Vici Syndrome

Mendelian MONDO:0009452 Pathograph 35 Show in embeddings browser

Vici syndrome is a severe, autosomal recessive, progressive multisystem neurodevelopmental disorder caused by loss-of-function variants in EPG5, a key regulator of the late (autophagosome-lysosome fusion) step of macroautophagy. It is one of the most extensive congenital disorders of autophagy. The classic phenotype is defined by a cardinal pentad - agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and combined immunodeficiency - together with profound developmental delay, acquired microcephaly, and failure to thrive. Defective autophagic clearance is especially consequential in long-lived neurons, cardiomyocytes, and skeletal muscle, while autophagy's distinct roles in lymphocyte homeostasis contribute to immune-system involvement.

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1
Definitions
1
Inheritance
10
Pathophys.
1
Histopath.
27
Phenotypes
2
Hypotheses
2
Gaps
35
Pathograph
1
Genes
1
Variants
11
Medical Actions
2
Differentials
2
Models
2
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
Mechanistic Nosology
proteotoxic disease
IUIS Category
combined immunodeficiency with syndromic features
ICIMD (Inherited Metabolic Disorders)
autophagy
📘

Definitions

1
Vici syndrome eight-feature diagnostic rule
Manifestation of all eight cardinal features (agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, profound developmental delay, progressive microcephaly, and failure to thrive) is a clinical rule for prioritizing EPG5 testing.
DIAGNOSTIC_CRITERIA Clinical rule for prioritizing molecular EPG5 testing
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation"
The eight-feature combination has 97% specificity and 89% sensitivity for an EPG5 mutation.
👪

Inheritance

1
Autosomal recessive HP:0000007
Vici syndrome is inherited in an autosomal recessive manner; most EPG5 variants are truncating and predicted to reduce EPG5 protein. Clinical severity varies among affected individuals.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (4 references)
PMID:23222957 SUPPORT Human Clinical
"We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome."
Establishes recessive EPG5 loss-of-function as the cause of Vici syndrome.
PMID:26917586 SUPPORT Human Clinical
"We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein."
Supports the predominance of truncating variants predicted to reduce EPG5 protein.
PMID:26927810 SUPPORT Human Clinical
"additional variable multisystem involvement that may affect virtually any organ system"
Supports variable expressivity of multisystem involvement among affected individuals.
+ 1 more reference
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Mechanistic Hypotheses

2
Tissue-Selective Injury from Defective Autophagy
tissue_selective_autophagy_injury EMERGING
Evidence balance 1 support
The primary fusion and cargo-clearance defect is established, but whether each organ manifestation follows directly from impaired autophagy or from secondary consequences such as altered mitochondrial quality control and protein accumulation remains unresolved.
Pathograph links
Block in Autophagic Flux with Accumulation of Autophagic Cargo -> Neurodevelopmental CNS Defect INDIRECT UNKNOWN INTERMEDIATES The developmental CNS phenotype is associated with the primary autophagy defect, but intervening tissue mechanisms remain unresolved.
Block in Autophagic Flux with Accumulation of Autophagic Cargo -> Progressive Neurodegeneration INDIRECT UNKNOWN INTERMEDIATES Cargo-clearance failure is linked to progressive neurodegeneration through incompletely resolved neuronal intermediates.
Block in Autophagic Flux with Accumulation of Autophagic Cargo -> Cardiomyocyte Autophagic Dysfunction INDIRECT UNKNOWN INTERMEDIATES Impaired clearance plausibly disrupts cardiomyocyte homeostasis, but direct Vici cardiac-cell causation is limited.
Block in Autophagic Flux with Accumulation of Autophagic Cargo -> Lymphocyte Autophagic Dysfunction INDIRECT UNKNOWN INTERMEDIATES Autophagy supports lymphocyte homeostasis, but EPG5-specific immune intermediates are incompletely defined.
Block in Autophagic Flux with Accumulation of Autophagic Cargo -> Melanocyte Dysfunction INDIRECT UNKNOWN INTERMEDIATES Clinical hypopigmentation supports a relationship with autophagy, but the melanocyte-specific chain remains unresolved.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"it remains unresolved if all manifestations of EPG5 deficiency are a direct conse- quence of the primary autophagy defect, or of the second- ary effects of defective autophagy"
The review explicitly identifies uncertainty in the route from the primary defect to organ manifestations.
?

Discussions and Knowledge Gaps

2
Because Vici syndrome is caused by a block at the late autophagosome-lysosome fusion step (not autophagosome formation), can autophagy-modulating or lysosome-directed therapies restore degradative flux, and in which tissues and developmental window would they need to act?
KNOWLEDGE GAP OPEN gap_vici_autophagy_therapeutics
Attached to
pathophysiology#Block in Autophagic Flux with Accumulation of Autophagic Cargo
EPG5 acts specifically at the fusion/maturation step, so classical autophagy-inducing agents (e.g. mTOR inhibitors) that increase autophagosome formation could worsen rather than relieve the downstream clearance block. No disease-modifying or autophagy-directed therapy has been evaluated clinically, and the congenital (agenesis of the corpus callosum) versus progressive (neurodegeneration, cardiomyopathy) components likely have different therapeutic windows. Defining a flux-restoring strategy and its timing is the central open question.
Proposed experiments
Screen for autolysosomal-flux restoration in EPG5-null cells
exp_vici_flux_restoration
Use EPG5-null patient iPSC-derived neurons and cardiomyocytes to screen lysosome-/fusion-directed compounds for restoration of degradative autophagic flux (p62/SQSTM1 turnover, LC3-II clearance), distinguishing agents that help from autophagy inducers that may aggravate cargo accumulation.
How faithfully do existing Drosophila and Epg5-null mouse models reproduce the human multisystem Vici phenotype beyond their neuronal and skeletal-muscle arms?
HUMAN MODEL MISMATCH OPEN hmm_vici_drosophila_model
Attached to
pathophysiology#Progressive Neurodegeneration
Drosophila EPG5 knock-down supports the neuronal arm, while an established Epg5-null mouse reproduces the autophagy defect, skeletal myopathy, and progressive neurodegeneration. Neither evidence base demonstrates reproduction of the full human combination of callosal agenesis, cardiomyopathy, cataracts, pigmentation, and combined immunodeficiency, so multisystem translational fidelity remains uncertain.
Proposed experiments
Cross-model comparison of EPG5 loss against the human cardinal pentad
exp_vici_model_fidelity
Systematically compare existing Drosophila and mouse models with zebrafish and human iPSC-derived systems for reproduction of each cardinal feature to identify which combination best captures the multisystem phenotype.
Show evidence (3 references)
PMID:26917586 SUPPORT Model Organism
"the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster"
The Drosophila model captures the neuronal phenotype but not the full multisystem pentad.
PMID:26927810 SUPPORT Model Organism
"The phenotype of epg5-/-KO mice recapitulates the autophagy defect and the skeletal muscle myopathy seen in humans with Vici syndrome"
The mouse model improves on Drosophila for muscle involvement but still leaves full multisystem fidelity unresolved.
PMID:26927810 SUPPORT Model Organism
"in addition exhibits clinical and pathological neurodegenerative features, in particular progressive motor deficit, muscle atrophy and damage of cortical 5 layer and spinal motor neurones"
The mouse also reproduces progressive motor and neurodegenerative features, while other cardinal systems remain untested.
⚙

Pathophysiology

10
EPG5 Loss of Function
Biallelic truncating (or other loss-of-function) EPG5 variants eliminate or severely reduce functional EPG5 protein, the metazoan-specific late-autophagy regulator.
EPG5 hgnc:29331 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPG5 (hgnc:29331). hgnc:29331 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Autophagosome-Lysosome Fusion EPG5 deficiency directly reduces autophagosome-lysosome fusion.
Show evidence (1 reference)
PMID:23222957 SUPPORT Human Clinical
"EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator"
Identifies EPG5 as the causative autophagy-regulator gene.
Impaired Autophagosome-Lysosome Fusion
EPG5 acts specifically at the late step of autophagy - the fusion of the autophagosome with a lysosome to form the degradative autolysosome. Its loss impairs this fusion/maturation step rather than autophagosome formation.
autophagosome-lysosome fusion GO:0061909 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagosome-lysosome fusion (GO:0061909). GO:0061909 is a biological process from the Gene Ontology. ↓ DECREASED
autolysosome GO:0044754 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves autolysosome (GO:0044754). GO:0044754 is a cellular component from the Gene Ontology.
Downstream
Block in Autophagic Flux with Accumulation of Autophagic Cargo Reduced fusion prevents autophagosomal clearance and causes cargo accumulation.
Show evidence (2 references)
PMID:23222957 SUPPORT In Vitro
"the fusion of LC3-positive puncta with lysosomes, as indicated by the colocalisation of LC3 with lysosome-associated membrane proteins (LAMP1), is reduced in Vici patient fibroblasts"
Direct experimental demonstration that autophagosome-lysosome fusion is reduced in Vici patient cells.
PMID:23222957 SUPPORT In Vitro
"Untreated patient-derived cells showed increased levels of p62/SQSTM1, Nbr1 and LC3, particularly of processed, lipidated LC3-II"
Patient cells accumulate LC3-II and autophagy receptors, the biochemical signature of a fusion/clearance block.
Block in Autophagic Flux with Accumulation of Autophagic Cargo
Failed fusion produces a severe block in autophagosomal clearance, so non-degradative autophagosomes/autolysosomes and their undegraded cargo (including p62/SQSTM1 and protein aggregates) accumulate. Degradative autophagy flux is lost even though upstream autophagosome formation proceeds.
Autophagy-Lens Fiber Maturation Link Tissue-Selective Injury from Defective Autophagy
autolysosome GO:0044754 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves autolysosome (GO:0044754). GO:0044754 is a cellular component from the Gene Ontology.
Downstream
Neurodevelopmental CNS Defect The developmental CNS phenotype is associated with the primary autophagy defect, but intervening tissue mechanisms remain unresolved. Tissue-Selective Injury from Defective Autophagy
Progressive Neurodegeneration Cargo-clearance failure is linked to progressive neurodegeneration through incompletely resolved neuronal intermediates. Tissue-Selective Injury from Defective Autophagy
Cardiomyocyte Autophagic Dysfunction Impaired clearance plausibly disrupts cardiomyocyte homeostasis, but direct Vici cardiac-cell causation is limited. Tissue-Selective Injury from Defective Autophagy
Lymphocyte Autophagic Dysfunction Autophagy supports lymphocyte homeostasis, but EPG5-specific immune intermediates are incompletely defined. Tissue-Selective Injury from Defective Autophagy
Skeletal Myopathy Autophagic vacuoles and stored cargo in patient muscle connect the clearance defect to myopathy.
Melanocyte Dysfunction Clinical hypopigmentation supports a relationship with autophagy, but the melanocyte-specific chain remains unresolved. Tissue-Selective Injury from Defective Autophagy
Lens Fiber Cell Dysfunction This proposed lens-fiber mechanism lacks direct confirmation in Vici lens tissue. Autophagy-Lens Fiber Maturation Link
Show evidence (2 references)
PMID:23222957 SUPPORT In Vitro
"severe block in autophagosomal clearance"
Patient/cell studies show a severe block in autophagosomal clearance.
PMID:23222957 SUPPORT In Vitro
"accumulation of autophagic cargo in autophagosomes"
Undegraded autophagic cargo accumulates because clearance is blocked.
Neurodevelopmental CNS Defect
Autophagy has a role in early neurodevelopment, so the flux block produces a structural neurodevelopmental defect - most characteristically agenesis of the corpus callosum, with pontine hypoplasia and delayed myelination - and profound developmental delay with acquired microcephaly.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
corpus callosum UBERON:0002336 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corpus callosum (UBERON:0002336). UBERON:0002336 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Agenesis of the corpus callosum The structural CNS defect manifests directly as callosal agenesis.
Profound global developmental delay Widespread neurodevelopmental abnormalities contribute to profound developmental delay.
Pontine hypoplasia Pontine hypoplasia is a structural component of the neurodevelopmental phenotype.
Delayed myelination Delayed myelination is a recurrent structural-developmental imaging feature.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"callosal agenesis and pontine hypoplasia, delayed myelination"
Consistent structural neurodevelopmental CNS features in the 50-patient series.
Progressive Neurodegeneration
Distinct from the congenital neurodevelopmental defect, long-lived neurons accumulate undegraded autophagic cargo over time, producing a progressive neurodegenerative course superimposed on the developmental phenotype.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
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
Microcephaly Acquired microcephaly and skill regression mark the progressive neurodegenerative component.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect"
Acquired microcephaly and skill regression in survivors indicate a neurodegenerative process distinct from the congenital neurodevelopmental defect.
Cardiomyocyte Autophagic Dysfunction
Autophagy is a key regulator of cardiac homeostasis. Impaired autophagic clearance therefore provides a plausible link to Vici cardiomyopathy, but the cited evidence establishes background cardiomyocyte biology rather than direct tissue-specific causation.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiomyopathy Cardiomyocyte homeostatic failure is the proposed cellular route to the clinical cardiomyopathy.
Show evidence (1 reference)
PMID:23222957 SUPPORT Other
"autophagy plays an important role in the constant renewal of the post-mitotic cardiomyocyte"
Autophagy is required for post-mitotic cardiomyocyte renewal, linking the clearance defect to cardiomyopathy.
Lymphocyte Autophagic Dysfunction
Autophagy is required for lymphocyte survival and homeostasis, providing a plausible route from EPG5 dysfunction to combined immunodeficiency. Human findings indicate prominent humoral impairment with a milder T-cell defect; the cited mouse result directly supports only the T-cell autophagy arm.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
Combined immunodeficiency Lymphocyte autophagy dysfunction plausibly contributes to combined immunodeficiency, while EPG5-specific B- and T-cell intermediates remain incomplete.
Recurrent infections Combined immune dysfunction increases susceptibility to recurrent and severe infections.
Show evidence (3 references)
PMID:23222957 SUPPORT Model Organism
"autophagy is also directly important for T-cell survival and proliferation"
The T-cell-specific atg5 knockout mouse shows autophagy is required for T-cell survival/proliferation, supporting the immunodeficiency arm.
PMID:36228046 SUPPORT Human Clinical
"cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive"
GeneReviews establishes combined immunodeficiency as part of classic Vici syndrome, without by itself proving the cellular mechanism.
PMID:26927810 SUPPORT Human Clinical
"Overall, these findings suggest prominent impairment of the humoral immune response with a milder defect of the T cell compartment"
Human immune findings establish that humoral dysfunction is more prominent than the T-cell defect.
Skeletal Myopathy
Skeletal muscle shows a myopathy with accumulation of autophagy substrates and abnormal glycogen storage plus autophagic vacuoles - consistent with a primary autophagic-clearance defect in muscle.
cell of skeletal muscle CL:0000188 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cell of skeletal muscle (CL:0000188). CL:0000188 is a cell type from the Cell Ontology.
Downstream
Myopathy Autophagic-vacuolar muscle pathology manifests clinically as myopathy.
Hypotonia Myopathic and neurologic involvement both contribute to marked hypotonia.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities"
Muscle histopathology shows autophagic vacuoles and abnormal glycogen, consistent with the clearance defect.
Melanocyte Dysfunction
Generalized hypopigmentation supports a functional relationship between melanogenesis and autophagy, but the melanocyte-specific route from EPG5 loss to reduced pigmentation remains incompletely resolved.
melanocyte CL:0000148 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves melanocyte (CL:0000148). CL:0000148 is a cell type from the Cell Ontology.
Downstream
Hypopigmentation of the skin The proposed melanocyte-autophagy defect manifests as relative cutaneous hypopigmentation.
Show evidence (1 reference)
PMID:23222957 SUPPORT Human Clinical
"The finding of generalized hypopigmentation in Vici syndrome supports a functional relationship between melanogenesis and the autophagic machinery"
The hypopigmentation of Vici syndrome links melanogenesis to the autophagic machinery.
Lens Fiber Cell Dysfunction
Cataracts are a cardinal feature of Vici syndrome; autophagy has been proposed to mediate the programmed organelle clearance required for lens fiber cell maturation and transparency, providing a plausible link between the clearance defect and cataract, though direct experimental confirmation in Vici lens tissue is lacking.
Autophagy-Lens Fiber Maturation Link
lens fiber cell CL:0011004 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lens fiber cell (CL:0011004). CL:0011004 is a cell type from the Cell Ontology.
Downstream
Cataract The proposed lens-fiber maturation defect may contribute to cataract, but direct Vici lens evidence is lacking. Autophagy-Lens Fiber Maturation Link
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Bilateral cataracts are one of the “classical ” diagnostic features of Vici syndrome"
The review supports the cataract association, but not the proposed lens-fiber autophagy mechanism.
✶

Histopathology

1
Autophagic vacuolar myopathy
Skeletal muscle biopsy shows accumulation of autophagy substrates, abnormal glycogen storage, autophagic vacuoles, and secondary mitochondrial abnormalities, the histopathological signature of the autophagic-clearance defect.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities"
Muscle histopathology in Vici syndrome.
⬡

Pathograph

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

27
Blood 1
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26927810 SUPPORT Human Clinical
"Some patients with Vici syndrome have been noted to develop profound anaemia"
The review documents profound anemia in some affected individuals.
PMID:26927810 SUPPORT Human Clinical
"it is currently uncer- tain if this is a secondary feature (for example related to recurrent severe infections) or, alternatively, reflects add- itional primary involvement of red cell lines"
The review explicitly leaves primary red-cell involvement versus secondary anemia unresolved.
Cardiovascular 2
Cardiomyopathy VERY_FREQUENT HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"in around 80 % of cases a cardiomyopathy, one of the 5 main diagnostic features, has been documented"
Cardiomyopathy is documented in about 80% of cases, supporting VERY_FREQUENT.
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Minor congenital heart defects comprising persistent foramen ovale and atrial septal de- fects have been reported in around 10 % of patients."
The review documents atrial septal defects among minor congenital cardiac abnormalities in about 10% of reported patients.
Digestive 2
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"Presentation was mainly neonatal, with marked hypotonia and feeding difficulties"
Neonatal presentation with feeding difficulties.
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Renal tubular acidosis + Cleft lip/palate + Coarse facial features + Hepatomegaly +"
The clinical-feature table records hepatomegaly among findings present in some children.
Ear 1
Sensorineural hearing loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26927810 SUPPORT Human Clinical
"Sensorineural hearing loss was recognized in an isolated case in 2010"
The review documents sensorineural hearing loss as part of the extended Vici phenotype.
PMID:26927810 SUPPORT Human Clinical
"Sensorineural hearing loss is a feature that may be easily overlooked in Vici syn- drome due to profound developmental delay and over- whelming multisystem involvement"
Supports why hearing loss can be clinically overlooked in this severe multisystem disorder.
Endocrine 1
Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"Hypothyroidism may require thyroid hormone replace- ment."
The clinical review directly identifies hypothyroidism as a manifestation requiring replacement treatment.
Eye 2
Cataract FREQUENT HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"in a recent series of 50 patients those were only documented in three- quarters of affected individuals"
Cataracts were documented in approximately three quarters of the classic-Vici series, supporting FREQUENT rather than VERY_FREQUENT.
Optic atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26927810 SUPPORT Human Clinical
"Thymic aplasia + Sensorineural deafness + Optic atrophy + Renal tubular acidosis +"
The clinical-feature table records optic atrophy in the + category.
PMID:26927810 SUPPORT Human Clinical
"++++ = present in almost all children, +++ = present in most children, ++ = present in more than half of children, + = present in some children"
The table legend defines + as present in some children.
Head and Neck 3
Microcephaly VERY_FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"acquired microcephaly are almost universal"
The review describes acquired microcephaly as almost universal in classic Vici syndrome.
Coarse facial features HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Renal tubular acidosis + Cleft lip/palate + Coarse facial features + Hepatomegaly +"
The clinical-feature table records coarse facial features among findings present in some children.
Cleft lip or palate Orofacial cleft HP:0000202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orofacial cleft (HP:0000202). HP:0000202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Renal tubular acidosis + Cleft lip/palate + Coarse facial features + Hepatomegaly +"
The clinical-feature table records cleft lip or palate among findings present in some children.
Immune 2
Combined immunodeficiency VERY_FREQUENT HP:0005387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Combined immunodeficiency (HP:0005387). HP:0005387 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26927810 SUPPORT Human Clinical
"disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency."
The review identifies combined immunodeficiency as a principal feature.
PMID:26927810 SUPPORT Human Clinical
"Hypopigmentation ++++ Immune problems ++++ Progressive microcephaly +++ Cardiomyopathy +++ Cataracts +++"
The clinical-feature table assigns immune problems the ++++ category.
PMID:26927810 SUPPORT Human Clinical
"++++ = present in almost all children, +++ = present in most children, ++ = present in more than half of children, + = present in some children"
The table legend defines ++++ as present in almost all children, supporting VERY_FREQUENT.
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36228046 SUPPORT Human Clinical
"respiratory infections as a result of primary immunodeficiency"
Recurrent respiratory infections from the primary immunodeficiency are a leading cause of death.
Integument 1
Hypopigmentation of the skin VERY_FREQUENT HP:0001010 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopigmentation of the skin (HP:0001010). HP:0001010 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"is one of the cardinal features of Vici syndrome and has been noted in almost all cases reported to date."
Hypopigmentation is reported in almost all cases, supporting VERY_FREQUENT.
Musculoskeletal 2
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"A skeletal myopathy is consistently associated"
The review documents skeletal myopathy as consistently associated; no numeric frequency band is inferred.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"Presentation was mainly neonatal, with marked hypotonia and feeding difficulties"
Neonatal presentation with marked hypotonia.
Nervous System 6
Agenesis of the corpus callosum VERY_FREQUENT Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26927810 SUPPORT Human Clinical
"disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency."
The review identifies callosal agenesis as a principal feature.
PMID:26927810 SUPPORT Human Clinical
"Absent corpus callosum ++++ Profound developmental delay ++++ Failure to thrive ++++"
The clinical-feature table assigns absent corpus callosum the ++++ category.
PMID:26927810 SUPPORT Human Clinical
"++++ = present in almost all children, +++ = present in most children, ++ = present in more than half of children, + = present in some children"
The table legend defines ++++ as present in almost all children, supporting VERY_FREQUENT.
Profound global developmental delay VERY_FREQUENT HP:0012736 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound global developmental delay (HP:0012736). HP:0012736 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal"
The review explicitly describes profound developmental delay as almost universal, supporting VERY_FREQUENT.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"Two-thirds of patients had a severe seizure disorder"
Two-thirds of the 50-patient cohort had a severe seizure disorder.
Delayed myelination HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"callosal agenesis and pontine hypoplasia, delayed myelination"
Delayed myelination is a consistent neuroradiological feature.
Areflexia FREQUENT HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"The majority of children have absent deep tendon re- flexes but those may be brisk in around a third."
Absent reflexes in a majority of children support the FREQUENT band.
Sleep apnea HP:0010535 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep apnea (HP:0010535). HP:0010535 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Both central and obstructive apnoea may require polysomnographic moni- toring"
The management review documents both central and obstructive sleep apnea.
Growth 1
Failure to thrive VERY_FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"progressive failure to thrive and acquired microcephaly are almost universal"
The review describes progressive failure to thrive as almost universal in classic Vici syndrome.
Other 3
Pontine hypoplasia Hypoplasia of the pons HP:0012110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the pons (HP:0012110). HP:0012110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"callosal agenesis and pontine hypoplasia, delayed myelination"
Pontine hypoplasia is a consistent neuroradiological feature.
Thymic aplasia or hypoplasia OCCASIONAL Aplasia/Hypoplasia of the thymus HP:0010515 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thymic aplasia or hypoplasia, annotated with Aplasia/Hypoplasia of the thymus (HP:0010515). HP:0010515 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Complete thymus aplasia or hypoplasia has been re- ported in around one fifth of patients"
Thymic aplasia or hypoplasia in about one fifth of patients supports the OCCASIONAL band.
Renal tubular acidosis HP:0001947 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal tubular acidosis (HP:0001947). HP:0001947 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Human Clinical
"Renal involvement comprising hydronephrosis, renal dysfunction and/or signs of renal tubular acidosis with associated electrolyte imbalances, in particular marked hypokalaemia, have been reported in around 15 % of cases"
The review supports renal tubular acidosis and electrolyte imbalance as uncommon but management-relevant manifestations.
🧬

Genetic Associations

1
EPG5
Gene: EPG5 hgnc:29331 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPG5 (hgnc:29331). hgnc:29331 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:23222957 SUPPORT Human Clinical
"We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome."
The human gene-discovery study establishes recessive EPG5 variants as causative.
Variants (1)
EPG5 pathogenic variants
Most EPG5 variants are private and truncating, predicted to reduce EPG5 protein. Three recurrent variants include two truncating alleles (p.Met2242Cysfs*5 and p.Arg417*) and the missense allele p.Gln336Arg and suggest possible founder effects. Compound heterozygosity was associated with longer survival in the reported cohort.
Show evidence (3 references)
PMID:26917586 SUPPORT Human Clinical
"most of them truncating and predicted to result in reduced EPG5 protein"
Most variants are truncating, reducing EPG5 protein.
PMID:26917586 SUPPORT Human Clinical
"Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg)"
Most variants are private; the three recurrent variants suggest possible founder effects.
PMID:26917586 SUPPORT Human Clinical
"Survival outcomes were significantly better in patients with compound heterozygous mutations"
Compound heterozygosity was associated with longer survival in the reported cohort.
💊

Medical Actions

11
Multidisciplinary supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No curative therapy exists. Management is multidisciplinary, supportive, and directed at the manifestations and complications present in each child.
Show evidence (2 references)
PMID:36228046 SUPPORT Other
"There is no cure for EPG5-related disorder."
GeneReviews states that no curative treatment is available.
PMID:36228046 SUPPORT Other
"Supportive multidisciplinary care to improve quality of life, optimize function, and reduce complications"
GeneReviews establishes multidisciplinary supportive care as the mainstay of management.
Immunoglobulin replacement and infection prophylaxis
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Combined immunodeficiency may require regular intravenous immunoglobulin infusions and antimicrobial prophylaxis. Active chest infections require early, aggressive antibacterial and antifungal treatment because they can progress to life-threatening sepsis.
Show evidence (2 references)
PMID:26927810 SUPPORT Other
"may require regular intraven- ous immunoglobulin infusions and antimicrobial prophylaxis"
The Vici review directly supports IV immunoglobulin and antimicrobial prophylaxis for the immunodeficiency.
PMID:36228046 SUPPORT Other
"rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) should be considered for chest infections to prevent episodes of life-threatening sepsis"
GeneReviews recommends aggressive early anti-infective treatment given the primary immunodeficiency.
Antiseizure medication
Action: anticonvulsant therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Seizures should be treated with appropriate antiseizure medication. Responses to drugs with potential autophagy-modulating properties, including carbamazepine, should be monitored closely after treatment starts.
Show evidence (2 references)
PMID:26927810 SUPPORT Other
"More than half of patients with Vici syndrome have seizures that ought to be managed with appropriate anti- convulsant therapy."
The review recommends appropriate anticonvulsant therapy for the common seizure disorder.
PMID:26927810 SUPPORT Other
"responses to anticonvulsants (or, indeed, other drugs) with potentially autophagy-modulating properties such as carbamazepine should perhaps be monitored closely following initiation of treatment."
The review recommends close monitoring when starting potentially autophagy-modulating drugs such as carbamazepine.
Cataract surgery
Action: cataract surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cataract surgery (NCIT:C157809). NCIT:C157809 is a clinical intervention from the NCI Thesaurus. Ontology label: Cataract Surgery NCIT:C157809
Cataract extraction may improve visual outcome, but candidacy should be decided individually in light of overall disease severity and prognosis.
Show evidence (2 references)
PMID:26927810 SUPPORT Other
"If cataracts are present surgical removal may improve visual outcome"
The review supports individualized cataract surgery as potentially vision-improving supportive treatment.
PMID:26927810 SUPPORT Other
"the indication for cataract surgery will have to be decided on an individual basis"
The review explicitly frames surgical candidacy as an individualized decision.
Proactive cardiomyopathy management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Cardiomyopathy identified on regular cardiac assessment may benefit from proactive medical management, with particular vigilance during intercurrent illness.
Target Phenotypes: Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"If a cardiomyopathy is identified on regular cardiac as- sessments, this may benefit from proactive medical man- agement; a deterioration of cardiac function during intercurrent illness has to be expected."
The review directly recommends proactive cardiac management and anticipatory care during illness.
Gastrostomy feeding
Action: gastrostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastrostomy (NCIT:C52006). NCIT:C52006 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy NCIT:C52006
Percutaneous gastrostomy feeding is often needed to provide adequate nutrition.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"most children require percutaneous feeding"
The review's investigation and management table states that most children require percutaneous feeding.
Noninvasive ventilatory support
Action: noninvasive ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is noninvasive ventilation, annotated with Non-Invasive Mechanical Ventilation (NCIT:C171457). NCIT:C171457 is a clinical intervention from the NCI Thesaurus. Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457
Central or obstructive sleep apnea may require noninvasive ventilatory support guided by sleep assessment.
Target Phenotypes: Sleep apnea HP:0010535 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sleep apnea (HP:0010535). HP:0010535 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"Both central and obstructive apnoea may require polysomnographic moni- toring, and non-invasive ventilatory support as indicated."
The review recommends sleep monitoring and noninvasive ventilation when indicated.
Thyroid hormone replacement
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Hypothyroidism should be treated with thyroid hormone replacement when present.
Target Phenotypes: Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"Hypothyroidism may require thyroid hormone replace- ment."
The review directly recommends thyroid hormone replacement for hypothyroidism.
Renal and electrolyte management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Renal dysfunction and electrolyte imbalance, especially severe hypokalemia, require anticipatory and active management.
Target Phenotypes: Renal tubular acidosis HP:0001947 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Renal tubular acidosis (HP:0001947). HP:0001947 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"Renal dysfunction and electrolyte imbalances ,i n particular profound hypokalaemia, will have to be antici- pated and managed actively."
The review recommends active anticipation and management of renal and electrolyte complications.
Blood transfusion for profound anemia
Action: blood transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is blood transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Profound anemia may require blood transfusion in some affected children.
Target Phenotypes: Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26927810 SUPPORT Other
"Profound anaemia may re- quire blood transfusion in some patients."
The review directly supports transfusion when profound anemia occurs.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive recurrence-risk counseling (25% per pregnancy), carrier testing, and reproductive options including prenatal/preimplantation testing.
Show evidence (1 reference)
PMID:36228046 SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected"
GeneReviews gives the 25% autosomal recessive recurrence risk underpinning counseling.
🔬

Diagnosis

2
EPG5 molecular genetic testing
Diagnosis is established by identifying biallelic pathogenic EPG5 variants on molecular testing in a proband with suggestive clinical findings; Vici syndrome should be considered once mitochondrial, glycogen, and lysosomal storage disorders have been excluded.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:36228046 SUPPORT Human Clinical
"confirmed by identification of biallelic pathogenic (or likely pathogenic) variants in EPG5 on molecular testing"
GeneReviews diagnostic criterion for EPG5-related disorder.
Baseline multisystem assessment and surveillance
Initial evaluation should include brain MRI, ophthalmology, cardiac ultrasound, immune-function testing, and renal, thyroid, and liver assessment. Surveillance is manifestation-directed, with continued cataract, cardiomyopathy, and immune monitoring emphasized because these features may evolve after presentation.
Show evidence (2 references)
PMID:26927810 SUPPORT Other
"Other useful diagnostic investigations to document the extent of multisystem involvement (summarized in Table 2) include an MRI of the brain (in particular to document the callosal agenesis, one of the key diagnostic features), EEG, ophthalmology assesment including slit lamp examination and..."
The review lists baseline neurologic, ocular, cardiac, abdominal, immune, thyroid, liver, and renal assessment.
PMID:26927810 SUPPORT Other
"some of these features (in particular cata- racts, cardiomyopathy and immunodeficiency) may only evolve over time and are not necessarily present from birth."
Supports continued surveillance because cataract, cardiac, and immune manifestations can evolve after birth.
🩻

Imaging Findings

1
Callosal agenesis and pontine hypoplasia on MRI
Brain MRI consistently shows agenesis of the corpus callosum and pontine hypoplasia with delayed myelination. Reduced opercularization and reduced white matter bulk are additional consistent abnormalities.
Mri
Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP)
Show evidence (2 references)
PMID:26917586 SUPPORT Human Clinical
"callosal agenesis and pontine hypoplasia, delayed myelination"
Consistent neuroradiological features on brain MRI.
PMID:26927810 SUPPORT Human Clinical
"other consistent radiological abnormalities include pontine hypoplasia, reduced opercularisation of the Sylvian fissures, delayed myelination and general reduc- tion in white matter bulk"
The review extends the characteristic MRI pattern to reduced opercularization and white-matter bulk.
📈

Progression

1
Classic Vici syndrome is a progressive, life-limiting disorder: median survival is about 24 months with only ~10% of children surviving beyond five years. The most common causes of death are respiratory infections from the primary immunodeficiency and cardiac failure from the progressive cardiomyopathy.
Show evidence (3 references)
PMID:26917586 SUPPORT Human Clinical
"median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age"
Natural-history survival data from the largest cohort.
PMID:36228046 SUPPORT Human Clinical
"the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure"
GeneReviews states the leading causes of death.
PMID:26927810 SUPPORT Human Clinical
"The degree of cardiac involvement and/or the extent of the associated immunodeficiency are the most important prognostic indicators."
The review identifies cardiac disease and immunodeficiency severity as the principal prognostic indicators.
📊

Prevalence

1
Worldwide
Cases In Literature Unknown
Incidence and population prevalence are unknown. A 2016 review counted around 50 genetically confirmed cases and judged the condition rare but probably underdiagnosed; this case count is not a population-rate denominator.
Show evidence (2 references)
PMID:26927810 SUPPORT Human Clinical
"The incidence of Vici syndrome is unknown."
The review explicitly states that incidence is unknown, so no numeric prevalence band is asserted.
PMID:26927810 SUPPORT Human Clinical
"around 50 genetically confirmed cases published to date"
Supports the historical cases-in-literature count without converting it to a population prevalence.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Vici Syndrome:

Mitochondrial, glycogen storage, and lysosomal storage disorders
Overlapping Features Multisystem neurodevelopmental disorders with overlapping features that should be excluded before diagnosing Vici syndrome; the cardinal pentad and EPG5 genotype distinguish it.
Distinguishing Features
  • Vici syndrome is considered once mitochondrial, glycogen, and lysosomal storage disorders have been excluded.
Show evidence (1 reference)
PMID:26917586 SUPPORT Human Clinical
"should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded"
Byrne frames these as the differential diagnoses to exclude.
🐁

Animal Models

2
Epg5-null knockout mouse Epg5 knockout model
Epg5-null mice reproduce the autophagy defect and skeletal-muscle myopathy and develop progressive motor and neurodegenerative abnormalities. The model supports the muscle and neuronal arms but does not establish fidelity to the full human cardinal phenotype.
Autophagy defect Skeletal muscle myopathy Progressive motor deficit and neurodegeneration
Species
Mus musculus
Show evidence (2 references)
PMID:26927810 SUPPORT Model Organism
"The phenotype of epg5-/-KO mice recapitulates the autophagy defect and the skeletal muscle myopathy seen in humans with Vici syndrome"
The established knockout mouse reproduces the core autophagy and myopathy phenotypes.
PMID:26927810 SUPPORT Model Organism
"in addition exhibits clinical and pathological neurodegenerative features, in particular progressive motor deficit, muscle atrophy and damage of cortical 5 layer and spinal motor neurones"
Supports the progressive motor and neurodegenerative abnormalities described for the knockout mouse.
epg5 (CG14299) RNAi knockdown Drosophila Autophagy-gene knockdown model
RNAi downregulation of the EPG5 ortholog epg5 (CG14299) in Drosophila produces autophagic abnormalities and progressive neurodegeneration, supporting the neurodevelopment-neurodegeneration link but capturing only the neuronal arm of the human multisystem phenotype.
Autophagic abnormalities Progressive neurodegeneration
Species
Drosophila melanogaster
Show evidence (1 reference)
PMID:26917586 SUPPORT Model Organism
"downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration"
The Drosophila epg5-knockdown model recapitulates the neurodegenerative arm.
{ }

Source YAML

click to show 
name: Vici Syndrome
creation_date: "2026-07-27T12:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Vici syndrome
  term:
    id: MONDO:0009452
    label: Vici syndrome
synonyms:
- absent corpus callosum-cataract-immunodeficiency syndrome
- immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum
references:
- reference: PMID:36228046
  title: "EPG5-Related Disorder"
  tags:
  - GeneReviews
- reference: PMID:26927810
  title: "Vici syndrome: a review"
description: >-
  Vici syndrome is a severe, autosomal recessive, progressive multisystem
  neurodevelopmental disorder caused by loss-of-function variants in EPG5, a key
  regulator of the late (autophagosome-lysosome fusion) step of macroautophagy. It
  is one of the most extensive congenital disorders of autophagy. The classic
  phenotype is defined by a cardinal pentad - agenesis of the corpus callosum,
  cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and combined
  immunodeficiency - together with profound developmental delay, acquired
  microcephaly, and failure to thrive. Defective autophagic clearance is especially
  consequential in long-lived neurons, cardiomyocytes, and skeletal muscle, while
  autophagy's distinct roles in lymphocyte homeostasis contribute to immune-system
  involvement.

classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Primary clinical home: a severe neurodevelopmental-then-neurodegenerative
      multisystem disorder with agenesis of the corpus callosum, epilepsy, and
      progressive brain atrophy.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: Autosomal recessive Mendelian disorder caused by biallelic EPG5 variants.
  mechanistic_category:
  - classification_value: proteotoxic disease
    notes: >-
      One of the congenital disorders of autophagy: EPG5 loss blocks
      autophagosome-lysosome fusion, so undegraded autophagic cargo (p62/SQSTM1,
      lipidated LC3-II) and protein aggregates accumulate - a proteostasis /
      proteotoxic mechanism.
  icimd_category:
  - classification_value: autophagy
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders of autophagy"
      under category "Disorders of the metabolism of complex molecules
      (degradation)". Vici syndrome is the prototype congenital disorder of autophagy.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS Table 2 (CID with syndromic features): the combined (T- and B-cell)
      immunodeficiency of Vici syndrome occurs within a syndromic multisystem
      disorder (the cardinal pentad). The immunodeficiency is one of the five
      cardinal diagnostic features rather than an incidental finding, and it is
      inseparable from the neurodevelopmental, ocular, cardiac and pigmentary
      manifestations caused by the same EPG5 autophagy defect — the defining
      Table 2 pattern.
    evidence:
    - reference: PMID:23222957
      reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a rare multisystem disorder characterized by callosal agenesis,
        cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation
      explanation: >-
        States both halves of the Table 2 criterion in one sentence: a combined
        immunodeficiency, carried within a defined multisystem syndrome.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    Vici syndrome is inherited in an autosomal recessive manner; most EPG5 variants
    are truncating and predicted to reduce EPG5 protein. Clinical severity varies
    among affected individuals.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome."
    explanation: Establishes recessive EPG5 loss-of-function as the cause of Vici syndrome.
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein."
    explanation: Supports the predominance of truncating variants predicted to reduce EPG5 protein.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "additional variable multisystem involvement that may affect virtually any organ system"
    explanation: Supports variable expressivity of multisystem involvement among affected individuals.
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Many individuals with EPG5-related disorder are born to consanguineous couples."
    explanation: GeneReviews documents consanguinity in many affected families, consistent with autosomal recessive inheritance.

genetic:
- name: EPG5
  gene_term:
    preferred_term: EPG5
    term:
      id: hgnc:29331
      label: EPG5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    EPG5 (18q12.3) is the human homolog of the metazoan-specific autophagy gene
    epg-5. Most reported variants are truncating loss-of-function alleles.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome."
    explanation: The human gene-discovery study establishes recessive EPG5 variants as causative.
  variants:
  - name: EPG5 pathogenic variants
    description: >-
      Most EPG5 variants are private and truncating, predicted to reduce EPG5
      protein. Three recurrent variants include two truncating alleles
      (p.Met2242Cysfs*5 and p.Arg417*) and the missense allele p.Gln336Arg and suggest
      possible founder effects. Compound heterozygosity was associated with longer
      survival in the reported cohort.
    evidence:
    - reference: PMID:26917586
      reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "most of them truncating and predicted to result in reduced EPG5 protein"
      explanation: Most variants are truncating, reducing EPG5 protein.
    - reference: PMID:26917586
      reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg)"
      explanation: Most variants are private; the three recurrent variants suggest possible founder effects.
    - reference: PMID:26917586
      reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Survival outcomes were significantly better in patients with compound heterozygous mutations"
      explanation: Compound heterozygosity was associated with longer survival in the reported cohort.

mechanistic_hypotheses:
- hypothesis_group_id: tissue_selective_autophagy_injury
  hypothesis_label: Tissue-Selective Injury from Defective Autophagy
  status: EMERGING
  description: >-
    The primary fusion and cargo-clearance defect is established, but whether each
    organ manifestation follows directly from impaired autophagy or from secondary
    consequences such as altered mitochondrial quality control and protein
    accumulation remains unresolved.
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it remains unresolved if all manifestations of EPG5 deficiency are a direct conse- quence of the primary autophagy defect, or of the second- ary effects of defective autophagy"
    explanation: The review explicitly identifies uncertainty in the route from the primary defect to organ manifestations.
- hypothesis_group_id: autophagy_lens_link
  hypothesis_label: Autophagy-Lens Fiber Maturation Link
  status: EMERGING
  description: >-
    Failed autophagic organelle clearance may impair lens fiber-cell maturation and
    contribute to cataract formation, but this mechanism has not been demonstrated
    directly in Vici lens tissue.

pathophysiology:
- name: EPG5 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic truncating (or other loss-of-function) EPG5 variants eliminate or
    severely reduce functional EPG5 protein, the metazoan-specific late-autophagy
    regulator.
  genes:
  - preferred_term: EPG5
    term:
      id: hgnc:29331
      label: EPG5
  downstream:
  - target: Impaired Autophagosome-Lysosome Fusion
    causal_link_type: DIRECT
    description: EPG5 deficiency directly reduces autophagosome-lysosome fusion.
    evidence:
    - reference: PMID:23222957
      reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the fusion of LC3-positive puncta with lysosomes, as indicated by the colocalisation of LC3 with lysosome-associated membrane proteins (LAMP1), is reduced in Vici patient fibroblasts"
      explanation: Patient fibroblasts directly demonstrate reduced fusion downstream of EPG5 deficiency.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator"
    explanation: Identifies EPG5 as the causative autophagy-regulator gene.
- name: Impaired Autophagosome-Lysosome Fusion
  biological_scale: CELLULAR
  description: >-
    EPG5 acts specifically at the late step of autophagy - the fusion of the
    autophagosome with a lysosome to form the degradative autolysosome. Its loss
    impairs this fusion/maturation step rather than autophagosome formation.
  biological_processes:
  - preferred_term: autophagosome-lysosome fusion
    term:
      id: GO:0061909
      label: autophagosome-lysosome fusion
    modifier: DECREASED
  cellular_components:
  - preferred_term: autolysosome
    term:
      id: GO:0044754
      label: autolysosome
  downstream:
  - target: Block in Autophagic Flux with Accumulation of Autophagic Cargo
    causal_link_type: DIRECT
    description: Reduced fusion prevents autophagosomal clearance and causes cargo accumulation.
    evidence:
    - reference: PMID:23222957
      reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "resulting in the accumulation of autophagic cargo in autophagosomes"
      explanation: Patient cells directly connect EPG5-associated clearance failure with accumulated cargo.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the fusion of LC3-positive puncta with lysosomes, as indicated by the colocalisation of LC3 with lysosome-associated membrane proteins (LAMP1), is reduced in Vici patient fibroblasts"
    explanation: Direct experimental demonstration that autophagosome-lysosome fusion is reduced in Vici patient cells.
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Untreated patient-derived cells showed increased levels of p62/SQSTM1, Nbr1 and LC3, particularly of processed, lipidated LC3-II"
    explanation: Patient cells accumulate LC3-II and autophagy receptors, the biochemical signature of a fusion/clearance block.
- name: Block in Autophagic Flux with Accumulation of Autophagic Cargo
  biological_scale: CELLULAR
  description: >-
    Failed fusion produces a severe block in autophagosomal clearance, so
    non-degradative autophagosomes/autolysosomes and their undegraded cargo
    (including p62/SQSTM1 and protein aggregates) accumulate. Degradative autophagy
    flux is lost even though upstream autophagosome formation proceeds.
  cellular_components:
  - preferred_term: autolysosome
    term:
      id: GO:0044754
      label: autolysosome
  downstream:
  - target: Neurodevelopmental CNS Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tissue_selective_autophagy_injury
    description: The developmental CNS phenotype is associated with the primary autophagy defect, but intervening tissue mechanisms remain unresolved.
  - target: Progressive Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tissue_selective_autophagy_injury
    description: Cargo-clearance failure is linked to progressive neurodegeneration through incompletely resolved neuronal intermediates.
  - target: Cardiomyocyte Autophagic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tissue_selective_autophagy_injury
    description: Impaired clearance plausibly disrupts cardiomyocyte homeostasis, but direct Vici cardiac-cell causation is limited.
  - target: Lymphocyte Autophagic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tissue_selective_autophagy_injury
    description: Autophagy supports lymphocyte homeostasis, but EPG5-specific immune intermediates are incompletely defined.
  - target: Skeletal Myopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Autophagic vacuoles and stored cargo in patient muscle connect the clearance defect to myopathy.
  - target: Melanocyte Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tissue_selective_autophagy_injury
    description: Clinical hypopigmentation supports a relationship with autophagy, but the melanocyte-specific chain remains unresolved.
  - target: Lens Fiber Cell Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - autophagy_lens_link
    description: This proposed lens-fiber mechanism lacks direct confirmation in Vici lens tissue.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "severe block in autophagosomal clearance"
    explanation: Patient/cell studies show a severe block in autophagosomal clearance.
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "accumulation of autophagic cargo in autophagosomes"
    explanation: Undegraded autophagic cargo accumulates because clearance is blocked.
- name: Neurodevelopmental CNS Defect
  biological_scale: TISSUE
  description: >-
    Autophagy has a role in early neurodevelopment, so the flux block produces a
    structural neurodevelopmental defect - most characteristically agenesis of the
    corpus callosum, with pontine hypoplasia and delayed myelination - and profound
    developmental delay with acquired microcephaly.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  downstream:
  - target: Agenesis of the corpus callosum
    causal_link_type: DIRECT
    description: The structural CNS defect manifests directly as callosal agenesis.
  - target: Profound global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Widespread neurodevelopmental abnormalities contribute to profound developmental delay.
  - target: Pontine hypoplasia
    causal_link_type: DIRECT
    description: Pontine hypoplasia is a structural component of the neurodevelopmental phenotype.
  - target: Delayed myelination
    causal_link_type: DIRECT
    description: Delayed myelination is a recurrent structural-developmental imaging feature.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosal agenesis and pontine hypoplasia, delayed myelination"
    explanation: Consistent structural neurodevelopmental CNS features in the 50-patient series.
- name: Progressive Neurodegeneration
  biological_scale: TISSUE
  description: >-
    Distinct from the congenital neurodevelopmental defect, long-lived neurons
    accumulate undegraded autophagic cargo over time, producing a progressive
    neurodegenerative course superimposed on the developmental phenotype.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Acquired microcephaly and skill regression mark the progressive neurodegenerative component.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect"
    explanation: Acquired microcephaly and skill regression in survivors indicate a neurodegenerative process distinct from the congenital neurodevelopmental defect.
- name: Cardiomyocyte Autophagic Dysfunction
  biological_scale: CELLULAR
  description: >-
    Autophagy is a key regulator of cardiac homeostasis. Impaired autophagic
    clearance therefore provides a plausible link to Vici cardiomyopathy, but the
    cited evidence establishes background cardiomyocyte biology rather than direct
    tissue-specific causation.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cardiomyocyte homeostatic failure is the proposed cellular route to the clinical cardiomyopathy.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "autophagy plays an important role in the constant renewal of the post-mitotic cardiomyocyte"
    explanation: Autophagy is required for post-mitotic cardiomyocyte renewal, linking the clearance defect to cardiomyopathy.
- name: Lymphocyte Autophagic Dysfunction
  biological_scale: CELLULAR
  description: >-
    Autophagy is required for lymphocyte survival and homeostasis, providing a
    plausible route from EPG5 dysfunction to combined immunodeficiency. Human findings
    indicate prominent humoral impairment with a milder T-cell defect; the cited mouse
    result directly supports only the T-cell autophagy arm.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Combined immunodeficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lymphocyte autophagy dysfunction plausibly contributes to combined immunodeficiency, while EPG5-specific B- and T-cell intermediates remain incomplete.
  - target: Recurrent infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Combined immune dysfunction increases susceptibility to recurrent and severe infections.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "autophagy is also directly important for T-cell survival and proliferation"
    explanation: The T-cell-specific atg5 knockout mouse shows autophagy is required for T-cell survival/proliferation, supporting the immunodeficiency arm.
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive"
    explanation: GeneReviews establishes combined immunodeficiency as part of classic Vici syndrome, without by itself proving the cellular mechanism.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, these findings suggest prominent impairment of the humoral immune response with a milder defect of the T cell compartment"
    explanation: Human immune findings establish that humoral dysfunction is more prominent than the T-cell defect.
- name: Skeletal Myopathy
  biological_scale: TISSUE
  description: >-
    Skeletal muscle shows a myopathy with accumulation of autophagy substrates and
    abnormal glycogen storage plus autophagic vacuoles - consistent with a primary
    autophagic-clearance defect in muscle.
  cell_types:
  - preferred_term: cell of skeletal muscle
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  downstream:
  - target: Myopathy
    causal_link_type: DIRECT
    description: Autophagic-vacuolar muscle pathology manifests clinically as myopathy.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Myopathic and neurologic involvement both contribute to marked hypotonia.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities"
    explanation: Muscle histopathology shows autophagic vacuoles and abnormal glycogen, consistent with the clearance defect.
- name: Melanocyte Dysfunction
  biological_scale: CELLULAR
  description: >-
    Generalized hypopigmentation supports a functional relationship between
    melanogenesis and autophagy, but the melanocyte-specific route from EPG5 loss to
    reduced pigmentation remains incompletely resolved.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  downstream:
  - target: Hypopigmentation of the skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The proposed melanocyte-autophagy defect manifests as relative cutaneous hypopigmentation.
  evidence:
  - reference: PMID:23222957
    reference_title: "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The finding of generalized hypopigmentation in Vici syndrome supports a functional relationship between melanogenesis and the autophagic machinery"
    explanation: The hypopigmentation of Vici syndrome links melanogenesis to the autophagic machinery.
- name: Lens Fiber Cell Dysfunction
  biological_scale: CELLULAR
  description: >-
    Cataracts are a cardinal feature of Vici syndrome; autophagy has been proposed to
    mediate the programmed organelle clearance required for lens fiber cell maturation
    and transparency, providing a plausible link between the clearance defect and
    cataract, though direct experimental confirmation in Vici lens tissue is lacking.
  cell_types:
  - preferred_term: lens fiber cell
    term:
      id: CL:0011004
      label: lens fiber cell
  downstream:
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - autophagy_lens_link
    description: The proposed lens-fiber maturation defect may contribute to cataract, but direct Vici lens evidence is lacking.
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral cataracts are one of the “classical ” diagnostic features of Vici syndrome"
    explanation: The review supports the cataract association, but not the proposed lens-fiber autophagy mechanism.

phenotypes:
- name: Agenesis of the corpus callosum
  description: >-
    One of the five principal features and classified as present in almost all
    children in the classic-Vici cohort review.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency."
    explanation: The review identifies callosal agenesis as a principal feature.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absent corpus callosum ++++ Profound developmental delay ++++ Failure to thrive ++++"
    explanation: The clinical-feature table assigns absent corpus callosum the ++++ category.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "++++ = present in almost all children, +++ = present in most children, ++ = present in more than half of children, + = present in some children"
    explanation: The table legend defines ++++ as present in almost all children, supporting VERY_FREQUENT.
- name: Cataract
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a recent series of 50 patients those were only documented in three- quarters of affected individuals"
    explanation: Cataracts were documented in approximately three quarters of the classic-Vici series, supporting FREQUENT rather than VERY_FREQUENT.
- name: Cardiomyopathy
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in around 80 % of cases a cardiomyopathy, one of the 5 main diagnostic features, has been documented"
    explanation: Cardiomyopathy is documented in about 80% of cases, supporting VERY_FREQUENT.
- name: Combined immunodeficiency
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency."
    explanation: The review identifies combined immunodeficiency as a principal feature.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypopigmentation ++++ Immune problems ++++ Progressive microcephaly +++ Cardiomyopathy +++ Cataracts +++"
    explanation: The clinical-feature table assigns immune problems the ++++ category.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "++++ = present in almost all children, +++ = present in most children, ++ = present in more than half of children, + = present in some children"
    explanation: The table legend defines ++++ as present in almost all children, supporting VERY_FREQUENT.
- name: Hypopigmentation of the skin
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypopigmentation of the skin
    term:
      id: HP:0001010
      label: Hypopigmentation of the skin
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is one of the cardinal features of Vici syndrome and has been noted in almost all cases reported to date."
    explanation: Hypopigmentation is reported in almost all cases, supporting VERY_FREQUENT.
- name: Microcephaly
  description: Typically acquired (postnatal) microcephaly.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acquired microcephaly are almost universal"
    explanation: The review describes acquired microcephaly as almost universal in classic Vici syndrome.
- name: Failure to thrive
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive failure to thrive and acquired microcephaly are almost universal"
    explanation: The review describes progressive failure to thrive as almost universal in classic Vici syndrome.
- name: Profound global developmental delay
  description: Byrne describes profound developmental delay as one of the three consistent additional features.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Profound global developmental delay
    term:
      id: HP:0012736
      label: Profound global developmental delay
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal"
    explanation: The review explicitly describes profound developmental delay as almost universal, supporting VERY_FREQUENT.
- name: Recurrent infections
  description: Consequence of the combined immunodeficiency.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory infections as a result of primary immunodeficiency"
    explanation: Recurrent respiratory infections from the primary immunodeficiency are a leading cause of death.
- name: Myopathy
  description: Skeletal myopathy with autophagic-vacuolar features.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A skeletal myopathy is consistently associated"
    explanation: The review documents skeletal myopathy as consistently associated; no numeric frequency band is inferred.
- name: Seizures
  description: Severe seizure disorder; EPG5 is within the early-onset epileptic encephalopathy group.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two-thirds of patients had a severe seizure disorder"
    explanation: Two-thirds of the 50-patient cohort had a severe seizure disorder.
- name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presentation was mainly neonatal, with marked hypotonia and feeding difficulties"
    explanation: Neonatal presentation with marked hypotonia.
- name: Feeding difficulties
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presentation was mainly neonatal, with marked hypotonia and feeding difficulties"
    explanation: Neonatal presentation with feeding difficulties.
- name: Pontine hypoplasia
  phenotype_term:
    preferred_term: Hypoplasia of the pons
    term:
      id: HP:0012110
      label: Hypoplasia of the pons
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosal agenesis and pontine hypoplasia, delayed myelination"
    explanation: Pontine hypoplasia is a consistent neuroradiological feature.
- name: Delayed myelination
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosal agenesis and pontine hypoplasia, delayed myelination"
    explanation: Delayed myelination is a consistent neuroradiological feature.
- name: Sensorineural hearing loss
  description: >-
    Hearing loss can be overlooked because profound developmental delay and other
    multisystem manifestations complicate clinical recognition.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensorineural hearing loss was recognized in an isolated case in 2010"
    explanation: The review documents sensorineural hearing loss as part of the extended Vici phenotype.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensorineural hearing loss is a feature that may be easily overlooked in Vici syn- drome due to profound developmental delay and over- whelming multisystem involvement"
    explanation: Supports why hearing loss can be clinically overlooked in this severe multisystem disorder.
- name: Optic atrophy
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thymic aplasia + Sensorineural deafness + Optic atrophy + Renal tubular acidosis +"
    explanation: The clinical-feature table records optic atrophy in the + category.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "++++ = present in almost all children, +++ = present in most children, ++ = present in more than half of children, + = present in some children"
    explanation: The table legend defines + as present in some children.
- name: Areflexia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of children have absent deep tendon re- flexes but those may be brisk in around a third."
    explanation: Absent reflexes in a majority of children support the FREQUENT band.
- name: Thymic aplasia or hypoplasia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Thymic aplasia or hypoplasia
    term:
      id: HP:0010515
      label: Aplasia/Hypoplasia of the thymus
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete thymus aplasia or hypoplasia has been re- ported in around one fifth of patients"
    explanation: Thymic aplasia or hypoplasia in about one fifth of patients supports the OCCASIONAL band.
- name: Sleep apnea
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both central and obstructive apnoea may require polysomnographic moni- toring"
    explanation: The management review documents both central and obstructive sleep apnea.
- name: Hypothyroidism
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypothyroidism may require thyroid hormone replace- ment." # codespell:ignore-line
    explanation: The clinical review directly identifies hypothyroidism as a manifestation requiring replacement treatment.
- name: Hepatomegaly
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal tubular acidosis + Cleft lip/palate + Coarse facial features + Hepatomegaly +"
    explanation: The clinical-feature table records hepatomegaly among findings present in some children.
- name: Coarse facial features
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal tubular acidosis + Cleft lip/palate + Coarse facial features + Hepatomegaly +"
    explanation: The clinical-feature table records coarse facial features among findings present in some children.
- name: Cleft lip or palate
  phenotype_term:
    preferred_term: Orofacial cleft
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal tubular acidosis + Cleft lip/palate + Coarse facial features + Hepatomegaly +"
    explanation: The clinical-feature table records cleft lip or palate among findings present in some children.
- name: Atrial septal defect
  description: Minor congenital cardiac defects occur in a minority of children in addition to progressive cardiomyopathy.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Minor congenital heart defects comprising persistent foramen ovale and atrial septal de- fects have been reported in around 10 % of patients."
    explanation: The review documents atrial septal defects among minor congenital cardiac abnormalities in about 10% of reported patients.
- name: Renal tubular acidosis
  description: Renal involvement can include tubular acidosis with clinically important electrolyte disturbances.
  phenotype_term:
    preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal involvement comprising hydronephrosis, renal dysfunction and/or signs of renal tubular acidosis with associated electrolyte imbalances, in particular marked hypokalaemia, have been reported in around 15 % of cases"
    explanation: The review supports renal tubular acidosis and electrolyte imbalance as uncommon but management-relevant manifestations.
- name: Anemia
  description: Profound anemia is reported in some children, although whether it is primary or secondary to severe infection remains uncertain.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients with Vici syndrome have been noted to develop profound anaemia"
    explanation: The review documents profound anemia in some affected individuals.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is currently uncer- tain if this is a secondary feature (for example related to recurrent severe infections) or, alternatively, reflects add- itional primary involvement of red cell lines"
    explanation: The review explicitly leaves primary red-cell involvement versus secondary anemia unresolved.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Incidence and population prevalence are unknown. A 2016 review counted around 50
    genetically confirmed cases and judged the condition rare but probably
    underdiagnosed; this case count is not a population-rate denominator.
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of Vici syndrome is unknown."
    explanation: The review explicitly states that incidence is unknown, so no numeric prevalence band is asserted.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "around 50 genetically confirmed cases published to date"
    explanation: Supports the historical cases-in-literature count without converting it to a population prevalence.

diagnosis:
- name: EPG5 molecular genetic testing
  description: >-
    Diagnosis is established by identifying biallelic pathogenic EPG5 variants on
    molecular testing in a proband with suggestive clinical findings; Vici syndrome
    should be considered once mitochondrial, glycogen, and lysosomal storage
    disorders have been excluded.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirmed by identification of biallelic pathogenic (or likely pathogenic) variants in EPG5 on molecular testing"
    explanation: GeneReviews diagnostic criterion for EPG5-related disorder.
- name: Baseline multisystem assessment and surveillance
  description: >-
    Initial evaluation should include brain MRI, ophthalmology, cardiac ultrasound,
    immune-function testing, and renal, thyroid, and liver assessment. Surveillance
    is manifestation-directed, with continued cataract, cardiomyopathy, and immune
    monitoring emphasized because these features may evolve after presentation.
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other useful diagnostic investigations to document the extent of multisystem involvement (summarized in Table 2) include an MRI of the brain (in particular to document the callosal agenesis, one of the key diagnostic features), EEG, ophthalmology assesment including slit lamp examination and VEPs, chest x-ray, cardiac assess- ment including cardiac ultrasound, an abdominal ultra- sound to document the extent of organ involvement, laboratory investigations assessing immune, thyroid, liver and renal function" # codespell:ignore-line
    explanation: The review lists baseline neurologic, ocular, cardiac, abdominal, immune, thyroid, liver, and renal assessment.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "some of these features (in particular cata- racts, cardiomyopathy and immunodeficiency) may only evolve over time and are not necessarily present from birth."
    explanation: Supports continued surveillance because cataract, cardiac, and immune manifestations can evolve after birth.

progression:
- notes: >-
    Classic Vici syndrome is a progressive, life-limiting disorder: median survival
    is about 24 months with only ~10% of children surviving beyond five years. The
    most common causes of death are respiratory infections from the primary
    immunodeficiency and cardiac failure from the progressive cardiomyopathy.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age"
    explanation: Natural-history survival data from the largest cohort.
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure"
    explanation: GeneReviews states the leading causes of death.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of cardiac involvement and/or the extent of the associated immunodeficiency are the most important prognostic indicators."
    explanation: The review identifies cardiac disease and immunodeficiency severity as the principal prognostic indicators.

histopathology:
- name: Autophagic vacuolar myopathy
  description: >-
    Skeletal muscle biopsy shows accumulation of autophagy substrates, abnormal
    glycogen storage, autophagic vacuoles, and secondary mitochondrial abnormalities,
    the histopathological signature of the autophagic-clearance defect.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities"
    explanation: Muscle histopathology in Vici syndrome.

treatments:
- name: Multidisciplinary supportive care
  description: >-
    No curative therapy exists. Management is multidisciplinary, supportive, and
    directed at the manifestations and complications present in each child.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There is no cure for EPG5-related disorder."
    explanation: GeneReviews states that no curative treatment is available.
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Supportive multidisciplinary care to improve quality of life, optimize function, and reduce complications"
    explanation: GeneReviews establishes multidisciplinary supportive care as the mainstay of management.
- name: Immunoglobulin replacement and infection prophylaxis
  description: >-
    Combined immunodeficiency may require regular intravenous immunoglobulin infusions
    and antimicrobial prophylaxis. Active chest infections require early, aggressive
    antibacterial and antifungal treatment because they can progress to life-threatening
    sepsis.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "may require regular intraven- ous immunoglobulin infusions and antimicrobial prophylaxis"
    explanation: The Vici review directly supports IV immunoglobulin and antimicrobial prophylaxis for the immunodeficiency.
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) should be considered for chest infections to prevent episodes of life-threatening sepsis"
    explanation: GeneReviews recommends aggressive early anti-infective treatment given the primary immunodeficiency.
- name: Antiseizure medication
  description: >-
    Seizures should be treated with appropriate antiseizure medication. Responses to
    drugs with potential autophagy-modulating properties, including carbamazepine,
    should be monitored closely after treatment starts.
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than half of patients with Vici syndrome have seizures that ought to be managed with appropriate anti- convulsant therapy."
    explanation: The review recommends appropriate anticonvulsant therapy for the common seizure disorder.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "responses to anticonvulsants (or, indeed, other drugs) with potentially autophagy-modulating properties such as carbamazepine should perhaps be monitored closely following initiation of treatment."
    explanation: The review recommends close monitoring when starting potentially autophagy-modulating drugs such as carbamazepine.
- name: Cataract surgery
  description: >-
    Cataract extraction may improve visual outcome, but candidacy should be decided
    individually in light of overall disease severity and prognosis.
  treatment_term:
    preferred_term: cataract surgery
    term:
      id: NCIT:C157809
      label: Cataract Surgery
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If cataracts are present surgical removal may improve visual outcome"
    explanation: The review supports individualized cataract surgery as potentially vision-improving supportive treatment.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the indication for cataract surgery will have to be decided on an individual basis"
    explanation: The review explicitly frames surgical candidacy as an individualized decision.
- name: Proactive cardiomyopathy management
  description: >-
    Cardiomyopathy identified on regular cardiac assessment may benefit from proactive
    medical management, with particular vigilance during intercurrent illness.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If a cardiomyopathy is identified on regular cardiac as- sessments, this may benefit from proactive medical man- agement; a deterioration of cardiac function during intercurrent illness has to be expected."
    explanation: The review directly recommends proactive cardiac management and anticipatory care during illness.
- name: Gastrostomy feeding
  description: Percutaneous gastrostomy feeding is often needed to provide adequate nutrition.
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "most children require percutaneous feeding"
    explanation: The review's investigation and management table states that most children require percutaneous feeding.
- name: Noninvasive ventilatory support
  description: Central or obstructive sleep apnea may require noninvasive ventilatory support guided by sleep assessment.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Both central and obstructive apnoea may require polysomnographic moni- toring, and non-invasive ventilatory support as indicated."
    explanation: The review recommends sleep monitoring and noninvasive ventilation when indicated.
- name: Thyroid hormone replacement
  description: Hypothyroidism should be treated with thyroid hormone replacement when present.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypothyroidism may require thyroid hormone replace- ment." # codespell:ignore-line
    explanation: The review directly recommends thyroid hormone replacement for hypothyroidism.
- name: Renal and electrolyte management
  description: Renal dysfunction and electrolyte imbalance, especially severe hypokalemia, require anticipatory and active management.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Renal dysfunction and electrolyte imbalances ,i n particular profound hypokalaemia, will have to be antici- pated and managed actively."
    explanation: The review recommends active anticipation and management of renal and electrolyte complications.
- name: Blood transfusion for profound anemia
  description: Profound anemia may require blood transfusion in some affected children.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_phenotypes:
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Profound anaemia may re- quire blood transfusion in some patients."
    explanation: The review directly supports transfusion when profound anemia occurs.
- name: Genetic counseling
  description: >-
    Autosomal recessive recurrence-risk counseling (25% per pregnancy), carrier
    testing, and reproductive options including prenatal/preimplantation testing.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36228046
    reference_title: "EPG5-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected"
    explanation: GeneReviews gives the 25% autosomal recessive recurrence risk underpinning counseling.

definitions:
- name: Vici syndrome eight-feature diagnostic rule
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    Manifestation of all eight cardinal features (agenesis of the corpus callosum,
    cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, profound
    developmental delay, progressive microcephaly, and failure to thrive) is a
    clinical rule for prioritizing EPG5 testing.
  scope: Clinical rule for prioritizing molecular EPG5 testing
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation"
    explanation: The eight-feature combination has 97% specificity and 89% sensitivity for an EPG5 mutation.

differential_diagnoses:
- name: Marinesco-Sjogren syndrome and related disorders
  description: >-
    Marinesco-Sjogren syndrome is a close syndromic mimic because cataracts and
    skeletal myopathy can occur with sensorineural hearing loss. Failure to thrive and
    acquired microcephaly are uncommon and developmental delay is usually less severe
    in Marinesco-Sjogren syndrome.
  distinguishing_features:
  - Shared cataract and skeletal myopathy make Marinesco-Sjogren syndrome a close clinical mimic.
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marinesco-Sjoegren syndrome (MSS) and related disorders share cataracts and a skel- etal muscle myopathy with or without sensorineural"
    explanation: The review specifically names Marinesco-Sjogren syndrome among syndromic Vici mimics and identifies the overlapping features.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive and acquired micro- cephaly are uncommon and the degree of deve- lopmental delay is also usually less severe"
    explanation: These differences help distinguish Marinesco-Sjogren syndrome from classic Vici syndrome.
- name: Mitochondrial, glycogen storage, and lysosomal storage disorders
  description: >-
    Multisystem neurodevelopmental disorders with overlapping features that should be
    excluded before diagnosing Vici syndrome; the cardinal pentad and EPG5 genotype
    distinguish it.
  distinguishing_features:
  - Vici syndrome is considered once mitochondrial, glycogen, and lysosomal storage disorders have been excluded.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded"
    explanation: Byrne frames these as the differential diagnoses to exclude.

imaging_findings:
- name: Callosal agenesis and pontine hypoplasia on MRI
  modality: MRI
  description: >-
    Brain MRI consistently shows agenesis of the corpus callosum and pontine
    hypoplasia with delayed myelination. Reduced opercularization and reduced white
    matter bulk are additional consistent abnormalities.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosal agenesis and pontine hypoplasia, delayed myelination"
    explanation: Consistent neuroradiological features on brain MRI.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other consistent radiological abnormalities include pontine hypoplasia, reduced opercularisation of the Sylvian fissures, delayed myelination and general reduc- tion in white matter bulk"
    explanation: The review extends the characteristic MRI pattern to reduced opercularization and white-matter bulk.

animal_models:
- name: Epg5-null knockout mouse
  species: Mus musculus
  category: Epg5 knockout model
  description: >-
    Epg5-null mice reproduce the autophagy defect and skeletal-muscle myopathy and
    develop progressive motor and neurodegenerative abnormalities. The model supports
    the muscle and neuronal arms but does not establish fidelity to the full human
    cardinal phenotype.
  associated_phenotypes:
  - Autophagy defect
  - Skeletal muscle myopathy
  - Progressive motor deficit and neurodegeneration
  evidence:
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The phenotype of epg5-/-KO mice recapitulates the autophagy defect and the skeletal muscle myopathy seen in humans with Vici syndrome"
    explanation: The established knockout mouse reproduces the core autophagy and myopathy phenotypes.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "in addition exhibits clinical and pathological neurodegenerative features, in particular progressive motor deficit, muscle atrophy and damage of cortical 5 layer and spinal motor neurones"
    explanation: Supports the progressive motor and neurodegenerative abnormalities described for the knockout mouse.
- name: epg5 (CG14299) RNAi knockdown Drosophila
  species: Drosophila melanogaster
  category: Autophagy-gene knockdown model
  description: >-
    RNAi downregulation of the EPG5 ortholog epg5 (CG14299) in Drosophila produces
    autophagic abnormalities and progressive neurodegeneration, supporting the
    neurodevelopment-neurodegeneration link but capturing only the neuronal arm of
    the human multisystem phenotype.
  associated_phenotypes:
  - Autophagic abnormalities
  - Progressive neurodegeneration
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration"
    explanation: The Drosophila epg5-knockdown model recapitulates the neurodegenerative arm.

discussions:
- discussion_id: gap_vici_autophagy_therapeutics
  prompt: >-
    Because Vici syndrome is caused by a block at the late autophagosome-lysosome
    fusion step (not autophagosome formation), can autophagy-modulating or
    lysosome-directed therapies restore degradative flux, and in which tissues and
    developmental window would they need to act?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Block in Autophagic Flux with Accumulation of Autophagic Cargo
  rationale: >-
    EPG5 acts specifically at the fusion/maturation step, so classical
    autophagy-inducing agents (e.g. mTOR inhibitors) that increase autophagosome
    formation could worsen rather than relieve the downstream clearance block. No
    disease-modifying or autophagy-directed therapy has been evaluated clinically,
    and the congenital (agenesis of the corpus callosum) versus progressive
    (neurodegeneration, cardiomyopathy) components likely have different therapeutic
    windows. Defining a flux-restoring strategy and its timing is the central open
    question.
  proposed_experiments:
  - experiment_id: exp_vici_flux_restoration
    name: Screen for autolysosomal-flux restoration in EPG5-null cells
    description: >-
      Use EPG5-null patient iPSC-derived neurons and cardiomyocytes to screen
      lysosome-/fusion-directed compounds for restoration of degradative autophagic
      flux (p62/SQSTM1 turnover, LC3-II clearance), distinguishing agents that help
      from autophagy inducers that may aggravate cargo accumulation.
- discussion_id: hmm_vici_drosophila_model
  prompt: >-
    How faithfully do existing Drosophila and Epg5-null mouse models reproduce the
    human multisystem Vici phenotype beyond their neuronal and skeletal-muscle arms?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Neurodegeneration
  rationale: >-
    Drosophila EPG5 knock-down supports the neuronal arm, while an established
    Epg5-null mouse reproduces the autophagy defect, skeletal myopathy, and progressive
    neurodegeneration. Neither evidence base demonstrates reproduction of the full
    human combination of callosal agenesis, cardiomyopathy, cataracts, pigmentation,
    and combined immunodeficiency, so multisystem translational fidelity remains
    uncertain.
  proposed_experiments:
  - experiment_id: exp_vici_model_fidelity
    name: Cross-model comparison of EPG5 loss against the human cardinal pentad
    description: >-
      Systematically compare existing Drosophila and mouse models with zebrafish and
      human iPSC-derived systems for reproduction of each cardinal feature to identify
      which combination best captures the multisystem phenotype.
  evidence:
  - reference: PMID:26917586
    reference_title: "EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster"
    explanation: The Drosophila model captures the neuronal phenotype but not the full multisystem pentad.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The phenotype of epg5-/-KO mice recapitulates the autophagy defect and the skeletal muscle myopathy seen in humans with Vici syndrome"
    explanation: The mouse model improves on Drosophila for muscle involvement but still leaves full multisystem fidelity unresolved.
  - reference: PMID:26927810
    reference_title: "Vici syndrome: a review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "in addition exhibits clinical and pathological neurodegenerative features, in particular progressive motor deficit, muscle atrophy and damage of cortical 5 layer and spinal motor neurones"
    explanation: The mouse also reproduces progressive motor and neurodegenerative features, while other cardinal systems remain untested.
review_notes: >-
  The 2026-07-27 Claude Code deep-research artifact predates this review and its
  serialized Output section contains only a trailing terminology addendum rather
  than the full narrative. It should be regenerated in a separate research pass;
  this PR does not treat that degraded artifact as evidence. The present review
  instead uses exact cached excerpts from the primary cohort, GeneReviews, and the
  full-text clinical review. Phenotype-to-mechanism edges remain intentionally
  absent where those sources establish occurrence but not a causal route.
📚

References & Deep Research

References

2
PMID:36228046
EPG5-Related Disorder
No top-level findings curated for this source.
PMID:26927810
Vici syndrome: a review
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
claude-haiku-4-5-20251001, claude-opus-5[1m] 2026-07-27T23:01:49.546529

That background OAK check finished — small addendum to §12's treatment ontology column, three more terms now verified rather than ⚠️:

Term ID Verified
pharmacotherapy MAXO:0000058 ✅
Pharmacotherapy NCIT:C15986 ✅
Surgical Procedure NCIT:C15329 ✅
Supportive Care NCIT:C15747 ✅

So MAXO:0000058 (pharmacotherapy) is a live alternative to NCIT:C15986 for the drug-treatment rows — heart-failure meds, antiseizure meds, thyroid replacement, antimicrobials, immunoglobulin replacement — each paired with a therapeutic_agent for the actual drug. Everything else in that table's ⚠️ column still stands: no MAXO term surfaced for IVIG specifically, for antibiotic/antifungal therapy, for cataract extraction, or for hearing aids, so those need a fresh OAK search at curation time (the MAXO search index in this repo's adapter matched only on near-exact labels, which is why several of my queries came back empty rather than genuinely absent — worth re-searching with different phrasings before concluding the terms don't exist).

Also incidental, not useful here but worth not confusing later: the same batch returned MAXO:0000765 central venous nutrition intake and MAXO:0001175 liver transplantation. Neither belongs in the Vici entry — parenteral nutrition isn't the documented feeding route (gastrostomy is), and there's no hepatic transplant indication in this disease. I only mention them so nobody sees them in the scrollback and thinks I was proposing them.