Hypomyelinating Leukodystrophy 15

Mendelian MONDO:0054782 Pathograph 12 Show in embeddings browser leukodystrophy

Hypomyelinating leukodystrophy 15 (HLD15) is an autosomal recessive hypomyelinating leukodystrophy caused by biallelic variants in EPRS1, which encodes the bifunctional cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase and is a subunit of the multi-tRNA synthetase complex (MSC). Affected children typically have severe global developmental delay with hypomyelination on MRI and a thin corpus callosum, commonly with optic atrophy, dysphagia, dystonia, ataxia and spasticity. The spectrum is wider than that classical presentation: a compound heterozygote reported in 2026 had only mild intellectual disability and did not come to neurological attention until her thirties, so severity ranges from infantile-onset severe disease to an adult-onset mild phenotype. HLD15 is one of several leukodystrophies caused by cytoplasmic aminoacyl-tRNA synthetase genes — RARS1 causes HLD9 and DARS1 causes HBSL — and the field's working hypothesis is that they converge on reduced translation capacity in the developing brain. What makes HLD15 mechanistically interesting is that the *route* to reduced EPRS1 protein differs between variants: one operates through impaired m6A-dependent mRNA export and translation, another through polymeric aggregation of the mutant protein. Both end in insufficient myelination, but they are not the same lesion, and one of them has been pharmacologically rescued in patient cells.

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1
Inheritance
6
Pathophys.
18
Phenotypes
4
Hypotheses
3
Gaps
12
Pathograph
1
Genes
5
Variants
1
Medical Actions
3
Differentials
2
Models
4
References
👪

Inheritance

1
Autosomal Recessive HP:0000007
Biallelic EPRS1 variants are required; reported families include compound heterozygotes and consanguineous pedigrees with homozygous variants whose unaffected parents are heterozygous carriers.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:29576217 SUPPORT Human Clinical
"Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase."
Biallelic variants in four unrelated individuals establish recessive inheritance.
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Mechanistic Hypotheses

4
Shared reduced-translation-capacity mechanism across aaRS leukodystrophies
reduced_translation_capacity EMERGING
Evidence balance 2 support
The unifying proposal that cytoplasmic aminoacyl-tRNA synthetase leukodystrophies, HLD15 among them, share a final common path of reduced translation capacity in the developing brain, whatever the proximate defect in the individual enzyme.
Pathograph links
Reduced EPRS1 Protein -> Reduced Translation Capacity in Developing Brain Less EPRS1 protein lowers aminoacylation capacity.
Show evidence (2 references)
PMID:29576217 SUPPORT Human Clinical
"We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting..."
The authors state this explicitly as a hypothesis, not a demonstrated result, which is why the status here is EMERGING.
PMID:29576217 SUPPORT In Vitro
"The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry."
A negative result against one of the three limbs this hypothesis proposes. For at least one variant, MSC assembly is intact, so "abnormal assembly of the multisynthetase complex" is not a general mechanism — which is why the hypothesis is curated as a three-part proposal rather than a settled pathway.
Variant-distal m6A site masking reduces EPRS1 expression
m6a_accessibility_defect EMERGING
Evidence balance 1 support
For the p.Pro1482Thr variant, reduced EPRS1 protein arises not from altered catalysis but from an RNA-level defect: the variant masks the accessibility of variant-distal m6A sites, impairing METTL3-mediated methylation and therefore nuclear export and translation of the EPRS1 mRNA.
Pathograph links
Biallelic EPRS1 Variants -> Impaired m6A-Dependent EPRS1 mRNA Export and Translation For p.Pro1482Thr, the variant masks m6A site accessibility — the proximate lesion is at the RNA level and is upstream of, not downstream of, the fall in protein.
Impaired m6A-Dependent EPRS1 mRNA Export and Translation -> Reduced EPRS1 Protein Defective export and translation of the transcript is why the protein is reduced — the causal direction PMID:38769304 reports.
Show evidence (1 reference)
PMID:38769304 SUPPORT In Vitro
"In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification."
States the distinguishing feature of this mechanism against the conventional sequence-altering model.
Mutant EPRS1 aggregation into Rab7 vesicles blocks oligodendrocyte differentiation
mutant_protein_aggregation EMERGING
Evidence balance 1 support
For the R339X nonsense variant, residual mutant protein forms polymeric aggregates in Rab7-positive vesicles, dysregulates Rab7 signalling and blocks the morphological differentiation of oligodendroglial cells — a gain-of-toxic-function route rather than simple loss of charging activity.
Pathograph links
Biallelic EPRS1 Variants -> Mutant EPRS1 Aggregation in Rab7 Vesicles For R339X, residual mutant protein mislocalizes and aggregates — a separate branch from the loss-of-protein route, not a consequence of it.
Show evidence (1 reference)
PMID:33805425 SUPPORT In Vitro
"Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells."
Establishes the aggregation phenotype in an oligodendroglial cell model.
Affected EPRS1 domain shapes the clinical phenotype
domain_dependent_phenotype EMERGING
Evidence balance 1 support
EPRS1 is bifunctional, carrying separate glutamyl-tRNA synthetase (GluRS) and prolyl-tRNA synthetase (ProRS) domains. The published series suggests the two are not clinically equivalent: ProRS-domain variants track with the typical hypomyelinating imaging pattern, while GluRS-domain variants track with seizures, deafness and less obvious hypomyelination. This is an axis of variant non-interchangeability independent of the molecular routes above — those distinguish how a variant lowers EPRS1 function, this distinguishes which of the enzyme's two functions is lost.
Show evidence (1 reference)
PMID:41721156 SUPPORT Other
"ProRS-domain variants often show the typical HLD15 imaging pattern, whereas GluRS-domain variants may be associated with seizures, deafness, and less obvious hypomyelination, though the number of reported cases is limited."
Graded PARTIAL and OTHER: the authors hedge explicitly ("may be associated", "though the number of reported cases is limited") and are summarizing eight published patients rather than testing the association. It is a pattern worth recording, not an established genotype-phenotype rule.
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Discussions and Knowledge Gaps

3
Do all HLD15 variants really converge on reduced translation capacity, or do the m6A-accessibility and protein-aggregation routes cause disease by mechanisms that are not simply "less EPRS1"?
KNOWLEDGE GAP hld15_one_mechanism_or_several
Attached to
mechanistic_hypotheses#reduced_translation_capacity
The R339X aggregation work describes mutant protein actively dysregulating Rab7 signalling and blocking oligodendroglial differentiation — a gain-of-toxic-function that a pure loss-of-capacity model does not predict. If that is right, variants may not be interchangeable, which matters directly for whether a translation-directed therapy would help every patient. Curated as three separate hypothesis groups rather than one so the distinction is not lost.
Does restoring EPRS1 expression in patient lymphoblastoid cells predict any benefit for myelination in the human brain?
HUMAN MODEL MISMATCH hld15_m6a_rescue_translational_validity
Attached to
pathophysiology#Impaired m6A-Dependent EPRS1 mRNA Export and Translation
PMID:38769304 rescued EPRS1 expression with morpholinos and with METTL3-dCas13b, but in lymphoblastoid cell lines — not in oligodendrocytes, and not in vivo. Myelination is a developmental window that may have closed by the time a patient is diagnosed, so a rescue of expression is not yet a rescue of disease. This is a model-fidelity question rather than an absence of evidence.
Is there any disease-modifying treatment for HLD15?
KNOWLEDGE GAP hld15_no_curated_treatments
Attached to
treatments#
No treatments are curated. Management reported in the sources is symptomatic. The m6A-directed rescue above is a cell-culture result, not a therapy, and curating it as a treatment would misrepresent its stage.
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Pathophysiology

6
Biallelic EPRS1 Variants
Biallelic variants in EPRS1. The variants are not equivalent: they act through different proximate routes, which is why this node branches rather than asserting a single consequence. No blanket functional_impact_category is set here — PMID:33805425 explicitly leaves open whether R339X acts by loss of function or by toxic gain of function, so the category is recorded per variant on the nodes below.
Mutant EPRS1 aggregation into Rab7 vesicles blocks oligodendrocyte differentiation Variant-distal m6A site masking reduces EPRS1 expression
Genetic context EPRS1 hgnc:3418 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns EPRS1 (hgnc:3418). hgnc:3418 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired m6A-Dependent EPRS1 mRNA Export and Translation For p.Pro1482Thr, the variant masks m6A site accessibility — the proximate lesion is at the RNA level and is upstream of, not downstream of, the fall in protein. Variant-distal m6A site masking reduces EPRS1 expression
Mutant EPRS1 Aggregation in Rab7 Vesicles For R339X, residual mutant protein mislocalizes and aggregates — a separate branch from the loss-of-protein route, not a consequence of it. Mutant EPRS1 aggregation into Rab7 vesicles blocks oligodendrocyte differentiation
Show evidence (2 references)
PMID:29576217 SUPPORT In Vitro
"However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts."
Direct measurement of reduced EPRS1 protein in patient fibroblasts.
PMID:29576217 SUPPORT In Vitro
"EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model."
Reduced enzymatic activity, measured in patient cells and in recombinant protein, complements the reduced protein amount.
Impaired m6A-Dependent EPRS1 mRNA Export and Translation
The p.Pro1482Thr variant reduces METTL3-mediated m6A writing and reading by YTHDC1 and YTHDF1/3, producing dual defects in nuclear export and cytoplasmic translation of the EPRS1 transcript. This is a rescuable lesion: antisense morpholinos exposing the m6A sites, or targeted RNA methylation with METTL3-dCas13b, restored expression in patient cells.
Variant-distal m6A site masking reduces EPRS1 expression
Experimental models
Patient lymphoblastoid cell lines (EPRS1 p.Pro1482Thr) CELL LINE Patient-derived cells in which the export and translation defect and its m6A basis were measured directly.
Patient lymphoblastoid cell lines (EPRS1 p.Pro1482Thr) CELL LINE Two independent rescue arms — antisense morpholinos exposing the m6A sites, and targeted RNA methylation with METTL3-dCas13b — restored expression, which is the therapeutic handle this entry records.
Downstream
Reduced EPRS1 Protein Defective export and translation of the transcript is why the protein is reduced — the causal direction PMID:38769304 reports. Variant-distal m6A site masking reduces EPRS1 expression
Show evidence (2 references)
PMID:38769304 SUPPORT In Vitro
"Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA."
Establishes the export and translation defect in patient-derived cells.
PMID:38769304 SUPPORT In Vitro
"The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor."
Rescue in both directions supports the causal role of m6A site accessibility, and identifies a therapeutic handle.
Reduced EPRS1 Protein
Reduced amount and reduced specific activity of the EPRS1 enzyme, measured in patient fibroblasts, lymphoblasts and recombinant protein. This is the convergence point of the loss-of-protein routes; the aggregation branch reaches myelination without passing through it.
Shared reduced-translation-capacity mechanism across aaRS leukodystrophies
Genetic context EPRS1 hgnc:3418 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns EPRS1 (hgnc:3418). hgnc:3418 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: LOSS_OF_FUNCTION
Downstream
Reduced Translation Capacity in Developing Brain Less EPRS1 protein lowers aminoacylation capacity. Shared reduced-translation-capacity mechanism across aaRS leukodystrophies
Show evidence (2 references)
PMID:38769304 SUPPORT In Vitro
"Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA."
States both the reduction and its cause, in that order.
PMID:38769304 SUPPORT In Vitro
"For nearly all EPRS1 and RARS1 variants, the relevant aminoacyl charging activity in patient fibroblasts is reduced by about 30–50% compared to healthy controls"
Quantifies the functional deficit across the EPRS1 and RARS1 variant sets — roughly a 30-50% reduction in charging activity in patient fibroblasts, which is the magnitude this node asserts.
Mutant EPRS1 Aggregation in Rab7 Vesicles
R339X mutant EPRS1 forms polymeric aggregates in Rab7-positive late endosomal vesicles and upregulates Rab7 regulatory signalling, blocking the morphological differentiation that oligodendroglial cells require to form myelin sheets.
Oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology.
Experimental models
FBD-102b oligodendroglial cells expressing EPRS1 R339X CELL LINE Reproduces the aggregation phenotype and the resulting block on morphological differentiation.
Downstream
Insufficient CNS Myelination Oligodendroglial cells that fail to differentiate cannot deposit myelin.
Show evidence (1 reference)
PMID:33805425 SUPPORT In Vitro
"Whereas cells expressing the wild-type proteins exhibited phenotypes with myelin web-like structures bearing processes following the induction of differentiation, cells expressing the R339X mutant proteins did not."
Links the aggregation phenotype to failed morphological differentiation, the cellular step that precedes myelination.
Reduced Translation Capacity in Developing Brain
Lowered aminoacylation capacity is proposed to limit the high protein synthesis demand of active myelination. This node is the hypothesized convergence point of the aaRS leukodystrophies and has not been measured directly in HLD15 brain tissue.
Translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Insufficient CNS Myelination Reduced translational output during the myelination window yields insufficient myelin deposition.
Global Developmental Delay Constrained translational capacity during brain development contributes to the global developmental impairment, beyond the myelin deficit alone.
Show evidence (1 reference)
PMID:29576217 SUPPORT Human Clinical
"We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting..."
Graded PARTIAL because the sentence is explicitly framed as a hypothesis the authors advance, not as a result they demonstrate.
Insufficient CNS Myelination
The defining tissue-level lesion: hypomyelination of central white matter with a thin corpus callosum on MRI.
Downstream
CNS Hypomyelination The tissue-level myelin deficit is what MRI reports as hypomyelination.
Thin Corpus Callosum Reduced myelinated commissural volume thins the corpus callosum.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"In brain imaging, HLD15 appears as a hypomyelinating leukodystrophy with thin corpus callosum."
Describes the imaging signature. Graded OTHER because this is the review framing of the paper rather than its own experimental result.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypomyelinating Leukodystrophy 15 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
Lists dysphagia among the HLD15 features.
Ear 1
Hearing Loss Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"Most HLD15 patients develop severe optic atrophy and some have hearing loss"
The same sentence already cited for optic atrophy also reports hearing loss in some patients.
Eye 4
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"Most HLD15 patients develop severe optic atrophy and some have hearing loss"
States optic atrophy in most patients. Graded OTHER because it is a review statement citing other work, not an original observation.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38769304 SUPPORT Human Clinical
"The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
Primary clinical observation.
Visual Loss Visual impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
Lists significant visual loss among the HLD15 features.
Amblyopia HP:0000646 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amblyopia (HP:0000646). HP:0000646 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
Lists variable amblyopia among the HLD15 features.
Head and Neck 1
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41721156 SUPPORT Other
"Khan et al. identified two siblings homozygous for a Zn2+‑binding–domain variant; these patients exhibited severe neurodevelopmental delay, ataxia, progressive spasticity and microcephaly, attributable to disrupted m6A modification of EPRS1 mRNA and consequent protein depletion"
Graded OTHER because this is PMID:41721156 restating another group's patients rather than reporting its own — the same secondary-restatement situation as the PMID:33805425 clinical statements. The primary observation is the next item.
PMID:38769304 SUPPORT Human Clinical
"The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
Primary clinical description of the proband by the group that reported him, so this is the HUMAN_CLINICAL evidence for microcephaly that the restatement above is only secondary to.
Musculoskeletal 2
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
Lists spasticity among the HLD15 features.
Axial Hypotonia HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38769304 SUPPORT Human Clinical
"The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
Primary clinical observation, in the same sentence that records the spasticity.
Nervous System 9
CNS Hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29576217 SUPPORT Human Clinical
"Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase."
Hypomyelination in all four originally reported individuals.
Thin Corpus Callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"In brain imaging, HLD15 appears as a hypomyelinating leukodystrophy with thin corpus callosum."
States the thin corpus callosum as part of the HLD15 imaging signature.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
Lists ataxia among the HLD15 features.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
Lists dystonia among the HLD15 features.
Cerebral White Matter Atrophy HP:0012762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral white matter atrophy (HP:0012762). HP:0012762 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41721156 SUPPORT Human Clinical
"Brain MRI revealed extensive cerebral white matter atrophy accompanied by hyperintensity on T2-weighted images, with thinning of the corpus callosum"
The authors' own patient, imaged directly.
PMID:41721156 SUPPORT Human Clinical
"hypomyelination; supratentorial atrophy; corpus callosum thinning"
Table 1 row for patients 1 and 2, showing the finding recurs beyond the index case. Patient-level imaging findings for two human patients, so HUMAN_CLINICAL, whoever first published them. Note the scope: this row evidences the finding's recurrence, not the 6-of-8 tally, which is a curator aggregation stated in the description.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41721156 SUPPORT Human Clinical
"hypomyelination; cerebellar atrophy; corpus callosum thinning"
Patient 8's own Table 1 MRI row (marked "*The present case" — the authors' own patient, imaged directly). The earlier quote for this row was a string shared with patients 3, 4, 6 and 7, so it did not identify the patient the claim is about; this row is unique to patient 8. The change is one of snippet specificity, not of evidence grade — both quotes are human patient-level imaging findings.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38769304 SUPPORT Human Clinical
"The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
Primary clinical observation, in the same sentence already cited for the developmental delay. Intellectual disability is named as a finding distinct from the delay rather than as a restatement of it.
PMID:41721156 SUPPORT Human Clinical
"a 40-year-old woman with mild intellectual disability, ataxia, dystonia"
The 2026 adult-onset case, where mild intellectual disability is the presenting feature rather than an accompaniment to severe delay.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41721156 SUPPORT Other
"ProRS-domain variants often show the typical HLD15 imaging pattern, whereas GluRS-domain variants may be associated with seizures, deafness, and less obvious hypomyelination, though the number of reported cases is limited."
Graded PARTIAL and OTHER: the source hedges ("may be associated", "the number of reported cases is limited") and is summarizing the published series rather than reporting its own seizure observation.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38769304 SUPPORT Human Clinical
"Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15."
Documents severe cognitive and motor impairment in the two reported siblings.
PMID:41721156 SUPPORT Human Clinical
"We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination."
A counterpoint rather than a confirmation: this patient's cognitive impairment was mild and adult-presenting. Graded PARTIAL because it supports developmental impairment as a feature while contradicting "severe" as a universal descriptor.
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Genetic Associations

1
EPRS1
Gene: EPRS1 hgnc:3418 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPRS1 (hgnc:3418). hgnc:3418 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:29576217 SUPPORT Human Clinical
"EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species."
Describes the gene product and its two catalytic activities.
PMID:41721156 SUPPORT Human Clinical
"Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in EPRS1, but exonic deletions have not been reported."
Extends the mutational spectrum beyond point variants: the first reported EPRS1 exonic deletion, which matters diagnostically because a single detected candidate variant may hide a structural second allele.
PMID:41721156 SUPPORT In Vitro
"RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele."
Demonstrates the deletion allele is degraded by nonsense-mediated decay, so the phenotype is driven by whatever residual function the surviving missense allele retains — a concrete instance of the reduced-EPRS1 mechanism above.
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Variants

5
EPRS1 p.Pro1115Arg
Shared by two of the four originally reported individuals. Reduces EPRS1 protein amount without disturbing assembly of the multi-tRNA synthetase complex, so this variant separates "less enzyme" from "broken complex".
Show evidence (1 reference)
PMID:29576217 SUPPORT In Vitro
"However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts."
Reduced protein in patient fibroblasts for this specific variant.
EPRS1 p.Pro1482Thr
Homozygous in two siblings. Acts at the RNA level, masking accessibility of variant-distal m6A sites and impairing nuclear export and translation of the EPRS1 transcript. The only HLD15 variant with a demonstrated rescue. Falls in the ProRS half of the bifunctional enzyme, the side the published series associates with the typical hypomyelinating imaging pattern. PMID:41721156 labels it a "Zn2+-binding-domain" variant, which is not a third category: the zinc-binding domain is a ProRS sub-domain, as the primary report's own domain figure shows.
Show evidence (2 references)
PMID:38769304 SUPPORT Other
"Domain structure of EPRS1 including ProRS sub-domains and Pro1482Thr substitution site"
Places the substitution within the ProRS sub-domain structure, which is what reconciles this variant's "Zn2+-binding-domain" label in the later series with its ProRS-domain assignment here. Graded OTHER: a figure legend describing domain architecture, not a study result.
PMID:38769304 SUPPORT In Vitro
"In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification."
Defines this variant's distinctive mechanism against the usual sequence-altering model.
EPRS1 R339X
A nonsense variant whose residual product forms polymeric aggregates in Rab7-positive vesicles and blocks oligodendroglial differentiation. Its source explicitly leaves open whether this is loss of function or toxic gain of function, which is why no blanket functional_impact_category is asserted for HLD15 as a whole.
Show evidence (1 reference)
PMID:33805425 SUPPORT In Vitro
"Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells."
Establishes the aggregation behaviour specific to this variant.
EPRS1 p.Leu1144Val
A ProRS-domain missense variant carried in trans with the exon-15 deletion in the 2026 adult-onset case. Because the deletion allele is silenced by nonsense-mediated decay, this allele alone determines residual EPRS1 function, making it the cleanest ProRS-domain exemplar available for the domain_dependent_phenotype hypothesis group: mild, adult-onset, with the typical hypomyelinating imaging pattern.
Show evidence (2 references)
PMID:41721156 SUPPORT Human Clinical
"Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of EPRS1 (c.3430 C > G; p.Leu1144Val, NM_004446.3)"
Assigns the variant to the prolyl-tRNA synthetase domain, which is what makes it an exemplar for the domain-dependent hypothesis. "Heterozygous" describes the whole-exome-sequencing result alone, not the final genotype: the second allele, the 220-bp exon-15 deletion, was found later by whole-genome sequencing (see the EPRS1 c.1743-30_1932del node below), making this variant one half of a compound-heterozygous genotype rather than a monoallelic finding.
PMID:41721156 SUPPORT Human Clinical
"The mild, adult‑onset phenotype is therefore consistent with relatively preserved residual activity compared with previously reported ProRS‑domain cases"
Graded PARTIAL: the authors infer relatively preserved residual activity from the mild phenotype and say in the same sentence that direct enzymatic assays are still needed, so the residual-activity claim is reasoned rather than measured.
EPRS1 c.1743-30_1932del (exon 15 deletion)
A 220-bp deletion spanning exon 15, in trans with p.Leu1144Val. The first exonic deletion reported in EPRS1; the transcript is cleared by nonsense-mediated decay, leaving the missense allele to determine the phenotype.
Show evidence (1 reference)
PMID:41721156 SUPPORT In Vitro
"RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele."
Documents the deletion's consequence and why the missense allele drives the phenotype.
🗃️

External Assertions

1
OMIM hypomyelinating leukodystrophy 15 record
OMIM disease record OMIM:617951
OMIM phenotype identifier for hypomyelinating leukodystrophy 15 (HLD15), recorded in PMID:33805425 alongside the R339X variant.
💊

Medical Actions

1
Symptomatic and Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. Management is symptomatic — for example anticonvulsant medication for patients with spasticity — alongside serial imaging and supportive care.
Show evidence (1 reference)
PMID:33805425 SUPPORT Other
"To date, no therapeutic strategy has been established, and symptomatic treatment, such as anticonvulsant medications for patients with spasticity, is the typical response"
States both the absence of disease-modifying therapy and the symptomatic measures used instead.
🔬

Diagnosis

1
Brain MRI with genetic confirmation
HLD15 is diagnosed on clinical and MRI features — hypomyelination with a thin corpus callosum — followed by genetic confirmation. Serial MRI is used to monitor the hypomyelination.
Show evidence (2 references)
PMID:38769304 SUPPORT Other
"patient management includes serial brain MRI to monitor hypomyelination, genetic testing to elucidate etiology, and symptomatic treatment of neurologic and other medical complications"
Describes the diagnostic and monitoring workflow.
PMID:41721156 SUPPORT Human Clinical
"highlights the importance of structural-variant analysis when only a single candidate variant is detected in recessive leukodystrophy"
A single detected candidate variant does not exclude HLD15; structural variant analysis is needed, as this case's exonic deletion shows.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Hypomyelinating Leukodystrophy 15:

Hypomyelinating Leukodystrophy 9 (RARS1)
Overlapping Features Another cytoplasmic aminoacyl-tRNA synthetase leukodystrophy, clinically and radiologically similar, with which HLD15 shares the proposed reduced-translation-capacity mechanism.
HBSL (DARS1)
Overlapping Features Hypomyelination with brainstem and spinal cord involvement and leg spasticity, the DARS1 member of the same aaRS leukodystrophy family.
Pelizaeus-Merzbacher Disease (HLD1, PLP1)
Overlapping Features The prototypic hypomyelinating leukodystrophy, X-linked and caused by a myelin structural protein rather than a translation factor. Contrasted directly with HLD15 in PMID:33805425.
🧫

Experimental Models

2
FBD-102b oligodendroglial cells expressing EPRS1 R339X CELL_LINE
Mouse FBD-102b cells, used by the authors as model oligodendrocytes, transfected with the HLD15-associated R339X nonsense variant.
Organism
house mouse NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in house mouse, annotated with Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Publication
PMID:33805425
Pathograph links
Mutant EPRS1 Aggregation in Rab7 Vesicles recapitulates fidelity: low Reproduces the aggregation phenotype and the resulting block on morphological differentiation.
Limitations: A mouse cell line described in its own source as "a mouse brain neuronal stem cell line" used as a model oligodendrocyte, not a human oligodendrocyte and not myelinating tissue. It is a transfection overexpression system, so aggregation may be favoured by expression level rather than by the variant alone, and no human EPRS1 aggregation has been shown.
Readouts
Myelin web-like structure formation on differentiation
Direction: DECREASED
Interpretation: Cells expressing R339X fail to form the myelin web-like structures that wild-type-expressing cells form, the cellular correlate of the differentiation block.
Show evidence (1 reference)
PMID:33805425 SUPPORT In Vitro
"Whereas cells expressing the wild-type proteins exhibited phenotypes with myelin web-like structures bearing processes following the induction of differentiation, cells expressing the R339X mutant proteins did not."
Reports the measurement behind this readout.
Show evidence (1 reference)
PMID:33805425 SUPPORT In Vitro
"Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells."
Establishes that this model is informative for the aggregation node.
Patient lymphoblastoid cell lines (EPRS1 p.Pro1482Thr) CELL_LINE
Immortalized lymphoblastoid lines from the two affected siblings homozygous for p.Pro1482Thr, used to measure the m6A-dependent expression defect and to test two rescue strategies.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:38769304
Pathograph links
Impaired m6A-Dependent EPRS1 mRNA Export and Translation measures fidelity: moderate Patient-derived cells in which the export and translation defect and its m6A basis were measured directly.
Limitations: Lymphoblastoid cells are not oligodendrocytes and do not myelinate, so the measurement establishes the molecular lesion but not its consequence for myelination.
Readouts
EPRS1 protein level
Direction: DECREASED
Interpretation: Markedly reduced EPRS1 protein in patient lines, attributable to the dual export/translation defect.
Show evidence (1 reference)
PMID:38769304 SUPPORT In Vitro
"Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA."
Reports the measurement and its stated cause.
Impaired m6A-Dependent EPRS1 mRNA Export and Translation rescues fidelity: moderate Two independent rescue arms — antisense morpholinos exposing the m6A sites, and targeted RNA methylation with METTL3-dCas13b — restored expression, which is the therapeutic handle this entry records.
Limitations: Rescue of expression in a lymphoblastoid line is not rescue of myelination, and myelination is developmentally timed: the window may have closed before diagnosis. See the HUMAN_MODEL_MISMATCH discussion.
Readouts
EPRS1 expression after m6A-directed rescue
Direction: RESTORED
Interpretation: Expression recovered under both rescue arms, supporting m6A site accessibility as the causal lesion.
Show evidence (1 reference)
PMID:38769304 SUPPORT In Vitro
"The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor."
Reports both rescue arms and their effect.
{ }

Source YAML

click to show 
name: Hypomyelinating Leukodystrophy 15
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Hypomyelinating leukodystrophy 15 (HLD15) is an autosomal recessive
  hypomyelinating leukodystrophy caused by biallelic variants in EPRS1, which
  encodes the bifunctional cytoplasmic glutamyl-prolyl-aminoacyl-tRNA
  synthetase and is a subunit of the multi-tRNA synthetase complex (MSC).
  Affected children typically have severe global developmental delay with
  hypomyelination on MRI and a thin corpus callosum, commonly with optic
  atrophy, dysphagia, dystonia, ataxia and spasticity. The spectrum is wider
  than that classical presentation: a compound heterozygote reported in 2026
  had only mild intellectual disability and did not come to neurological
  attention until her thirties, so severity ranges from infantile-onset severe
  disease to an adult-onset mild phenotype. HLD15 is one of several leukodystrophies
  caused by cytoplasmic aminoacyl-tRNA synthetase genes — RARS1 causes HLD9 and
  DARS1 causes HBSL — and the field's working hypothesis is that they converge
  on reduced translation capacity in the developing brain. What makes HLD15
  mechanistically interesting is that the *route* to reduced EPRS1 protein
  differs between variants: one operates through impaired m6A-dependent mRNA
  export and translation, another through polymeric aggregation of the mutant
  protein. Both end in insufficient myelination, but they are not the same
  lesion, and one of them has been pharmacologically rescued in patient cells.
disease_term:
  preferred_term: Hypomyelinating leukodystrophy 15
  term:
    id: MONDO:0054782
    label: leukodystrophy, hypomyelinating, 15
synonyms:
- HLD15
- EPRS1-related hypomyelinating leukodystrophy
- leukodystrophy, hypomyelinating, 15
parents:
- leukodystrophy
external_assertions:
- name: OMIM hypomyelinating leukodystrophy 15 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:617951
  description: >-
    OMIM phenotype identifier for hypomyelinating leukodystrophy 15 (HLD15),
    recorded in PMID:33805425 alongside the R339X variant.
references:
- reference: PMID:29576217
  title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
  findings: []
- reference: PMID:38769304
  title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
  findings: []
- reference: PMID:33805425
  title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
  findings: []
- reference: PMID:41721156
  title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
  findings: []
inheritance:
- name: Autosomal Recessive
  description: >-
    Biallelic EPRS1 variants are required; reported families include compound
    heterozygotes and consanguineous pedigrees with homozygous variants whose
    unaffected parents are heterozygous carriers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase."
    explanation: >-
      Biallelic variants in four unrelated individuals establish recessive
      inheritance.
mechanistic_hypotheses:
- hypothesis_group_id: reduced_translation_capacity
  hypothesis_label: Shared reduced-translation-capacity mechanism across aaRS leukodystrophies
  status: EMERGING
  description: >-
    The unifying proposal that cytoplasmic aminoacyl-tRNA synthetase
    leukodystrophies, HLD15 among them, share a final common path of reduced
    translation capacity in the developing brain, whatever the proximate defect
    in the individual enzyme.
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain."
    explanation: >-
      The authors state this explicitly as a hypothesis, not a demonstrated
      result, which is why the status here is EMERGING.
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry."
    explanation: >-
      A negative result against one of the three limbs this hypothesis
      proposes. For at least one variant, MSC assembly is intact, so
      "abnormal assembly of the multisynthetase complex" is not a general
      mechanism — which is why the hypothesis is curated as a three-part
      proposal rather than a settled pathway.
- hypothesis_group_id: m6a_accessibility_defect
  hypothesis_label: Variant-distal m6A site masking reduces EPRS1 expression
  status: EMERGING
  description: >-
    For the p.Pro1482Thr variant, reduced EPRS1 protein arises not from altered
    catalysis but from an RNA-level defect: the variant masks the accessibility
    of variant-distal m6A sites, impairing METTL3-mediated methylation and
    therefore nuclear export and translation of the EPRS1 mRNA.
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification."
    explanation: >-
      States the distinguishing feature of this mechanism against the
      conventional sequence-altering model.
- hypothesis_group_id: mutant_protein_aggregation
  hypothesis_label: Mutant EPRS1 aggregation into Rab7 vesicles blocks oligodendrocyte differentiation
  status: EMERGING
  description: >-
    For the R339X nonsense variant, residual mutant protein forms polymeric
    aggregates in Rab7-positive vesicles, dysregulates Rab7 signalling and
    blocks the morphological differentiation of oligodendroglial cells — a
    gain-of-toxic-function route rather than simple loss of charging activity.
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells."
    explanation: >-
      Establishes the aggregation phenotype in an oligodendroglial cell model.
- hypothesis_group_id: domain_dependent_phenotype
  hypothesis_label: Affected EPRS1 domain shapes the clinical phenotype
  status: EMERGING
  description: >-
    EPRS1 is bifunctional, carrying separate glutamyl-tRNA synthetase (GluRS)
    and prolyl-tRNA synthetase (ProRS) domains. The published series suggests
    the two are not clinically equivalent: ProRS-domain variants track with the
    typical hypomyelinating imaging pattern, while GluRS-domain variants track
    with seizures, deafness and less obvious hypomyelination. This is an axis of
    variant non-interchangeability independent of the molecular routes above —
    those distinguish how a variant lowers EPRS1 function, this distinguishes
    which of the enzyme's two functions is lost.
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ProRS-domain variants often show the typical HLD15 imaging pattern, whereas GluRS-domain variants may be associated with seizures, deafness, and less obvious hypomyelination, though the number of reported cases is limited."
    explanation: >-
      Graded PARTIAL and OTHER: the authors hedge explicitly ("may be
      associated", "though the number of reported cases is limited") and are
      summarizing eight published patients rather than testing the association.
      It is a pattern worth recording, not an established genotype-phenotype
      rule.
pathophysiology:
- name: Biallelic EPRS1 Variants
  biological_scale: MOLECULAR
  description: >-
    Biallelic variants in EPRS1. The variants are not equivalent: they act
    through different proximate routes, which is why this node branches rather
    than asserting a single consequence. No blanket functional_impact_category
    is set here — PMID:33805425 explicitly leaves open whether R339X acts by
    loss of function or by toxic gain of function, so the category is recorded
    per variant on the nodes below.
  genetic_context:
    gene:
      preferred_term: EPRS1
      term:
        id: hgnc:3418
        label: EPRS1
  downstream:
  - target: Impaired m6A-Dependent EPRS1 mRNA Export and Translation
    description: >-
      For p.Pro1482Thr, the variant masks m6A site accessibility — the
      proximate lesion is at the RNA level and is upstream of, not downstream
      of, the fall in protein.
    hypothesis_groups:
    - m6a_accessibility_defect
  - target: Mutant EPRS1 Aggregation in Rab7 Vesicles
    description: >-
      For R339X, residual mutant protein mislocalizes and aggregates — a
      separate branch from the loss-of-protein route, not a consequence of it.
    hypothesis_groups:
    - mutant_protein_aggregation
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts."
    explanation: >-
      Direct measurement of reduced EPRS1 protein in patient fibroblasts.
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model."
    explanation: >-
      Reduced enzymatic activity, measured in patient cells and in recombinant
      protein, complements the reduced protein amount.
- name: Impaired m6A-Dependent EPRS1 mRNA Export and Translation
  biological_scale: MOLECULAR
  description: >-
    The p.Pro1482Thr variant reduces METTL3-mediated m6A writing and reading by
    YTHDC1 and YTHDF1/3, producing dual defects in nuclear export and
    cytoplasmic translation of the EPRS1 transcript. This is a rescuable lesion:
    antisense morpholinos exposing the m6A sites, or targeted RNA methylation
    with METTL3-dCas13b, restored expression in patient cells.
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA."
    explanation: >-
      Establishes the export and translation defect in patient-derived cells.
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor."
    explanation: >-
      Rescue in both directions supports the causal role of m6A site
      accessibility, and identifies a therapeutic handle.
  downstream:
  - target: Reduced EPRS1 Protein
    description: >-
      Defective export and translation of the transcript is why the protein is
      reduced — the causal direction PMID:38769304 reports.
    hypothesis_groups:
    - m6a_accessibility_defect
- name: Reduced EPRS1 Protein
  biological_scale: MOLECULAR
  description: >-
    Reduced amount and reduced specific activity of the EPRS1 enzyme, measured
    in patient fibroblasts, lymphoblasts and recombinant protein. This is the
    convergence point of the loss-of-protein routes; the aggregation branch
    reaches myelination without passing through it.
  genetic_context:
    gene:
      preferred_term: EPRS1
      term:
        id: hgnc:3418
        label: EPRS1
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA."
    explanation: >-
      States both the reduction and its cause, in that order.
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "For nearly all EPRS1 and RARS1 variants, the relevant aminoacyl charging activity in patient fibroblasts is reduced by about 30–50% compared to healthy controls"
    explanation: >-
      Quantifies the functional deficit across the EPRS1 and RARS1 variant sets
      — roughly a 30-50% reduction in charging activity in patient fibroblasts,
      which is the magnitude this node asserts.
  downstream:
  - target: Reduced Translation Capacity in Developing Brain
    description: >-
      Less EPRS1 protein lowers aminoacylation capacity.
    hypothesis_groups:
    - reduced_translation_capacity
- name: Mutant EPRS1 Aggregation in Rab7 Vesicles
  biological_scale: CELLULAR
  description: >-
    R339X mutant EPRS1 forms polymeric aggregates in Rab7-positive late
    endosomal vesicles and upregulates Rab7 regulatory signalling, blocking the
    morphological differentiation that oligodendroglial cells require to form
    myelin sheets.
  cell_types:
  - preferred_term: Oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Whereas cells expressing the wild-type proteins exhibited phenotypes with myelin web-like structures bearing processes following the induction of differentiation, cells expressing the R339X mutant proteins did not."
    explanation: >-
      Links the aggregation phenotype to failed morphological differentiation,
      the cellular step that precedes myelination.
  downstream:
  - target: Insufficient CNS Myelination
    description: >-
      Oligodendroglial cells that fail to differentiate cannot deposit myelin.
- name: Reduced Translation Capacity in Developing Brain
  biological_scale: CELLULAR
  description: >-
    Lowered aminoacylation capacity is proposed to limit the high protein
    synthesis demand of active myelination. This node is the hypothesized
    convergence point of the aaRS leukodystrophies and has not been measured
    directly in HLD15 brain tissue.
  biological_processes:
  - preferred_term: Translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain."
    explanation: >-
      Graded PARTIAL because the sentence is explicitly framed as a hypothesis
      the authors advance, not as a result they demonstrate.
  downstream:
  - target: Insufficient CNS Myelination
    description: >-
      Reduced translational output during the myelination window yields
      insufficient myelin deposition.
  - target: Global Developmental Delay
    description: >-
      Constrained translational capacity during brain development contributes
      to the global developmental impairment, beyond the myelin deficit alone.
- name: Insufficient CNS Myelination
  biological_scale: TISSUE
  description: >-
    The defining tissue-level lesion: hypomyelination of central white matter
    with a thin corpus callosum on MRI.
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In brain imaging, HLD15 appears as a hypomyelinating leukodystrophy with thin corpus callosum."
    explanation: >-
      Describes the imaging signature. Graded OTHER because this is the review
      framing of the paper rather than its own experimental result.
  downstream:
  - target: CNS Hypomyelination
    description: >-
      The tissue-level myelin deficit is what MRI reports as hypomyelination.
  - target: Thin Corpus Callosum
    description: >-
      Reduced myelinated commissural volume thins the corpus callosum.
phenotypes:
- category: Neurological
  name: CNS Hypomyelination
  description: >-
    Diffuse hypomyelination of cerebral white matter on MRI.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase."
    explanation: >-
      Hypomyelination in all four originally reported individuals.
- category: Neurological
  name: Thin Corpus Callosum
  description: >-
    Thinning of the corpus callosum accompanying the hypomyelination.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In brain imaging, HLD15 appears as a hypomyelinating leukodystrophy with thin corpus callosum."
    explanation: >-
      States the thin corpus callosum as part of the HLD15 imaging signature.
- category: Ophthalmological
  name: Optic Atrophy
  description: >-
    Severe optic atrophy develops in most patients.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most HLD15 patients develop severe optic atrophy and some have hearing loss"
    explanation: >-
      States optic atrophy in most patients. Graded OTHER because it is a review
      statement citing other work, not an original observation.
- category: Neurological
  name: Ataxia
  description: >-
    Ataxia is among the recognized HLD15 features.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
    explanation: >-
      Lists ataxia among the HLD15 features.
- category: Neurological
  name: Spasticity
  description: >-
    Spasticity, often progressive and lower-limb predominant.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
    explanation: >-
      Lists spasticity among the HLD15 features.
- category: Neurological
  name: Dystonia
  description: >-
    Dystonia is among the recognized HLD15 movement features.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
    explanation: >-
      Lists dystonia among the HLD15 features.
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Swallowing difficulty, contributing to feeding problems.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
    explanation: >-
      Lists dysphagia among the HLD15 features.
- category: Neurological
  name: Cerebral White Matter Atrophy
  description: >-
    Supratentorial white matter atrophy, a curator tally read off the Table 1
    imaging column for 6 of the 8 published biallelic-EPRS1 patients (patients
    1, 2, 3, 4, 6 and 7), with cortical atrophy — a distinct finding — in a
    seventh (patient 5). No single quotable sentence carries that count;
    it is aggregated across the eight rows rather than asserted by the source.
    Distinct from the hypomyelination: tissue is lost, not merely
    under-myelinated. The narrative below reports "extensive cerebral white
    matter atrophy" in patient 8 (the present case), but that patient's own
    Table 1 row lists only cerebellar atrophy, not supratentorial atrophy — the
    two are not interchangeable, and the Cerebellar Atrophy phenotype in this
    entry relies on the table row rather than this narrative sentence.
  phenotype_term:
    preferred_term: Cerebral white matter atrophy
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed extensive cerebral white matter atrophy accompanied by hyperintensity on T2-weighted images, with thinning of the corpus callosum"
    explanation: >-
      The authors' own patient, imaged directly.
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypomyelination; supratentorial atrophy; corpus callosum thinning"
    explanation: >-
      Table 1 row for patients 1 and 2, showing the finding recurs beyond the
      index case. Patient-level imaging findings for two human patients, so
      HUMAN_CLINICAL, whoever first published them. Note the scope: this row
      evidences the finding's recurrence, not the 6-of-8 tally, which is a
      curator aggregation stated in the description.
- category: Neurological
  name: Cerebellar Atrophy
  description: >-
    Cerebellar atrophy, reported in 5 of the 8 published patients.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypomyelination; cerebellar atrophy; corpus callosum thinning"
    explanation: >-
      Patient 8's own Table 1 MRI row (marked "*The present case" — the authors'
      own patient, imaged directly). The earlier quote for this row was a string
      shared with patients 3, 4, 6 and 7, so it did not identify the patient the
      claim is about; this row is unique to patient 8. The change is one of
      snippet specificity, not of evidence grade — both quotes are human
      patient-level imaging findings.
- category: Neurological
  name: Microcephaly
  description: >-
    Microcephaly, reported in the two siblings homozygous for p.Pro1482Thr.
    PMID:41721156 files that variant under a "Zn2+-binding-domain" label; the
    zinc-binding domain is a ProRS sub-domain, so this is the same variant the
    variants: section lists as ProRS-domain, not a separate one.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Khan et al. identified two siblings homozygous for a Zn2+‑binding–domain variant; these patients exhibited severe neurodevelopmental delay, ataxia, progressive spasticity and microcephaly, attributable to disrupted m6A modification of EPRS1 mRNA and consequent protein depletion"
    explanation: >-
      Graded OTHER because this is PMID:41721156 restating another group's
      patients rather than reporting its own — the same secondary-restatement
      situation as the PMID:33805425 clinical statements. The primary
      observation is the next item.
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
    explanation: >-
      Primary clinical description of the proband by the group that reported
      him, so this is the HUMAN_CLINICAL evidence for microcephaly that the
      restatement above is only secondary to.
- category: Ophthalmological
  name: Nystagmus
  description: >-
    Rotatory nystagmus, reported on serial neurological examination of the
    proband.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
    explanation: >-
      Primary clinical observation.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Intellectual disability, recorded alongside the developmental delay in the
    two siblings and tabulated for three of the eight published patients. In the
    adult-onset 2026 case it is the presenting feature and is mild, which is the
    milder end of the severity spectrum this entry records.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
    explanation: >-
      Primary clinical observation, in the same sentence already cited for the
      developmental delay. Intellectual disability is named as a finding
      distinct from the delay rather than as a restatement of it.
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 40-year-old woman with mild intellectual disability, ataxia, dystonia"
    explanation: >-
      The 2026 adult-onset case, where mild intellectual disability is the
      presenting feature rather than an accompaniment to severe delay.
- category: Neurological
  name: Axial Hypotonia
  description: >-
    Axial hypotonia coexisting with progressive lower-limb spasticity — the
    mixed tone pattern typical of a hypomyelinating leukodystrophy.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Proband, Sibling 1, is an 18-year-old male with severe global developmental delays and intellectual disability, ataxia, microcephaly, rotatory nystagmus, axial hypotonia, and progressive bilateral lower limb spasticity on serial neurological examinations."
    explanation: >-
      Primary clinical observation, in the same sentence that records the
      spasticity.
- category: Neurological
  name: Seizures
  description: >-
    Epilepsy, reported in 2 of the 8 published patients and associated in the
    source with GluRS-domain rather than ProRS-domain variants.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ProRS-domain variants often show the typical HLD15 imaging pattern, whereas GluRS-domain variants may be associated with seizures, deafness, and less obvious hypomyelination, though the number of reported cases is limited."
    explanation: >-
      Graded PARTIAL and OTHER: the source hedges ("may be associated",
      "the number of reported cases is limited") and is summarizing the
      published series rather than reporting its own seizure observation.
- category: Otologic
  name: Hearing Loss
  description: >-
    Hearing loss occurs in a subset of patients.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most HLD15 patients develop severe optic atrophy and some have hearing loss"
    explanation: >-
      The same sentence already cited for optic atrophy also reports hearing
      loss in some patients.
- category: Ophthalmological
  name: Visual Loss
  description: >-
    Significant visual loss, with amblyopia in some patients, accompanying the
    optic atrophy.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
    explanation: >-
      Lists significant visual loss among the HLD15 features.
- category: Ophthalmological
  name: Amblyopia
  description: >-
    Variable amblyopia is reported as part of the visual phenotype.
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The features of HLD15 include significant visual loss with variable amblyopia and dysphagia as well as dystonia, ataxia, and spasticity, although the severity of the disorder is variable."
    explanation: >-
      Lists variable amblyopia among the HLD15 features.
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Severe cognitive and motor impairment with childhood onset.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15."
    explanation: >-
      Documents severe cognitive and motor impairment in the two reported
      siblings.
  - reference: PMID:41721156
    reference_title: "Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination."
    explanation: >-
      A counterpoint rather than a confirmation: this patient's cognitive
      impairment was mild and adult-presenting. Graded PARTIAL because it
      supports developmental impairment as a feature while contradicting
      "severe" as a universal descriptor.
genetic:
- name: EPRS1
  gene_term:
    preferred_term: EPRS1
    term:
      id: hgnc:3418
      label: EPRS1
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic EPRS1 variants cause HLD15. EPRS1 is bifunctional, carrying both
    glutamyl- and prolyl-tRNA synthetase domains, and is a subunit of the
    multi-tRNA synthetase complex.
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species."
    explanation: >-
      Describes the gene product and its two catalytic activities.
  - reference: PMID:41721156
    reference_title: "Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in EPRS1, but exonic deletions have not been reported."
    explanation: >-
      Extends the mutational spectrum beyond point variants: the first reported
      EPRS1 exonic deletion, which matters diagnostically because a single
      detected candidate variant may hide a structural second allele.
  - reference: PMID:41721156
    reference_title: "Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele."
    explanation: >-
      Demonstrates the deletion allele is degraded by nonsense-mediated decay,
      so the phenotype is driven by whatever residual function the surviving
      missense allele retains — a concrete instance of the reduced-EPRS1
      mechanism above.
experimental_models:
- name: FBD-102b oligodendroglial cells expressing EPRS1 R339X
  experimental_model_type: CELL_LINE
  description: >-
    Mouse FBD-102b cells, used by the authors as model oligodendrocytes,
    transfected with the HLD15-associated R339X nonsense variant.
  publication: PMID:33805425
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  modeled_mechanisms:
  - target: Mutant EPRS1 Aggregation in Rab7 Vesicles
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces the aggregation phenotype and the resulting block on
      morphological differentiation.
    limitations: >-
      A mouse cell line described in its own source as "a mouse brain neuronal
      stem cell line" used as a model oligodendrocyte, not a human
      oligodendrocyte and not myelinating tissue. It is a transfection
      overexpression system, so aggregation may be favoured by expression level
      rather than by the variant alone, and no human EPRS1 aggregation has been
      shown.
    readouts:
    - name: Myelin web-like structure formation on differentiation
      target: Mutant EPRS1 Aggregation in Rab7 Vesicles
      direction: DECREASED
      interpretation: >-
        Cells expressing R339X fail to form the myelin web-like structures that
        wild-type-expressing cells form, the cellular correlate of the
        differentiation block.
      evidence:
      - reference: PMID:33805425
        reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Whereas cells expressing the wild-type proteins exhibited phenotypes with myelin web-like structures bearing processes following the induction of differentiation, cells expressing the R339X mutant proteins did not."
        explanation: >-
          Reports the measurement behind this readout.
    evidence:
    - reference: PMID:33805425
      reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells."
      explanation: >-
        Establishes that this model is informative for the aggregation node.
- name: Patient lymphoblastoid cell lines (EPRS1 p.Pro1482Thr)
  experimental_model_type: CELL_LINE
  description: >-
    Immortalized lymphoblastoid lines from the two affected siblings homozygous
    for p.Pro1482Thr, used to measure the m6A-dependent expression defect and
    to test two rescue strategies.
  publication: PMID:38769304
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: Impaired m6A-Dependent EPRS1 mRNA Export and Translation
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Patient-derived cells in which the export and translation defect and its
      m6A basis were measured directly.
    limitations: >-
      Lymphoblastoid cells are not oligodendrocytes and do not myelinate, so
      the measurement establishes the molecular lesion but not its consequence
      for myelination.
    readouts:
    - name: EPRS1 protein level
      target: Impaired m6A-Dependent EPRS1 mRNA Export and Translation
      direction: DECREASED
      interpretation: >-
        Markedly reduced EPRS1 protein in patient lines, attributable to the
        dual export/translation defect.
      evidence:
      - reference: PMID:38769304
        reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA."
        explanation: >-
          Reports the measurement and its stated cause.
  - target: Impaired m6A-Dependent EPRS1 mRNA Export and Translation
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Two independent rescue arms — antisense morpholinos exposing the m6A
      sites, and targeted RNA methylation with METTL3-dCas13b — restored
      expression, which is the therapeutic handle this entry records.
    limitations: >-
      Rescue of expression in a lymphoblastoid line is not rescue of
      myelination, and myelination is developmentally timed: the window may
      have closed before diagnosis. See the HUMAN_MODEL_MISMATCH discussion.
    readouts:
    - name: EPRS1 expression after m6A-directed rescue
      target: Impaired m6A-Dependent EPRS1 mRNA Export and Translation
      direction: RESTORED
      interpretation: >-
        Expression recovered under both rescue arms, supporting m6A site
        accessibility as the causal lesion.
      evidence:
      - reference: PMID:38769304
        reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor."
        explanation: >-
          Reports both rescue arms and their effect.
variants:
- name: EPRS1 p.Pro1115Arg
  description: >-
    Shared by two of the four originally reported individuals. Reduces EPRS1
    protein amount without disturbing assembly of the multi-tRNA synthetase
    complex, so this variant separates "less enzyme" from "broken complex".
  evidence:
  - reference: PMID:29576217
    reference_title: "Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts."
    explanation: >-
      Reduced protein in patient fibroblasts for this specific variant.
- name: EPRS1 p.Pro1482Thr
  description: >-
    Homozygous in two siblings. Acts at the RNA level, masking accessibility of
    variant-distal m6A sites and impairing nuclear export and translation of
    the EPRS1 transcript. The only HLD15 variant with a demonstrated rescue.
    Falls in the ProRS half of the bifunctional enzyme, the side the published
    series associates with the typical hypomyelinating imaging pattern.
    PMID:41721156 labels it a "Zn2+-binding-domain" variant, which is not a
    third category: the zinc-binding domain is a ProRS sub-domain, as the
    primary report's own domain figure shows.
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Domain structure of EPRS1 including ProRS sub-domains and Pro1482Thr substitution site"
    explanation: >-
      Places the substitution within the ProRS sub-domain structure, which is
      what reconciles this variant's "Zn2+-binding-domain" label in the later
      series with its ProRS-domain assignment here. Graded OTHER: a figure
      legend describing domain architecture, not a study result.
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification."
    explanation: >-
      Defines this variant's distinctive mechanism against the usual
      sequence-altering model.
- name: EPRS1 R339X
  description: >-
    A nonsense variant whose residual product forms polymeric aggregates in
    Rab7-positive vesicles and blocks oligodendroglial differentiation. Its
    source explicitly leaves open whether this is loss of function or toxic
    gain of function, which is why no blanket functional_impact_category is
    asserted for HLD15 as a whole.
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that the HLD15-associated nonsense mutation of Arg339-to-Ter (R339X) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells."
    explanation: >-
      Establishes the aggregation behaviour specific to this variant.
- name: EPRS1 p.Leu1144Val
  description: >-
    A ProRS-domain missense variant carried in trans with the exon-15 deletion in
    the 2026 adult-onset case. Because the deletion allele is silenced by
    nonsense-mediated decay, this allele alone determines residual EPRS1
    function, making it the cleanest ProRS-domain exemplar available for the
    domain_dependent_phenotype hypothesis group: mild, adult-onset, with the
    typical hypomyelinating imaging pattern.
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of EPRS1 (c.3430 C > G; p.Leu1144Val, NM_004446.3)"
    explanation: >-
      Assigns the variant to the prolyl-tRNA synthetase domain, which is what
      makes it an exemplar for the domain-dependent hypothesis. "Heterozygous"
      describes the whole-exome-sequencing result alone, not the final
      genotype: the second allele, the 220-bp exon-15 deletion, was found
      later by whole-genome sequencing (see the EPRS1 c.1743-30_1932del node
      below), making this variant one half of a compound-heterozygous genotype
      rather than a monoallelic finding.
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mild, adult‑onset phenotype is therefore consistent with relatively preserved residual activity compared with previously reported ProRS‑domain cases"
    explanation: >-
      Graded PARTIAL: the authors infer relatively preserved residual activity
      from the mild phenotype and say in the same sentence that direct enzymatic
      assays are still needed, so the residual-activity claim is reasoned rather
      than measured.
- name: EPRS1 c.1743-30_1932del (exon 15 deletion)
  description: >-
    A 220-bp deletion spanning exon 15, in trans with p.Leu1144Val. The first
    exonic deletion reported in EPRS1; the transcript is cleared by
    nonsense-mediated decay, leaving the missense allele to determine the
    phenotype.
  evidence:
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele."
    explanation: >-
      Documents the deletion's consequence and why the missense allele drives
      the phenotype.
differential_diagnoses:
- name: Hypomyelinating Leukodystrophy 9 (RARS1)
  description: >-
    Another cytoplasmic aminoacyl-tRNA synthetase leukodystrophy, clinically and
    radiologically similar, with which HLD15 shares the proposed
    reduced-translation-capacity mechanism.
- name: HBSL (DARS1)
  description: >-
    Hypomyelination with brainstem and spinal cord involvement and leg
    spasticity, the DARS1 member of the same aaRS leukodystrophy family.
- name: Pelizaeus-Merzbacher Disease (HLD1, PLP1)
  description: >-
    The prototypic hypomyelinating leukodystrophy, X-linked and caused by a
    myelin structural protein rather than a translation factor. Contrasted
    directly with HLD15 in PMID:33805425.
treatments:
- name: Symptomatic and Supportive Care
  description: >-
    No disease-modifying therapy exists. Management is symptomatic — for
    example anticonvulsant medication for patients with spasticity — alongside
    serial imaging and supportive care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33805425
    reference_title: "Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To date, no therapeutic strategy has been established, and symptomatic treatment, such as anticonvulsant medications for patients with spasticity, is the typical response"
    explanation: >-
      States both the absence of disease-modifying therapy and the symptomatic
      measures used instead.
diagnosis:
- name: Brain MRI with genetic confirmation
  description: >-
    HLD15 is diagnosed on clinical and MRI features — hypomyelination with a
    thin corpus callosum — followed by genetic confirmation. Serial MRI is used
    to monitor the hypomyelination.
  evidence:
  - reference: PMID:38769304
    reference_title: "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patient management includes serial brain MRI to monitor hypomyelination, genetic testing to elucidate etiology, and symptomatic treatment of neurologic and other medical complications"
    explanation: >-
      Describes the diagnostic and monitoring workflow.
  - reference: PMID:41721156
    reference_title: Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highlights the importance of structural-variant analysis when only a single candidate variant is detected in recessive leukodystrophy"
    explanation: >-
      A single detected candidate variant does not exclude HLD15; structural
      variant analysis is needed, as this case's exonic deletion shows.
discussions:
- discussion_id: hld15_one_mechanism_or_several
  kind: KNOWLEDGE_GAP
  attaches_to:
  - mechanistic_hypotheses#reduced_translation_capacity
  prompt: >-
    Do all HLD15 variants really converge on reduced translation capacity, or
    do the m6A-accessibility and protein-aggregation routes cause disease by
    mechanisms that are not simply "less EPRS1"?
  rationale: >-
    The R339X aggregation work describes mutant protein actively dysregulating
    Rab7 signalling and blocking oligodendroglial differentiation — a
    gain-of-toxic-function that a pure loss-of-capacity model does not predict.
    If that is right, variants may not be interchangeable, which matters
    directly for whether a translation-directed therapy would help every
    patient. Curated as three separate hypothesis groups rather than one so the
    distinction is not lost.
- discussion_id: hld15_m6a_rescue_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Impaired m6A-Dependent EPRS1 mRNA Export and Translation
  prompt: >-
    Does restoring EPRS1 expression in patient lymphoblastoid cells predict any
    benefit for myelination in the human brain?
  rationale: >-
    PMID:38769304 rescued EPRS1 expression with morpholinos and with
    METTL3-dCas13b, but in lymphoblastoid cell lines — not in oligodendrocytes,
    and not in vivo. Myelination is a developmental window that may have closed
    by the time a patient is diagnosed, so a rescue of expression is not yet a
    rescue of disease. This is a model-fidelity question rather than an absence
    of evidence.
- discussion_id: hld15_no_curated_treatments
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#
  prompt: >-
    Is there any disease-modifying treatment for HLD15?
  rationale: >-
    No treatments are curated. Management reported in the sources is
    symptomatic. The m6A-directed rescue above is a cell-culture result, not a
    therapy, and curating it as a treatment would misrepresent its stage.
notes: >-
  The entry name follows the dismech convention set by
  Hypomyelinating_Leukodystrophy_7 and _10 rather than the MONDO label ordering
  ("leukodystrophy, hypomyelinating, 15"); the MONDO label is used verbatim in
  disease_term and retained as a synonym.

  Evidence grading warrants attention. HLD15's clinical phenotype list here
  (optic atrophy, dysphagia, dystonia, ataxia, spasticity) comes from the
  introduction of PMID:33805425, a cell-biology paper reviewing the entity and
  citing other work for those features. Those items are graded OTHER rather
  than HUMAN_CLINICAL because the citing paper reports no patients of its own —
  it is a secondary statement. A curator with access to the primary clinical
  cohorts should regrade them and cite those directly.

  Two negative claims in earlier versions of this entry were too broad and are
  corrected here. There was no top-level references block and no OMIM
  assertion; OMIM 617951 was in the cached text of PMID:33805425 all along. And
  `parents:` named "Hypomyelinating Leukodystrophy", which matches no entry or
  grouping in kb/ — it now uses the descriptive parent the sibling HLD10 entry
  uses.

  Orphanet was not consulted for this entry. `just refresh-orphadata` currently
  fails: the checksums pinned in data/orphadata/MANIFEST.yaml are for the
  2025-12-09 snapshot and Orphadata now serves a 2026-06-23 release at the same
  URLs. Bumping that pin rebuilds all 345 committed ORPHA cache files, which is
  out of scope for a disease curation. Tracked separately.

  There is a second axis of variant non-interchangeability beyond the molecular
  routes modelled in the pathograph. The three hypothesis groups there
  distinguish *how* a variant reduces EPRS1 function; the fourth group
  (domain_dependent_phenotype) distinguishes *which of the enzyme's two
  functions* is lost, since EPRS1 carries separate GluRS and ProRS synthetase
  domains. The published series associates ProRS-domain variants with the
  typical hypomyelinating imaging pattern and GluRS-domain variants with
  seizures, deafness and less obvious hypomyelination. It is recorded as
  EMERGING and graded PARTIAL because the source hedges and rests on eight
  patients; do not read it as an established genotype-phenotype rule.

  The severity spectrum is wider than the original cohort suggested and the
  entry should not be read as describing a uniformly severe infantile disease.
  PMID:41721156 reports a woman whose only childhood signs were slightly
  below-average school performance and mild sports coordination difficulty, who
  worked in an office job and did not develop disabling symptoms until her
  thirties. That case also carries the first EPRS1 exonic deletion, so a single
  detected point variant in a suspected case does not exclude HLD15 without
  structural-variant analysis.

  Note also that PMID:33805425's own experiments are in a mouse oligodendroglial
  cell line (FBD-102b), so its mechanism evidence is IN_VITRO while its clinical
  statements are OTHER. Two different gradings from one paper is correct here
  and is exactly the case CLAUDE.md's "split evidence items so each gets a
  single evidence_source" rule is describing.
📚

References & Deep Research

References

4
PMID:29576217
Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.
No top-level findings curated for this source.
PMID:38769304
Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m(6)A site accessibility.
No top-level findings curated for this source.
PMID:33805425
Hypomyelinating Leukodystrophy 15 (HLD15)-Associated Mutation of EPRS1 Leads to Its Polymeric Aggregation in Rab7-Positive Vesicle Structures, Inhibiting Oligodendroglial Cell Morphological Differentiation.
No top-level findings curated for this source.
PMID:41721156
Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15.
No top-level findings curated for this source.