AARS1-related Leukoencephalopathy (MONDO:1010132): Research Report

Prepared: 2026-10-14 How sources were checked. Most claims below come from abstracts or full texts cached locally in references_cache/ for the draft entry kb/disorders/AARS1-related_Leukoencephalopathy.yaml. I re-read each one this session. A few identifiers and recent papers came from web search only. Those are marked [web, not cached], and they need just fetch-reference before anyone uses them as evidence. Where a quote is shown, it is copied from the cached text.

1. Disease Information

Overview. AARS1-related leukoencephalopathy is a disorder of the central nervous system's white matter. It is caused by defects in AARS1, the cytoplasmic alanyl-tRNA synthetase (AlaRS). This enzyme attaches alanine to tRNA^Ala and also proofreads the product, removing serine or glycine attached by mistake. The disease is a spectrum:

1. Early-infantile form (DEE29). Biallelic, autosomal recessive variants cause an epileptic encephalopathy that starts in early infancy. Features include deficient or persistently delayed myelination, progressive microcephaly, spasticity, peripheral neuropathy and clubfoot (PMID:25817015, PMID:28493438).
2. Later-onset recessive form. Onset is after the first year of life. MRI shows a progressive leukoencephalopathy that starts in the posterior white matter and later reaches the frontal white matter. Decline is rapid (PMID:34446925).
3. Adult-onset forms with axonal spheroids.
4. Swedish-type hereditary diffuse leukoencephalopathy with spheroids (HDLS-S) is autosomal dominant. It has been reported in a single large Swedish family and is attributed to AARS1 p.Cys152Phe (PMID:31775912).
5. One consanguineous Chinese family had recessive adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), homozygous for p.Thr606Ile (PMID:37106376).

"Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter." (PMID:34446925)

Identifiers

Synonyms. AARS1-related white matter disease; AARS-related epileptic encephalopathy with deficient myelination; DEE29; EIEE29; HDLS-S (Swedish-type HDLS); AARS1-associated ALSP.

Source type. All data come from aggregated case reports and small cohorts. The largest series is 11 individuals (PMID:34446925). No EHR or registry data exist.

Related conditions that are not this disease (AARS1 allelic disorders): - CMT2N (autosomal dominant axonal neuropathy). This is a separate peripheral nerve disease, not a leukoencephalopathy. - Trichothiodystrophy 8, nonphotosensitive (MONDO:0030517). Here AARS1 variants make the protein unstable (PMID:33909043). The draft entry already lists it, and it should stay a separate or sibling concept rather than a subtype.

2. Etiology

• Cause. The disease is monogenic, caused by germline AARS1 variants.
• The recessive forms come from biallelic loss of function: reduced aminoacylation, protein instability, and in some cases loss of editing.
• The dominant HDLS-S form (p.Cys152Phe) is reported in a single family, and its mechanism is unproven.
• Genetic risk factors. Biallelic variants are causal. Consanguinity raises the risk of homozygosity: the homozygous p.Arg751Gly case (PMID:25817015) and the homozygous p.Thr606Ile family (PMID:37106376).
• Environmental risk or protective factors. None reported.
• Gene–environment interactions. None reported. Febrile or metabolic stress is a plausible trigger, since cellular stress worsens translation errors, but this has not been documented for AARS1. Treat it as a hypothesis only.
• Protective genetic factors or modifiers. None reported.

3. Phenotypes

Frequencies are qualitative, because the case series are very small. Counts come from the index reports (n = 3 + 2) and the Helman cohort (n = 11).

HPO caveat. These HPO IDs are suggestions from memory, except where they match bindings already in the draft entry (HP:0003429, HP:0200134, HP:0000253, HP:0001257, HP:0001762, HP:0001284, HP:0009830, HP:0002352, HP:0034381). Under the repository's term contract, look up every other ID before binding it.

Quality of life. No formal instrument data exist. - The infantile form leaves children profoundly dependent. - In the ALSP case the patient was wheelchair-dependent by age 25, two years after onset (PMID:37106376). - HDLS-S has a median survival under 10 years (PMID:31775912).

4. Genetic and Molecular Information

Gene. AARS1 (alanyl-tRNA synthetase 1, cytoplasmic). hgnc:20; OMIM *601065 [web]. The protein has four parts: an aminoacylation domain, a tRNA-recognition domain, an editing domain and a C-terminal domain (C-Ala).

Reported disease variants (all germline)

"The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation." (PMID:28493438)

"...trio analysis did not find any mutations related to CSF1R or AARS2, but revealed a homozygous nonsynonymous variant AARS1:NM_001605:exon14:c.1817C > T:p.Thr606Ile" (PMID:37106376, full text)

Variant classification. - ClinVar lists p.Gly913Asp with conflicting interpretations (3 submissions) [web]. - GenCC carries AARS1 submissions [web: SGC-107335, SGC-179765]. A curation summary seen in search results says the dominant HDLS-S form has no additional unrelated cases. The tiers themselves were not read. Per repository policy they must be copied from the source, never assigned.

Not supporting evidence. PMID:38689878 reports a heterozygous AARS1 p.Arg695* inherited together with a CACNA1A variant in two sisters with epileptic encephalopathy. It shows neither biallelic AARS1 disease nor a leukoencephalopathy. At most it is NO_EVIDENCE for this entry and should not be cited as support.

Other genomic findings. - Allele frequencies: the reported variants are rare or absent in gnomAD. Exact figures were not retrieved; check gnomAD. - Modifier genes: none reported. - Epigenetic findings: none reported. - Chromosomal abnormalities: none reported. AARS1 sits within 16q22, but deletions of the region are not described as producing this phenotype.

5. Environmental Information

There are no known environmental, lifestyle or infectious contributors. This should be stated as not applicable.

6. Mechanism / Pathophysiology

Causal chain (numbered; inferred steps flagged)

1. Biallelic AARS1 loss-of-function variants lead to reduced AlaRS abundance or catalytic efficiency. Evidence: protein destabilization in patient lymphoblastoid cells and a 70–90% loss of aminoacylation (PMID:28493438); reduced fibroblast AlaRS activity (PMID:34446925, PMID:25817015). Demonstrated.
2. The disease branches at this step.
3. 2a. Reduced aminoacylation leads to a lower supply of charged tRNA^Ala and slower translation in cells with high protein-synthesis demand. Inferred from enzyme kinetics; direct human cell data on translation are limited.
4. 2b. Loss of editing (p.Tyr690Leufs3; mouse sticky) leads to misacylated tRNA (Ser-tRNA^Ala) and serine wrongly inserted at alanine codons. Demonstrated* in vitro (PMID:28493438) and in mouse (PMID:16906134).
5. Branch 2b leads to misfolded proteins accumulating, chaperones increasing, and the unfolded protein response switching on in neurons. Demonstrated in the mouse sti model only (PMID:16906134).

   "low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response."

6. Loss of translational capacity or fidelity in oligodendrocytes, which need large amounts of myelin protein, leads to failure of CNS myelination. This explains the hypomyelination (infantile form) or the progressive white matter degeneration (late forms). Inferred: no oligodendrocyte-specific AARS1 model has been reported.
7. In neurons, the same defects lead to neuronal or axonal degeneration: Purkinje cell loss in the mouse (PMID:16906134) and axonal spheroids in adult human brains (PMID:31775912, PMID:37106376). Demonstrated in mouse; human pathology is correlative.
8. Cortical network dysfunction plus failed myelination produce epileptic encephalopathy, developmental delay and progressive microcephaly (PMID:25817015, PMID:28493438). Mechanistic link inferred.
9. Loss of white matter and long tracts leads to spasticity, extrapyramidal signs and visual pathway loss. Peripheral axon involvement leads to neuropathy and areflexia.
10. The adult-onset forms progress to diffuse white matter liquefaction ("widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front", PMID:31775912), and to dementia and death.

Unresolved branch: the dominant form. It is not established how a heterozygous p.Cys152Phe causes HDLS-S. Possibilities include a dominant-negative effect on the AlaRS dimer, as proposed for CMT2N, but this is untested for this variant. Record it as a KNOWLEDGE_GAP.

Emerging non-canonical biology [web, not cached]. AARS1 also senses lactate and acts as a lactyltransferase: - It lactylates p53 (Zong et al., Cell 2024, PMID:38653238). - AARS1 and AARS2 lactylate cGAS (Li et al., Nature 2024, PMID:39322678).

No one has shown that this matters in the leukoencephalopathy. It is a hypothesis to note, not a node to curate.

Checklist items

• Molecular function: GO:0004813 alanine-tRNA ligase activity. Editing activity: suggested GO:0002196 Ser-tRNA(Ala) hydrolase activity (verify before binding).
• Biological processes: GO:0006419 alanyl-tRNA aminoacylation; GO:0106074 aminoacyl-tRNA metabolism involved in translational fidelity; GO:0006986 response to unfolded protein; GO:0022010 central nervous system myelination. All four are in the draft. GO:0030968 endoplasmic reticulum unfolded protein response is a more specific candidate; verify it.
• Cell types:
• CL:0000128 oligodendrocyte, CL:0000121 Purkinje cell (mouse); both in the draft.
• Suggested, to verify: CL:0000540 neuron; CL:0000129 microglial cell and CL:0000235 macrophage (end-stage pathology).
• Metabolic and immune involvement: no primary metabolic defect or immune mechanism is reported. The macrophages and pigmented glia are best read as a downstream reaction to tissue destruction.
• Molecular profiling (transcriptomics, proteomics, single-cell, CRISPR screens): no disease-specific datasets were found.

7. Anatomical Structures Affected

8. Temporal Development

• Onset.
• Infantile form: neonatal to early infancy, with clubfoot already present at birth.
• Late form: after 12 months, including childhood (PMID:34446925).
• Adult forms: about age 23 in ALSP (PMID:37106376) and in adulthood in HDLS-S (PMID:31775912).
• Course.
• Infantile form: static-to-progressive (progressive microcephaly, refractory epilepsy).
• Late and adult forms: rapidly progressive. In ALSP the patient lost walking within about 2 years. In HDLS-S, frontal symptoms come first, followed by "a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms" (PMID:31775912).
• Stages. No formal staging exists. Suggested progression: phases: infantile/presymptomatic onset; progressive leukoencephalopathy; end-stage white matter liquefaction.
• Remission. None reported.
• Critical periods. Developmental myelination in infancy (inferred).

9. Inheritance and Population

• Inheritance.
• Autosomal recessive (HP:0000007) for DEE29 and the late and ALSP forms.
• Autosomal dominant (HP:0000006) for HDLS-S, in a single family.
• Penetrance and expressivity.
• The recessive form appears fully penetrant. Expressivity varies widely, from infantile to adult onset.
• In HDLS-S, the dominant segregation suggests high penetrance, but this rests on one pedigree.
• Prevalence. Not known; ultra-rare. Fewer than about 20 recessive cases are published. Use measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE or NOT_YET_DOCUMENTED.
• For context only: leukodystrophy incidence overall has been estimated at "approximately 1/50,000 to 1/7663" (PMID:42650065). That figure is not specific to AARS1 and should not be used as AARS1 prevalence.
• Founder effects. None established. The only possible example is the HDLS-S family's western Swedish origin.
• Consanguinity. Documented in homozygous cases (PMID:37106376).
• Anticipation and germline mosaicism. Neither is reported.
• Carrier frequency. Not established.
• Demographics. Cases reported from the USA, Europe (Italy, Germany, Hungary, UK, Sweden), China and Ecuador. Both sexes are affected.

10. Diagnostics

• Imaging (MRI). This is the main clue.
• Infantile form: deficient or persistently delayed myelination with atrophy.
• Late form: leukoencephalopathy that begins posteriorly and spreads frontally.
• Adult forms: symmetric periventricular and corpus callosum FLAIR hyperintensity. In ALSP, diffusion restriction is described as resembling CSF1R-ALSP (PMID:37106376).
• EEG. Epileptiform activity in the infantile form. The EEG was normal in the adult ALSP case.
• Nerve conduction studies. Axonal and demyelinating neuropathy.
• Functional assay. AlaRS aminoacylation activity in fibroblasts or lymphoblastoid cells supports pathogenicity (PMID:34446925, PMID:28493438). This is a research test rather than a routine clinical one.
• Pathology. Axonal spheroids, pigmented glia and macrophages; end-stage white matter liquefaction (PMID:31775912).
• Genetic testing.
• Exome or genome sequencing found every reported case.
• Leukodystrophy and epilepsy gene panels should include AARS1.
• In adult CSF1R-negative spheroid leukoencephalopathy, test AARS1 and AARS2 (PMID:31775912, PMID:37106376).
• CMA, karyotype, FISH and repeat-expansion testing are not indicated.
• Differential diagnosis.
• CSF1R-ALSP and AARS2-ALSP (mitochondrial AlaRS).
• Other hypomyelinating leukodystrophies: POLR3-related, PMD/PLP1, and other aminoacyl-tRNA synthetase disorders (RARS1, DARS1, EPRS1, KARS1).
• Other DEEs.
• Nonphotosensitive TTD due to AARS1, which has brittle hair (PMID:33909043).
• Screening. No newborn screening exists. Cascade carrier testing within families is appropriate.

11. Outcome / Prognosis

• Infantile form. Severe, lifelong disability. Survival data are not systematically reported.
• Late form. "a similarly rapid progressive clinical decline" (PMID:34446925).
• HDLS-S. Median survival is under 10 years from onset (PMID:31775912).
• Prognostic factors and biomarkers. None validated. Age at onset is the main determinant of phenotype.
• Complications. Refractory epilepsy, feeding difficulty or cachexia (PMID:37106376), contractures, visual loss.

12. Treatment

No disease-modifying therapy and no clinical trials were found. Management is supportive:

Experimental and speculative approaches (none tested in AARS1 disease): - Amino acid supplementation, which has been tried in other cytoplasmic tRNA synthetase disorders (e.g., IARS1, LARS1). - Gene replacement.

The 2026 review discusses "emerging therapeutic perspectives" (PMID:42650065), but none are clinically validated. Any such content would at most fit a KNOWLEDGE_GAP discussion, not a treatment.

13. Prevention

• Primary prevention. Not applicable.
• Reproductive options. Genetic counseling (25% recurrence risk for the recessive forms; 50% for the dominant HDLS-S form), carrier testing of relatives, prenatal diagnosis or PGT once the familial variants are known.
• Tertiary prevention. Seizure control, prevention of contractures and nutritional management.
• Vaccination, public health and environmental measures. Not applicable.

14. Other Species / Natural Disease

• No naturally occurring animal disease was found; OMIA was not searched.
• AlaRS editing is conserved down to bacteria; the sticky paper used E. coli experiments (PMID:16906134).
• Mouse ortholog: Aars1 (MGI; verify the identifier before use).

15. Model Organisms

Notes on the sti mouse. - The p.Ala734Glu genotype is from my memory of the paper. The cached abstract does not state it, so verify it from the full text. - For curation, the sti mouse should be a PARTIALLY_RECAPITULATES link to the misfolding/UPR node, with fidelity: LOW against the hypomyelination node. This is a case for a HUMAN_MODEL_MISMATCH discussion.

Missing models. No oligodendrocyte-specific or knock-in model of the recessive human variants was found. This is a clear knowledge gap.

Evidence Summary and Curation Notes

1. Strongest human evidence:
2. PMID:25817015 (index DEE; loss of function)
3. PMID:28493438 (aminoacylation and editing loss; progressive microcephaly)
4. PMID:34446925 (spectrum; late-onset form)
5. Adult forms rest on one family each: PMID:31775912 (AD, HDLS-S) and PMID:37106376 (AR, ALSP). Use directness/notes to say that these assertions come from a single family.
6. Mechanistic evidence is mainly mouse (PMID:16906134, MODEL_ORGANISM). Keep it separate from human evidence.
7. PMID:35168888 (Leidi et al. correspondence) has no cached content, so it cannot provide snippets.
8. PMID:38689878 should not be cited as support (§4).
9. PMID:33909043 (TTD8) belongs to an allelic, distinct disease. Do not merge its phenotypes into this entry.
10. Identifiers not cached: run just fetch-reference for every [web]-tagged identifier (ORPHA:442835, PMID:38653238, PMID:39322678) before citing it. Look up every HPO, GO, CL and UBERON term not already in the draft before binding it.

Sources

Cached locally (references_cache/): PMID:16906134, 25817015, 28493438, 31775912, 33909043, 34446925, 35168888, 37106376, 38689878, 42650065.

Web (not cached): - MedGen C4225361 mirror - ClinVar RCV000995470 (p.Gly913Asp) - LOVD DEE29 (OMIM:616339) - DOID:0080451 - MONDO:1010132 node - GenCC SGC-107335, GenCC SGC-179765 - Wu et al. 2023, PMC10142409 - CeGaT summary of Helman 2021 - AARS1/AARS2 lactate-sensor review, PMC12373605 - Zong 2024 Cell (PMID 38653238) - Li 2024 Nature (PMID 39322678) - Neurogenetics 2026 article (not reviewed)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:34446925 (abstract only): "a similarly rapid progressive clinical decline"
• closest text in source: "However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• DOID:0080451 (5 mentions) - the report calls it "DOID"; DOID calls it developmental and epileptic encephalopathy 29
• HP:0001257 (2 mentions) - the report calls it "Spasticity / hypertonia, hyperreflexia"; HP calls it Spasticity

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0000007 (1 mention) - the report calls it "Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names
• HP:0000006 (1 mention) - the report calls it "Autosomal dominant"; HP calls it Autosomal dominant inheritance, and lists "Autosomal dominant" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM.