triggers for anticipatory counseling and illness planning.
🔬

Biochemical Markers

6
Cerebrospinal fluid L-serine (DECREASED)
Pathograph Readouts
Readout Of Low L-Serine and Downstream Metabolites Negative Diagnostic
Lower CSF L-serine reports the central biochemical consequence of PHGDH deficiency.
Show evidence (1 reference)
PMID:19235232 SUPPORT Human Clinical
"low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)"
Directly supports CSF L-serine as a biochemical readout.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"remain the preferred diagnostic procedure to confirm serine deficiency"
The full-text discussion identifies CSF amino-acid analysis as the preferred confirmatory procedure.
Fasting plasma L-serine (DECREASED)
Pathograph Readouts
Readout Of Low L-Serine and Downstream Metabolites Negative Diagnostic
A low or borderline-low fasting value supports the biochemical diagnosis; a nonfasting value is less reliable.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"amino acids should be analysed after an overnight fast"
Supports fasting collection for plasma amino-acid interpretation.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"need to recognise the significance of low or borderline low values of plasma serine"
Supports low or borderline-low plasma serine as a diagnostic clue.
Cerebrospinal fluid and plasma glycine (VARIABLE)
Pathograph Readouts
Readout Of Low L-Serine and Downstream Metabolites Negative Diagnostic
Low glycine can accompany serine deficiency, but normal glycine does not exclude PHGDH deficiency.
Show evidence (1 reference)
PMID:12118526 SUPPORT Human Clinical
"low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid"
Supports variable glycine reduction as a readout of the biochemical defect.
Show evidence (2 references)
PMID:12118526 SUPPORT Human Clinical
"low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid"
Establishes variable glycine reduction.
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"with a normal value for glycine"
Shows that glycine can remain normal in juvenile PHGDH deficiency.
Cerebrospinal fluid D-serine (DECREASED)
Pathograph Readouts
Readout Of Low L-Serine and Downstream Metabolites Negative Diagnostic
Decreased CSF D-serine is a secondary biochemical consequence of reduced serine availability.
Show evidence (1 reference)
PMID:19235232 SUPPORT Human Clinical
"low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)"
Supports decreased D-serine as a readout of the central biochemical state.
Show evidence (1 reference)
PMID:19235232 SUPPORT Human Clinical
"low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)"
Directly reports decreased CSF D-serine.
PHGDH activity in cultured fibroblasts (DECREASED)
Pathograph Readouts
Readout Of PHGDH Enzyme Deficiency Negative Diagnostic
Reduced cultured-fibroblast activity functionally reports the enzyme defect.
Show evidence (1 reference)
PMID:19235232 SUPPORT In Vitro
"Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations."
Directly maps the assay readout to reduced PHGDH activity.
Show evidence (1 reference)
PMID:19235232 SUPPORT In Vitro
"Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations."
Direct functional evidence for reduced PHGDH activity in patient fibroblasts.
Plasma phospholipid species (DECREASED)
Pathograph Readouts
Readout Of Serine-Dependent CNS Biosynthetic and Signaling Insufficiency Negative
Decreased plasma phospholipid species report one candidate downstream pathway but do not prove CNS causality.
Show evidence (1 reference)
PMID:29269105 SUPPORT Human Clinical
"Metabolomic profiling performed at baseline showed low phospholipid species"
Maps the exploratory plasma readout to the candidate lipid branch without asserting clinical causality.
Show evidence (1 reference)
PMID:29269105 SUPPORT Human Clinical
"Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin."
Reports the exploratory plasma metabolomic abnormality.
🔬

Diagnosis

4
Fasting plasma amino acid analysis
Measure plasma amino acids after an overnight fast. Low or borderline-low L-serine supports the diagnosis, but dietary influence and mild cases can make plasma results less sensitive than CSF.
clinical laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"amino acids should be analysed after an overnight fast"
Supports fasting plasma collection.
Cerebrospinal fluid amino acid analysis
Low CSF L-serine is the central biochemical finding and is the preferred confirmatory biochemical procedure when plasma serine is borderline or the phenotype suggests PHGDH deficiency.
clinical laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (2 references)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"remain the preferred diagnostic procedure to confirm serine deficiency"
Supports CSF analysis as the preferred biochemical confirmation.
PMID:19235232 SUPPORT Human Clinical
"low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)"
Defines the characteristic CSF profile.
PHGDH molecular genetic testing
Demonstration of biallelic pathogenic variants in PHGDH establishes this focal diagnosis. Biallelic PSAT1 or PSPH variants establish different serine biosynthesis disorders and must not be accepted as confirmation of PHGDH deficiency.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:19235232 SUPPORT Human Clinical
"five novel mutations in five patients with 3-PGDH deficiency"
Supports PHGDH molecular confirmation in affected patients.
PMID:37347880 SUPPORT Other
"biallelic pathogenic variants in PHGDH, PSAT1, or PSPH identified by molecular genetic testing"
GeneReviews supports molecular confirmation of the broader group; the exact focal entry is restricted to PHGDH.
PHGDH enzyme activity assay in cultured fibroblasts
Reduced PHGDH activity in cultured fibroblasts is a historical functional adjunct when molecular findings require clarification.
clinical laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:19235232 SUPPORT In Vitro
"Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations."
Supports the functional enzyme assay.
🩻

Imaging Findings

1
Cerebral hypomyelination and white-matter attenuation on MRI
Pretreatment brain MRI showed hypomyelination and profound white-matter attenuation in four individuals. Increased white-matter volume and progress of myelination during amino-acid treatment occurred in only two of four.
Mri Infantile Four-patient MRI series; the finding is characteristic but not pathognomonic.
Cerebral hypomyelination HP:0006808 Human Phenotype Ontology (HP) brain white matter UBERON:0003544 Uberon multi-species anatomy ontology (UBERON) Cerebral hypomyelination HP:0006808 Human Phenotype Ontology (HP)
Show evidence (2 references)
PMID:11508546 SUPPORT Human Clinical
"Pre-treatment MRI demonstrated hypomyelination and profound white matter attenuation in all patients."
Establishes the pretreatment imaging pattern in the four-person series.
PMID:11508546 SUPPORT Human Clinical
"During treatment, a significant increase in white matter volume was found and a progress of myelination in two patients."
Qualifies treatment-associated imaging improvement as occurring in two of four individuals.
📈

Progression

4
Prenatal multisystem disease with pre- or perinatal lethality
Neu-Laxova Age: Prenatal period through early infancy
PHGDH-related Neu-Laxova syndrome 1 is the severe prenatal end of the spectrum, with growth restriction, microcephaly, congenital anomalies, and frequent pre- or early-postnatal death.
Show evidence (2 references)
PMID:25152457 SUPPORT Human Clinical
"Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality."
Defines the prenatal or early-postnatal lethal natural history of Neu-Laxova syndrome.
PMID:32579715 SUPPORT Human Clinical
"Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality."
Independently supports the severe prenatal spectrum in a cohort including PHGDH-related families.
Congenital and infantile neurodevelopmental disease
Infantile Age: Birth through early childhood
The classic presentation begins with congenital microcephaly and severe developmental impairment; seizures and spasticity are variable, and MRI can show hypomyelination and profound white-matter attenuation.
Show evidence (2 references)
PMID:28135894 SUPPORT Human Clinical
"presented with psychomotor delay, growth failure, microcephaly, and spasticity"
Describes the shared infantile presentation in six PHGDH-deficient individuals from three families.
PMID:28135894 SUPPORT Human Clinical
"The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3."
Shows that seizures are not invariant even in the infantile presentation.
School-age absence-seizure presentation
Juvenile Age: Childhood through adolescence
A milder PHGDH-specific presentation has been reported in two siblings with normal or near-normal head size, absence seizures, mild developmental delay, behavioral abnormalities, and normal brain MRI.
Show evidence (1 reference)
DOI:10.1007/s10545-010-9249-5 SUPPORT Human Clinical
"two siblings with juvenile onset of absence seizures and mild developmental delay"
Defines the PHGDH-specific juvenile presentation in two siblings.
Reported adult axonal neuropathy presentation
Adult Age: Adulthood
The adult presentation is based on one 31-year-old individual with chronic axonal sensorimotor polyneuropathy, slight ataxia, mild lifelong developmental impairment, and congenital cataracts. Its frequency and natural history are unknown.
Show evidence (1 reference)
PMID:22393170 SUPPORT Human Clinical
"A 31-year-old man with congenital cataracts, mild psychomotor retardation, slight cerebellar ataxia, and chronic axonal sensorimotor polyneuropathy."
Documents the single PHGDH-specific adult neuropathy case.
📊

Prevalence

1
Worldwide
Unknown Rare
No population prevalence estimate is established; published evidence consists of small cohorts and case reports.
Show evidence (1 reference)
PMID:19235232 SUPPORT Human Clinical
"Three-phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare recessive inborn error in the biosynthesis of the amino acid L-serine"
Characterizes PHGDH deficiency as rare without supplying a quantitative prevalence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from 3-Phosphoglycerate Dehydrogenase Deficiency:

PSAT deficiency Not Yet Curated MONDO:0012596
Overlapping Features PSAT1 deficiency causes an overlapping autosomal recessive serine-biosynthesis disorder with low serine and infantile or prenatal neurologic disease.
Distinguishing Features
  • Biallelic PSAT1 variants, rather than PHGDH variants, establish this diagnosis.
Show evidence (1 reference)
PMID:37347880 SUPPORT Other
"biallelic pathogenic variants in PHGDH, PSAT1, or PSPH identified by molecular genetic testing"
Supports gene-specific molecular differentiation within the serine-deficiency group.
PSPH deficiency Not Yet Curated MONDO:0013531
Overlapping Features PSPH deficiency can produce overlapping serine-deficiency biochemistry and neurodevelopmental disease.
Distinguishing Features
  • Biallelic PSPH variants, rather than PHGDH variants, establish this diagnosis.
Show evidence (1 reference)
PMID:25152457 SUPPORT Human Clinical
"a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase"
Establishes PSPH as a distinct causal gene in the serine-biosynthesis/NLS differential.
Neu-Laxova syndrome 2 Not Yet Curated MONDO:0014466
Overlapping Features Neu-Laxova syndrome 2 overlaps the prenatal malformation and lethal presentation of PHGDH-related NLS1.
Distinguishing Features
  • Neu-Laxova syndrome 2 is caused by biallelic PSAT1 variants; PHGDH-related disease is Neu-Laxova syndrome 1.
Show evidence (1 reference)
PMID:25152457 SUPPORT Human Clinical
"six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease"
Supports PSAT1-related NLS as a genetically distinct differential.
📊

Related Datasets

1
Genome-wide analysis of Phgdh inactivation in murine embryonic head geo:GSE8555
D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures.
mouse MICROARRAY n=8
PMID:18228065
Identified by GEO DataSets index search for 3-Phosphoglycerate Dehydrogenase Deficiency (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: 3-Phosphoglycerate Dehydrogenase Deficiency
creation_date: "2026-07-08T12:00:00Z"
category: Mendelian
synonyms:
- PHGDH deficiency
- 3-PGDH deficiency
- Phosphoglycerate dehydrogenase deficiency
description: >-
  3-Phosphoglycerate dehydrogenase deficiency is an autosomal recessive
  L-serine-biosynthesis disorder caused by biallelic pathogenic variants in
  PHGDH. Reduced activity of the first enzyme in the phosphorylated serine
  pathway causes low cerebrospinal-fluid L-serine and D-serine, variably low
  glycine in plasma and CSF, and usually low or borderline-low fasting plasma
  L-serine. PHGDH-related disease spans a classic
  infantile neurodevelopmental presentation, a milder juvenile presentation
  with absence seizures, a single reported adult neuropathy presentation, and
  the severe prenatal Neu-Laxova syndrome 1 spectrum. L-serine treatment most
  consistently improves seizures; developmental recovery is variable and
  appears strongly dependent on treatment timing. The human pathways linking
  serine deficiency to neurodevelopmental injury, hypomyelination, peripheral
  neuropathy, and prenatal multisystem malformations remain incompletely
  resolved.
classifications:
  icimd_category:
  - classification_value: gly_and_ser
    notes: >-
      ICIMD places PHGDH deficiency among disorders of glycine and serine
      metabolism. This entry is restricted to PHGDH-related disease rather than
      the broader serine-deficiency-disorder grouping.
    evidence:
    - reference: PMID:19235232
      reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a rare recessive inborn error in the biosynthesis of the amino acid L-serine
      explanation: Supports classification as an inherited disorder of serine metabolism.
disease_term:
  preferred_term: PHGDH deficiency
  term:
    id: MONDO:0011152
    label: PHGDH deficiency
parents:
- Metabolic Disease
- Inborn Error of Metabolism
- Neurometabolic disorder due to serine deficiency
inheritance:
- name: Autosomal recessive inheritance with variable expressivity
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    Affected individuals carry biallelic germline PHGDH variants. Expressivity
    ranges from prenatal Neu-Laxova syndrome 1 to infantile, juvenile, and a
    reported adult presentation; clinical severity cannot currently be predicted
    reliably from routine biochemical measurements or variant position alone.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is an autosomal recessive disorder caused by a defect in the synthesis of the amino acid L-serine.
    explanation: Directly states the autosomal recessive inheritance of PHGDH deficiency.
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families.
    explanation: Establishes biallelic PHGDH variation in families with Neu-Laxova syndrome.
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      each sib of an affected individual has at conception a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance
      of inheriting neither of the familial pathogenic variants.
    explanation: >-
      GeneReviews states the recurrence risks when both parents are known
      heterozygotes; these figures do not replace family-specific counseling.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: No population prevalence estimate is established; published evidence consists of small cohorts and case reports.
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three-phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare recessive inborn error in the biosynthesis of the amino acid L-serine
    explanation: Characterizes PHGDH deficiency as rare without supplying a quantitative prevalence.
progression:
- phase: Prenatal multisystem disease with pre- or perinatal lethality
  subtype: Neu-Laxova
  age_range: Prenatal period through early infancy
  notes: >-
    PHGDH-related Neu-Laxova syndrome 1 is the severe prenatal end of the
    spectrum, with growth restriction, microcephaly, congenital anomalies, and
    frequent pre- or early-postnatal death.
  evidence:
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality.
    explanation: Defines the prenatal or early-postnatal lethal natural history of Neu-Laxova syndrome.
  - reference: PMID:32579715
    reference_title: Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality.
    explanation: Independently supports the severe prenatal spectrum in a cohort including PHGDH-related families.
- phase: Congenital and infantile neurodevelopmental disease
  subtype: Infantile
  age_range: Birth through early childhood
  notes: >-
    The classic presentation begins with congenital microcephaly and severe
    developmental impairment; seizures and spasticity are variable, and MRI can
    show hypomyelination and profound white-matter attenuation.
  evidence:
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: presented with psychomotor delay, growth failure, microcephaly, and spasticity
    explanation: Describes the shared infantile presentation in six PHGDH-deficient individuals from three families.
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3.
    explanation: Shows that seizures are not invariant even in the infantile presentation.
- phase: School-age absence-seizure presentation
  subtype: Juvenile
  age_range: Childhood through adolescence
  notes: >-
    A milder PHGDH-specific presentation has been reported in two siblings with
    normal or near-normal head size, absence seizures, mild developmental delay,
    behavioral abnormalities, and normal brain MRI.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two siblings with juvenile onset of absence seizures and mild developmental delay
    explanation: Defines the PHGDH-specific juvenile presentation in two siblings.
- phase: Reported adult axonal neuropathy presentation
  subtype: Adult
  age_range: Adulthood
  notes: >-
    The adult presentation is based on one 31-year-old individual with chronic
    axonal sensorimotor polyneuropathy, slight ataxia, mild lifelong
    developmental impairment, and congenital cataracts. Its frequency and
    natural history are unknown.
  evidence:
  - reference: PMID:22393170
    reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 31-year-old man with congenital cataracts, mild psychomotor retardation, slight cerebellar ataxia, and chronic axonal sensorimotor polyneuropathy.
    explanation: Documents the single PHGDH-specific adult neuropathy case.
mechanistic_hypotheses:
- hypothesis_group_id: serine_derived_cns_insufficiency_model
  hypothesis_label: Serine-derived CNS biosynthesis and signaling insufficiency
  status: EMERGING
  applies_to_subtypes:
  - Infantile
  - Juvenile
  description: >-
    Low L-serine may impair phospholipid synthesis and reduce glycine and
    D-serine availability, contributing to hypomyelination,
    neurodevelopmental impairment, and seizures. The precursor relationships
    are established, but the phenotype-causing intermediates are incompletely
    demonstrated in patients.
  evidence:
  - reference: PMID:29269105
    reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine.
    explanation: Supports a serine-to-phospholipid link in a mixed cohort, but not a causal link to neurologic manifestations.
  - reference: PMID:31548413
    reference_title: The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: inhibition of astrocytic Phgdh suppressed the de novo synthesis of l-and d-serine and reduced the NMDAR synaptic potentials and long-term potentiation
    explanation: Provides model-system support for a PHGDH-dependent serine/NMDA-signaling pathway, not proof of the human disease mechanism.
pathophysiology:
- name: PHGDH Enzyme Deficiency
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic PHGDH variants reduce 3-phosphoglycerate dehydrogenase activity,
    the first and rate-limiting step of the phosphorylated pathway of de novo
    L-serine biosynthesis.
  genes:
  - preferred_term: PHGDH
    term:
      id: hgnc:8923
      label: PHGDH
  molecular_functions:
  - preferred_term: phosphoglycerate dehydrogenase activity
    term:
      id: GO:0004617
      label: phosphoglycerate dehydrogenase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: L-serine biosynthetic process
    term:
      id: GO:0006564
      label: L-serine biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations.
    explanation: Patient fibroblast assays demonstrate reduced PHGDH activity from disease-associated missense variants.
  downstream:
  - target: Low L-Serine and Downstream Metabolites
    causal_link_type: DIRECT
    description: Reduced PHGDH activity decreases de novo L-serine synthesis and can secondarily reduce glycine and D-serine.
    evidence:
    - reference: PMID:12118526
      reference_title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid.
      explanation: Directly links the enzyme defect to the characteristic serine and variable glycine reduction.
  - target: Prenatal Neu-Laxova Multisystem Developmental Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe biallelic PHGDH dysfunction can produce Neu-Laxova syndrome 1, but the developmental intermediates are unresolved.
    evidence:
    - reference: PMID:25152457
      reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: PHGDH missense mutations in three unrelated families of our cohort
      explanation: Links PHGDH variation to Neu-Laxova syndrome while leaving the developmental mechanism unspecified.
- name: Low L-Serine and Downstream Metabolites
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    PHGDH deficiency causes low L-serine in cerebrospinal fluid and usually low
    or borderline-low fasting plasma L-serine. Glycine and D-serine can also be
    reduced, but glycine may remain normal in milder PHGDH disease.
  chemical_entities:
  - preferred_term: L-serine
    term:
      id: CHEBI:17115
      label: L-serine
    modifier: DECREASED
  - preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
    modifier: DECREASED
  - preferred_term: D-serine
    term:
      id: CHEBI:16523
      label: D-serine
    modifier: DECREASED
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)
    explanation: Defines the central biochemical abnormality in PHGDH deficiency.
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: his plasma serine was at the lower end of the normal range
    explanation: Shows that plasma serine can be only borderline low in a mild PHGDH presentation.
  downstream:
  - target: Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
    hypothesis_groups:
    - serine_derived_cns_insufficiency_model
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Serine-derived phospholipid synthesis and glycine/D-serine availability.
    description: Candidate metabolic and signaling consequences may contribute to CNS disease, but their relative causal importance in patients is unresolved.
    evidence:
    - reference: PMID:29269105
      reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Metabolomic profiling performed at baseline showed low phospholipid species
      explanation: Supports a human phospholipid abnormality, but the cohort included three PHGDH and one PSAT1 case and did not establish neurologic causality.
    - reference: PMID:31548413
      reference_title: The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: impaired LTP, supporting an l-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist d-serine
      explanation: Supports one signaling intermediate in a model system rather than in human PHGDH deficiency.
  - target: Adult Axonal Neuropathy Syndrome
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Low serine is associated with the reported adult neuropathy presentation, but the nerve-injury mechanism is unknown.
    evidence:
    - reference: PMID:22393170
      reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Amino acid analysis showed low serine levels in plasma and cerebrospinal fluid
      explanation: Associates low serine with the single adult PHGDH case without establishing the intervening mechanism.
- name: Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
  role: consequence
  mechanism_confidence: PROVISIONAL
  subtypes:
  - Infantile
  - Juvenile
  description: >-
    Human metabolomics and model-system data support altered serine-derived
    phospholipids and PHGDH-dependent NMDA-coagonist supply. Neither pathway has
    been shown to be the dominant cause of human microcephaly, hypomyelination,
    seizures, or developmental impairment.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: phospholipid metabolic process
    term:
      id: GO:0006644
      label: phospholipid metabolic process
    modifier: DECREASED
  - preferred_term: ionotropic glutamate receptor signaling pathway
    term:
      id: GO:0035235
      label: ionotropic glutamate receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:29269105
    reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: normalization of most of the low phospholipid compounds in the 4 children
    explanation: Shows treatment-responsive phospholipid abnormalities without proving that they mediate clinical disease.
  - reference: PMID:31548413
    reference_title: The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of l-serine from glucose.
    explanation: Narrows PHGDH-dependent serine-shuttle evidence to an astrocyte-centered model system.
  downstream:
  - target: Infantile and Juvenile Neurologic Disease
    hypothesis_groups:
    - serine_derived_cns_insufficiency_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: These candidate pathways may contribute to the established CNS phenotype, but required human intermediates remain unproven.
    evidence:
    - reference: PMID:29269105
      reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations
      explanation: The authors explicitly frame neurologic causality as a suggestion rather than a demonstrated pathway.
- name: Infantile and Juvenile Neurologic Disease
  role: outcome
  mechanism_confidence: ESTABLISHED
  subtypes:
  - Infantile
  - Juvenile
  description: >-
    PHGDH-specific reports establish infantile and juvenile neurologic
    presentations, while the molecular steps from serine deficiency to each
    manifestation remain incompletely resolved.
  evidence:
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency
    explanation: Establishes the PHGDH-specific infantile clinical association.
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: very mild form of genetically confirmed 3-PGDH deficiency in two siblings
    explanation: Establishes the genetically confirmed juvenile presentation.
  downstream:
  - target: Congenital microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28135894
      reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: presented with psychomotor delay, growth failure, microcephaly, and spasticity
      explanation: Supports congenital/infantile microcephaly in the PHGDH-specific cohort.
  - target: Severe global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28135894
      reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype
      explanation: Supports the severe infantile neurodevelopmental presentation.
  - target: Infantile seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28135894
      reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: seizures with pronounced happy affect in 3 sisters in family 3
      explanation: Supports seizures in half of this six-person infantile cohort and preserves their variability.
  - target: Spastic tetraplegia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1007/s10545-010-9249-5
      reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a severe spastic quadriplegia becomes evident during the first years of life
      explanation: Describes the classic infantile motor phenotype.
  - target: Cerebral hypomyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:11508546
      reference_title: Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pre-treatment MRI demonstrated hypomyelination and profound white matter attenuation in all patients.
      explanation: Supports hypomyelination in the four-person MRI series.
  - target: Juvenile absence seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1007/s10545-010-9249-5
      reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two siblings with juvenile onset of absence seizures and mild developmental delay
      explanation: Supports absence seizures in both reported juvenile siblings.
  - target: Mild global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1007/s10545-010-9249-5
      reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two siblings with juvenile onset of absence seizures and mild developmental delay
      explanation: Supports mild developmental delay in the juvenile presentation.
  - target: Atypical behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1007/s10545-010-9249-5
      reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: improvement of well-being and behaviour
      explanation: Supports a treatment-responsive behavioral component in the two juvenile siblings.
- name: Adult Axonal Neuropathy Syndrome
  role: outcome
  mechanism_confidence: PROVISIONAL
  subtypes:
  - Adult
  description: >-
    One genetically confirmed adult case had chronic axonal sensorimotor
    polyneuropathy with slight cerebellar ataxia, congenital cataracts, and mild
    lifelong developmental impairment. This is a case-level association, not a
    well-characterized common subtype.
  evidence:
  - reference: PMID:22393170
    reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To describe a case of serine synthesis defect due to 3-phosphoglycerate dehydrogenase deficiency in an adult with prominent chronic polyneuropathy.
    explanation: Defines the PHGDH-specific adult case report.
  downstream:
  - target: Peripheral axonal neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22393170
      reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: chronic axonal sensorimotor polyneuropathy
      explanation: Supports the neuropathy in one adult.
  - target: Adult ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22393170
      reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: slight cerebellar ataxia
      explanation: Supports mild ataxia in the same single adult.
  - target: Adult congenital cataracts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22393170
      reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: congenital cataracts
      explanation: Supports congenital cataracts in the same single adult.
- name: Prenatal Neu-Laxova Multisystem Developmental Disruption
  role: outcome
  mechanism_confidence: ESTABLISHED
  subtypes:
  - Neu-Laxova
  description: >-
    Biallelic PHGDH variants cause Neu-Laxova syndrome 1, a severe prenatal
    multisystem phenotype. Neu-Laxova syndromes caused by PSAT1 or PSPH are
    separate genetic disorders and are differentials for this focal entry.
  evidence:
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NLS represents the severe end of serine-deficiency disorders
    explanation: Places PHGDH-related NLS1 at the severe end of the serine-deficiency spectrum.
  downstream:
  - target: Congenital microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37347880
      reference_title: Serine Deficiency Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts, characteristic dysmorphic features, limb anomalies, and collodion-like ichthyosis
      explanation: GeneReviews summarizes the NLS feature bundle; PMID:25152457 supplies the PHGDH-specific subtype link.
  - target: Intrauterine growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37347880
      reference_title: Serine Deficiency Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts, characteristic dysmorphic features, limb anomalies, and collodion-like ichthyosis
      explanation: Supports severe fetal growth restriction in NLS.
  - target: Neu-Laxova congenital cataracts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37347880
      reference_title: Serine Deficiency Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts, characteristic dysmorphic features, limb anomalies, and collodion-like ichthyosis
      explanation: Supports congenital bilateral cataracts in NLS.
  - target: Ichthyosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37347880
      reference_title: Serine Deficiency Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts, characteristic dysmorphic features, limb anomalies, and collodion-like ichthyosis
      explanation: Supports collodion-like ichthyosis in NLS.
phenotypes:
- category: Nervous System
  name: Congenital microcephaly
  subtypes:
  - Infantile
  - Neu-Laxova
  description: >-
    Primary microcephaly is characteristic of classic infantile PHGDH deficiency
    and is severe in the prenatal Neu-Laxova syndrome 1 spectrum, but is not
    required in the juvenile or reported adult presentations.
  phenotype_term:
    preferred_term: Primary microcephaly
    term:
      id: HP:0011451
      label: Primary microcephaly
  evidence:
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: presented with psychomotor delay, growth failure, microcephaly, and spasticity
    explanation: Supports microcephaly in the PHGDH-specific infantile cohort.
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts
    explanation: Supports microcephaly in the NLS feature bundle.
- category: Nervous System
  name: Severe global developmental delay
  subtype: Infantile
  severity: SEVERE
  description: Severe psychomotor or global developmental delay is typical of the classic infantile presentation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype
    explanation: Supports severe developmental impairment in infantile disease.
- category: Nervous System
  name: Infantile seizures
  subtype: Infantile
  description: Seizures can be severe in classic disease but were absent in three of six individuals in one PHGDH-specific cohort.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: RECURRENT
  evidence:
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3
    explanation: Establishes variable seizure expression in the six-person infantile cohort.
- category: Nervous System
  name: Spastic tetraplegia
  subtype: Infantile
  description: Severe spastic quadriplegia can emerge during early childhood in classic infantile PHGDH deficiency.
  phenotype_term:
    preferred_term: Spastic tetraplegia
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a severe spastic quadriplegia becomes evident during the first years of life
    explanation: Describes the classic infantile motor outcome in the PHGDH-specific review of prior cases.
- category: Nervous System
  name: Cerebral hypomyelination
  subtype: Infantile
  description: Brain MRI can show hypomyelination with profound white-matter attenuation.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: PMID:11508546
    reference_title: Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pre-treatment MRI demonstrated hypomyelination and profound white matter attenuation in all patients.
    explanation: Documents the finding in all four individuals in the MRI series.
- category: Nervous System
  name: Juvenile absence seizures
  subtype: Juvenile
  description: Absence seizures were the presenting seizure type in both reported juvenile siblings.
  phenotype_term:
    preferred_term: Generalized non-motor (absence) seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
    temporality: RECURRENT
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two siblings with juvenile onset of absence seizures and mild developmental delay
    explanation: Supports absence seizures in both juvenile siblings.
- category: Nervous System
  name: Mild global developmental delay
  subtype: Juvenile
  severity: MILD
  description: The two reported juvenile siblings had mild developmental delay rather than infantile developmental arrest.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two siblings with juvenile onset of absence seizures and mild developmental delay
    explanation: Supports the milder developmental phenotype.
- category: Nervous System
  name: Atypical behavior
  subtype: Juvenile
  description: Behavioral and well-being changes were reported in the juvenile siblings and improved after L-serine.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: improvement of well-being and behaviour
    explanation: Supports a behavioral component but does not define a specific psychiatric phenotype.
- category: Growth
  name: Intrauterine growth retardation
  subtype: Neu-Laxova
  description: Severe fetal growth restriction is part of the Neu-Laxova syndrome 1 presentation.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, microcephaly
    explanation: GeneReviews identifies severe fetal growth deficiency in NLS.
- category: Eye
  name: Neu-Laxova congenital cataracts
  subtype: Neu-Laxova
  description: Bilateral congenital cataracts are part of the Neu-Laxova malformation pattern.
  phenotype_term:
    preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: microcephaly, congenital bilateral cataracts, characteristic dysmorphic features
    explanation: Supports congenital bilateral cataracts in NLS.
- category: Integument
  name: Ichthyosis
  subtype: Neu-Laxova
  description: Collodion-like ichthyosis is part of the Neu-Laxova syndrome 1 malformation pattern.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: limb anomalies, and collodion-like ichthyosis
    explanation: Supports the characteristic skin phenotype in NLS.
- category: Nervous System
  name: Peripheral axonal neuropathy
  subtype: Adult
  description: Chronic axonal sensorimotor polyneuropathy was the dominant manifestation in one adult PHGDH case.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:22393170
    reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: chronic axonal sensorimotor polyneuropathy
    explanation: Supports this manifestation in a single adult.
- category: Nervous System
  name: Adult ataxia
  subtype: Adult
  description: Slight cerebellar ataxia accompanied the adult neuropathy presentation in one individual.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:22393170
    reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: slight cerebellar ataxia
    explanation: Supports mild ataxia in the single adult case.
- category: Eye
  name: Adult congenital cataracts
  subtype: Adult
  description: Congenital cataracts were present in the single reported adult neuropathy case.
  phenotype_term:
    preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:22393170
    reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: congenital cataracts
    explanation: Supports congenital cataracts in one adult.
imaging_findings:
- name: Cerebral hypomyelination and white-matter attenuation on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  located_in:
    preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  diagnostic: false
  subtype: Infantile
  context: Four-patient MRI series; the finding is characteristic but not pathognomonic.
  description: >-
    Pretreatment brain MRI showed hypomyelination and profound white-matter
    attenuation in four individuals. Increased white-matter volume and progress
    of myelination during amino-acid treatment occurred in only two of four.
  evidence:
  - reference: PMID:11508546
    reference_title: Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pre-treatment MRI demonstrated hypomyelination and profound white matter attenuation in all patients.
    explanation: Establishes the pretreatment imaging pattern in the four-person series.
  - reference: PMID:11508546
    reference_title: Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During treatment, a significant increase in white matter volume was found and a progress of myelination in two patients.
    explanation: Qualifies treatment-associated imaging improvement as occurring in two of four individuals.
biochemical:
- name: Cerebrospinal fluid L-serine
  presence: DECREASED
  notes: >-
    Low CSF L-serine is the most reliable biochemical marker. Meals have limited
    short-term influence on CSF serine compared with plasma.
  biomarker_term:
    preferred_term: L-serine
    term:
      id: CHEBI:17115
      label: L-serine
  readouts:
  - target: Low L-Serine and Downstream Metabolites
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower CSF L-serine reports the central biochemical consequence of PHGDH deficiency.
    evidence:
    - reference: PMID:19235232
      reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)
      explanation: Directly supports CSF L-serine as a biochemical readout.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: remain the preferred diagnostic procedure to confirm serine deficiency
    explanation: The full-text discussion identifies CSF amino-acid analysis as the preferred confirmatory procedure.
- name: Fasting plasma L-serine
  presence: DECREASED
  notes: Plasma serine may be low or only borderline low and should be measured fasting because dietary amino acids alter plasma values.
  biomarker_term:
    preferred_term: L-serine
    term:
      id: CHEBI:17115
      label: L-serine
  readouts:
  - target: Low L-Serine and Downstream Metabolites
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: A low or borderline-low fasting value supports the biochemical diagnosis; a nonfasting value is less reliable.
    evidence:
    - reference: DOI:10.1007/s10545-010-9249-5
      reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: amino acids should be analysed after an overnight fast
      explanation: Supports fasting collection for plasma amino-acid interpretation.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: need to recognise the significance of low or borderline low values of plasma serine
    explanation: Supports low or borderline-low plasma serine as a diagnostic clue.
- name: Cerebrospinal fluid and plasma glycine
  presence: VARIABLE
  notes: Glycine can be decreased but may be normal in the juvenile PHGDH presentation; it is not a required diagnostic abnormality.
  biomarker_term:
    preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
  readouts:
  - target: Low L-Serine and Downstream Metabolites
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low glycine can accompany serine deficiency, but normal glycine does not exclude PHGDH deficiency.
    evidence:
    - reference: PMID:12118526
      reference_title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid
      explanation: Supports variable glycine reduction as a readout of the biochemical defect.
  evidence:
  - reference: PMID:12118526
    reference_title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid
    explanation: Establishes variable glycine reduction.
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with a normal value for glycine
    explanation: Shows that glycine can remain normal in juvenile PHGDH deficiency.
- name: Cerebrospinal fluid D-serine
  presence: DECREASED
  biomarker_term:
    preferred_term: D-serine
    term:
      id: CHEBI:16523
      label: D-serine
  readouts:
  - target: Low L-Serine and Downstream Metabolites
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Decreased CSF D-serine is a secondary biochemical consequence of reduced serine availability.
    evidence:
    - reference: PMID:19235232
      reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)
      explanation: Supports decreased D-serine as a readout of the central biochemical state.
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)
    explanation: Directly reports decreased CSF D-serine.
- name: PHGDH activity in cultured fibroblasts
  presence: DECREASED
  notes: A functional adjunct that can demonstrate reduced enzyme activity; molecular confirmation is now the definitive diagnostic test.
  readouts:
  - target: PHGDH Enzyme Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced cultured-fibroblast activity functionally reports the enzyme defect.
    evidence:
    - reference: PMID:19235232
      reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations.
      explanation: Directly maps the assay readout to reduced PHGDH activity.
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations.
    explanation: Direct functional evidence for reduced PHGDH activity in patient fibroblasts.
- name: Plasma phospholipid species
  presence: DECREASED
  notes: >-
    Low glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin
    species were observed in a four-child mixed serine-biosynthesis cohort,
    including three with PHGDH deficiency. This is an exploratory mechanistic
    readout, not an established diagnostic test.
  readouts:
  - target: Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    interpretation: Decreased plasma phospholipid species report one candidate downstream pathway but do not prove CNS causality.
    evidence:
    - reference: PMID:29269105
      reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Metabolomic profiling performed at baseline showed low phospholipid species
      explanation: Maps the exploratory plasma readout to the candidate lipid branch without asserting clinical causality.
  evidence:
  - reference: PMID:29269105
    reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin.
    explanation: Reports the exploratory plasma metabolomic abnormality.
genetic:
- name: PHGDH
  gene_term:
    preferred_term: PHGDH
    term:
      id: hgnc:8923
      label: PHGDH
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic pathogenic PHGDH variants cause this disorder. Missense and
    frameshift variants occur across functional domains and can reduce enzyme
    activity. Residual activity as a predictor of clinical subtype remains a
    hypothesis rather than an established genotype-phenotype rule.
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We now describe five novel mutations in five patients with 3-PGDH deficiency; one frameshift mutation
    explanation: Establishes multiple PHGDH variant classes in affected individuals.
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PHGDH missense mutations in three unrelated families of our cohort
    explanation: Extends the PHGDH association to Neu-Laxova syndrome 1.
has_subtypes:
- name: Infantile
  display_name: Infantile PHGDH deficiency
  description: Classic severe neurodevelopmental presentation with congenital microcephaly, severe delay, variable seizures and spasticity, and possible hypomyelination.
  evidence:
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency
    explanation: Supports the PHGDH-specific infantile subtype.
- name: Juvenile
  display_name: Juvenile-onset PHGDH deficiency
  description: Milder presentation reported in two siblings with absence seizures, mild developmental delay, behavioral abnormalities, and no obligatory microcephaly or MRI abnormality.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two siblings with juvenile onset of absence seizures and mild developmental delay
    explanation: Defines the juvenile subtype.
- name: Adult
  display_name: Reported adult PHGDH neuropathy presentation
  description: Case-level presentation reported in one adult with axonal sensorimotor polyneuropathy, slight ataxia, congenital cataracts, and mild developmental impairment.
  evidence:
  - reference: PMID:22393170
    reference_title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To describe a case of serine synthesis defect due to 3-phosphoglycerate dehydrogenase deficiency in an adult with prominent chronic polyneuropathy.
    explanation: Supports an adult presentation but only from one case.
- name: Neu-Laxova
  display_name: Neu-Laxova syndrome 1
  subtype_term:
    preferred_term: Neu-Laxova syndrome 1
    term:
      id: MONDO:0009736
      label: Neu-Laxova syndrome 1
  description: >-
    PHGDH-related Neu-Laxova syndrome 1 is the severe prenatal end of this exact
    disease. Neu-Laxova syndromes caused by PSAT1 or PSPH are genetically
    distinct and are not included in this subtype.
  evidence:
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PHGDH missense mutations in three unrelated families of our cohort
    explanation: Establishes PHGDH-related NLS1 within the heterogeneous Neu-Laxova group.
diagnosis:
- name: Fasting plasma amino acid analysis
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: >-
    Measure plasma amino acids after an overnight fast. Low or borderline-low
    L-serine supports the diagnosis, but dietary influence and mild cases can
    make plasma results less sensitive than CSF.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: amino acids should be analysed after an overnight fast
    explanation: Supports fasting plasma collection.
- name: Cerebrospinal fluid amino acid analysis
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: >-
    Low CSF L-serine is the central biochemical finding and is the preferred
    confirmatory biochemical procedure when plasma serine is borderline or the
    phenotype suggests PHGDH deficiency.
  evidence:
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: remain the preferred diagnostic procedure to confirm serine deficiency
    explanation: Supports CSF analysis as the preferred biochemical confirmation.
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF)
    explanation: Defines the characteristic CSF profile.
- name: PHGDH molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    Demonstration of biallelic pathogenic variants in PHGDH establishes this
    focal diagnosis. Biallelic PSAT1 or PSPH variants establish different serine
    biosynthesis disorders and must not be accepted as confirmation of PHGDH
    deficiency.
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: five novel mutations in five patients with 3-PGDH deficiency
    explanation: Supports PHGDH molecular confirmation in affected patients.
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: biallelic pathogenic variants in PHGDH, PSAT1, or PSPH identified by molecular genetic testing
    explanation: GeneReviews supports molecular confirmation of the broader group; the exact focal entry is restricted to PHGDH.
- name: PHGDH enzyme activity assay in cultured fibroblasts
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: Reduced PHGDH activity in cultured fibroblasts is a historical functional adjunct when molecular findings require clarification.
  evidence:
  - reference: PMID:19235232
    reference_title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations.
    explanation: Supports the functional enzyme assay.
differential_diagnoses:
- name: PSAT deficiency
  disease_term:
    preferred_term: PSAT deficiency
    term:
      id: MONDO:0012596
      label: PSAT deficiency
  description: PSAT1 deficiency causes an overlapping autosomal recessive serine-biosynthesis disorder with low serine and infantile or prenatal neurologic disease.
  distinguishing_features:
  - Biallelic PSAT1 variants, rather than PHGDH variants, establish this diagnosis.
  evidence:
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: biallelic pathogenic variants in PHGDH, PSAT1, or PSPH identified by molecular genetic testing
    explanation: Supports gene-specific molecular differentiation within the serine-deficiency group.
- name: PSPH deficiency
  disease_term:
    preferred_term: PSPH deficiency
    term:
      id: MONDO:0013531
      label: PSPH deficiency
  description: PSPH deficiency can produce overlapping serine-deficiency biochemistry and neurodevelopmental disease.
  distinguishing_features:
  - Biallelic PSPH variants, rather than PHGDH variants, establish this diagnosis.
  evidence:
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase
    explanation: Establishes PSPH as a distinct causal gene in the serine-biosynthesis/NLS differential.
- name: Neu-Laxova syndrome 2
  disease_term:
    preferred_term: Neu-Laxova syndrome 2
    term:
      id: MONDO:0014466
      label: Neu-Laxova syndrome 2
  description: Neu-Laxova syndrome 2 overlaps the prenatal malformation and lethal presentation of PHGDH-related NLS1.
  distinguishing_features:
  - Neu-Laxova syndrome 2 is caused by biallelic PSAT1 variants; PHGDH-related disease is Neu-Laxova syndrome 1.
  evidence:
  - reference: PMID:25152457
    reference_title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease
    explanation: Supports PSAT1-related NLS as a genetically distinct differential.
treatments:
- name: L-Serine supplementation
  action_category: THERAPEUTIC
  description: >-
    Oral L-serine bypasses the biosynthetic block and restores serine
    concentrations. Repeated small cohorts show the clearest benefit for seizure
    control and sometimes spasticity or well-being. Developmental improvement is
    inconsistent, especially after established injury; MRI improvement occurred
    in two of four treated individuals in one series.
  treatment_term:
    preferred_term: amino acid supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: L-serine
      term:
        id: CHEBI:17115
        label: L-serine
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  target_mechanisms:
  - target: PHGDH Enzyme Deficiency
    treatment_effect: BYPASSES
    description: Exogenous L-serine supplies pathway product downstream of deficient PHGDH.
    evidence:
    - reference: PMID:12118526
      reference_title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: oral treatment with the deficient amino acids
      explanation: Supports substrate replacement as the treatment rationale but does not directly assay pathway flux.
  - target: Low L-Serine and Downstream Metabolites
    treatment_effect: RESTORES
    description: Supplementation normalizes plasma and CSF serine in treated patients.
    evidence:
    - reference: DOI:10.1007/s10545-010-9249-5
      reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The values of CSF and plasma serine normalised during treatment.
      explanation: Directly supports biochemical restoration in a juvenile patient.
  evidence:
  - reference: PMID:12118526
    reference_title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A major reduction in seizure frequency occurred in all patients; two patients became free of seizures.
    explanation: Reports seizure benefit in five treated patients; psychomotor progress occurred in only one, diagnosed early and treated at high dose.
  - reference: PMID:28135894
    reference_title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2.
    explanation: Supports seizure/spasticity response and limited developmental recovery in a PHGDH-specific cohort.
  - reference: PMID:11508546
    reference_title: Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a significant increase in white matter volume was found and a progress of myelination in two patients
    explanation: Supports treatment-associated imaging improvement in two of four individuals.
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: L-serine therapy is more effective than anti-seizure medication for treatment of seizures
    explanation: >-
      GeneReviews supports L-serine as the preferred disease-directed treatment
      for seizures while the primary cohorts above define the small evidence base.
- name: Adjunct glycine supplementation
  action_category: THERAPEUTIC
  description: >-
    Glycine has been added when high-dose L-serine did not control seizures. The
    evidence is limited to two siblings and should not be generalized as a
    universal requirement.
  treatment_term:
    preferred_term: amino acid supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: glycine
      term:
        id: CHEBI:15428
        label: glycine
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Low L-Serine and Downstream Metabolites
    treatment_effect: RESTORES
    description: Adjunct glycine supplies one variably deficient downstream amino acid.
    evidence:
    - reference: PMID:9708551
      reference_title: Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Addition of glycine 200 mg/kg/day resulted in complete disappearance of seizures.
      explanation: Demonstrates clinical response in two siblings but does not separately quantify mechanism restoration.
  evidence:
  - reference: PMID:9708551
    reference_title: Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: L-Serine up to 500 mg/kg/day was not sufficient for seizure control. Addition of glycine 200 mg/kg/day resulted in complete disappearance of seizures.
    explanation: Supports adjunct glycine after inadequate L-serine response in two siblings.
- name: Maternal prenatal L-serine supplementation
  action_category: THERAPEUTIC
  context: Single molecularly diagnosed affected fetus; unreplicated case report, not established routine care.
  description: >-
    Maternal L-serine was given after declining fetal head circumference in one
    affected pregnancy. Fetal head growth increased and development was reported
    as unremarkable at 48 months, but efficacy, safety, dose, and generalizability
    remain unestablished.
  treatment_term:
    preferred_term: amino acid supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: L-serine
      term:
        id: CHEBI:17115
        label: L-serine
  target_phenotypes:
  - preferred_term: Primary microcephaly
    term:
      id: HP:0011451
      label: Primary microcephaly
  target_mechanisms:
  - target: Low L-Serine and Downstream Metabolites
    treatment_effect: RESTORES
    description: Maternal supplementation was intended to supply serine to the affected fetus.
    evidence:
    - reference: PMID:15610810
      reference_title: Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: L-serine was then given to the mother
      explanation: Documents the intervention but does not directly demonstrate fetal biochemical normalization.
  evidence:
  - reference: PMID:15610810
    reference_title: Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: L-serine was then given to the mother, which resulted in an enlarged fetal head circumference to the 76th percentile at 31 weeks.
    explanation: Supports the reported response in one fetus; no replication or comparator establishes general efficacy.
- name: Longitudinal clinical surveillance
  action_category: MONITORING
  description: >-
    Follow-up should be individualized across the broad PHGDH spectrum and
    monitor seizures, tone and contractures, development and behavior, growth and
    nutrition, feeding and constipation, respiratory and musculoskeletal issues,
    and family support needs. GeneReviews recommends dental evaluation every six
    months.
  evidence:
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surveillance: Monitor for seizures, changes in tone, contractures,
      developmental and educational needs, behavior issues, growth and nutrition,
      constipation and feeding issues, respiratory issues, musculoskeletal
      manifestations, and family needs at each visit. Dental evaluation every six
      months.
    explanation: >-
      GeneReviews gives the multisystem surveillance domains and dental interval
      for serine deficiency disorders.
- name: Seizure-trigger avoidance counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Families should receive anticipatory counseling and illness planning around
    recognized seizure triggers, including infection and physical or emotional
    stress.
  evidence:
  - reference: PMID:37347880
    reference_title: Serine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Agents/circumstances to avoid: Known triggers of seizure activity (e.g.,
      infection, physical stress, emotional stress).
    explanation: >-
      GeneReviews identifies clinically relevant seizure triggers for anticipatory
      counseling and illness planning.
discussions:
- discussion_id: gap_phgdh_treatment_timing_and_generalizability
  prompt: How reproducible, safe, dose-dependent, and timing-dependent are early postnatal and antenatal L-serine benefits in PHGDH deficiency?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Seizure improvement is repeated across small cohorts, but developmental
    recovery is inconsistent. One antenatally treated fetus had improved head
    growth and an unremarkable 48-month outcome, which establishes precedent but
    not general efficacy or safety.
  attaches_to:
  - pathophysiology#Low L-Serine and Downstream Metabolites
  - pathophysiology#Infantile and Juvenile Neurologic Disease
  proposed_experiments:
  - experiment_id: phgdh_prospective_treatment_registry
    name: Prospective genotype- and treatment-timing registry
    description: >-
      Enroll molecularly confirmed PHGDH cases before treatment and collect
      standardized dose, treatment-age, seizure, development, amino-acid, and
      longitudinal MRI outcomes, with a separately governed prenatal cohort.
    decision_criterion: A reproducible dose/timing-response relationship across independent families with prospectively defined biochemical and clinical outcomes.
    would_support:
    - pathophysiology#Low L-Serine and Downstream Metabolites
  evidence:
  - reference: PMID:15610810
    reference_title: Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At birth, the girl's head circumference was normal, and at 48 months' follow-up, her psychomotor development has been unremarkable.
    explanation: Defines the promising but unreplicated prenatal observation.
  - reference: PMID:12118526
    reference_title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine.
    explanation: Shows the limited and timing-associated developmental response that a prospective registry must resolve.
- discussion_id: gap_phgdh_genotype_residual_activity
  prompt: Which PHGDH variant, domain, or residual-activity features, if any, predict infantile, juvenile, adult, or Neu-Laxova syndrome 1 presentation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Residual enzyme activity is hypothesized to influence severity, yet severe
    and mild presentations can have overlapping serine concentrations and
    fibroblast activity. No clinically reliable genotype-phenotype rule is
    established.
  attaches_to:
  - pathophysiology#PHGDH Enzyme Deficiency
  proposed_experiments:
  - experiment_id: phgdh_variant_function_registry
    name: Standardized PHGDH variant-function and phenotype study
    description: >-
      Measure expression, stability, kinetics, and pathway flux for PHGDH
      variants under one protocol and link results to harmonized longitudinal
      clinical phenotypes and treatment exposure.
    decision_criterion: Prespecified functional measurements predict subtype and severity in an independent validation cohort beyond treatment timing and family background.
    would_support:
    - pathophysiology#PHGDH Enzyme Deficiency
  evidence:
  - reference: PMID:32579715
    reference_title: Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability
    explanation: States the residual-activity model explicitly as a postulate requiring further functional study.
  - reference: DOI:10.1007/s10545-010-9249-5
    reference_title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mild clinical phenotype could not be predicted from the biochemical or molecular analysis
    explanation: Shows why routine measurements cannot yet predict clinical severity.
- discussion_id: gap_phgdh_tissue_selective_vulnerability
  prompt: Which serine-derived pathways produce central nervous system, peripheral nerve, eye/skin, and prenatal multisystem phenotypes in PHGDH deficiency?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Human phospholipid profiles and an astrocytic PHGDH-dependent serine shuttle
    provide candidate mechanisms, but neither explains the full tissue and
    subtype spectrum or has been causally validated in human disease models.
  attaches_to:
  - pathophysiology#Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
  - pathophysiology#Adult Axonal Neuropathy Syndrome
  - pathophysiology#Prenatal Neu-Laxova Multisystem Developmental Disruption
  proposed_experiments:
  - experiment_id: phgdh_isogenic_tissue_flux_models
    name: Isogenic human tissue-selective serine-flux models
    description: >-
      Compare matched PHGDH-deficient and corrected neural progenitor,
      astrocyte-neuron, oligodendrocyte, peripheral-nerve, lens, and fetal
      developmental models using isotope-resolved serine, lipid, nucleotide,
      glycine, and D-serine flux with L-serine rescue.
    decision_criterion: A tissue-specific deficit is reproduced across variants, corrected by isogenic repair, and rescued by pathway-specific supplementation in parallel with disease-relevant cellular readouts.
    would_support:
    - pathophysiology#Serine-Dependent CNS Biosynthetic and Signaling Insufficiency
  evidence:
  - reference: PMID:29269105
    reference_title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin
    explanation: Supplies a human metabolic candidate requiring tissue-level causal testing.
  - reference: PMID:31548413
    reference_title: The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: implicate both d-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism
    explanation: Supplies a model-system signaling candidate requiring translation to human PHGDH deficiency.
references:
- reference: PMID:9708551
  title: Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency.
  findings: []
- reference: PMID:11508546
  title: Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
  findings: []
- reference: PMID:12118526
  title: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids."
  findings: []
- reference: PMID:15610810
  title: Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.
  findings: []
- reference: PMID:19235232
  title: Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
  findings: []
- reference: PMID:22393170
  title: A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
  findings: []
- reference: PMID:25152457
  title: Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
  findings: []
- reference: PMID:28135894
  title: "Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges."
  findings: []
- reference: PMID:29269105
  title: Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
  findings: []
- reference: PMID:31548413
  title: The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
  findings: []
- reference: PMID:32579715
  title: Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.
  findings: []
- reference: PMID:37347880
  title: Serine Deficiency Disorders.
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s10545-010-9249-5
  title: Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
  findings: []
notes: >-
  IEMbase package seed WP-003 (GitHub issue 5558), classification code 1.6.01.02;
  OMIM:601815; ORPHA:79351. The entry is anchored to the exact PHGDH leaf
  MONDO:0011152. PHGDH-related Neu-Laxova syndrome 1 (MONDO:0009736) is modeled
  as its severe prenatal subtype; PSAT1- and PSPH-related serine-deficiency
  disorders remain separate disease entries and differentials. Mechanistic
  claims were recalibrated so that only the enzyme-to-low-serine chain is
  established, while proposed lipid and NMDA-signaling bridges remain explicit
  emerging hypotheses.
datasets:
- accession: geo:GSE8555
  title: Genome-wide analysis of Phgdh inactivation in murine embryonic head
  description: D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  sample_count: 8
  publication: PMID:18228065
  notes: Identified by GEO DataSets index search for 3-Phosphoglycerate Dehydrogenase Deficiency (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

References

13
PMID:9708551
Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency.
No top-level findings curated for this source.
PMID:11508546
Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.
No top-level findings curated for this source.
PMID:12118526
Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids.
No top-level findings curated for this source.
PMID:15610810
Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.
No top-level findings curated for this source.
PMID:19235232
Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.
No top-level findings curated for this source.
PMID:22393170
A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
No top-level findings curated for this source.
PMID:25152457
Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
No top-level findings curated for this source.
PMID:28135894
Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges.
No top-level findings curated for this source.
PMID:29269105
Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
No top-level findings curated for this source.
PMID:31548413
The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle.
No top-level findings curated for this source.
PMID:32579715
Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.
No top-level findings curated for this source.
PMID:37347880
Serine Deficiency Disorders.
No top-level findings curated for this source.
DOI:10.1007/s10545-010-9249-5
Expanding the clinical spectrum of 3‐phosphoglycerate dehydrogenase deficiency
No top-level findings curated for this source.