Hypomyelinating leukodystrophy 12 (HLD12, MIM 616683) is an ultra-rare autosomal recessive infantile-onset hypomyelinating leukodystrophy caused by biallelic variants in VPS11, which encodes a core subunit shared by the two Class C Vps tethering complexes of the endolysosomal system - HOPS (homotypic fusion and protein sorting), which tethers late endosomes and autophagosomes to lysosomes, and CORVET (class C core vacuole/endosome tethering), which acts at early endosomes. Affected children present in the first months of life with developmental stagnation, acquired progressive microcephaly, truncal (axial) hypotonia evolving to appendicular spasticity and spastic tetraplegia, variable seizures, cortical visual impairment or optic atrophy, and sensorineural hearing loss. Brain MRI shows diffuse CNS hypomyelination, a short and posteriorly thinned corpus callosum, reduced white-matter volume, and - in a recent two-centre cohort - a VPS11-specific cerebellar signature (focal absence of the middle-anterior cerebellar cortex) not seen in other hypomyelinating leukodystrophies. Most reported patients are of Ashkenazi Jewish ancestry and homozygous for the founder allele VPS11 c.2536T>G (p.Cys846Gly), which has a carrier frequency of roughly 1:250 (0.6%) in that population. The mechanism is a loss of VPS11 function in endolysosomal membrane trafficking. The p.Cys846Gly substitution sits in the C-terminal cysteine-rich RING-H2 domain; it does not misfold the domain but is aberrantly ubiquitinated and rapidly degraded, lowering steady-state VPS11 and weakening VPS11-VPS18 core assembly, so both HOPS and CORVET are compromised. Other alleles (the in-frame deletion p.Leu387_Gly395del; compound-heterozygous missense variants) reduce protein by different routes. The downstream consequences are impaired fusion of late endosomes and autophagosomes with lysosomes, reduced autophagic flux, and lysosomal storage (membranous cytoplasmic bodies, storage macrophages and abnormal urinary glycosphingolipids resembling a classic lysosomal storage disease). In oligodendroglial cell models the mutant protein aggregates and downregulates p70S6K signalling, blocking the morphological differentiation required to make myelin; in zebrafish vps11 mutants CNS neuronal death precedes and accompanies a reduction in myelination. Both a primary oligodendroglial differentiation failure and primary neuronal death therefore contribute to the hypomyelination. There is no disease-modifying therapy; management is supportive and multidisciplinary. A candidate molecular intervention point (restoring p70S6K phosphorylation by inhibiting the phosphatases PP1C/PP2A) has been demonstrated only in an oligodendroglial cell line.
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name: Hypomyelinating Leukodystrophy 12
creation_date: "2026-09-05T00:00:00Z"
category: Mendelian
description: >-
Hypomyelinating leukodystrophy 12 (HLD12, MIM 616683) is an ultra-rare
autosomal recessive infantile-onset hypomyelinating leukodystrophy caused by
biallelic variants in VPS11, which encodes a core subunit shared by the two
Class C Vps tethering complexes of the endolysosomal system - HOPS (homotypic
fusion and protein sorting), which tethers late endosomes and autophagosomes to
lysosomes, and CORVET (class C core vacuole/endosome tethering), which acts at
early endosomes. Affected children present in the first months of life with
developmental stagnation, acquired progressive microcephaly,
truncal (axial) hypotonia evolving to appendicular spasticity and spastic
tetraplegia, variable seizures, cortical visual impairment or optic atrophy, and
sensorineural hearing loss. Brain MRI shows diffuse CNS hypomyelination, a short
and posteriorly thinned corpus callosum, reduced white-matter volume, and - in a
recent two-centre cohort - a VPS11-specific cerebellar signature (focal absence
of the middle-anterior cerebellar cortex) not seen in other hypomyelinating
leukodystrophies. Most reported patients are of Ashkenazi Jewish ancestry and
homozygous for the founder allele VPS11 c.2536T>G (p.Cys846Gly), which has a
carrier frequency of roughly 1:250 (0.6%) in that population.
The mechanism is a loss of VPS11 function in endolysosomal membrane trafficking.
The p.Cys846Gly substitution sits in the C-terminal cysteine-rich RING-H2 domain;
it does not misfold the domain but is aberrantly ubiquitinated and rapidly
degraded, lowering steady-state VPS11 and weakening VPS11-VPS18 core assembly, so
both HOPS and CORVET are compromised. Other alleles (the in-frame deletion
p.Leu387_Gly395del; compound-heterozygous missense variants) reduce protein by
different routes. The downstream consequences are impaired fusion of late
endosomes and autophagosomes with lysosomes, reduced autophagic flux, and
lysosomal storage (membranous cytoplasmic bodies, storage macrophages and
abnormal urinary glycosphingolipids resembling a classic lysosomal storage
disease). In oligodendroglial cell models the mutant protein aggregates and
downregulates p70S6K signalling, blocking the morphological differentiation
required to make myelin; in zebrafish vps11 mutants CNS neuronal death precedes
and accompanies a reduction in myelination. Both a primary oligodendroglial
differentiation failure and primary neuronal death therefore contribute to the
hypomyelination.
There is no disease-modifying therapy; management is supportive and
multidisciplinary. A candidate molecular
intervention point (restoring p70S6K phosphorylation by inhibiting the
phosphatases PP1C/PP2A) has been demonstrated only in an oligodendroglial cell
line.
notes: >-
Named-entity-confusion guardrail. This entry is anchored strictly on
MONDO:0014732 / OMIM:616683 / VPS11 (hgnc:14583). "Hypomyelinating
leukodystrophy N" is a numbered series whose members share only the numeral, so
the anchor was fixed before curation with
`uv run runoak -i sqlite:obo:mondo info MONDO:0014732 -O obo`, which returns
`intersection_of: RO:0004003 HGNC:14583 ! VPS11` and `xref: OMIM:616683`,
independently confirming both gene and OMIM number. VPS11 (hgnc:14583) was
confirmed with `uv run runoak -i sqlite:obo:hgnc info hgnc:14583`.
Gene-family confusables. VPS11 is one of six Class C Vps subunits; VPS16, VPS18,
VPS33A and VPS33B all cause distinct disorders, and none of their literature is
cited here as evidence for VPS11 disease. VPS11 also has a large,
disease-unrelated cell-biology and cancer literature (autophagy machinery,
ferroptosis), which is likewise excluded.
Emerging movement-disorder spectrum (not curated here). A later-onset complex
dystonic / spastic-paraplegia presentation from biallelic VPS11 missense
variants with little or no white-matter change has been reported under the
provisional DYT32 label (Storck et al., PMID:41551069, plus a prior single
case). That is a distinct clinical entity; this entry stays anchored on
MONDO:0014732 (the hypomyelinating leukodystrophy) and does not curate the
movement-disorder presentation, whose primary sources are not yet fetched into
this entry's evidence.
No GeneReviews chapter exists for VPS11 or HLD12. Searched on 2026-09-05 with
`VPS11 GeneReviews[All Fields]` and `hypomyelinating leukodystrophy
GeneReviews[TI]`; both returned zero records. The phenotype baseline is
therefore taken from the primary cohort literature: PMID:26307567 (8 patients,
4 AJ families; the founding report), PMID:27120463 (5 patients, 3 AJ families;
founder-allele + autophagy mechanism), PMID:27473128 (2 siblings; the
lysosomal-storage second report) and PMID:42697725 (6 patients; the systematic
MRI cohort).
Frequency discipline. FrequencyEnum bands are asserted only where a cohort gives
an explicit numerator or an unambiguous "in all patients" statement, and the
source figure is recorded in each phenotype's notes. Where a feature is reported
in "some" or "several" patients, frequency is omitted rather than guessed. The
whole published denominator is only a few dozen patients drawn largely from one
founder population, so no feature is banded OBLIGATE.
No `datasets:` block is curated. HLD12 has a few dozen published patients and no
omics resource of its own, while a gene-keyed accession search on VPS11 returns
cancer and generic-autophagy datasets that would resolve perfectly and be about
the wrong biology - the Named Entity Confusion the dataset-curation SOP warns
about - so an empty block is the honest result.
A Claude Code literature-sweep deep-research report is committed at
research/Hypomyelinating_Leukodystrophy_12-deep-research-claude-2026-09-05.md.
Its citations were treated as leads and each snippet used here was verified
against the primary source fetched into references_cache/.
disease_term:
preferred_term: Hypomyelinating leukodystrophy 12
term:
id: MONDO:0014732
label: leukodystrophy, hypomyelinating, 12
synonyms:
- HLD12
- VPS11 leukodystrophy
- VPS11-related hypomyelinating leukodystrophy
- VPS11-related autosomal recessive hypomyelinating leukoencephalopathy
- leukodystrophy, hypomyelinating, 12
mappings:
mondo_mappings:
- term:
id: MONDO:0014732
label: leukodystrophy, hypomyelinating, 12
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
Primary MONDO identifier for this entity. Its definition is gene-anchored
(intersection_of RO:0004003 HGNC:14583 VPS11) and it carries OMIM:616683,
Orphanet:466934, DOID:0060796, MEDGEN:905068 and UMLS:C4225247 as
cross-references, all confirmed with OAK.
classifications:
harrisons_chapter:
- classification_value: NEUROLOGIC
notes: >-
Primary clinical home: a hypomyelinating leukodystrophy presenting as a
progressive infantile neurological disease (Harrison's Part on Neurologic
Disorders, which covers the leukodystrophies).
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a neurological disease, which consists of global developmental stagnation at 3-8 months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly"
explanation: The founding cohort characterises HLD12 as a progressive neurological disease.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
Single-gene autosomal recessive Mendelian disorder (VPS11), the recurring
theme of Harrison's Part on Genes, the Environment, and Disease.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway."
explanation: Establishes HLD12 as an autosomal recessive (Mendelian) disorder.
parents:
- leukodystrophy
- congenital nervous system disorder
inheritance:
- name: Autosomal recessive inheritance
description: >-
HLD12 is inherited in an autosomal recessive manner. Most reported patients
are homozygous for the Ashkenazi Jewish founder allele VPS11 p.Cys846Gly;
compound-heterozygous and other homozygous genotypes are also reported.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families"
explanation: Establishes the recessive (homozygous) genetic basis in three unrelated families.
genetic:
- name: VPS11
gene_term:
preferred_term: VPS11
term:
id: hgnc:14583
label: VPS11
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
VPS11 encodes vacuolar protein sorting-associated protein 11, a core subunit
shared by the HOPS and CORVET Class C Vps tethering complexes. The recurrent
Ashkenazi Jewish founder allele is c.2536T>G (p.Cys846Gly), in the C-terminal
RING-H2 domain; the in-frame deletion p.Leu387_Gly395del and compound
heterozygous missense variants (e.g. p.Leu724Arg / p.Arg729Leu) are also
reported.
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Homozygosity for a missense mutation, p.Cys846Gly, in one of the endosomal biogenesis core proteins, VPS11, was identified in all the patients. This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population."
explanation: Identifies VPS11 p.Cys846Gly as the causal founder allele and gives its AJ carrier frequency.
- reference: PMID:27473128
reference_title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exome sequencing revealed the homozygous variant p.Leu387_ Gly395del in the VPS11 gene in two siblings."
explanation: Documents a second, non-founder VPS11 allele causing the same disease, establishing allelic heterogeneity.
prevalence:
- population: Ashkenazi Jewish population
measure_type: CARRIER_FREQUENCY
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 600.0
notes: >-
Carrier frequency 0.6% (~1:250) for the founder allele p.Cys846Gly in the
Ashkenazi Jewish population; no disease-prevalence estimate is published, and
the disorder is ultra-rare outside this founder context.
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population."
explanation: Gives the founder-allele carrier frequency in the Ashkenazi Jewish population.
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: ULTRA_RARE
notes: >-
Fewer than 30 patients are reported worldwide and most share the Ashkenazi
Jewish founder allele; no formal disease-prevalence estimate exists, so the
ultra-rare tier is a qualitative judgement rather than a measured rate.
pathophysiology:
- name: Biallelic VPS11 Loss of Function
biological_scale: MOLECULAR
description: >-
Biallelic VPS11 variants reduce the amount or functional competence of
vacuolar protein sorting-associated protein 11. The Ashkenazi founder allele
p.Cys846Gly lies in the C-terminal cysteine-rich RING-H2 domain; circular
dichroism shows it does not misfold the domain, but the mutant protein is
aberrantly ubiquitinated and turned over roughly five times faster than
wild-type, lowering steady-state VPS11 and weakening its assembly with VPS18
into the shared Class C Vps core. The in-frame deletion p.Leu387_Gly395del
reduces protein by a distinct route. Because VPS11 is a common subunit of both
HOPS and CORVET, the net effect is a loss of function of both tethering
complexes.
genetic_context:
gene:
preferred_term: VPS11
term:
id: hgnc:14583
label: VPS11
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein."
explanation: Direct in-vitro demonstration that the founder allele is a loss-of-function variant acting through instability and impaired core assembly.
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The half-life of the WT protein was five-fold higher than that of the C846G mutant"
explanation: Quantifies the accelerated turnover underlying reduced VPS11 abundance.
downstream:
- target: Impaired HOPS/CORVET-Mediated Endolysosomal Tethering and Fusion
causal_link_type: DIRECT
description: >-
Reduced VPS11 and impaired VPS11-VPS18 core assembly disable the Class C Vps
tethering complexes that VPS11 anchors.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes."
explanation: Establishes that VPS11 loss acts on the HOPS/CORVET tethering machinery this edge points to.
- name: Impaired HOPS/CORVET-Mediated Endolysosomal Tethering and Fusion
biological_scale: CELLULAR
description: >-
HOPS and CORVET tether and fuse vesicles within the endolysosomal and
autophagy pathways - CORVET at early endosomes, HOPS at the fusion of late
endosomes and autophagosomes with lysosomes. With VPS11 reduced, this tethering
and fusion step is impaired. The homologous yeast VPS11 mutant shows moderate
impairment of fusion of the late endosome to the vacuole, and the trafficking
defect is conserved from yeast to human.
biological_processes:
- preferred_term: late endosome to lysosome transport
modifier: DECREASED
term:
id: GO:1902774
label: late endosome to lysosome transport
- preferred_term: organelle membrane fusion
modifier: DECREASED
term:
id: GO:0090174
label: organelle membrane fusion
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The homologous yeast mutant had moderate impairment of fusion of the late endosome to the vacuole in Mup1-GFP transport assay."
explanation: Functional assay showing the p.Cys846Gly-homologous mutation impairs late endosome-to-vacuole (lysosome) fusion.
downstream:
- target: Impaired Autophagic Flux
causal_link_type: DIRECT
description: >-
Blocked fusion of autophagosomes with lysosomes stalls autophagic
degradation.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Reduced VPS11 expression leads to an impaired autophagic activity in human cells."
explanation: Directly links reduced VPS11 to the downstream autophagy defect.
- target: Lysosomal Storage
causal_link_type: DIRECT
description: >-
Impaired endosome-lysosome fusion produces intracellular storage material.
evidence:
- reference: PMID:27473128
reference_title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Electron microscopy of a skin biopsy revealed clusters of membranous cytoplasmic bodies in dermal unmyelinated nerve axons, and numbers of vacuoles in eccrine sweat glands, similar to what is seen in a classic lysosomal storage disease (LSD)."
explanation: Ultrastructural storage material in patient tissue evidences the lysosomal consequence of the trafficking block.
- name: Impaired Autophagic Flux
biological_scale: CELLULAR
description: >-
Loss of VPS11-dependent autophagosome-lysosome fusion reduces autophagic flux.
In VPS11-depleted human cells the autophagy substrates p62 and LC3 accumulate,
immature autophagosomes build up and autolysosome formation falls; inducing
autophagy no longer clears the markers, indicating a block at the fusion/flux
step rather than at autophagosome biosynthesis.
biological_processes:
- preferred_term: autophagosome-lysosome fusion
modifier: DECREASED
term:
id: GO:0061909
label: autophagosome-lysosome fusion
- preferred_term: macroautophagy
modifier: DECREASED
term:
id: GO:0016236
label: macroautophagy
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "knockdown of VPS11 caused accumulation of the autophagy markers, p62"
explanation: Accumulation of the autophagy substrates p62 and LC3 on VPS11 knockdown demonstrates the reduced autophagic flux this node encodes.
downstream:
- target: Oligodendroglial Differentiation Failure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Autophagy-lysosome dysfunction is proposed to underlie the myelination
defect, though whether it acts through oligodendrocytes or neurons is not
fully resolved.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway"
explanation: The authors attribute the leukoencephalopathy to the autophagy-lysosome trafficking defect; the link to differentiation is inferential, hence indirect with unknown intermediates.
- target: CNS Neuronal Death
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Loss of autophagic-lysosomal clearance is the proposed route to CNS
neuronal death in the zebrafish vps11 mutant; the intermediates between
the flux block and neuronal apoptosis are not established.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: >-
Links the VPS11 lesion to CNS neuronal death in vivo; the step from the
autophagy-lysosome block to apoptosis is inferential, hence indirect.
- name: Lysosomal Storage
biological_scale: CELLULAR
description: >-
VPS11 deficiency produces morphological and biochemical features of lysosomal
storage: membranous cytoplasmic bodies in unmyelinated dermal axons, vacuolated
eccrine sweat glands, bone-marrow storage macrophages with micro-vacuolated
cytoplasm, and urinary glycosphingolipid changes reminiscent of prosaposin
deficiency. This places VPS11 disease within the broader lysosomal-storage
field and distinguishes it from primary hypomyelinating leukodystrophies with
no storage.
biological_processes:
- preferred_term: lysosomal transport
modifier: DECREASED
term:
id: GO:0007041
label: lysosomal transport
evidence:
- reference: PMID:27473128
reference_title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone marrow cytology showed a high number of storage macrophages with a micro-vacuolated cytoplasm."
explanation: Independent tissue evidence of lysosomal storage in VPS11 deficiency.
- name: Oligodendroglial Differentiation Failure
conforms_to: "cns_myelin_failure#Oligodendrocyte Differentiation Arrest and Death"
biological_scale: CELLULAR
description: >-
Myelin is made by oligodendrocytes only after they undergo morphological
differentiation into large web-like membrane structures. In an oligodendroglial
cell-line model, the C846G mutant VPS11 forms aggregates and downregulates
signalling through p70S6K (a kinase that, via mTOR, promotes oligodendroglial
differentiation and myelination), and the mutant cells fail to adopt the
differentiated web-like phenotype. Blocked oligodendroglial differentiation is
a proximate cause of the hypomyelination.
cell_types:
- preferred_term: oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
biological_processes:
- preferred_term: oligodendrocyte differentiation
modifier: DECREASED
term:
id: GO:0048709
label: oligodendrocyte differentiation
evidence:
- reference: PMID:32316234
reference_title: "PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cells harboring the C846G mutant constructs decrease differentiated phenotypes with web-like structures following differentiation, whereas parental cells exhibit them suitably."
explanation: Shows the disease allele blocks oligodendroglial morphological differentiation in a cell model.
- reference: PMID:32316234
reference_title: "PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the HLD12-associated Cys846-to-Gly (C846G) mutation of VPS11 leads to its aggregate formation with downregulated signaling through 70 kDa S6 protein kinase (p70S6K) in the oligodendroglial cell line FBD-102b as the model"
explanation: Identifies aggregate formation and p70S6K downregulation as the molecular basis of the differentiation block.
downstream:
- target: CNS Hypomyelination
causal_link_type: DIRECT
description: >-
Oligodendrocytes that cannot differentiate cannot elaborate myelin,
producing hypomyelination.
evidence:
- reference: PMID:32316234
reference_title: "PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The primary reason for myelination defects is incomplete or negligible oligodendroglial differentiation"
explanation: States the differentiation-to-hypomyelination link this edge encodes.
- name: CNS Neuronal Death
biological_scale: CELLULAR
description: >-
In the zebrafish vps11(plt) mutant, TUNEL labelling shows significant apoptotic
neuronal death in the midbrain (and milder death in the hindbrain), and this
neuronal death at 3-5 days post-fertilization precedes the reduction in
myelination seen at 7 dpf. This ordering argues that a primary neuronal defect
contributes to the disease, with myelination failure at least partly secondary
- consistent with the microcephaly, seizures and severe cognitive impairment
seen in patients.
biological_processes:
- preferred_term: neuron apoptotic process
modifier: INCREASED
term:
id: GO:0051402
label: neuron apoptotic process
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the neuronal death was observed at 3 and 5 dpf, which preceded the significant reduction in myelination observed at 7 dpf"
explanation: Zebrafish evidence that neuronal death precedes and may drive the myelination defect.
downstream:
- target: CNS Hypomyelination
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Neuronal activity is required for normal myelination, so primary neuronal
dysfunction/death can produce secondary hypomyelination.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: In the zebrafish model the myelination reduction follows neuronal death, supporting a neuron-first mechanism in which hypomyelination is at least partly secondary; the extrapolation to human disease is inferential.
- target: Progressive microcephaly
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Progressive neuronal loss and brain atrophy underlie the acquired postnatal
microcephaly.
- target: Global developmental delay
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Ongoing neuronal loss compounds the hypomyelination-driven failure to
acquire developmental milestones, underlying the progressive
developmental stagnation.
- target: Seizures
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Cortical neuronal dysfunction and injury lower the seizure threshold.
- name: CNS Hypomyelination
conforms_to: "cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath"
biological_scale: TISSUE
description: >-
The convergent endpoint of the oligodendroglial and neuronal arms is a diffuse
deficit of central myelin. Zebrafish vps11 mutants show a significant reduction
in myelin basic protein immunolocalisation, and patient MRI shows diffuse
hypomyelination with a short, posteriorly thinned corpus callosum, reduced
white-matter volume and a VPS11-specific cerebellar signature. This tissue-level
hypomyelination is what produces the progressive neurological phenotype.
biological_processes:
- preferred_term: myelination
modifier: DECREASED
term:
id: GO:0042552
label: myelination
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: Model-organism evidence for reduced CNS myelination downstream of VPS11 loss.
- reference: PMID:42697725
reference_title: "MRI Pattern with a Distinctive Cerebellar Signature in VPS11-Related Hypomyelinating Leukodystrophy: A Comparative Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "demonstrated the following findings in all patients: 1) a distinct cerebellar signature characterized by focal absence of the cerebellar cortex in the middle-anterior hemispheric portions; 2) diffuse hypomyelination"
explanation: Diffuse hypomyelination is a core, all-patient MRI finding in the human cohort.
downstream:
- target: Global developmental delay
causal_link_type: DIRECT
description: >-
Diffuse hypomyelination underlies the failure to acquire developmental
milestones.
- target: Spastic tetraplegia
causal_link_type: DIRECT
description: >-
Corticospinal-tract hypomyelination produces the progressive four-limb
spasticity.
- target: Axial hypotonia
causal_link_type: DIRECT
description: >-
Central hypomyelination underlies the truncal hypotonia that coexists with
appendicular spasticity.
- target: Cerebral visual impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cortical visual impairment reflects hypomyelination and neuronal injury in
the visual pathway and cortex; the precise route is not resolved.
- target: Sensorineural hearing impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Hearing loss is reported in a subset of patients; whether it is central
(auditory-pathway hypomyelination) or peripheral is not established.
phenotypes:
- name: Global developmental delay
category: Neurologic
description: >-
Onset is in the first months of life with developmental stagnation; patients
become severely developmentally delayed, typically non-verbal and
non-ambulatory.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
frequency: VERY_FREQUENT
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a neurological disease, which consists of global developmental stagnation at 3-8 months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly"
explanation: Documents global developmental stagnation with early infantile onset in the founding cohort.
notes: Reported in all 8 patients in PMID:26307567 and all 5 in PMID:27120463.
- name: Progressive microcephaly
category: Neurologic
description: >-
Head growth is normal or near-normal at birth and then falls off, producing
acquired postnatal microcephaly.
phenotype_term:
preferred_term: Progressive microcephaly
term:
id: HP:0000253
label: Progressive microcephaly
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder"
explanation: Documents acquired (progressive, postnatal) microcephaly.
- name: Axial hypotonia
category: Neurologic
description: >-
Truncal (axial) hypotonia is an early feature, typically coexisting with
appendicular spasticity.
phenotype_term:
preferred_term: Truncal hypotonia
term:
id: HP:0008936
label: Axial hypotonia
evidence:
- reference: PMID:27473128
reference_title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The children presented with primary and severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly."
explanation: Reports trunk and neck (axial) hypotonia in the two siblings.
- name: Spastic tetraplegia
category: Neurologic
description: >-
Appendicular spasticity increases over time and evolves to spastic
tetraplegia/quadriplegia.
phenotype_term:
preferred_term: Spastic tetraplegia
term:
id: HP:0002510
label: Spastic tetraplegia
evidence:
- reference: PMID:27473128
reference_title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly"
explanation: Reports spastic tetraplegia as part of the core phenotype.
- name: Seizures
category: Neurologic
description: >-
Seizures are variable and include tonic-clonic, febrile and myoclonic
seizures.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder"
explanation: Documents a variable seizure disorder in the founding cohort.
- name: Cerebral visual impairment
category: Neurologic
description: >-
Cortical (cerebral) visual impairment, and in some patients optic atrophy, are
common; several patients become cortically blind.
phenotype_term:
preferred_term: Cortical visual impairment
term:
id: HP:0100704
label: Cerebral visual impairment
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures."
explanation: Reports cortical blindness (cerebral visual impairment) in all five patients.
- name: Sensorineural hearing impairment
category: Neurologic
description: >-
Hearing loss is reported in a subset of patients.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:27473128
reference_title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly"
explanation: Documents hearing loss in the two-sibling report.
- name: CNS hypomyelination on MRI
category: Neuroimaging
description: >-
Brain MRI shows diffuse CNS hypomyelination with a short, posteriorly thinned
corpus callosum, reduced white-matter volume, and a VPS11-specific cerebellar
signature (focal absence of the middle-anterior cerebellar cortex) that
distinguishes it from other hypomyelinating leukodystrophies.
phenotype_term:
preferred_term: Cerebral hypomyelination
term:
id: HP:0006808
label: Cerebral hypomyelination
frequency: VERY_FREQUENT
evidence:
- reference: PMID:42697725
reference_title: "MRI Pattern with a Distinctive Cerebellar Signature in VPS11-Related Hypomyelinating Leukodystrophy: A Comparative Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the cerebellar signature was observed exclusively in VPS11-HLD (6/6 vs. 0/21, respectively, p < .001)"
explanation: Systematic cohort MRI study showing diffuse hypomyelination plus a VPS11-specific cerebellar signature.
notes: Diffuse hypomyelination present in all 6 patients in PMID:42697725.
reports_on:
- target: CNS Hypomyelination
relationship: READOUT_OF
endpoint_context: DIAGNOSTIC
interpretation: >-
Brain MRI reads out the tissue-level hypomyelination as diffuse white-matter
signal abnormality and the VPS11-specific cerebellar signature.
- name: Thin corpus callosum
category: Neuroimaging
description: >-
The corpus callosum is short and thin, most marked posteriorly, on brain MRI.
phenotype_term:
preferred_term: Thin corpus callosum
term:
id: HP:0033725
label: Thin corpus callosum
evidence:
- reference: PMID:42697725
reference_title: "MRI Pattern with a Distinctive Cerebellar Signature in VPS11-Related Hypomyelinating Leukodystrophy: A Comparative Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "short corpus callosum with marked thinning of the posterior portion"
explanation: Reports the short, posteriorly thinned corpus callosum in the MRI cohort.
reports_on:
- target: CNS Hypomyelination
relationship: READOUT_OF
endpoint_context: DIAGNOSTIC
interpretation: >-
The short, posteriorly thinned corpus callosum on MRI is a structural readout
of the white-matter hypomyelination and volume loss.
diagnosis:
- name: Molecular genetic testing for biallelic VPS11 variants
description: >-
Diagnosis is confirmed by identifying biallelic pathogenic VPS11 variants,
usually by exome or gene-panel sequencing. In individuals of Ashkenazi Jewish
ancestry the recurrent founder allele c.2536T>G (p.Cys846Gly) is the expected
variant and is a target of AJ carrier screening.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause"
explanation: Establishes exome sequencing detection of the biallelic VPS11 founder variant as the diagnostic route.
- name: Brain MRI hypomyelination pattern
description: >-
Brain MRI shows diffuse hypomyelination with a short, posteriorly thinned
corpus callosum and a VPS11-specific cerebellar signature (focal absence of the
middle-anterior cerebellar cortex) that helps distinguish HLD12 from other
hypomyelinating leukodystrophies and can prompt targeted VPS11 testing.
evidence:
- reference: PMID:42697725
reference_title: "MRI Pattern with a Distinctive Cerebellar Signature in VPS11-Related Hypomyelinating Leukodystrophy: A Comparative Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "identify reproducible imaging features that may aid in distinguishing it from other hypomyelinating leukodystrophies"
explanation: Supports the MRI pattern (including the cerebellar signature) as a diagnostic discriminator for VPS11-HLD.
treatments:
- name: Multidisciplinary supportive care
description: >-
There is no disease-modifying therapy. Management is supportive and
multidisciplinary, addressing spasticity, seizures, feeding and aspiration
risk, visual and hearing impairment, and developmental needs.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
- name: Antiseizure pharmacotherapy
description: >-
Seizures (tonic-clonic, febrile, myoclonic) are managed with antiseizure
medication as part of supportive care.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Genetic counseling and carrier screening
description: >-
Because VPS11 p.Cys846Gly is a common Ashkenazi Jewish founder allele
(carrier frequency ~1:250), the authors recommend adding it to the AJ carrier
screening panel; genetic counseling is offered to affected families.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:26307567
reference_title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The VPS11 p.Cys846Gly mutation should be added to the AJ carrier screening panel."
explanation: Supports carrier screening / genetic counseling as a management recommendation.
animal_models:
- name: Zebrafish vps11 mutant
species: Zebrafish
genotype: vps11(plt), truncated RING-H2 domain
publication: PMID:27120463
description: >-
The zebrafish vps11(plt) mutant carries a truncated RING-H2 domain and shows
extensive CNS neuronal death in the hindbrain and midbrain followed by reduced
CNS myelination, supplying the in vivo link from the VPS11 lesion to neuronal
death and hypomyelination.
genes:
- preferred_term: VPS11
term:
id: hgnc:14583
label: VPS11
modeled_mechanisms:
- target: CNS Neuronal Death
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Extensive neuronal death in the hindbrain and midbrain of the mutant larva.
limitations: >-
The zebrafish allele is a truncated RING-H2 domain, not the human founder
missense p.Cys846Gly, so it models a different and more severe VPS11 lesion;
larval neuroanatomy also differs from the human CNS.
readouts:
- name: CNS neuronal death
target: CNS Neuronal Death
direction: INCREASED
interpretation: Extensive hindbrain/midbrain neuronal death in the mutant larva.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: The measured neuronal-death readout in the mutant larva.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: Supports the mutant larva as informative for the CNS neuronal-death node.
- target: CNS Hypomyelination
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Reduced CNS myelin basic protein immunolocalisation in the mutant larva.
limitations: >-
The truncated RING-H2 allele is not the human founder missense; the larval
myelination reduction is a partial correlate of the diffuse human
hypomyelination.
readouts:
- name: CNS myelination
target: CNS Hypomyelination
direction: DECREASED
interpretation: Significant reduction in CNS myelination in the mutant larva.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: The measured myelination readout in the mutant larva.
evidence:
- reference: PMID:27120463
reference_title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain"
explanation: Supports the mutant larva as informative for the hypomyelination node.
references:
- reference: PMID:26307567
title: "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients."
- reference: PMID:27120463
title: "A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects."
- reference: PMID:27473128
title: "The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement."
- reference: PMID:32316234
title: "PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation."
- reference: PMID:42697725
title: "MRI Pattern with a Distinctive Cerebellar Signature in VPS11-Related Hypomyelinating Leukodystrophy: A Comparative Cohort Study."
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Named-entity-confusion guardrail. This entry is anchored strictly on MONDO:0014732 / OMIM:616683 / VPS11 (hgnc:14583). "Hypomyelinating leukodystrophy N" is a numbered series whose members share only the numeral, so the anchor was fixed before curation with `uv run runoak -i sqlite:obo:mondo info MONDO:0014732 -O obo`, which returns `intersection_of: RO:0004003 HGNC:14583 ! VPS11` and `xref: OMIM:616683`, independently confirming both gene and OMIM number. VPS11 (hgnc:14583) was confirmed with `uv run runoak -i sqlite:obo:hgnc info hgnc:14583`. Gene-family confusables. VPS11 is one of six Class C Vps subunits; VPS16, VPS18, VPS33A and VPS33B all cause distinct disorders, and none of their literature is cited here as evidence for VPS11 disease. VPS11 also has a large, disease-unrelated cell-biology and cancer literature (autophagy machinery, ferroptosis), which is likewise excluded. Emerging movement-disorder spectrum (not curated here). A later-onset complex dystonic / spastic-paraplegia presentation from biallelic VPS11 missense variants with little or no white-matter change has been reported under the provisional DYT32 label (Storck et al., PMID:41551069, plus a prior single case). That is a distinct clinical entity; this entry stays anchored on MONDO:0014732 (the hypomyelinating leukodystrophy) and does not curate the movement-disorder presentation, whose primary sources are not yet fetched into this entry's evidence. No GeneReviews chapter exists for VPS11 or HLD12. Searched on 2026-09-05 with `VPS11 GeneReviews[All Fields]` and `hypomyelinating leukodystrophy GeneReviews[TI]`; both returned zero records. The phenotype baseline is therefore taken from the primary cohort literature: PMID:26307567 (8 patients, 4 AJ families; the founding report), PMID:27120463 (5 patients, 3 AJ families; founder-allele + autophagy mechanism), PMID:27473128 (2 siblings; the lysosomal-storage second report) and PMID:42697725 (6 patients; the systematic MRI cohort). Frequency discipline. FrequencyEnum bands are asserted only where a cohort gives an explicit numerator or an unambiguous "in all patients" statement, and the source figure is recorded in each phenotype's notes. Where a feature is reported in "some" or "several" patients, frequency is omitted rather than guessed. The whole published denominator is only a few dozen patients drawn largely from one founder population, so no feature is banded OBLIGATE. No `datasets:` block is curated. HLD12 has a few dozen published patients and no omics resource of its own, while a gene-keyed accession search on VPS11 returns cancer and generic-autophagy datasets that would resolve perfectly and be about the wrong biology - the Named Entity Confusion the dataset-curation SOP warns about - so an empty block is the honest result. A Claude Code literature-sweep deep-research report is committed at research/Hypomyelinating_Leukodystrophy_12-deep-research-claude-2026-09-05.md. Its citations were treated as leads and each snippet used here was verified against the primary source fetched into references_cache/.
Create: Hypomyelinating Leukodystrophy 12 (VPS11) · 2026-09-05T16:08:33Z · View source
De novo curation of HLD12 (MONDO:0014732, VPS11/hgnc:14583, OMIM:616683) as a DISEASE entry. Deep research via claude_code literature sweep (research/Hypomyelinating_Leukodystrophy_12-deep-research-claude-2026-09-05.md; 12/12 report citations resolved, 0 not found). All KB evidence snippets verified against primary sources fetched into references_cache (PMID:26307567, 27120463, 27473128, 32316234, 42697725). Pathograph: biallelic VPS11 LoF -> impaired HOPS/CORVET endolysosomal tethering/fusion -> impaired autophagic flux + lysosomal storage; oligodendroglial differentiation failure and CNS neuronal death converge on CNS hypomyelination. Founder allele p.Cys846Gly recorded. GeneReviews searched, none exists. Validated: just validate, validate-terms, validate-disorders (30/30 snippets), check-entity-refs/causal-targets/duplicate-keys/enum-values/qualifier-terms/snippet-length/title-snippets/snippet-grading. Named-entity-confusion preflight: VPS11 dominant, OMIM 616683 matches.
Overview. Hypomyelinating leukodystrophy 12 (HLD12), also called "VPS11-related autosomal recessive hypomyelinating leukodystrophy" or "genetic leukoencephalopathy (gLE)," is an autosomal recessive, infantile-onset neurodegenerative disorder of central white matter caused by biallelic loss-of-function variants in VPS11, a core subunit of the HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) endolysosomal tethering complexes. The disorder was first delineated by Edvardson et al. (2015) in Ashkenazi Jewish families and independently confirmed by Zhang et al. (2016) [PMID:26307567 (Edvardson et al., Am J Hum Genet — original description; PMC version PMC4847778 is the Ann Clin Transl Neurol companion/independent report); PMID:27120463 (Zhang et al., PLoS Genetics 12:e1005848)].
Key identifiers: - OMIM: #616683 — LEUKODYSTROPHY, HYPOMYELINATING, 12; HLD12 (gene-disease entry VPS11: 608549) — omim.org/entry/616683 - MONDO: MONDO:0014732 (as provided) - Orphanet: ORPHA:466934 — "VPS11-related autosomal recessive hypomyelinating leukodystrophy" — orpha.net/en/disease/detail/466934 - MedGen: C4225247 — ncbi.nlm.nih.gov/medgen/905068 - GARD: "Hypomyelinating leukodystrophy 12" — rarediseases.info.nih.gov/diseases/17837 - Gene: VPS11 (HGNC:14583), chromosome 11q23 - Disease Ontology:* DOID:0060796
Synonyms: genetic leukoencephalopathy (gLE); VPS11-related leukoencephalopathy; hypomyelination and developmental delay associated with VPS11 mutation (as in the original title, "Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients").
Data provenance. Nearly all clinical knowledge derives from aggregated case-series reports built from individual patients identified through whole-exome sequencing in three research cohorts (Ashkenazi Jewish founder cohort, n=5 across 3 families; one non-Ashkenazi consanguineous family, n=2 siblings; one adult dystonia case, n=1), rather than large-scale disease registries or EHR-derived data — consistent with an ultra-rare Mendelian disorder.
Primary cause: Biallelic (homozygous or compound heterozygous) loss-of-function variants in VPS11, encoding a core subunit shared by the HOPS and CORVET vesicle-tethering complexes essential for late endosome–lysosome and autophagosome–lysosome fusion.
No environmental, infectious, or lifestyle risk factors have been reported; this is a purely monogenic disorder. In the 2025 dystonia case, an intercurrent infection triggered acute neurological decompensation/coma, suggesting catabolic/febrile stress can precipitate acute exacerbation in VPS11-deficient individuals with residual function — an important gene-environment interaction candidate but not yet mechanistically dissected.
None reported.
Aside from the infection-triggered exacerbation noted above, no systematic gene-environment interaction data exist. The disorder's severity gradient (infantile null-like c.2536T>G allele vs. milder compound-heterozygous missense alleles in the adult dystonia case) suggests a genotype-severity correlation rather than an environmental modifier, consistent with residual HOPS complex function scaling with clinical severity.
Onset is in infancy, typically 3–7 months of age, with developmental delay and hypotonia as presenting signs (Edvardson et al.; Zhang et al.). Course is progressive in the classic (c.2536T>G homozygous) form, with children becoming non-ambulatory and non-verbal.
| Phenotype | Frequency/notes | Suggested HP term |
|---|---|---|
| Global developmental delay | All patients (infantile onset) | HP:0001263 |
| Severe intellectual disability | Nearly universal by follow-up | HP:0010864 |
| Hypotonia | Presenting feature | HP:0001252 |
| Spasticity | Progressive | HP:0001257 |
| Non-ambulatory status | By childhood/adolescence in classic form | HP:0002540 (loss of ability to walk) |
| Absent speech / non-verbal | By follow-up | HP:0001344 or HP:0002465 (dysarthria)/HP:0001621 (loss of speech) |
| Acquired microcephaly | <2nd percentile | HP:0000252 |
| Cortical blindness / cortical visual impairment | All patients | HP:0100704 |
| Optic atrophy | Reported in older patients (Family III, 19 y) | HP:0000648 |
| Seizures (tonic-clonic, febrile) | Multiple patients | HP:0001250 / HP:0002373 (febrile seizures) |
| Sensorineural hearing loss | Reported | HP:0000407 |
| Autonomic dysfunction (neurogenic bladder, constipation, temperature instability) | Reported | HP:0000112 (nephrogenic diabetes insipidus n/a) — use HP:0000980-adjacent autonomic terms, e.g., HP:0012204 (neurogenic bladder) |
| Oromotor dysfunction / G-tube feeding due to aspiration risk | Reported (Patient A) | HP:0002015 (dysphagia) |
| Joint contractures | Reported | HP:0001371 |
| Lysosomal storage (in the p.Leu387_Gly395del family) | "massive lysosomal involvement" on tissue biopsy | relates to HP:0011016 (abnormal lysosome) — not a standard HP term; describe in notes |
The 2025 compound-heterozygous case (Storck et al.) demonstrates that milder/hypomorphic biallelic VPS11 variants produce a multiphasic disorder beginning with exercise-triggered paroxysmal gait disturbance at age 12, remission, then at 17 the emergence of cerebellar ataxia, myoclonus, pyramidal signs, and cervical dystonia, with an infection-triggered coma and subsequent partial recovery to "cerebellar ataxia and spastic paraplegia" at age 21. This overlaps with Dystonia 32 (DYT32), a provisional/limited-evidence OMIM gene-disease entry for VPS11-associated adult-onset generalized dystonia (a single early case had been reported before this confirmatory second case).
Causal gene: VPS11 (Vacuolar Protein Sorting 11 Homolog), HGNC:14583, OMIM *608549, chromosome 11q23, encoding a core subunit of the "Vps-C" (class C Vps) complex shared by HOPS and CORVET.
Pathogenic variants: 1. c.2536T>G, p.(Cys846Gly) — homozygous missense, exon 15, RING-H2 zinc-finger domain; Ashkenazi Jewish founder allele; classified pathogenic (ClinVar VCV000218366). 2. p.Leu387_Gly395del — homozygous in-frame deletion, non-Ashkenazi consanguineous family (PMID:27473128). 3. c.2171T>G, p.(Leu724Arg) and c.2186G>T, p.(Arg729Leu) — compound heterozygous missense variants, both absent from gnomAD, classified likely pathogenic (ACMG class IV: PS3+PM2+PP3) in the 2025 dystonia report. 4. A separate single case (per PanelApp/search summary) reported c.136C>T (p.Pro46Ser) biallelic in adult-onset generalized dystonia — the "first" DYT32 case preceding the 2025 confirmatory report.
Population frequency (gnomAD/ExAC): c.2536T>G — ExAC frequency ≈1.6×10⁻⁴ in non-Finnish Europeans (essentially the Ashkenazi Jewish subpopulation), zero homozygotes in gnomAD/ExAC controls; the two 2025 dystonia variants are absent from gnomAD entirely, consistent with private/ultra-rare compound heterozygous alleles.
Variant type/class: All reported pathogenic alleles are missense or small in-frame deletion, not truncating — consistent with the essential, dosage-sensitive nature of VPS11 (complete null alleles may be embryonic lethal, as is typical for core HOPS/CORVET subunits).
Functional consequence — loss of function via protein instability, not misfolding: - The p.C846G mutant protein shows markedly reduced steady-state expression despite equal transfection, with a five-fold shorter half-life than wild-type. - Circular dichroism assays showed the mutation does not grossly disrupt protein folding — instability arises by a different mechanism. - The mutant shows a significant increase in ubiquitination compared to wild-type, indicating accelerated proteasomal/ubiquitin-mediated degradation as the proximate mechanism of loss of function. - The mutation significantly decreases the interaction between VPS11 and endogenous VPS18, compromising assembly of the Vps-C tethering core shared by HOPS and CORVET.
Somatic vs. germline: Exclusively germline; no somatic or oncologic association.
Chromosomal abnormalities: None reported; this is a single-gene, sequence-level disorder, not a copy-number/structural disease.
Epigenetics: No disease-specific DNA methylation or histone-modification data have been reported for HLD12.
Modifier genes: None established; phenotypic variation across alleles (null-like p.C846G vs. hypomorphic compound-heterozygous missense) appears to reflect allelic severity (residual HOPS/CORVET function) rather than a distinct modifier locus.
Gene-disease validity: VPS11 is an established/asserted cause of both HLD12 (OMIM #616683) and, more provisionally, Dystonia 32 (DYT32) — described in the literature as having "limited evidence" for the dystonia association until the 2025 confirmatory second case (Storck et al.), which the authors argue supports broadening the VPS11 clinical spectrum to include both white-matter (hypomyelinating) and pure/complex dystonic presentations.
Loss-of-function via destabilization and accelerated ubiquitin-mediated turnover, not classical misfolding/aggregation; secondary loss of protein-protein interaction (VPS11–VPS18) impairs macromolecular complex assembly. Suggested UniProt: VPS11_HUMAN (Q9H270); relevant domain: RING-H2 zinc finger (InterPro/Pfam RING domain).
Neurodegeneration via apoptosis (not oxidative stress or ischemia per se in the reported data) combined with a primary defect in oligodendrocyte myelin elaboration — VPS11 is highly expressed in mouse oligodendrocytes and co-localizes with myelin-associated glycoprotein (MAG) in the inner myelin tongue, forming a "bead-like" periodic structure alternating with myelin basic protein along myelin internodes, and is notably absent from axons (Skoff et al. 2021, ASN Neuro, PMID:33874780). This supports a cell-autonomous oligodendrocyte trafficking defect as contributing to hypomyelination, in addition to upstream neuronal loss.
Impaired lysosomal degradative capacity (functional analog of a lysosomal storage disorder), reduced VPS11 protein steady-state level, disrupted VPS11–VPS18 binding.
No transcriptomic, proteomic, metabolomic, or single-cell/spatial datasets specific to VPS11-HLD12 patient tissue have been published to date (data gap). The zebrafish studies used immunolabeling (Caspase-3, Mbp) and behavioral assays (optokinetic response, acoustic/tap startle, light/dark locomotion) rather than omics profiling.
Suggested GO/CL terms for pathophysiology curation: - GO:0007032 (endosome organization), GO:0000045 (autophagosome assembly), GO:0061912 (selective autophagosome maturation), GO:0006914 (autophagy), GO:0016236 (macroautophagy) - CL:0000128 (oligodendrocyte), CL:0000540 (neuron) - GO Cellular Component: GO:0005764 (lysosome), GO:0031410 (cytoplasmic vesicle), GO:0005768 (endosome)
Organ level: Primary — central nervous system (cerebral and cerebellar white matter, corpus callosum); secondary — eyes (optic nerve/cortical visual pathways), ears (sensorineural hearing loss), autonomic nervous system (bladder, GI motility, thermoregulation), musculoskeletal system (joint contractures secondary to spasticity).
Tissue/cell level: Oligodendrocytes (myelin-forming glia — primary site of VPS11 expression and likely primary cellular defect per Skoff et al.); CNS neurons, particularly hindbrain/midbrain populations in the zebrafish model (site of apoptosis); axons are notably devoid of VPS11 immunoreactivity, implicating oligodendrocyte-intrinsic and neuron-intrinsic (not axonal) mechanisms.
Cell Ontology: CL:0000128 (oligodendrocyte); CL:0000540 (neuron); CL:0000617 (GABAergic neuron, if relevant to dystonia circuitry — not specifically demonstrated).
Subcellular level: Late endosomes, lysosomes, autophagosomes (GO:0005764, GO:0000421 autophagosome membrane, GO:0031410 cytoplasmic vesicle); the myelin "inner tongue" cytoplasmic compartment specifically (Skoff et al.).
Anatomical localization (UBERON): UBERON:0002336 (cerebral white matter); UBERON:0002336-adjacent corpus callosum term UBERON:0002336 / more specifically UBERON:0002336 is white matter generally — corpus callosum is UBERON:0002336... (use UBERON:0002336 for white matter, UBERON:0002336 not precise for corpus callosum; corpus callosum = UBERON:0002336 is incorrect, correct term is UBERON:0002336 (white matter) and UBERON:0001880 (corpus callosum)); periventricular white matter; optic nerve (UBERON:0001876); cerebellum (UBERON:0002037) — cerebellar atrophy reported in the canine model and in the adult human dystonia case.
Lateralization: Bilateral, symmetric involvement throughout (consistent across all reported MRI descriptions).
Epidemiology: Ultra-rare. No formal incidence/prevalence estimate has been published; total reported cases in the literature to date are approximately 8–9 (5 in the original Ashkenazi cohort per Edvardson, overlapping with Zhang's 5 patients from 3 families; 2 siblings in the non-Ashkenazi consanguineous family; 1–2 adult dystonia cases). Given the 1:250 Ashkenazi Jewish carrier frequency, the expected homozygote birth prevalence in that specific population would be roughly 1 in 250,000, though under-ascertainment is likely given the disorder's recent (2015–2016) delineation.
Inheritance pattern: Autosomal recessive (all reported cases — homozygous or compound heterozygous).
Penetrance: Appears complete for the classic homozygous p.C846G genotype (all identified homozygotes to date are symptomatic); penetrance/expressivity for hypomorphic compound-heterozygous alleles is less certain given only single-family reports.
Expressivity: Variable — ranging from severe infantile panencephalopathy (null-like allele) to a later-onset complex dystonic-ataxic syndrome (partial-function compound heterozygous alleles), indicating an allelic severity spectrum rather than uniform expressivity for a single genotype.
Genetic anticipation: Not reported/not applicable (not a repeat-expansion disorder).
Germline mosaicism: Not specifically reported.
Founder effects: Well-established founder mutation (c.2536T>G) in the Ashkenazi Jewish population, traced to a shared ~299 kb haplotype block across three unrelated families.
Consanguinity: Documented in both the non-Ashkenazi p.Leu387_Gly395del family and the 2025 compound-heterozygous dystonia case ("female from a consanguineous union").
Carrier frequency: 1:250 for c.2536T>G in Ashkenazi Jews (Zhang et al., 2016).
Population demographics: Reported cases are of Ashkenazi Jewish descent (majority) and non-Jewish/other ancestries (minority, consanguineous families); no data on broader ethnic/geographic distribution beyond these reports. No formal sex-ratio data (autosomal recessive inheritance predicts equal male:female distribution; reported cases include both sexes, e.g., "Patient A" described as female).
Laboratory/biomarker tests: No specific blood/urine biomarker exists; diagnosis relies on imaging plus molecular genetic testing. Skin fibroblast studies (autophagy flux assays, electron microscopy for lysosomal/vacuolar storage) have been used as research-level functional confirmation in individual cases (e.g., 2025 dystonia case fibroblast EM) but are not standardized clinical diagnostics.
Imaging (primary diagnostic modality): Brain MRI showing: - Diminished periventricular white-matter volume - Thin/hypoplastic corpus callosum - Delayed myelination with T2/FLAIR hyperintense white-matter signal abnormalities - Prominent, scalloped lateral ventricles - Serial imaging (e.g., 9 months to 5 years) shows a pattern of delayed but not absent myelination, distinguishing this from a primary demyelinating process — "indicating delayed myelination syndrome rather than active demyelination."
Genetic testing: Whole-exome sequencing (WES) is the modality by which every reported case has been diagnosed; this reflects the current standard approach for undiagnosed leukoencephalopathies given genetic heterogeneity. Targeted VPS11 single-gene sequencing or hypomyelinating-leukodystrophy gene panels (many commercial panels include VPS11; e.g., the CMGG Leukodystrophy and Leukoencephalopathy gene panel) are reasonable once the phenotype is recognized, particularly in Ashkenazi Jewish patients where targeted testing for c.2536T>G could serve as a rapid first-tier test. Chromosomal microarray and karyotyping are not primarily diagnostic (this is a sequence-level, not copy-number, disorder) but are typically performed to exclude alternative etiologies in the standard leukodystrophy diagnostic workup.
Differential diagnosis: Other hypomyelinating leukodystrophies (Pelizaeus-Merzbacher disease/PLP1, HLD1–HLD20 series including HLD10/PYCR2), other HOPS-complex disorders (VPS16-, VPS41-, VPS33A-, VPS18-related HOPSANDs, some with mucopolysaccharidosis-like presentations), lysosomal storage disorders more broadly given the lysosomal-storage histopathology, and other causes of infantile-onset dystonia/ataxia for the milder allelic spectrum.
Screening: Given the Ashkenazi Jewish founder effect and 1:250 carrier frequency, VPS11 c.2536T>G is a plausible candidate for inclusion in Ashkenazi Jewish genetic carrier screening panels, analogous to other AJ founder-mutation disorders, though the search results did not confirm current formal inclusion in ACMG/ACOG-endorsed panels.
No formal survival statistics, life-expectancy data, or mortality registries exist for this ultra-rare disorder (data gap). Based on published natural history: - The classic (homozygous p.C846G) form is severely disabling: by school age/adolescence, patients are non-ambulatory, non-verbal, cortically blind, and dependent on gastrostomy feeding due to aspiration risk — the oldest reported patient (Family III, homozygous founder mutation) was followed to 19 years of age with profound intellectual disability, indicating survival into young adulthood is possible with supportive care, though quality of life is severely impaired. - Complications: Aspiration (from oromotor dysfunction), seizures, joint contractures, autonomic dysfunction (neurogenic bladder, constipation, temperature instability). - The milder compound-heterozygous dystonic phenotype shows a relapsing course with a severe infection-triggered coma, followed by partial recovery to a residual but non-fatal deficit (cerebellar ataxia + spastic paraplegia) at last follow-up (age 21) — suggesting this end of the spectrum carries a better, though still substantially morbid, prognosis. - Prognostic factors: Genotype severity (null-like vs. hypomorphic alleles) is the clearest prognostic determinant identified to date; no biomarker-based prognostic model exists.
No disease-modifying or FDA-approved therapy exists. Management is entirely supportive/symptomatic: - Gastrostomy tube feeding for aspiration risk (NCIT:C122040 — Gastrostomy, or generically NCIT:C15747 Supportive Care) - Anticonvulsant pharmacotherapy for seizures (NCIT:C15986 Pharmacotherapy) - Physical/occupational therapy for hypotonia, spasticity, and contractures (NCIT:C15302 Physical Therapy) - Management of autonomic complications (neurogenic bladder, constipation) - Genetic counseling for at-risk families (NCIT:C15240 Genetic Counseling), particularly relevant given the well-defined Ashkenazi Jewish founder allele and demonstrated consanguinity in other reported families.
Experimental/proposed therapeutic directions (not yet in clinical trials): - The discoverers explicitly propose E3-ubiquitin-ligase inhibition as a candidate strategy to stabilize the mutant VPS11 protein and rescue its accelerated degradation ("E3-ligases represent potential therapeutic targets to modulate the ubiquitin-proteasome system activity...to regulate proteome homeostasis" — Zhang et al., PMID:27120463). - The 2022 zebrafish behavioral model (Banerjee et al., Sci Rep, PMID:35241734) was explicitly developed as a preclinical drug-screening platform, stating the model would allow "testing potential pharmacological interventions for gLE." - No gene therapy, cell therapy, RNA-based therapy, or targeted small-molecule trials specific to VPS11-HLD12 were identified in the available literature or ClinicalTrials.gov/WHO ICTRP searches performed for this report.
Pharmacogenomics: None reported (not applicable — no approved pharmacotherapy targets the underlying defect).
Given the well-characterized Ashkenazi Jewish founder mutation and demonstrated consanguinity risk in non-Ashkenazi families: - Secondary prevention: Carrier screening (targeted c.2536T>G testing) in the Ashkenazi Jewish population is the most actionable prevention strategy, analogous to existing AJ founder-disease carrier panels, though formal incorporation into standard AJ carrier screening programs was not confirmed in the sources reviewed. - Genetic counseling: Recommended for identified carrier couples and consanguineous families; prenatal/preimplantation genetic testing is technically feasible once a familial variant is known (standard practice for known monogenic recessive disorders), though no VPS11-specific prenatal diagnosis literature was identified. - Primary/behavioral/public health prevention: Not applicable (purely genetic etiology with no modifiable environmental primary cause identified, aside from the general recommendation to avoid/promptly treat febrile infections in known carriers of hypomorphic alleles, per the 2025 case's infection-triggered decompensation). - Immunization/prophylaxis: Not specifically studied, though prompt treatment of febrile illness could plausibly reduce the risk of infection-triggered decompensation described in the milder allelic phenotype (inference, not directly demonstrated).
Naturally occurring veterinary disease — Rottweiler dogs (neuroaxonal dystrophy, NAD): A homozygous missense mutation in canine VPS11 (g.14777774T>C; p.His835Arg, in the same Zinc-RING finger domain affected in human disease) causes an autosomal recessive neuroaxonal dystrophy in Rottweilers (Ekenstedt et al., PMID:29945969, PMC6071611): - Clinical presentation: Young-adult onset, mild progressive postural deficits, ataxia, hypermetria, intention tremor, and nystagmus. - Pathology: Mild cerebellar atrophy, numerous axonal spheroids, and demyelination in the vestibular nucleus, geniculate nuclei, trigeminal sensory nucleus, gracile/cuneate nuclei, and spinal dorsal horn. - Population genetics: Among 288 genotyped Rottweilers, 7 were homozygous and 13 heterozygous; mutant allele frequency ≈2.3%. - Cross-species conservation: Human and canine VPS11 share 98.2% amino-acid identity. - Comparative relevance: The authors explicitly recommend VPS11 be considered a candidate gene for unexplained human neuroaxonal dystrophy, and this milder, later-onset canine phenotype is informative for understanding the human allelic-severity spectrum (compare to the 2025 human adult dystonic/ataxic case). - Taxonomy: NCBI Taxon 9615 (Canis lupus familiaris); breed term for Rottweiler in VBO would apply if curating breed-specific susceptibility.
No other naturally occurring animal disease (wildlife, other companion species) has been reported for VPS11.
Two independent zebrafish vps11 loss-of-function lines have been characterized: 1. vps11(plt)wsu1 — a previously characterized allele with a premature stop codon truncating the RING-H2 domain (used in Zhang et al., PMID:27120463). 2. vps11(−/−)wsu3 — a newly TALEN-generated null allele (used in Banerjee et al., 2022, PMID:35241734).
Key findings: - Neuronal apoptosis: Mild hindbrain and significant midbrain neuronal death (active Caspase-3–positive), detectable at 3–5 dpf, preceding myelination defects. - Myelination: Progressive reduction in myelin basic protein (Mbp) expression — moderate at 5 dpf, reaching 38% of control levels by 7 dpf (p<0.05). - Vision: Both mutant lines show progressive loss of optokinetic response, with near-zero OKR gain and severely impaired visual acuity by 5–7 dpf, despite retained basic light/dark discrimination. - Sensorimotor function: Progressive decline in acoustic/tap-startle locomotor response by 7 dpf, with an unexpected faster habituation rate in mutants versus siblings — a novel behavioral phenotype suggesting altered sensory processing beyond simple motor deficit. - Translational value: Explicitly proposed by its authors as a platform for pharmacological intervention screening for VPS11-related genetic leukoencephalopathy. - Resources: ZFIN Gene ZDB-GENE-050731-5; allele documented at ZFIN ZDB-FIG-160519-7.
No VPS11 knockout/knock-in mouse model of the human disease has been reported to date (a full VPS11 null is expected to be embryonic lethal given its essential role in the Vps-C core, consistent with the absence of viable human null homozygotes). Mouse tissue (oligodendrocytes) has, however, been used descriptively to characterize normal Vps11 protein localization (Skoff et al., 2021, PMID:33874780), showing strong oligodendrocyte expression co-localized with MAG in the myelin inner tongue and absence from axons — informative for mechanism but not a disease model per se.
No model to date fully recapitulates the human infantile hypomyelinating phenotype with concurrent white-matter MRI correlate; the zebrafish model captures neuronal death, hypomyelination, and behavioral/visual deficits but zebrafish CNS myelination architecture and developmental timeline differ substantially from human, and no rescue/therapeutic efficacy data in vivo have yet been published.
Note on evidence gaps: No mortality/survival statistics, formal prevalence estimates, transcriptomic/proteomic/single-cell datasets, clinical trial records, or mouse genetic models specific to VPS11-HLD12 were located; these should be recorded as absent rather than inferred if this report is used to populate a knowledge-base entry.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 12 |
| Resolved | 12 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 12 |
| On topic | 12 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
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| Terms checked | 50 |
| Resolved | 46 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 2 |
| Terms whose name was checked | 29 |
| Terms named correctly | 14 |
| Terms named as a different term | 10 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0001263 (1 mention) - the report calls it "All patients (infantile onset)"; HP calls it Global developmental delayHP:0010864 (1 mention) - the report calls it "Nearly universal by follow-up"; HP calls it Severe intellectual disabilityHP:0001252 (1 mention) - the report calls it "Presenting feature"; HP calls it HypotoniaHP:0001257 (1 mention) - the report calls it "Progressive"; HP calls it SpasticityHP:0000252 (1 mention) - the report calls it "<2nd percentile"; HP calls it MicrocephalyHP:0011016 (1 mention) - the report calls it "abnormal lysosome"; HP calls it obsolete Abnormality of urine glucose concentrationCL:0000617 (1 mention) - the report calls it "GABAergic neuron, if relevant to dystonia circuitry — not specifically demonstrated"; CL calls it GABAergic neuronUBERON:0002336 (10 mentions) - the report calls it "cerebral white matter", "white matter"; UBERON calls it corpus callosumUBERON:0001880 (2 mentions) - the report calls it "corpus callosum"; UBERON calls it bed nucleus of stria terminalisUBERON:0001876 (2 mentions) - the report calls it "optic nerve"; UBERON calls it amygdalaThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0011016 (obsolete Abnormality of urine glucose concentration) (1 mention) - replaced by HP:0003076GO:0061912 (obsolete selective autophagy) (1 mention)The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0002540 (1 mention) - the report calls it "loss of ability to walk"; HP calls it Inability to walkHP:0100704 (1 mention) - the report calls it "All patients"; HP calls it Cerebral visual impairmentGO:0061912 (1 mention) - the report calls it "selective autophagosome maturation"; GO calls it obsolete selective autophagyGO:0016236 (2 mentions) - the report calls it "macroautophagy", "autophagy/macroautophagy"; GO calls it macroautophagyNCIT:C15986 (2 mentions) - the report calls it "Pharmacotherapy — anticonvulsants"; NCIT calls it PharmacotherapyThe report gives these identifiers more than one name of its own:
GO:0016236 - called "macroautophagy", "autophagy/macroautophagy"UBERON:0002336 - called "cerebral white matter", "white matter"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.