Developmental And Epileptic Encephalopathy 40

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Inheritance

1

Autosomal recessive inheritance HP:0000007

The reported family was consanguineous, and the three affected siblings were homozygous for the same GUF1 missense variant (c.1825G>T, p.(Ala609Ser)). Only one family has been reported with segregation data, so the recessive mode rests on that single pedigree together with Orphanet's gene-disease assertion.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:26486472 SUPPORT Human Clinical

"we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."

Homozygosity for one variant in three affected siblings of a consanguineous family is the segregation pattern that establishes recessive inheritance here.

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Discussions and Knowledge Gaps

2

Do DEE40 patients actually have a measurable respiratory chain or bioenergetic deficit, and is it present in neural tissue?

KNOWLEDGE GAP OPEN gap_human_neuronal_bioenergetics

Attached to

pathophysiology#Defective Respiratory Chain Complex Assembly pathophysiology#Neuronal Energy Failure and Epileptic Encephalopathy

Every respiratory chain observation supporting this entry comes from yeast, worm, or cultured human cancer cells. No muscle or fibroblast respiratory chain enzymology, lactate, or oxidative phosphorylation measurement has been published for a GUF1 patient, and the discovering authors present the link to West syndrome as a suggestion. Until such a measurement exists, the central effector node of this entry is supported only by cross-species inference, which is also why no conformance to a mitochondrial mechanism module is declared (see notes).

Proposed experiments

Respiratory chain assessment in GUF1 patient-derived cells

exp_guf1_patient_respiratory_chain

Measure respiratory chain complex activities, assembly by blue-native electrophoresis, and mitochondrial translation rates in fibroblasts or iPSC-derived neurons from a GUF1 p.(Ala609Ser) homozygote against controls, to establish whether the assembly defect seen in model systems is present in patient cells and whether it is neuron-selective.

Show evidence (1 reference)

PMID:26486472 SUPPORT INDIRECT Human Clinical

"We suggest a new link between improper assembly of respiratory chain complexes and WS."

The authors' own framing of the mechanism as a suggestion is what this gap records. Classified INDIRECT because it evidences the state of the argument rather than a measurement.

Why does mtEF4 knockout in the mouse produce testis-restricted disease while the human variant produces an epileptic encephalopathy with no reported fertility phenotype?

HUMAN MODEL MISMATCH OPEN gap_mouse_spares_nervous_system

Attached to

pathophysiology#Neuronal Energy Failure and Epileptic Encephalopathy animal_models#mtEF4 knockout mouse

This is a mismatch rather than an absence of evidence: the mouse knockout was made and characterised, and its phenotype is male infertility from testis-specific oxidative phosphorylation failure, with somatic tissues compensating through mTOR-driven cytoplasmic translation. The organ affected in the mouse is not the organ affected in the reported human family. Either the developing human brain cannot mount the somatic compensation that mouse somatic tissues can, or the human missense allele acts differently from a null, or the mouse neurological phenotype was simply not looked for. The distinction matters because the mouse is currently the only mammalian in vivo system available for this gene, and reading it as a model of DEE40 would misstate what has been shown.

Proposed experiments

Neurological phenotyping of mtEF4-deficient mice

exp_neuro_phenotyping_mtef4_mouse

Perform EEG, seizure-susceptibility and developmental assessment in constitutive and neuron-specific mtEF4 knockout mice, and measure mTOR pathway activity and cytoplasmic translation rates in brain, to test whether the nervous system is genuinely spared or merely unexamined, and whether neuronal compensation differs from that in other somatic tissues.

Knock-in of the patient allele

exp_knockin_a609s_mouse

Generate a mouse carrying the orthologous p.(Ala609Ser) substitution rather than a null allele, to test whether the human missense variant produces a neurological phenotype that complete ablation does not.

Show evidence (1 reference)

PMID:27065197 SUPPORT Model Organism

"Here we report that genetic ablation of mitochondrial EF4 (mtEF4) in mice causes testis-specific dysfunction in oxidative phosphorylation, leading to male infertility."

Documents the tissue specificity of the mouse phenotype, which is the mismatch with the human presentation that this discussion records.

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Pathophysiology

4

Biallelic GUF1 Variants

The initiating lesion is a homozygous GUF1 missense variant. In the reported family the allele is c.1825G>T, p.(Ala609Ser), which substitutes an alanine conserved across all eukaryotic organisms and positioned within the tRNA-binding moiety of the protein. Note that the functional consequence is reported as a modification of activity under suboptimal conditions rather than as a clean null, so this node is deliberately not labelled a loss of function.

GUF1 hgnc:25799

Downstream

Impaired Mitochondrial Translation Elongation Fidelity The variant alters mtEF4 activity in the conditions under which the factor is required, as measured by yeast complementation.

Show evidence (1 reference)

PMID:26486472 SUPPORT Human Clinical

"The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor."

Locates the disease allele within the tRNA-binding region of mtEF4 and establishes the residue's conservation, the basis for treating it as the initiating lesion.

Impaired Mitochondrial Translation Elongation Fidelity

GUF1/mtEF4 is a quality-control factor of mitochondrial protein synthesis rather than a core elongation engine: it binds mitoribosomes in a GTP-dependent manner, remobilizes stalled ribosomes, and transiently inhibits elongation so that synthesis remains accurate. No modifier is asserted on the elongation process below because the reported direction is condition-dependent — yeast lacking Guf1 show diminished synthesis rates at low temperature, whereas mouse mtEF4 deletion accelerates mitochondrial translation at the cost of producing unstable proteins. What is consistent across systems is the loss of fidelity, not a single direction of rate change.

mitochondrial translational elongation GO:0070125

GTPase activity GO:0003924

Experimental models

Yeast guf1-null complementation assay OTHER The complementation assay reads out how well a given GUF1 allele supports mitochondrial protein synthesis under the suboptimal conditions in which the factor is required, which is the functional grading behind the pathogenicity claim.

Animal models

mtEF4 knockout mouse Mouse recapitulates Deleting mtEF4 in the mouse produces exactly the fidelity defect this node models — mitochondrial translation runs faster and yields unstable proteins — giving the node a mammalian in vivo measurement.

Downstream

Defective Respiratory Chain Complex Assembly Because the mitochondrially translated polypeptides are the core subunits of the respiratory chain complexes, infidelity in their synthesis yields products that cannot be assembled into functional complexes.

Show evidence (4 references)

PMID:26486472 SUPPORT Other

"GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis."

States the molecular role of the gene product that this node models. Evidence source is OTHER because the sentence is background molecular biology synthesised from model-system work, not a clinical observation made in this study.

PMID:18442968 SUPPORT In Vitro

"The observed defects in Guf1-deficient mitochondria are consistent with a function of Guf1 as a fidelity factor of mitochondrial protein synthesis."

Establishes the fidelity-factor role in the yeast ortholog, the conserved function whose disruption this node describes.

PMID:18442968 SUPPORT In Vitro

"It binds to mitochondrial ribosomes in a GTP-dependent manner."

Supports the GTPase and ribosome-engagement molecular function annotated on this node.

+ 1 more reference

Defective Respiratory Chain Complex Assembly

Loss of mtEF4 function impairs biogenesis of the oxidative phosphorylation complexes, with complex IV the most consistently affected across model systems: cytochrome oxidase assembly fails in Guf1-deficient yeast at restrictive temperature, respiratory chain supercomplexes containing complex IV are disrupted in mtef4-null C. elegans at low temperature, and knockout of mtEF4 in human cells induces respiratory chain complex defects and apoptosis. This node is the mechanistic pivot the discovering authors proposed for the epilepsy, and it is supported entirely by non-human or non-neural systems — no respiratory chain measurement has been reported in a DEE40 patient.

mitochondrial respiratory chain complex assembly GO:0033108 ↓ DECREASED

Animal models

mtef4-null Caenorhabditis elegans Caenorhabditis elegans recapitulates Loss of mtEF4 in the worm disrupts assembly of respiratory chain supercomplexes containing complex IV, the assembly failure this node models.

Downstream

Neuronal Energy Failure and Epileptic Encephalopathy The step from respiratory chain assembly failure to infantile spasms is the link the discovering authors proposed, by analogy with the broader association between respiratory chain defects and infantile epilepsy. The intervening events in developing human neurons have not been demonstrated.

Show evidence (3 references)

PMID:24837196 SUPPORT Model Organism

"At low temperature (15°C), mtef4 deletion reduces mitochondrial translation and disrupts the assembly of respiratory chain supercomplexes containing complex IV."

A whole-organism metazoan result tying mtEF4 loss to disrupted complex IV supercomplex assembly.

PMID:29572227 SUPPORT In Vitro

"Knockout of mtEF4 induced respiratory chain complex defects and apoptosis, while its overexpression stimulated cancer development."

Shows the same consequence for the human protein in cultured cells. Cited only for the respiratory chain phenotype of mtEF4 loss; the tumour biology that is this paper's subject is not relevant to DEE40.

PMID:30693836 SUPPORT Other

"We will discuss the influence of mtEF4 on the electron transport chain, especially at respiratory chain complex IV, which could result in cytochrome c peroxidase formation, electron leakage from electron transport chain and ROS increase."

A review summarising the complex IV focus of the mtEF4 respiratory phenotype and the proposed ROS consequence. Evidence source is OTHER because this is a review, and the ROS arm is stated as a possibility ("could result in"), so it is not asserted as a node here.

Neuronal Energy Failure and Epileptic Encephalopathy

The clinical endpoint is an early-infantile developmental and epileptic encephalopathy presenting as West syndrome. The energy-failure framing is inherited from the general association between respiratory chain disorders and infantile epilepsy rather than from any measurement in GUF1 patients, which is why this node carries no biological process annotation asserting a bioenergetic deficit in human neural tissue.

Animal models

mtEF4 knockout mouse Mouse fails to recapitulate The mouse knockout does not reproduce the human neurological endpoint. The reported consequence of mtEF4 ablation is testis-specific oxidative phosphorylation dysfunction causing male infertility; somatic tissues, which include the brain, compensate by upregulating mTOR-driven cytoplasmic translation to match the accelerated mitochondrial rate.

Show evidence (1 reference)

PMID:26486472 SUPPORT Human Clinical

"To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS."

Establishes that the affected siblings' clinical endpoint was isolated West syndrome, the phenotype this consequence node represents.

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Pathograph

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

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Phenotypes

5

Metabolism 1

Refractory epilepsy Refractory drug response HP:0020174

Show evidence (1 reference)

PMID:37820178 SUPPORT INDIRECT Human Clinical

"Targeted next-generation sequencing molecular genetics results were reviewed, and 3 ALDH7A1, 1 AARS, 3 CACNA1A, 1 CTNNB1, 1 DCX, 2 DBH, 2 DOCK7, 1 FOLR1, 2 GABRB3, 2 GCH1, 1 VGRIN2B, 1 GUF1, 3 KCNQ2, 2 KCNT1, 1 NECAP1, 1 PCDH19, 1 PNPO, 1 SCN8A, 1 SCN9A, 4 SCN1A, 2 SLC25A22, 1 SLC2A1, 2 SPTAN1,..."

Classified INDIRECT: documents that a GUF1 patient was among those genotyped in a cohort defined by refractory epilepsy, establishing the drug-resistance by enrolment criterion rather than by individual report.

Nervous System 4

Infantile spasms HP:0012469

Show evidence (2 references)

PMID:26486472 SUPPORT INDIRECT Human Clinical

"West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."

Classified INDIRECT: the paper states the siblings had isolated West syndrome and separately defines that syndrome by this triad, so the spasms follow from the diagnosis rather than from a per-patient description. The accessible record for this paper does not include the case narratives.

ORPHA:697160 SUPPORT Other

"GUF1 | GTP binding elongation factor GUF1 | hgnc:25799 | Disease-causing germline mutation(s) in"

Orphanet's gene-disease row placing GUF1 among the causes of infantile epileptic spasms syndrome, independent of the primary report.

Hypsarrhythmia HP:0002521

Show evidence (1 reference)

PMID:26486472 SUPPORT INDIRECT Human Clinical

"West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."

Classified INDIRECT for the same reason as the spasms phenotype: the EEG pattern follows from the stated West syndrome diagnosis rather than from a reported per-patient EEG in the accessible record.

Developmental regression HP:0002376

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:26486472 SUPPORT INDIRECT Human Clinical

"West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."

Classified INDIRECT: regression follows from the West syndrome diagnosis applied to these siblings rather than from an individual case description.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:37820178 SUPPORT INDIRECT Human Clinical

"In this retrospective cohort study, patients with refractory epilepsy and global developmental delay, defined as epileptic encephalopathy, who applied to the Aydın 7Maternity and Children's Hospital Genetic Diagnosis Center and were followed in the pediatric neurology clinic of our hospital,..."

Classified INDIRECT: this is the cohort inclusion criterion, and a GUF1 patient was among those enrolled, so the delay is inferred from cohort membership rather than reported individually.

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Genetic Associations

1

GUF1 (Pathogenic Variants)

Gene: GUF1 hgnc:25799 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:26486472 SUPPORT Human Clinical

"We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."

The variant-level gene-disease observation on which the entry rests.

ORPHA:697160 SUPPORT Other

"GUF1 | GTP binding elongation factor GUF1 | hgnc:25799 | Disease-causing germline mutation(s) in"

Orphanet's curated gene-disease assertion for GUF1, corroborating the causative relationship recorded here.

PMID:37820178 SUPPORT Human Clinical

"An identifiable underlying genetic cause was identified in 48 (25%) out of 198 patients."

Establishes the diagnostic-yield context of the panel cohort in which one further GUF1 patient was identified.

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Medical Actions

1

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Because DEE40 is autosomal recessive and the reported family was consanguineous, recurrence-risk counselling and carrier testing are part of family care. No disease-modifying or GUF1-specific therapy exists, and no antiseizure drug response has been reported in a GUF1 patient (see notes).

Show evidence (1 reference)

PMID:26486472 SUPPORT Human Clinical

"we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."

Establishes the consanguineous, biallelic recurrence situation that makes recurrence-risk counselling relevant.

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Diagnosis

4

Electroencephalography

EEG demonstrating hypsarrhythmia is what establishes the West syndrome presentation through which DEE40 has come to clinical attention; the pattern is pathognomonic for the syndrome. Etiologic diagnosis then requires sequencing.

electroencephalography NCIT:C38054

Show evidence (1 reference)

PMID:26486472 SUPPORT INDIRECT Human Clinical

"West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."

The paper calls hypsarrhythmia pathognomonic of the syndrome the siblings carried, and hypsarrhythmia is an EEG finding, which is what makes EEG the presentation-defining test. Classified INDIRECT because the sentence is definitional rather than a report of the patients' own EEG recordings.

Brain magnetic resonance imaging

Cranial imaging is performed to exclude a structural cause for the seizures rather than to identify a DEE40-specific lesion. In the panel cohort that ascertained a GUF1 patient, imaging was done in every patient and found no structural anomaly capable of causing the seizures — an exclusionary result. No DEE40-specific neuroimaging finding has been described.

brain magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:37820178 SUPPORT INDIRECT Human Clinical

"Cranial imaging was performed in all patients. There was no structural anomaly that could cause a seizure."

Establishes imaging as a routine exclusionary step in the cohort that included a GUF1 patient. Classified INDIRECT because the finding is reported for the whole 198-patient cohort rather than for the GUF1 patient individually.

Whole exome sequencing

GUF1 was identified as the candidate gene by exome sequencing of a consanguineous multiplex family, and exome or genome sequencing remains the route to a DEE40 diagnosis.

whole exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:26486472 SUPPORT Human Clinical

"we exome-sequenced the members of a consanguineous family affected with isolated WS"

Establishes exome sequencing as the method that produced the diagnosis.

Targeted next-generation sequencing epilepsy panel

GUF1 is included on targeted epilepsy gene panels, which is how the one further reported patient was ascertained.

targeted next-generation sequencing gene panel NCIT:C198412

Show evidence (1 reference)

PMID:37820178 SUPPORT Human Clinical

"Targeted next-generation sequencing molecular genetics results were reviewed"

Documents the targeted panel as the diagnostic modality in the cohort that identified a GUF1 patient.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

DEE40 is ultra-rare and has no estimated population prevalence. The reported literature amounts to three affected siblings in one consanguineous family (2016) and one further patient carrying a GUF1 variant in a 198-patient targeted next-generation sequencing cohort (2023) — four patients in total by that count, which is a dated lower bound rather than a current total. The 1:3500 figure quoted in the primary report is the birth incidence of West syndrome from all causes, not of GUF1-related disease, and must not be read as a DEE40 rate.

Show evidence (1 reference)

PMID:26486472 SUPPORT Human Clinical

"We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."

The three-sibling count from the index family, kept as a literature case count rather than converted to a population rate.

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Experimental Models

1

Yeast guf1-null complementation assay OTHER

Saccharomyces cerevisiae lacking GUF1 has cold- and heat-sensitive growth defects on non-fermentable carbon sources and defective cytochrome oxidase assembly. Complementing that strain with human GUF1 alleles grades their function, and this is the assay that supplied the only functional evidence for the patient variant.

Organism

Saccharomyces cerevisiae NCBITaxon:4932

Publication

PMID:26486472

Pathograph links

Impaired Mitochondrial Translation Elongation Fidelity measures fidelity: moderate observes: cellular The complementation assay reads out how well a given GUF1 allele supports mitochondrial protein synthesis under the suboptimal conditions in which the factor is required, which is the functional grading behind the pathogenicity claim.

Limitations: A yeast growth readout is several steps removed from a human neuronal phenotype, and the reported effect is a modification of activity under suboptimal conditions rather than a clear-cut loss, so the assay establishes that the variant is functionally consequential without quantifying how consequential it is for human brain development.

Show evidence (1 reference)

PMID:26486472 SUPPORT In Vitro

"Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments."

The assay result grading the patient allele, which is the measurement this model contributes.

Show evidence (1 reference)

PMID:18442968 SUPPORT In Vitro

"Mutants lacking Guf1 show cold- and heat-sensitive growth defects on non-fermentable carbon sources that are especially pronounced under nutrient-limiting conditions."

Characterises the yeast null phenotype that makes the complementation readout interpretable.

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Animal Models

2

mtEF4 knockout mouse Genetic

Whole-animal and germline-specific mtEF4 knockout mice were made to test the physiological requirement for the factor. The result is informative for the translation node of this entry and, equally importantly, is a negative result for the neurological one: the phenotype is testis-restricted male infertility, with somatic tissues compensating through mTOR-driven cytoplasmic translation. No epilepsy or encephalopathy phenotype is reported.

Species

Mouse

Genotype

mtEF4 (Guf1) knockout, including germline-specific conditional deletion

Publication

PMID:27065197

Pathograph links

Impaired Mitochondrial Translation Elongation Fidelity recapitulates fidelity: moderate observes: organism Deleting mtEF4 in the mouse produces exactly the fidelity defect this node models — mitochondrial translation runs faster and yields unstable proteins — giving the node a mammalian in vivo measurement.

Limitations: A complete knockout models null activity, whereas the human allele is a missense variant whose activity is altered rather than abolished, so the severity is not matched. The direction of the rate change is also opposite to that seen in cold-stressed yeast, so this model fixes the fidelity claim but not a direction of translational rate change.

Show evidence (1 reference)

PMID:27065197 SUPPORT Model Organism

"Deletion of mtEF4 accelerated mitochondrial translation at the cost of producing unstable proteins."

Supports treating the knockout mouse as informative for the translation-fidelity node.

Neuronal Energy Failure and Epileptic Encephalopathy fails to recapitulate fidelity: low observes: organism The mouse knockout does not reproduce the human neurological endpoint. The reported consequence of mtEF4 ablation is testis-specific oxidative phosphorylation dysfunction causing male infertility; somatic tissues, which include the brain, compensate by upregulating mTOR-driven cytoplasmic translation to match the accelerated mitochondrial rate.

Limitations: This is a reported absence of a neurological phenotype in a study designed around fertility, not a dedicated neurological or EEG assessment, so it is weaker than a deliberate negative finding. The compensation mechanism was characterised in somatic tissue generally rather than in neurons specifically, and mouse and human may differ in the developmental window over which such compensation is available.

Show evidence (2 references)

PMID:27065197 REFUTE Model Organism

"Here we report that genetic ablation of mitochondrial EF4 (mtEF4) in mice causes testis-specific dysfunction in oxidative phosphorylation, leading to male infertility."

The phenotype of mtEF4 ablation in the mouse is testis-specific and does not include the encephalopathy this node models, which refutes the mouse as a model of the human neurological endpoint.

+ 1 more reference

mtef4-null Caenorhabditis elegans Genetic

Deleting the C. elegans mtEF4 ortholog produces mitochondrial dysfunction, growth delay and reduced brood size at normal temperature, and at low temperature reduces mitochondrial translation and disrupts complex IV-containing respiratory chain supercomplexes. It is the model that connects the translation defect to respiratory chain assembly in a whole metazoan.

Species

Caenorhabditis elegans

Genotype

mtef4 (C. elegans mtEF4 ortholog) deletion

Publication

PMID:24837196

Pathograph links

Defective Respiratory Chain Complex Assembly recapitulates fidelity: moderate observes: organism Loss of mtEF4 in the worm disrupts assembly of respiratory chain supercomplexes containing complex IV, the assembly failure this node models.

Limitations: The supercomplex disruption is observed at 15°C rather than at the animal's optimal temperature, so it is a cold-stress phenotype and may overstate what happens at mammalian body temperature. C. elegans has no nervous system comparable to the developing human cortex, so the model speaks to the assembly node only and not to the neurological consequence.

Show evidence (1 reference)

PMID:24837196 SUPPORT Model Organism

"At low temperature (15°C), mtef4 deletion reduces mitochondrial translation and disrupts the assembly of respiratory chain supercomplexes containing complex IV."

Supports treating the worm deletion as informative for the respiratory chain assembly node.

Show evidence (1 reference)

PMID:24837196 SUPPORT Model Organism

"At worms' optimum growing temperature (20°C), mtef4 deletion leads to self-brood size reduction, growth delay and mitochondrial dysfunction."

Establishes that the deletion causes mitochondrial dysfunction in this organism even without cold stress.

{ }

Source YAML

click to show

name: Developmental And Epileptic Encephalopathy 40
creation_date: "2026-09-05T19:12:28Z"
description: >-
  DEE40 (EIEE40; OMIM 617065) is an autosomal recessive developmental and
  epileptic encephalopathy attributed to biallelic variants in GUF1, which
  encodes the nuclear genome-encoded mitochondrial translation elongation factor
  EF-4 (mtEF4), the eukaryotic homolog of bacterial LepA. The mechanism runs
  through mitochondrial protein synthesis rather than through an ion channel:
  mtEF4 is a fidelity factor that remobilizes stalled mitoribosomes and
  transiently inhibits elongation, and its disruption compromises assembly of
  the respiratory chain complexes whose core subunits are made inside the
  mitochondrion. The single reported family presented with isolated West
  syndrome — infantile spasms with hypsarrhythmia and developmental regression.
  The evidence base is deliberately small: one consanguineous family with three
  affected siblings (2016), a single additional GUF1 patient in a targeted
  gene-panel cohort (2023), and functional work in yeast, worm, and mouse rather
  than in human neural tissue. The final step from respiratory chain assembly
  failure to the epilepsy is proposed by the discovering authors and has not
  been measured in patients.
category: Mendelian
parents:
- Genetic Developmental and Epileptic Encephalopathy
synonyms:
- DEE40
- EIEE40
- early infantile epileptic encephalopathy 40
- epileptic encephalopathy, early infantile, 40
- GUF1 early infantile epileptic encephalopathy
- early infantile epileptic encephalopathy caused by mutation in GUF1
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 40
  term:
    id: MONDO:0014895
    label: developmental and epileptic encephalopathy, 40
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    The reported family was consanguineous, and the three affected siblings were
    homozygous for the same GUF1 missense variant (c.1825G>T, p.(Ala609Ser)).
    Only one family has been reported with segregation data, so the recessive
    mode rests on that single pedigree together with Orphanet's gene-disease
    assertion.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."
    explanation: >-
      Homozygosity for one variant in three affected siblings of a consanguineous
      family is the segregation pattern that establishes recessive inheritance
      here.
pathophysiology:
- name: Biallelic GUF1 Variants
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The initiating lesion is a homozygous GUF1 missense variant. In the reported
    family the allele is c.1825G>T, p.(Ala609Ser), which substitutes an alanine
    conserved across all eukaryotic organisms and positioned within the
    tRNA-binding moiety of the protein. Note that the functional consequence is
    reported as a modification of activity under suboptimal conditions rather
    than as a clean null, so this node is deliberately not labelled a loss of
    function.
  genes:
  - preferred_term: GUF1
    term:
      id: hgnc:25799
      label: GUF1
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor."
    explanation: >-
      Locates the disease allele within the tRNA-binding region of mtEF4 and
      establishes the residue's conservation, the basis for treating it as the
      initiating lesion.
  downstream:
  - target: Impaired Mitochondrial Translation Elongation Fidelity
    causal_link_type: DIRECT
    description: >-
      The variant alters mtEF4 activity in the conditions under which the factor
      is required, as measured by yeast complementation.
    evidence:
    - reference: PMID:26486472
      reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments."
      explanation: >-
        The functional assay linking the patient allele to altered elongation
        factor activity, which is the next node.
- name: Impaired Mitochondrial Translation Elongation Fidelity
  biological_scale: MOLECULAR
  description: >-
    GUF1/mtEF4 is a quality-control factor of mitochondrial protein synthesis
    rather than a core elongation engine: it binds mitoribosomes in a
    GTP-dependent manner, remobilizes stalled ribosomes, and transiently inhibits
    elongation so that synthesis remains accurate. No modifier is asserted on the
    elongation process below because the reported direction is
    condition-dependent — yeast lacking Guf1 show diminished synthesis rates at
    low temperature, whereas mouse mtEF4 deletion accelerates mitochondrial
    translation at the cost of producing unstable proteins. What is consistent
    across systems is the loss of fidelity, not a single direction of rate
    change.
  biological_processes:
  - preferred_term: mitochondrial translational elongation
    term:
      id: GO:0070125
      label: mitochondrial translational elongation
  molecular_functions:
  - preferred_term: GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis."
    explanation: >-
      States the molecular role of the gene product that this node models.
      Evidence source is OTHER because the sentence is background molecular
      biology synthesised from model-system work, not a clinical observation
      made in this study.
  - reference: PMID:18442968
    reference_title: The membrane-bound GTPase Guf1 promotes mitochondrial protein synthesis under suboptimal conditions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The observed defects in Guf1-deficient mitochondria are consistent with a function of Guf1 as a fidelity factor of mitochondrial protein synthesis."
    explanation: >-
      Establishes the fidelity-factor role in the yeast ortholog, the conserved
      function whose disruption this node describes.
  - reference: PMID:18442968
    reference_title: The membrane-bound GTPase Guf1 promotes mitochondrial protein synthesis under suboptimal conditions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "It binds to mitochondrial ribosomes in a GTP-dependent manner."
    explanation: >-
      Supports the GTPase and ribosome-engagement molecular function annotated on
      this node.
  - reference: PMID:27065197
    reference_title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of mtEF4 accelerated mitochondrial translation at the cost of producing unstable proteins."
    explanation: >-
      The mammalian in vivo result, and the reason this node asserts a fidelity
      defect without asserting a direction of rate change: here loss of mtEF4
      speeds translation up rather than slowing it.
  downstream:
  - target: Defective Respiratory Chain Complex Assembly
    causal_link_type: DIRECT
    description: >-
      Because the mitochondrially translated polypeptides are the core subunits
      of the respiratory chain complexes, infidelity in their synthesis yields
      products that cannot be assembled into functional complexes.
    evidence:
    - reference: PMID:18442968
      reference_title: The membrane-bound GTPase Guf1 promotes mitochondrial protein synthesis under suboptimal conditions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "At elevated temperatures, Guf1-deficient mutants exhibit defects in the assembly of cytochrome oxidase, suggesting that the polypeptides produced are not functional."
      explanation: >-
        Directly connects the translation-fidelity defect to failed cytochrome
        oxidase assembly, which is the causal step this edge asserts.
- name: Defective Respiratory Chain Complex Assembly
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Loss of mtEF4 function impairs biogenesis of the oxidative phosphorylation
    complexes, with complex IV the most consistently affected across model
    systems: cytochrome oxidase assembly fails in Guf1-deficient yeast at
    restrictive temperature, respiratory chain supercomplexes containing complex
    IV are disrupted in mtef4-null C. elegans at low temperature, and knockout of
    mtEF4 in human cells induces respiratory chain complex defects and apoptosis.
    This node is the mechanistic pivot the discovering authors proposed for the
    epilepsy, and it is supported entirely by non-human or non-neural systems —
    no respiratory chain measurement has been reported in a DEE40 patient.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex assembly
    term:
      id: GO:0033108
      label: mitochondrial respiratory chain complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:24837196
    reference_title: Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At low temperature (15°C), mtef4 deletion reduces mitochondrial translation and disrupts the assembly of respiratory chain supercomplexes containing complex IV."
    explanation: >-
      A whole-organism metazoan result tying mtEF4 loss to disrupted complex IV
      supercomplex assembly.
  - reference: PMID:29572227
    reference_title: Human Elongation Factor 4 Regulates Cancer Bioenergetics by Acting as a Mitochondrial Translation Switch.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knockout of mtEF4 induced respiratory chain complex defects and apoptosis, while its overexpression stimulated cancer development."
    explanation: >-
      Shows the same consequence for the human protein in cultured cells. Cited
      only for the respiratory chain phenotype of mtEF4 loss; the tumour biology
      that is this paper's subject is not relevant to DEE40.
  - reference: PMID:30693836
    reference_title: Mitochondrial translation factor EF4 regulates oxidative phosphorylation complexes and the production of ROS.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We will discuss the influence of mtEF4 on the electron transport chain, especially at respiratory chain complex IV, which could result in cytochrome c peroxidase formation, electron leakage from electron transport chain and ROS increase."
    explanation: >-
      A review summarising the complex IV focus of the mtEF4 respiratory
      phenotype and the proposed ROS consequence. Evidence source is OTHER
      because this is a review, and the ROS arm is stated as a possibility
      ("could result in"), so it is not asserted as a node here.
  downstream:
  - target: Neuronal Energy Failure and Epileptic Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The step from respiratory chain assembly failure to infantile spasms is the
      link the discovering authors proposed, by analogy with the broader
      association between respiratory chain defects and infantile epilepsy. The
      intervening events in developing human neurons have not been demonstrated.
    evidence:
    - reference: PMID:26486472
      reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We suggest a new link between improper assembly of respiratory chain complexes and WS."
      explanation: >-
        Classified INDIRECT because the authors offer this as a suggested link
        rather than a demonstrated mechanism; no patient respiratory chain or
        neuronal measurement is reported.
- name: Neuronal Energy Failure and Epileptic Encephalopathy
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoint is an early-infantile developmental and epileptic
    encephalopathy presenting as West syndrome. The energy-failure framing is
    inherited from the general association between respiratory chain disorders
    and infantile epilepsy rather than from any measurement in GUF1 patients,
    which is why this node carries no biological process annotation asserting a
    bioenergetic deficit in human neural tissue.
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS."
    explanation: >-
      Establishes that the affected siblings' clinical endpoint was isolated West
      syndrome, the phenotype this consequence node represents.
phenotypes:
- name: Infantile spasms
  category: Neurologic
  description: >-
    The reported siblings had isolated West syndrome, of which infantile spasms
    are the defining seizure type. Orphanet independently lists GUF1 as a
    disease-causing gene for infantile epileptic spasms syndrome.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."
    explanation: >-
      Classified INDIRECT: the paper states the siblings had isolated West
      syndrome and separately defines that syndrome by this triad, so the spasms
      follow from the diagnosis rather than from a per-patient description. The
      accessible record for this paper does not include the case narratives.
  - reference: ORPHA:697160
    reference_title: Infantile epileptic spasms syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GUF1 | GTP binding elongation factor GUF1 | hgnc:25799 | Disease-causing germline mutation(s) in"
    explanation: >-
      Orphanet's gene-disease row placing GUF1 among the causes of infantile
      epileptic spasms syndrome, independent of the primary report.
- name: Hypsarrhythmia
  category: Neurologic
  description: >-
    Hypsarrhythmia is the pathognomonic interictal EEG pattern of West syndrome,
    the diagnosis carried by the reported siblings.
  phenotype_term:
    preferred_term: Hypsarrhythmia
    term:
      id: HP:0002521
      label: Hypsarrhythmia
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."
    explanation: >-
      Classified INDIRECT for the same reason as the spasms phenotype: the EEG
      pattern follows from the stated West syndrome diagnosis rather than from a
      reported per-patient EEG in the accessible record.
- name: Developmental regression
  category: Neurologic
  description: >-
    Loss of acquired developmental skills is the third element of the West
    syndrome triad by which the affected siblings were characterised.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."
    explanation: >-
      Classified INDIRECT: regression follows from the West syndrome diagnosis
      applied to these siblings rather than from an individual case description.
- name: Global developmental delay
  category: Neurologic
  description: >-
    A further GUF1 patient was ascertained in a paediatric cohort whose entry
    criterion was refractory epilepsy together with global developmental delay.
    The delay is therefore established for that patient by cohort membership.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37820178
    reference_title: Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this retrospective cohort study, patients with refractory epilepsy and global developmental delay, defined as epileptic encephalopathy, who applied to the Aydın 7Maternity and Children's Hospital Genetic Diagnosis Center and were followed in the pediatric neurology clinic of our hospital, between July 2018 and July 2021, were included."
    explanation: >-
      Classified INDIRECT: this is the cohort inclusion criterion, and a GUF1
      patient was among those enrolled, so the delay is inferred from cohort
      membership rather than reported individually.
- name: Refractory epilepsy
  category: Neurologic
  description: >-
    The same cohort required drug-resistant epilepsy for enrolment, so the
    reported GUF1 patient's epilepsy was refractory.
  phenotype_term:
    preferred_term: Refractory epilepsy
    term:
      id: HP:0020174
      label: Refractory drug response
  evidence:
  - reference: PMID:37820178
    reference_title: Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted next-generation sequencing molecular genetics results were reviewed, and 3 ALDH7A1, 1 AARS, 3 CACNA1A, 1 CTNNB1, 1 DCX, 2 DBH, 2 DOCK7, 1 FOLR1, 2 GABRB3, 2 GCH1, 1 VGRIN2B, 1 GUF1, 3 KCNQ2, 2 KCNT1, 1 NECAP1, 1 PCDH19, 1 PNPO, 1 SCN8A, 1 SCN9A, 4 SCN1A, 2 SLC25A22, 1 SLC2A1, 2 SPTAN1, 2 SZT2, 4 TBC1D24, 2 TH, and 1 PCDH19 (X chromosome) mutations were detected in three of the patients using the next-generation sequencing method."
    explanation: >-
      Classified INDIRECT: documents that a GUF1 patient was among those
      genotyped in a cohort defined by refractory epilepsy, establishing the
      drug-resistance by enrolment criterion rather than by individual report.
genetic:
- name: GUF1
  gene_term:
    preferred_term: GUF1
    term:
      id: hgnc:25799
      label: GUF1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    GUF1 (GTP binding elongation factor GUF1) is the only gene implicated in
    DEE40 (MONDO:0014895; OMIM 617065). The single reported segregating allele is
    the homozygous missense c.1825G>T, p.(Ala609Ser), found in three affected
    siblings of one consanguineous family by exome sequencing. A second,
    unspecified GUF1 variant was reported in one patient of a 198-patient
    targeted-panel cohort. The gene-disease relationship therefore rests on a
    single multiplex pedigree plus a supportive functional assay, and Orphanet
    lists GUF1 among the disease-causing genes for infantile epileptic spasms
    syndrome. External gene-disease validity curation reflects the same thin
    base: Genomics England PanelApp lists GUF1 at AMBER (confidence level 2) on
    its early onset or syndromic epilepsy panel, and at RED (level 1) on its
    mitochondrial disorders panel (PanelApp API, checked 2026-09-06; recorded as
    prose because PanelApp is not a snippet-citable structured source in this
    repository). No functional_impact_category is asserted: the yeast assay
    reports that the variant's activity is "modified in suboptimal environments"
    rather than abolished, which does not license a loss-of-function call.
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."
    explanation: >-
      The variant-level gene-disease observation on which the entry rests.
  - reference: ORPHA:697160
    reference_title: Infantile epileptic spasms syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GUF1 | GTP binding elongation factor GUF1 | hgnc:25799 | Disease-causing germline mutation(s) in"
    explanation: >-
      Orphanet's curated gene-disease assertion for GUF1, corroborating the
      causative relationship recorded here.
  - reference: PMID:37820178
    reference_title: Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An identifiable underlying genetic cause was identified in 48 (25%) out of 198 patients."
    explanation: >-
      Establishes the diagnostic-yield context of the panel cohort in which one
      further GUF1 patient was identified.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    DEE40 is ultra-rare and has no estimated population prevalence. The reported
    literature amounts to three affected siblings in one consanguineous family
    (2016) and one further patient carrying a GUF1 variant in a 198-patient
    targeted next-generation sequencing cohort (2023) — four patients in total by
    that count, which is a dated lower bound rather than a current total. The
    1:3500 figure quoted in the primary report is the birth incidence of West
    syndrome from all causes, not of GUF1-related disease, and must not be read
    as a DEE40 rate.
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."
    explanation: >-
      The three-sibling count from the index family, kept as a literature case
      count rather than converted to a population rate.
diagnosis:
- name: Electroencephalography
  description: >-
    EEG demonstrating hypsarrhythmia is what establishes the West syndrome
    presentation through which DEE40 has come to clinical attention; the pattern
    is pathognomonic for the syndrome. Etiologic diagnosis then requires
    sequencing.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births."
    explanation: >-
      The paper calls hypsarrhythmia pathognomonic of the syndrome the siblings
      carried, and hypsarrhythmia is an EEG finding, which is what makes EEG the
      presentation-defining test. Classified INDIRECT because the sentence is
      definitional rather than a report of the patients' own EEG recordings.
- name: Brain magnetic resonance imaging
  description: >-
    Cranial imaging is performed to exclude a structural cause for the seizures
    rather than to identify a DEE40-specific lesion. In the panel cohort that
    ascertained a GUF1 patient, imaging was done in every patient and found no
    structural anomaly capable of causing the seizures — an exclusionary result.
    No DEE40-specific neuroimaging finding has been described.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:37820178
    reference_title: Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cranial imaging was performed in all patients. There was no structural anomaly that could cause a seizure."
    explanation: >-
      Establishes imaging as a routine exclusionary step in the cohort that
      included a GUF1 patient. Classified INDIRECT because the finding is
      reported for the whole 198-patient cohort rather than for the GUF1 patient
      individually.
- name: Whole exome sequencing
  description: >-
    GUF1 was identified as the candidate gene by exome sequencing of a
    consanguineous multiplex family, and exome or genome sequencing remains the
    route to a DEE40 diagnosis.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we exome-sequenced the members of a consanguineous family affected with isolated WS"
    explanation: >-
      Establishes exome sequencing as the method that produced the diagnosis.
- name: Targeted next-generation sequencing epilepsy panel
  description: >-
    GUF1 is included on targeted epilepsy gene panels, which is how the one
    further reported patient was ascertained.
  diagnosis_term:
    preferred_term: targeted next-generation sequencing gene panel
    term:
      id: NCIT:C198412
      label: Multi-gene Panel Sequencing
  evidence:
  - reference: PMID:37820178
    reference_title: Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted next-generation sequencing molecular genetics results were reviewed"
    explanation: >-
      Documents the targeted panel as the diagnostic modality in the cohort that
      identified a GUF1 patient.
treatments:
- name: Genetic counseling
  description: >-
    Because DEE40 is autosomal recessive and the reported family was
    consanguineous, recurrence-risk counselling and carrier testing are part of
    family care. No disease-modifying or GUF1-specific therapy exists, and no
    antiseizure drug response has been reported in a GUF1 patient (see notes).
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings."
    explanation: >-
      Establishes the consanguineous, biallelic recurrence situation that makes
      recurrence-risk counselling relevant.
animal_models:
- name: mtEF4 knockout mouse
  species: Mouse
  genotype: mtEF4 (Guf1) knockout, including germline-specific conditional deletion
  category: Genetic
  publication: PMID:27065197
  description: >-
    Whole-animal and germline-specific mtEF4 knockout mice were made to test the
    physiological requirement for the factor. The result is informative for the
    translation node of this entry and, equally importantly, is a negative result
    for the neurological one: the phenotype is testis-restricted male infertility,
    with somatic tissues compensating through mTOR-driven cytoplasmic
    translation. No epilepsy or encephalopathy phenotype is reported.
  modeled_mechanisms:
  - target: Impaired Mitochondrial Translation Elongation Fidelity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Deleting mtEF4 in the mouse produces exactly the fidelity defect this node
      models — mitochondrial translation runs faster and yields unstable
      proteins — giving the node a mammalian in vivo measurement.
    limitations: >-
      A complete knockout models null activity, whereas the human allele is a
      missense variant whose activity is altered rather than abolished, so the
      severity is not matched. The direction of the rate change is also opposite
      to that seen in cold-stressed yeast, so this model fixes the fidelity claim
      but not a direction of translational rate change.
    evidence:
    - reference: PMID:27065197
      reference_title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of mtEF4 accelerated mitochondrial translation at the cost of producing unstable proteins."
      explanation: >-
        Supports treating the knockout mouse as informative for the
        translation-fidelity node.
  - target: Neuronal Energy Failure and Epileptic Encephalopathy
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The mouse knockout does not reproduce the human neurological endpoint. The
      reported consequence of mtEF4 ablation is testis-specific oxidative
      phosphorylation dysfunction causing male infertility; somatic tissues,
      which include the brain, compensate by upregulating mTOR-driven cytoplasmic
      translation to match the accelerated mitochondrial rate.
    limitations: >-
      This is a reported absence of a neurological phenotype in a study designed
      around fertility, not a dedicated neurological or EEG assessment, so it is
      weaker than a deliberate negative finding. The compensation mechanism was
      characterised in somatic tissue generally rather than in neurons
      specifically, and mouse and human may differ in the developmental window
      over which such compensation is available.
    evidence:
    - reference: PMID:27065197
      reference_title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Here we report that genetic ablation of mitochondrial EF4 (mtEF4) in mice causes testis-specific dysfunction in oxidative phosphorylation, leading to male infertility."
      explanation: >-
        The phenotype of mtEF4 ablation in the mouse is testis-specific and does
        not include the encephalopathy this node models, which refutes the mouse
        as a model of the human neurological endpoint.
    - reference: PMID:27065197
      reference_title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Somatic tissues overcame this defect by activating mechanistic (mammalian) target of rapamycin (mTOR), thereby increasing rates of cytoplasmic translation to match rates of mitochondrial translation."
      explanation: >-
        Gives the mechanism by which somatic tissues escape the defect, which is
        the proposed explanation for why the mouse spares the nervous system.
- name: mtef4-null Caenorhabditis elegans
  species: Caenorhabditis elegans
  genotype: mtef4 (C. elegans mtEF4 ortholog) deletion
  category: Genetic
  publication: PMID:24837196
  description: >-
    Deleting the C. elegans mtEF4 ortholog produces mitochondrial dysfunction,
    growth delay and reduced brood size at normal temperature, and at low
    temperature reduces mitochondrial translation and disrupts complex
    IV-containing respiratory chain supercomplexes. It is the model that connects
    the translation defect to respiratory chain assembly in a whole metazoan.
  modeled_mechanisms:
  - target: Defective Respiratory Chain Complex Assembly
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Loss of mtEF4 in the worm disrupts assembly of respiratory chain
      supercomplexes containing complex IV, the assembly failure this node
      models.
    limitations: >-
      The supercomplex disruption is observed at 15°C rather than at the animal's
      optimal temperature, so it is a cold-stress phenotype and may overstate what
      happens at mammalian body temperature. C. elegans has no nervous system
      comparable to the developing human cortex, so the model speaks to the
      assembly node only and not to the neurological consequence.
    evidence:
    - reference: PMID:24837196
      reference_title: Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At low temperature (15°C), mtef4 deletion reduces mitochondrial translation and disrupts the assembly of respiratory chain supercomplexes containing complex IV."
      explanation: >-
        Supports treating the worm deletion as informative for the respiratory
        chain assembly node.
  evidence:
  - reference: PMID:24837196
    reference_title: Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At worms' optimum growing temperature (20°C), mtef4 deletion leads to self-brood size reduction, growth delay and mitochondrial dysfunction."
    explanation: >-
      Establishes that the deletion causes mitochondrial dysfunction in this
      organism even without cold stress.
experimental_models:
- name: Yeast guf1-null complementation assay
  description: >-
    Saccharomyces cerevisiae lacking GUF1 has cold- and heat-sensitive growth
    defects on non-fermentable carbon sources and defective cytochrome oxidase
    assembly. Complementing that strain with human GUF1 alleles grades their
    function, and this is the assay that supplied the only functional evidence for
    the patient variant.
  experimental_model_type: OTHER
  organism:
    preferred_term: Saccharomyces cerevisiae
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  publication: PMID:26486472
  modeled_mechanisms:
  - target: Impaired Mitochondrial Translation Elongation Fidelity
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The complementation assay reads out how well a given GUF1 allele supports
      mitochondrial protein synthesis under the suboptimal conditions in which
      the factor is required, which is the functional grading behind the
      pathogenicity claim.
    limitations: >-
      A yeast growth readout is several steps removed from a human neuronal
      phenotype, and the reported effect is a modification of activity under
      suboptimal conditions rather than a clear-cut loss, so the assay
      establishes that the variant is functionally consequential without
      quantifying how consequential it is for human brain development.
    evidence:
    - reference: PMID:26486472
      reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments."
      explanation: >-
        The assay result grading the patient allele, which is the measurement
        this model contributes.
  evidence:
  - reference: PMID:18442968
    reference_title: The membrane-bound GTPase Guf1 promotes mitochondrial protein synthesis under suboptimal conditions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutants lacking Guf1 show cold- and heat-sensitive growth defects on non-fermentable carbon sources that are especially pronounced under nutrient-limiting conditions."
    explanation: >-
      Characterises the yeast null phenotype that makes the complementation
      readout interpretable.
discussions:
- discussion_id: gap_human_neuronal_bioenergetics
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do DEE40 patients actually have a measurable respiratory chain or
    bioenergetic deficit, and is it present in neural tissue?
  attaches_to:
  - "pathophysiology#Defective Respiratory Chain Complex Assembly"
  - "pathophysiology#Neuronal Energy Failure and Epileptic Encephalopathy"
  rationale: >-
    Every respiratory chain observation supporting this entry comes from yeast,
    worm, or cultured human cancer cells. No muscle or fibroblast respiratory
    chain enzymology, lactate, or oxidative phosphorylation measurement has been
    published for a GUF1 patient, and the discovering authors present the link to
    West syndrome as a suggestion. Until such a measurement exists, the central
    effector node of this entry is supported only by cross-species inference,
    which is also why no conformance to a mitochondrial mechanism module is
    declared (see notes).
  proposed_experiments:
  - experiment_id: exp_guf1_patient_respiratory_chain
    name: Respiratory chain assessment in GUF1 patient-derived cells
    description: >-
      Measure respiratory chain complex activities, assembly by blue-native
      electrophoresis, and mitochondrial translation rates in fibroblasts or
      iPSC-derived neurons from a GUF1 p.(Ala609Ser) homozygote against controls,
      to establish whether the assembly defect seen in model systems is present
      in patient cells and whether it is neuron-selective.
  evidence:
  - reference: PMID:26486472
    reference_title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest a new link between improper assembly of respiratory chain complexes and WS."
    explanation: >-
      The authors' own framing of the mechanism as a suggestion is what this gap
      records. Classified INDIRECT because it evidences the state of the argument
      rather than a measurement.
- discussion_id: gap_mouse_spares_nervous_system
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does mtEF4 knockout in the mouse produce testis-restricted disease while
    the human variant produces an epileptic encephalopathy with no reported
    fertility phenotype?
  attaches_to:
  - "pathophysiology#Neuronal Energy Failure and Epileptic Encephalopathy"
  - "animal_models#mtEF4 knockout mouse"
  rationale: >-
    This is a mismatch rather than an absence of evidence: the mouse knockout was
    made and characterised, and its phenotype is male infertility from
    testis-specific oxidative phosphorylation failure, with somatic tissues
    compensating through mTOR-driven cytoplasmic translation. The organ affected
    in the mouse is not the organ affected in the reported human family. Either
    the developing human brain cannot mount the somatic compensation that mouse
    somatic tissues can, or the human missense allele acts differently from a
    null, or the mouse neurological phenotype was simply not looked for. The
    distinction matters because the mouse is currently the only mammalian in vivo
    system available for this gene, and reading it as a model of DEE40 would
    misstate what has been shown.
  proposed_experiments:
  - experiment_id: exp_neuro_phenotyping_mtef4_mouse
    name: Neurological phenotyping of mtEF4-deficient mice
    description: >-
      Perform EEG, seizure-susceptibility and developmental assessment in
      constitutive and neuron-specific mtEF4 knockout mice, and measure mTOR
      pathway activity and cytoplasmic translation rates in brain, to test
      whether the nervous system is genuinely spared or merely unexamined, and
      whether neuronal compensation differs from that in other somatic tissues.
  - experiment_id: exp_knockin_a609s_mouse
    name: Knock-in of the patient allele
    description: >-
      Generate a mouse carrying the orthologous p.(Ala609Ser) substitution rather
      than a null allele, to test whether the human missense variant produces a
      neurological phenotype that complete ablation does not.
  evidence:
  - reference: PMID:27065197
    reference_title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we report that genetic ablation of mitochondrial EF4 (mtEF4) in mice causes testis-specific dysfunction in oxidative phosphorylation, leading to male infertility."
    explanation: >-
      Documents the tissue specificity of the mouse phenotype, which is the
      mismatch with the human presentation that this discussion records.
notes: >-
  Scale of the evidence. This entry is deliberately shallow because the
  literature is. Human evidence for DEE40 consists of one consanguineous family
  with three affected siblings (PMID:26486472) and one further GUF1 patient
  counted in a targeted-panel cohort (PMID:37820178). Everything mechanistic
  comes from yeast, C. elegans, mouse, or cultured human cancer cells. Phenotypes
  are curated only where the cached source supports them: the accessible record
  for the primary paper carries the abstract and reference list but not the case
  narratives, so features that would be expected in an early infantile
  encephalopathy — microcephaly, hypotonia, specific neuroimaging findings — are
  deliberately absent rather than assumed. The three West syndrome triad
  phenotypes are marked directness INDIRECT because they follow from the stated
  syndrome diagnosis rather than from per-patient description.

  Deliberate non-conformances. No conforms_to is declared, and two candidate
  modules were considered and rejected. The mitochondrial_dysfunction module
  scopes itself to the aging hallmark and expects its central effector node to
  carry decreased oxidative phosphorylation and increased reactive oxygen species;
  neither has been measured in a GUF1 patient, and the ROS arm is stated as a
  possibility even in the mtEF4 review (PMID:30693836). The
  complex_iv_assembly_deficiency module models isolated cytochrome c oxidase
  deficiency as a human biochemical diagnosis, and no COX enzymology exists for
  any DEE40 patient; the complex IV signal here is entirely from yeast and worm.
  Declaring either conformance would assert measurements that have not been made
  (see gap_human_neuronal_bioenergetics). This should be revisited if patient
  respiratory chain data are published.

  No antiseizure treatment is curated. Neither human report describes the
  seizure response of a GUF1 patient to any specific drug. The 2023 cohort paper
  discusses antiseizure regimens in two places, and neither licenses a DEE40
  treatment entry. Its Dravet syndrome passage names agents for a different
  patient with a different gene, so attributing those to DEE40 would be
  named-entity confusion. Its West syndrome passage reports that the risk of
  developing Lennox-Gastaut syndrome was lower in patients who received a
  ketogenic diet, prednisone, or ACTH — but that is a cohort-level association
  in mixed-etiology West syndrome, made while recounting a 98-patient follow-up
  study, reported for LGS risk rather than for seizure response, and the paper
  never states that its GUF1 patient was among its four West syndrome patients.
  Curating those agents here would attribute a population-level
  infantile-spasms observation to a four-patient disease that no source
  connects them to. Only genetic counselling is curated, which the recessive
  consanguineous pedigree supports directly.

  Prevalence caveat. The 1:3500 live-birth figure in the primary report is the
  incidence of West syndrome from all causes and is recorded in the prevalence
  notes explicitly as not a DEE40 rate.
references:
- reference: PMID:26486472
  title: West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.
- reference: PMID:37820178
  title: Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.
- reference: PMID:18442968
  title: The membrane-bound GTPase Guf1 promotes mitochondrial protein synthesis under suboptimal conditions.
- reference: PMID:27065197
  title: Mammalian elongation factor 4 regulates mitochondrial translation essential for spermatogenesis.
- reference: PMID:24837196
  title: Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans.
- reference: PMID:29572227
  title: Human Elongation Factor 4 Regulates Cancer Bioenergetics by Acting as a Mitochondrial Translation Switch.
- reference: PMID:30693836
  title: Mitochondrial translation factor EF4 regulates oxidative phosphorylation complexes and the production of ROS.
- reference: ORPHA:697160
  title: Infantile epileptic spasms syndrome

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References & Deep Research

References

8

PMID:26486472

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1.