VPS53-Related Pontocerebellar Hypoplasia Type 2E

Mendelian MONDO:0014370 Pathograph 5 Show in embeddings browser Pontocerebellar Hypoplasia Neurodevelopmental Disorder congenital disorder of glycosylation type II

VPS53-related pontocerebellar hypoplasia type 2E is an autosomal recessive GARP-complex vesicular-trafficking disorder caused by biallelic VPS53 variants. VPS53 deficiency impairs endosome-to-Golgi retrograde recycling, causing abnormal CD63-positive endosomal or vesicular bodies in patient fibroblasts and downstream disruption of sphingolipid homeostasis, lysosomal function, and Golgi glycoprotein processing. The clinical syndrome overlaps historical progressive cerebello-cerebral atrophy type 2 and includes severe neurodevelopmental impairment, progressive microcephaly, epilepsy, spasticity, pontocerebellar/cerebello-cerebral atrophy, and occasional hepatic or hearing involvement.

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1
Inheritance
5
Pathophys.
7
Phenotypes
5
Pathograph
1
Genes
1
Deep Research
🏷

Classifications

👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
VPS53-related PCH2E/PCCA2 is reported with biallelic VPS53 founder variants and autosomal recessive segregation.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:24577744 SUPPORT Human Clinical
"compound heterozygous mutations in VPS53, segregating as expected for autosomal recessive heredity within all four families"
The discovery report directly supports autosomal recessive VPS53 disease.
⚙

Pathophysiology

5
VPS53 GARP-complex retrograde-trafficking defect
Biallelic VPS53 variants disrupt the GARP complex, impairing retrograde recycling of endocytic vesicles to the Golgi.
VPS53 hgnc:25608
retrograde transport, endosome to Golgi GO:0042147 ↓ DECREASED Golgi vesicle transport GO:0048193 ⚠ ABNORMAL
Golgi apparatus GO:0005794
Downstream
Abnormal endosomal vesicular bodies GARP dysfunction produces abnormal endosomal or vesicular-body morphology in patient fibroblasts.
Show evidence (2 references)
PMID:24577744 SUPPORT Human Clinical
"Autosomal recessive PCCA type 2 is caused by VPS53 mutations."
The discovery report establishes VPS53 as the causal disease gene.
PMID:24577744 SUPPORT Other
"The Golgi-associated retrograde protein (GARP) complex is involved in the retrograde pathway recycling endocytic vesicles to Golgi"
This defines the primary vesicular-trafficking process disrupted by VPS53 disease.
Abnormal endosomal vesicular bodies
Patient fibroblasts show swollen and abnormally numerous CD63-positive vesicular bodies consistent with disrupted intermediate recycling or late endosomal trafficking downstream of VPS53/GARP dysfunction.
fibroblast CL:0000057
endosome organization GO:0007032 ⚠ ABNORMAL retrograde transport, endosome to Golgi GO:0042147 ↓ DECREASED
Downstream
Sphingolipid and lysosomal homeostasis disruption Endosomal trafficking disruption is mechanistically linked to downstream sphingolipid and lysosomal homeostasis abnormalities in GARP deficiency.
Show evidence (1 reference)
PMID:24577744 SUPPORT In Vitro
"Immunofluorescent microscopy demonstrated swollen and abnormally numerous CD63 positive vesicular bodies, likely intermediate recycling/late endosomes, in fibroblasts of affected individuals."
Patient fibroblast microscopy directly supports abnormal endosomal vesicular bodies.
Sphingolipid and lysosomal homeostasis disruption
GARP deficiency reroutes or misbalances sphingolipid trafficking, causing accumulation of sphingolipid intermediates and lysosomal dysfunction in model systems and PCCA2 patient fibroblasts.
fibroblast CL:0000057
lysosome organization GO:0007040 ⚠ ABNORMAL
Downstream
Neurologic and hepatic tissue dysfunction Endosomal, lysosomal, lipid, and Golgi-processing disruption converges on severe neurodevelopmental disease and can include hepatic involvement.
Show evidence (2 references)
PMID:26357016 SUPPORT In Vitro
"GARP deficiency leads to accumulation of sphingolipid synthesis intermediates, changes in sterol distribution, and lysosomal dysfunction."
The GARP lipid-homeostasis study defines the downstream sphingolipid and lysosomal defect.
PMID:26357016 SUPPORT In Vitro
"PCCA2 fibroblasts exhibited increases in sphingosine, sphinganine, and ceramides compared with control fibroblasts."
Patient fibroblast lipidomics supports accumulation of sphingolipid intermediates in VPS53-related disease.
GARP-dependent Golgi glycosylation machinery failure
VPS53-containing GARP activity is required to maintain Golgi glycosylation enzymes. Loss of VPS53 or related GARP subunits causes abnormal processing of N-linked and O-linked glycoproteins.
protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL protein O-linked glycosylation GO:0006493 ⚠ ABNORMAL
Show evidence (1 reference)
PMID:34161137 SUPPORT In Vitro
"KO of VPS53 or VPS54 in RPE1 cells caused N- and O-glycosylation defects in plasma membrane, intracellular, and secreted glycoproteins."
VPS53 knockout human-cell experiments support defective Golgi N- and O-glycosylation downstream of GARP dysfunction.
Neurologic and hepatic tissue dysfunction
VPS53-related GARP dysfunction causes a severe pontocerebellar or cerebello-cerebral neurodevelopmental disorder and, in at least one report, liver disease and deafness.
Show evidence (3 references)
PMID:24577744 SUPPORT Human Clinical
"Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental retardation, progressive microcephaly, spasticity and early onset epilepsy"
The discovery report defines the major neurologic phenotype.
PMID:39842660 SUPPORT Human Clinical
"Pathogenic variants in VPS53 are associated with pontocerebellar hypoplasia type 2E (PCH2E), characterized by microcephaly, severe neurodevelopmental impairment and epilepsy."
The 2025 case report summarizes the core PCH2E neurologic phenotype.
PMID:39842660 PARTIAL Human Clinical
"the classic phenotypic features along with liver disease and deafness"
A single report supports hepatic and hearing involvement as possible extension features.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for VPS53-Related Pontocerebellar Hypoplasia Type 2E Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Ear 1
Hearing impairment Hearing impairment HP:0000365
Show evidence (1 reference)
PMID:39842660 SUPPORT Human Clinical
"classic phenotypic features along with liver disease and deafness"
Deafness maps to the HPO hearing impairment term.
Musculoskeletal 1
Spasticity Spasticity HP:0001257
Show evidence (1 reference)
PMID:24577744 SUPPORT Human Clinical
"progressive microcephaly, spasticity and early onset epilepsy"
The discovery report explicitly includes spasticity.
Nervous System 3
Seizures Seizure HP:0001250
Show evidence (1 reference)
PMID:24577744 SUPPORT Human Clinical
"spasticity and early onset epilepsy"
The discovery report explicitly includes early-onset epilepsy.
Cerebellar hypoplasia Cerebellar hypoplasia HP:0001321
Show evidence (1 reference)
PMID:39842660 SUPPORT Human Clinical
"Pathogenic variants in VPS53 are associated with pontocerebellar hypoplasia type 2E (PCH2E)"
The report explicitly identifies the VPS53 disorder as PCH2E.
Global developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:39842660 SUPPORT Human Clinical
"microcephaly, severe neurodevelopmental impairment and epilepsy."
The report supports severe neurodevelopmental impairment.
Other 2
Microcephaly Progressive microcephaly HP:0000253
Show evidence (1 reference)
PMID:24577744 SUPPORT Human Clinical
"progressive microcephaly, spasticity and early onset epilepsy"
The discovery report explicitly includes progressive microcephaly.
Abnormality of the liver Abnormality of the liver HP:0001392
Show evidence (1 reference)
PMID:39842660 SUPPORT Human Clinical
"classic phenotypic features along with liver disease and deafness"
A 2025 case report explicitly adds liver disease to the VPS53-related PCH2E phenotype; the generic HPO liver abnormality term is used because the cached abstract does not specify a narrower hepatic diagnosis.
🧬

Genetic Associations

1
VPS53 biallelic pathogenic variants (Loss of function mutation)
Gene: VPS53 hgnc:25608 relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:24577744 SUPPORT Human Clinical
"Whole exome sequencing identified only two mutations within this locus, which were common to the affected individuals: compound heterozygous mutations in VPS53"
Exome sequencing identified biallelic VPS53 variants shared by affected individuals.
{ }

Source YAML

click to show 
name: VPS53-Related Pontocerebellar Hypoplasia Type 2E
creation_date: "2026-07-06T12:00:00Z"
category: Mendelian
description: >-
  VPS53-related pontocerebellar hypoplasia type 2E is an autosomal recessive
  GARP-complex vesicular-trafficking disorder caused by biallelic VPS53
  variants. VPS53 deficiency impairs endosome-to-Golgi retrograde recycling,
  causing abnormal CD63-positive endosomal or vesicular bodies in patient
  fibroblasts and downstream disruption of sphingolipid homeostasis, lysosomal
  function, and Golgi glycoprotein processing. The clinical syndrome overlaps
  historical progressive cerebello-cerebral atrophy type 2 and includes severe
  neurodevelopmental impairment, progressive microcephaly, epilepsy, spasticity,
  pontocerebellar/cerebello-cerebral atrophy, and occasional hepatic or hearing
  involvement.
disease_term:
  preferred_term: pontocerebellar hypoplasia type 2E
  term:
    id: MONDO:0014370
    label: pontocerebellar hypoplasia type 2E
parents:
- Pontocerebellar Hypoplasia
- Neurodevelopmental Disorder
- congenital disorder of glycosylation type II
synonyms:
- VPS53-related PCH2E
- pontocerebellar hypoplasia type 2E
- PCH2E
- progressive cerebello-cerebral atrophy type 2
- PCCA2
- VPS53 deficiency
notes: >-
  The local PCH2 candidate was audited and not edited: that entry models the
  TSEN54/TSEN-complex PCH2 mechanism, while this MONDO:0014370 disease is a
  distinct VPS53/GARP-complex retrograde-trafficking disorder. VPS53-related
  disease is therefore curated as its own disorder entry with vesicular
  trafficking as the primary ICIMD placement and glycosylation as a downstream
  Golgi-machinery consequence.
external_assertions:
- name: OMIM pontocerebellar hypoplasia type 2E record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:615851
  description: >-
    OMIM phenotype identifier for VPS53-related pontocerebellar hypoplasia type
    2E / progressive cerebello-cerebral atrophy type 2.
classifications:
  icimd_category:
  - classification_value: vesicular_trafficking
    notes: >-
      WP-068 classification 19.6.68.01: Complex Molecule and Organelle
      Metabolism, disorders of organelle biogenesis, dynamics and interactions,
      disorders of vesicular trafficking.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    VPS53-related PCH2E/PCCA2 is reported with biallelic VPS53 founder variants
    and autosomal recessive segregation.
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      compound heterozygous mutations in VPS53, segregating as expected for
      autosomal recessive heredity within all four families
    explanation: >-
      The discovery report directly supports autosomal recessive VPS53 disease.
pathophysiology:
- name: VPS53 GARP-complex retrograde-trafficking defect
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  description: >-
    Biallelic VPS53 variants disrupt the GARP complex, impairing retrograde
    recycling of endocytic vesicles to the Golgi.
  genes:
  - preferred_term: VPS53
    term:
      id: hgnc:25608
      label: VPS53
  biological_processes:
  - preferred_term: retrograde transport, endosome to Golgi
    modifier: DECREASED
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive PCCA type 2 is caused by VPS53 mutations."
    explanation: >-
      The discovery report establishes VPS53 as the causal disease gene.
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Golgi-associated retrograde protein (GARP) complex is involved in the
      retrograde pathway recycling endocytic vesicles to Golgi
    explanation: >-
      This defines the primary vesicular-trafficking process disrupted by VPS53
      disease.
  downstream:
  - target: Abnormal endosomal vesicular bodies
    causal_link_type: DIRECT
    description: >-
      GARP dysfunction produces abnormal endosomal or vesicular-body morphology
      in patient fibroblasts.
    evidence:
    - reference: PMID:24577744
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Immunofluorescent microscopy demonstrated swollen and abnormally
        numerous CD63 positive vesicular bodies, likely intermediate
        recycling/late endosomes, in fibroblasts of affected individuals.
      explanation: >-
        Patient fibroblast microscopy directly supports abnormal endosomal
        vesicular bodies.
- name: Abnormal endosomal vesicular bodies
  description: >-
    Patient fibroblasts show swollen and abnormally numerous CD63-positive
    vesicular bodies consistent with disrupted intermediate recycling or late
    endosomal trafficking downstream of VPS53/GARP dysfunction.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: endosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007032
      label: endosome organization
  - preferred_term: retrograde transport, endosome to Golgi
    modifier: DECREASED
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluorescent microscopy demonstrated swollen and abnormally numerous
      CD63 positive vesicular bodies, likely intermediate recycling/late
      endosomes, in fibroblasts of affected individuals.
    explanation: >-
      Patient fibroblast microscopy directly supports abnormal endosomal
      vesicular bodies.
  downstream:
  - target: Sphingolipid and lysosomal homeostasis disruption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired GARP-mediated endosome-to-Golgi retrograde recycling
    description: >-
      Endosomal trafficking disruption is mechanistically linked to downstream
      sphingolipid and lysosomal homeostasis abnormalities in GARP deficiency.
- name: Sphingolipid and lysosomal homeostasis disruption
  description: >-
    GARP deficiency reroutes or misbalances sphingolipid trafficking, causing
    accumulation of sphingolipid intermediates and lysosomal dysfunction in
    model systems and PCCA2 patient fibroblasts.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  chemical_entities:
  - preferred_term: sphingomyelin
    modifier: ABNORMAL
    term:
      id: CHEBI:64583
      label: sphingomyelin
  biological_processes:
  - preferred_term: lysosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007040
      label: lysosome organization
  evidence:
  - reference: PMID:26357016
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      GARP deficiency leads to accumulation of sphingolipid synthesis
      intermediates, changes in sterol distribution, and lysosomal dysfunction.
    explanation: >-
      The GARP lipid-homeostasis study defines the downstream sphingolipid and
      lysosomal defect.
  - reference: PMID:26357016
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PCCA2 fibroblasts exhibited increases in sphingosine, sphinganine, and
      ceramides compared with control fibroblasts.
    explanation: >-
      Patient fibroblast lipidomics supports accumulation of sphingolipid
      intermediates in VPS53-related disease.
  downstream:
  - target: Neurologic and hepatic tissue dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Endosomal, lysosomal, lipid, and Golgi-processing disruption converges on
      severe neurodevelopmental disease and can include hepatic involvement.
- name: GARP-dependent Golgi glycosylation machinery failure
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    VPS53-containing GARP activity is required to maintain Golgi glycosylation
    enzymes. Loss of VPS53 or related GARP subunits causes abnormal processing
    of N-linked and O-linked glycoproteins.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  chemical_entities:
  - preferred_term: N-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  - preferred_term: O-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59521
      label: O-glycan
  evidence:
  - reference: PMID:34161137
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      KO of VPS53 or VPS54 in RPE1 cells caused N- and O-glycosylation defects
      in plasma membrane, intracellular, and secreted glycoproteins.
    explanation: >-
      VPS53 knockout human-cell experiments support defective Golgi N- and
      O-glycosylation downstream of GARP dysfunction.
- name: Neurologic and hepatic tissue dysfunction
  description: >-
    VPS53-related GARP dysfunction causes a severe pontocerebellar or
    cerebello-cerebral neurodevelopmental disorder and, in at least one report,
    liver disease and deafness.
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental
      retardation, progressive microcephaly, spasticity and early onset epilepsy
    explanation: >-
      The discovery report defines the major neurologic phenotype.
  - reference: PMID:39842660
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in VPS53 are associated with pontocerebellar
      hypoplasia type 2E (PCH2E), characterized by microcephaly, severe
      neurodevelopmental impairment and epilepsy.
    explanation: >-
      The 2025 case report summarizes the core PCH2E neurologic phenotype.
  - reference: PMID:39842660
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the classic phenotypic features along with liver disease and deafness"
    explanation: >-
      A single report supports hepatic and hearing involvement as possible
      extension features.
phenotypes:
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  description: >-
    Progressive microcephaly is part of the historical PCCA2 presentation.
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive microcephaly, spasticity and early onset epilepsy"
    explanation: >-
      The discovery report explicitly includes progressive microcephaly.
- category: Neurological
  name: Seizures
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Early-onset epilepsy is a core VPS53-related PCH2E feature.
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spasticity and early onset epilepsy"
    explanation: >-
      The discovery report explicitly includes early-onset epilepsy.
- category: Neurological
  name: Cerebellar hypoplasia
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  description: >-
    The disease is classified as pontocerebellar hypoplasia type 2E and overlaps
    progressive cerebello-cerebral atrophy.
  evidence:
  - reference: PMID:39842660
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in VPS53 are associated with pontocerebellar
      hypoplasia type 2E (PCH2E)
    explanation: >-
      The report explicitly identifies the VPS53 disorder as PCH2E.
- category: Neurological
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Severe neurodevelopmental impairment is reported in VPS53-related PCH2E.
  evidence:
  - reference: PMID:39842660
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, severe neurodevelopmental impairment and epilepsy."
    explanation: >-
      The report supports severe neurodevelopmental impairment.
- category: Neurological
  name: Spasticity
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  description: >-
    Spasticity is part of the historical progressive cerebello-cerebral atrophy
    type 2 presentation.
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive microcephaly, spasticity and early onset epilepsy"
    explanation: >-
      The discovery report explicitly includes spasticity.
- category: Hepatic
  name: Abnormality of the liver
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  description: >-
    Liver disease was reported as an extension feature in one VPS53-related
    PCH2E case.
  evidence:
  - reference: PMID:39842660
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "classic phenotypic features along with liver disease and deafness"
    explanation: >-
      A 2025 case report explicitly adds liver disease to the VPS53-related
      PCH2E phenotype; the generic HPO liver abnormality term is used because
      the cached abstract does not specify a narrower hepatic diagnosis.
- category: Hearing
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  description: >-
    Deafness was reported as an extension feature in one VPS53-related PCH2E
    case.
  evidence:
  - reference: PMID:39842660
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "classic phenotypic features along with liver disease and deafness"
    explanation: >-
      Deafness maps to the HPO hearing impairment term.
genetic:
- name: VPS53 biallelic pathogenic variants
  association: Loss of function mutation
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: VPS53
    term:
      id: hgnc:25608
      label: VPS53
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    Reported pathogenic alleles include VPS53 founder variants affecting the
    C-terminal region needed for GARP-complex function.
  evidence:
  - reference: PMID:24577744
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified only two mutations within this locus,
      which were common to the affected individuals: compound heterozygous
      mutations in VPS53
    explanation: >-
      Exome sequencing identified biallelic VPS53 variants shared by affected
      individuals.
📚

References & Deep Research

Deep Research

1
VPS53-Related Pontocerebellar Hypoplasia Type 2E Deep Research Fallback ▸

VPS53-Related Pontocerebellar Hypoplasia Type 2E Deep Research Fallback

Scope

No provider-generated deep research artifact was present on the WP-068 branch. This fallback audit documents the literature scope used to curate and review the VPS53-related entry from cached PubMed references.

Evidence Scope Used For Curation

  • PMID:24577744 for the VPS53/PCCA2 discovery report, autosomal recessive segregation, GARP-complex retrograde transport biology, patient fibroblast CD63-positive vesicular-body abnormalities, and the neurologic phenotype of profound developmental impairment, progressive microcephaly, spasticity, and early-onset epilepsy.
  • PMID:26357016 for GARP deficiency causing sphingolipid-intermediate accumulation, altered sterol distribution, lysosomal dysfunction, and sphingolipid abnormalities in PCCA2 patient fibroblasts.
  • PMID:34161137 for the broader GARP-dependent Golgi N- and O-glycosylation defect, including VPS53 knockout effects in human cells.
  • PMID:39842660 for a later VPS53-related PCH2E case with classic neurologic features plus liver disease and deafness.

Curation Conclusions

The supported model is biallelic VPS53 dysfunction causing GARP-complex retrograde-trafficking failure, abnormal endosomal vesicular bodies, downstream sphingolipid/lysosomal disruption, and Golgi glycoprotein-processing defects. The phenotype set should cover progressive microcephaly, epilepsy, pontocerebellar/cerebello-cerebral involvement, severe neurodevelopmental impairment, spasticity, and the reported hepatic and hearing extension features.