AARS1-related Leukoencephalopathy

Mendelian MONDO:1010132 Pathograph 30 Show in embeddings browser leukodystrophy aminoacyl-tRNA synthetase disorder

AARS1-related leukoencephalopathy is central nervous system white-matter disease caused by pathogenic variants in AARS1, which encodes cytoplasmic alanyl-tRNA synthetase (AlaRS). AlaRS charges tRNA-Ala with alanine and proofreads (edits) mischarged tRNA-Ala. The spectrum has two inheritance arms. Biallelic loss-of-function variants cause an infantile-onset epileptic encephalopathy with persistently deficient myelination, progressive microcephaly and spasticity (developmental and epileptic encephalopathy 29), together with a later-onset progressive leukoencephalopathy and a non-photosensitive trichothiodystrophy presentation (curated in Trichothiodystrophy). A heterozygous aminoacylation-domain variant segregates with a rapidly progressive adult-onset leukoencephalopathy with axonal spheroids in the Swedish HDLS kindred (hereditary diffuse leukoencephalopathy with spheroids 2). In the recessive cases studied, alanine-tRNA charging activity is reduced, and some variants also destabilize the protein or abolish editing. Dominant AARS1 axonal neuropathy (Charcot-Marie-Tooth disease type 2N) is a separate allelic disorder curated in Charcot-Marie-Tooth_Disease_Type_2. There is no disease-modifying therapy.

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2
Inheritance
7
Pathophys.
24
Phenotypes
2
Gaps
30
Pathograph
1
Genes
6
Variants
1
Medical Actions
5
Subtypes
1
Models
1
Deep Research
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Inheritance

2
Autosomal Recessive HP:0000007
Biallelic AARS1 variants cause the infantile-onset epileptic encephalopathy, the later-onset recessive leukoencephalopathy, the adult-onset recessive ALSP family and TTD8.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:25817015 SUPPORT Human Clinical
"the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS."
Compound heterozygous and homozygous probands establish recessive inheritance.
PMID:37106376 SUPPORT Human Clinical
"His parents and brother carried the same heterozygous variant"
Heterozygous relatives of the homozygous adult-onset proband.
PMID:37106376 SUPPORT Human Clinical
"His parents and younger brother had no neurological symptoms, as confirmed by electromyogram and magnetic resonance imaging (MRI)."
The heterozygous carriers are unaffected, consistent with recessive inheritance in this family.
Autosomal Dominant HP:0000006
Applies only to the HDLS2 presentation. The Swedish HDLS kindred shows dominant segregation of a heterozygous AARS1 variant; this rests on a single family.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:31775912 SUPPORT Human Clinical
"Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern."
Dominant segregation of the disease in the HDLS-S kindred.
PMID:31775912 SUPPORT INDIRECT Human Clinical
"We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease."
The heterozygous variant is named only as the probable cause in this one family.
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Subtypes

5
Developmental and epileptic encephalopathy 29 (infantile-onset, recessive) MONDO:0014593
The predominant presentation of biallelic AARS1 variants: infantile-onset refractory epileptic encephalopathy with persistently deficient myelination, progressive microcephaly, spasticity and peripheral neuropathy.
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
Index description of the recessive infantile-onset presentation.
Later-onset recessive AARS1 leukoencephalopathy
Biallelic AARS1 disease with onset after the first year of life and a progressive, posterior-predominant leukoencephalopathy that extends to the frontal white matter, with rapid clinical decline. No separate MONDO term.
Show evidence (1 reference)
PMID:34446925 SUPPORT Human Clinical
"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."
Defines the later-onset recessive group in an 11-patient cohort.
Hereditary diffuse leukoencephalopathy with spheroids 2 (adult-onset) MONDO:0030634
Adult-onset, rapidly progressive leukoencephalopathy with neuroaxonal spheroids, described as dominant in the Swedish HDLS kindred carrying the heterozygous p.Cys152Phe aminoacylation-domain variant. This rests on a single family, and the authors call the variant the probable cause. Distinct from the CSF1R-related disorder curated in Hereditary_Diffuse_Leukoencephalopathy_with_Spheroids.
Show evidence (1 reference)
PMID:31775912 SUPPORT Human Clinical
"We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease."
Assigns the Swedish HDLS kindred to AARS1.
Adult-onset recessive AARS1 leukoencephalopathy with spheroids and pigmented glia
One consanguineous family with a homozygous p.Thr606Ile variant and heterozygous unaffected relatives: onset in the early twenties with gait difficulty, then dysarthria, visual loss and cognitive decline, with axonal spheroids on biopsy. The authors treat it as a recessive entity separate from the dominant Swedish kindred. No separate MONDO term; single family.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"In this study, we associated a recessive AARS1 variant with ALSP (AARS1-AR-ALSP)."
Defines the recessive adult-onset spheroid presentation.
Trichothiodystrophy 8, nonphotosensitive MONDO:0030517
Biallelic AARS1 variants that destabilize AlaRS cause non-photosensitive trichothiodystrophy. MONDO places TTD8 under AARS1-related leukoencephalopathy, so the row is kept here for discoverability, but its hair, skin and developmental phenotypes are curated with the other non-photosensitive TTD genes in Trichothiodystrophy.
Show evidence (1 reference)
PMID:33909043 SUPPORT Human Clinical
"Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD."
Establishes AARS1 as a non-photosensitive TTD gene.
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Discussions and Knowledge Gaps

2
How does a single heterozygous aminoacylation-domain variant (p.Cys152Phe) cause adult-onset spheroid leukoencephalopathy, when heterozygous carriers in the recessive adult-onset family are unaffected?
KNOWLEDGE GAP aars1_dominant_hdls_mechanism
Attached to
pathophysiology#Heterozygous AARS1 p.Cys152Phe Variant pathophysiology#Neuroaxonal Degeneration with Spheroids
The variant did not change splicing or brain expression, its effect on AlaRS activity has not been reported, and the dominant presentation rests on one family. In the recessive ALSP family the parents and brother carry the variant heterozygously (PMID:37106376). A dominant-negative effect on the AlaRS dimer is possible but untested.
Does the editing-defect mechanism shown in the sticky mouse operate in human AARS1 leukoencephalopathy, which is a white matter disease and is mainly caused by loss of aminoacylation?
HUMAN MODEL MISMATCH aars1_sticky_mouse_fidelity
Attached to
pathophysiology#Neuronal Misfolded Protein Accumulation pathophysiology#Deficient CNS Myelination
The sticky mouse shows Purkinje cell death from mistranslation, not hypomyelination, and only one human variant has been shown to abolish editing. No model carrying a recessive human variant, and no oligodendrocyte-specific model, has been reported.
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Pathophysiology

7
Biallelic AARS1 Loss of Function
Recessive AARS1 variants reduce alanyl-tRNA synthetase function, through reduced aminoacylation activity, reduced protein abundance, or both.
AARS1 hgnc:20 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AARS1 (hgnc:20). hgnc:20 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
alanine-tRNA ligase activity GO:0004813 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased alanine-tRNA ligase activity (GO:0004813). GO:0004813 is a molecular function from the Gene Ontology.
Downstream
Reduced Alanyl-tRNA Charging
Defective tRNA-Ala Editing
Neuroaxonal Degeneration with Spheroids Applies to the adult-onset recessive ALSP family. The intermediate steps between the homozygous variant and spheroid formation are not known.
Show evidence (2 references)
PMID:25817015 SUPPORT In Vitro
"The two identified mutations were found to result in a significant reduction in function."
Functional testing of the index recessive variants shows loss of function.
PMID:28493438 SUPPORT In Vitro
"A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance."
Patient cells show reduced AlaRS protein.
Heterozygous AARS1 p.Cys152Phe Variant
The heterozygous aminoacylation-domain variant segregating in the Swedish HDLS kindred, named by the authors as the probable cause. It does not alter splicing or brain expression, and its effect on AlaRS activity has not been reported, so no functional impact category is assigned.
AARS1 hgnc:20 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AARS1 (hgnc:20). hgnc:20 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE
Downstream
Neuroaxonal Degeneration with Spheroids Applies to HDLS2; the mechanism linking the variant to spheroids is unknown.
Show evidence (1 reference)
PMID:31775912 SUPPORT INDIRECT Human Clinical
"The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain."
Locates the variant and excludes splicing or expression effects; its consequence for the enzyme is not tested.
Reduced Alanyl-tRNA Charging
Reduced aminoacylation of tRNA-Ala lowers the supply of charged tRNA-Ala for cytoplasmic translation.
cytoplasmic alanyl-tRNA aminoacylation GO:0006419 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytoplasmic alanyl-tRNA aminoacylation, annotated with alanyl-tRNA aminoacylation (GO:0006419). GO:0006419 is a biological process from the Gene Ontology.
Downstream
Deficient CNS Myelination
Show evidence (3 references)
PMID:28493438 SUPPORT In Vitro
"The mutations decrease aminoacylation efficiency by 70%-90%."
Direct measurement of reduced aminoacylation by the recessive variants.
PMID:34446925 SUPPORT In Vitro
"AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes."
Reduced activity measured in patient fibroblasts across both recessive presentations.
PMID:37106376 SUPPORT In Vitro
"In aminoacylation and misaminoacylation assays, the AlaRS T606I variant showed deficient aminoacylation efficiency"
The adult-onset recessive variant also reduces aminoacylation.
Defective tRNA-Ala Editing
AlaRS hydrolyses mischarged tRNA-Ala (for example Ser-tRNA-Ala). Loss of editing raises mistranslation at alanine codons. In the reported human case this applies to one variant only; the downstream consequence comes from the sticky mouse.
aminoacyl-tRNA metabolism involved in translational fidelity GO:0106074 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074). GO:0106074 is a biological process from the Gene Ontology.
Downstream
Neuronal Misfolded Protein Accumulation
Show evidence (1 reference)
PMID:28493438 SUPPORT In Vitro
"The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation."
One patient variant abolishes editing.
Neuronal Misfolded Protein Accumulation
In the sticky mouse, an editing-domain Aars missense variant causes accumulation of misfolded proteins, chaperone upregulation and the unfolded protein response in Purkinje cells, followed by their death. Whether this occurs in human AARS1 disease has not been shown.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
response to unfolded protein GO:0006986 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to unfolded protein (GO:0006986). GO:0006986 is a biological process from the Gene Ontology.
Animal models
Sticky mouse (Aars editing-domain missense) Mouse partially recapitulates
Show evidence (1 reference)
PMID:16906134 SUPPORT Model Organism
"These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response."
Mouse evidence that an AlaRS editing defect causes neuronal protein misfolding.
Deficient CNS Myelination
Recessive AARS1 disease shows persistently deficient myelination on MRI, or a progressive leukoencephalopathy in later-onset cases. Oligodendrocytes are bound because CNS myelination is their function; no oligodendrocyte-level data exist, and the cellular step between reduced charging and the myelin defect has not been established.
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.
central nervous system myelination GO:0022010 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased central nervous system myelination (GO:0022010). GO:0022010 is a biological process from the Gene Ontology.
cerebral white matter UBERON:0002316 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral white matter, annotated with white matter (UBERON:0002316). UBERON:0002316 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
CNS hypomyelination
Leukoencephalopathy
Thin corpus callosum
Spasticity
Show evidence (1 reference)
PMID:25817015 SUPPORT INDIRECT Human Clinical
"The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease..."
The authors attribute the central myelin defect to reduced alanyl-tRNA charging; this is an inference from genetics and enzyme activity, not a measurement in oligodendrocytes.
Neuroaxonal Degeneration with Spheroids
Applies to the adult-onset HDLS2 and recessive ALSP presentations. They are marked by neuroaxonal degeneration with spheroids, ending in white matter liquefaction in the Swedish kindred. How AARS1 variants produce it is unknown.
cerebral white matter UBERON:0002316 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral white matter, annotated with white matter (UBERON:0002316). UBERON:0002316 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Central nervous system axonal spheroid
Central nervous system axonal spheroid (recessive adult-onset)
Extrapyramidal signs
Visual impairment
Personality changes
Cognitive decline
Dysarthria
Hyperreflexia
Visual impairment (recessive adult-onset)
Show evidence (2 references)
PMID:31775912 SUPPORT Human Clinical
"Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front."
Neuropathology of end-stage HDLS-S.
PMID:31775912 SUPPORT Human Clinical
"Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern."
Neuraxonal degeneration with spheroids is the defining lesion.
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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 AARS1-related Leukoencephalopathy 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

24
Eye 2
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:31775912 SUPPORT Human Clinical
"The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
Optic tract symptoms in HDLS-S.
Visual impairment (recessive adult-onset) HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blurred vision, annotated with Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"At age 25, he was wheelchair-dependent with progressive dysarthria, blurred vision and cognitive decline."
Blurred vision in the recessive AARS1 ALSP proband.
Head and Neck 1
Progressive microcephaly HP:0000253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive microcephaly (HP:0000253). HP:0000253 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28493438 SUPPORT Human Clinical
"Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity."
Progressive microcephaly in recessive siblings.
Limbs 1
Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clubfoot, annotated with Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
Clubfoot in the index cases.
Musculoskeletal 3
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:28493438 SUPPORT Human Clinical
"Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity."
Spasticity in recessive siblings.
Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28493438 SUPPORT Human Clinical
"She had failure to thrive, microcephaly and generalized hypotonia at birth, and spent 6 days in the Neonatal Intensive Care Unit because of apnea and poor feeding."
Neonatal hypotonia in a recessive sibling.
Basal ganglia calcification HP:0002135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia calcification (HP:0002135). HP:0002135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"CT scan (Fig. 1e-1) revealed symmetric patchy calcifications in the basal ganglia."
CT finding in a single proband.
Nervous System 15
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:28493438 SUPPORT Human Clinical
"Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity."
Hypomyelination in recessive siblings.
Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34446925 SUPPORT Human Clinical
"The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination."
Epileptic encephalopathy is the predominant presentation.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent deep tendon reflexes, annotated with Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
Absent reflexes in the index cases.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease..."
Peripheral neuropathy accompanies the central disease.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34446925 SUPPORT Human Clinical
"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."
Imaging hallmark of the later-onset group.
Central nervous system axonal spheroid HP:0034381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Central nervous system axonal spheroid (HP:0034381). HP:0034381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31775912 SUPPORT Human Clinical
"Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern."
Axonal spheroids are the histopathological hallmark.
Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28493438 SUPPORT Human Clinical
"Similar to the previously reported autosomal recessive cases, the affected individuals demonstrated congenital and progressive microcephaly, central hypomyelination and severe early-onset epilepsy, including infantile spasms and Lennox-Gastaut syndrome."
Infantile spasms in both recessive siblings.
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:28493438 SUPPORT Human Clinical
"The corpus callosum was fully formed but very thin."
MRI finding in one of the recessive siblings (a single case).
Cognitive decline Mental deterioration HP:0001268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive decline, annotated with Mental deterioration (HP:0001268). HP:0001268 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"At age 25, he was wheelchair-dependent with progressive dysarthria, blurred vision and cognitive decline."
Cognitive decline in the recessive AARS1 ALSP proband.
Extrapyramidal signs Abnormality of extrapyramidal motor function HP:0002071 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Extrapyramidal symptoms, annotated with Abnormality of extrapyramidal motor function (HP:0002071). HP:0002071 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25817015 SUPPORT Human Clinical
"Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
Extrapyramidal symptoms in the infantile index cases.
PMID:31775912 SUPPORT Human Clinical
"The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
Extrapyramidal involvement in adult-onset HDLS-S.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"At age 25, he was wheelchair-dependent with progressive dysarthria, blurred vision and cognitive decline."
Progressive dysarthria in a single adult proband.
Central nervous system axonal spheroid (recessive adult-onset) HP:0034381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axonal spheroids on brain biopsy, annotated with Central nervous system axonal spheroid (HP:0034381). HP:0034381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"Biopsy showed mild loss of neurofilaments (Fig. 1h-1, i-1), swollen neurons (Fig. 1h-1), and sporadic spheroids (Fig. 1i-1)."
Spheroids on the proband's brain biopsy.
Personality changes HP:0000751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Personality changes (HP:0000751). HP:0000751 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31775912 SUPPORT Human Clinical
"Briefly, at age 46 this previously healthy manual worker suffered a progressive personality change with striking passivity and loss of responsibility at work and at home."
Personality change at onset in one HDLS-S family member.
PMID:31775912 SUPPORT Human Clinical
"The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
Frontal-lobe symptoms dominate the initial stage of HDLS-S.
Hyperreflexia HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"Physical examination showed marasmus (1.73 m height, 40 kg weight, body mass index 13.36), hypertonia, hyperreflexia and decreased muscle strength."
Hyperreflexia in a single adult proband; the infantile index cases instead had absent reflexes.
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 (1 reference)
PMID:28493438 SUPPORT Human Clinical
"The younger sister (MC32501) had a similar clinical course with congenital microcephaly and global developmental delay."
Global developmental delay in a recessive sibling.
Growth 2
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28493438 SUPPORT Human Clinical
"She had failure to thrive, microcephaly and generalized hypotonia at birth, and spent 6 days in the Neonatal Intensive Care Unit because of apnea and poor feeding."
Neonatal failure to thrive in a recessive sibling.
Cachexia HP:0004326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Marasmus, annotated with Cachexia (HP:0004326). HP:0004326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"Physical examination showed marasmus (1.73 m height, 40 kg weight, body mass index 13.36), hypertonia, hyperreflexia and decreased muscle strength."
Severe wasting (BMI 13.4) in a single adult proband.
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Genetic Associations

1
AARS1
Gene: AARS1 hgnc:20 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AARS1 (hgnc:20). hgnc:20 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families"
Identifies AARS1 as the causal gene.
Variants (6)
p.Lys81Thr
Compound heterozygous with p.Arg751Gly in two siblings with DEE29.
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS."
Reports the variant and its zygosity.
p.Arg751Gly
Homozygous in one DEE29 patient and compound heterozygous with p.Lys81Thr in two siblings.
Show evidence (1 reference)
PMID:25817015 SUPPORT Human Clinical
"the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS."
Reports the variant and its zygosity.
c.2067dupC (p.Tyr690Leufs*3)
Compound heterozygous with p.Gly913Asp in two siblings; abolishes editing and reduces protein abundance.
Show evidence (1 reference)
PMID:28493438 SUPPORT Human Clinical
"Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp)."
Reports the variant and its zygosity.
c.2738G>A (p.Gly913Asp)
Compound heterozygous with p.Tyr690Leufs*3 in two siblings.
Show evidence (1 reference)
PMID:28493438 SUPPORT Human Clinical
"Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp)."
Reports the variant and its zygosity.
p.Cys152Phe
Heterozygous in the dominant Swedish HDLS kindred; the probable cause, single family.
Show evidence (1 reference)
PMID:31775912 SUPPORT Human Clinical
"We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease."
Reports the variant.
c.1817C>T (p.Thr606Ile)
Homozygous in the recessive adult-onset ALSP family; reduces aminoacylation.
Show evidence (1 reference)
PMID:37106376 SUPPORT Human Clinical
"revealed a homozygous nonsynonymous variant AARS1:NM_001605:exon14:c.1817C > T:p.Thr606Ile"
Reports the variant and its zygosity.
💊

Medical Actions

1
ACTH for infantile spasms
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticotropin CHEBI:3892 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticotropin (CHEBI:3892). CHEBI:3892 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
Infantile spasms in one recessive patient responded to ACTH only transiently before seizures recurred. This is a single-patient observation, and seizure control is otherwise reported as refractory.
Target Phenotypes: Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28493438 SUPPORT DIRECT Human Clinical
"The infantile spasms transiently responded to adrenocorticotropic hormone (ACTH) therapy but then she had recurrent spasms and seizures, as well as occasional atypical absence seizures."
A transient response in one patient; does not establish lasting benefit.
🔬

Diagnosis

2
Brain MRI
MRI shows persistently deficient myelination in infantile-onset disease, a posterior-predominant leukoencephalopathy that spreads frontally in later-onset recessive disease, and periventricular and corpus callosum hyperintensity in adult-onset disease.
brain MRI NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:34446925 SUPPORT Human Clinical
"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."
The later-onset recessive MRI pattern.
PMID:37106376 SUPPORT Human Clinical
"Similar to patients with CSF1R-ALSP and AARS2-ALSP from our ALSP cohort, brain MRI of the patient revealed predominant symmetric hyperintensity of periventricular white matter and the corpus callosum in FLAIR"
The adult-onset recessive MRI pattern, which resembles CSF1R- and AARS2-related ALSP.
Exome sequencing
Every reported case was identified by exome or genome sequencing. In adults with spheroid leukoencephalopathy and no CSF1R variant, AARS1 and AARS2 should both be tested.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:25817015 SUPPORT Human Clinical
"Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families"
Exome sequencing identified the index recessive families.
PMID:31775912 SUPPORT Human Clinical
"These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies."
Supports testing AARS1 in CSF1R-negative adult spheroid leukoencephalopathy.
📈

Progression

3
Infantile onset (recessive)
Age: Neonatal period to early infancy
Refractory epilepsy, deficient myelination and progressive microcephaly begin in early infancy; clubfoot can be present at birth.
Show evidence (1 reference)
PMID:34446925 SUPPORT Human Clinical
"The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination."
Onset of the predominant recessive form.
Later-onset progressive leukoencephalopathy (recessive)
Age: After the first year of life
Posterior-predominant white matter disease that extends frontally, with rapid clinical decline.
Show evidence (1 reference)
PMID:34446925 SUPPORT Human Clinical
"However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline."
Course of the later-onset recessive form.
Adult-onset spheroid leukoencephalopathy
Age: Adulthood
Frontal-lobe symptoms followed by rapidly advancing encephalopathy, ending in white matter liquefaction. Median survival in the Swedish kindred was under ten years.
Show evidence (1 reference)
PMID:31775912 SUPPORT Human Clinical
"Median survival is less than 10 years."
Survival in HDLS-S, a single family.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists. The largest series has 11 individuals with biallelic variants; the adult-onset forms are each known from one family.
Show evidence (1 reference)
PMID:34446925 SUPPORT Human Clinical
"We identified 11 affected individuals."
The largest reported cohort.
🐁

Animal Models

1
Sticky mouse (Aars editing-domain missense)
The sticky mouse carries an editing-domain Aars missense variant and develops Purkinje cell loss and ataxia. It models the editing defect, not the hypomyelination of the human disease.
Species
Mouse
Genotype
Aars sti/sti (editing-domain missense)
Publication
PMID:16906134
Pathograph links
Neuronal Misfolded Protein Accumulation partially recapitulates fidelity: low
Limitations: Models an editing defect in cerebellar neurons; human AARS1 leukoencephalopathy is mainly an aminoacylation defect with white-matter disease, and only one human variant has been shown to abolish editing.
Show evidence (1 reference)
PMID:16906134 SUPPORT Model Organism
"We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs."
Defines the model and its editing defect.
{ }

Source YAML

click to show 
name: AARS1-related Leukoencephalopathy
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
description: >-
  AARS1-related leukoencephalopathy is central nervous system white-matter
  disease caused by pathogenic variants in AARS1, which encodes cytoplasmic
  alanyl-tRNA synthetase (AlaRS). AlaRS charges tRNA-Ala with alanine and
  proofreads (edits) mischarged tRNA-Ala. The spectrum has two inheritance
  arms. Biallelic loss-of-function variants cause an infantile-onset epileptic
  encephalopathy with persistently deficient myelination, progressive
  microcephaly and spasticity (developmental and epileptic encephalopathy 29),
  together with a later-onset progressive leukoencephalopathy and a
  non-photosensitive trichothiodystrophy presentation (curated in
  Trichothiodystrophy). A heterozygous
  aminoacylation-domain variant segregates with a rapidly progressive
  adult-onset leukoencephalopathy with axonal spheroids in the Swedish HDLS
  kindred (hereditary diffuse leukoencephalopathy with spheroids 2). In the
  recessive cases studied, alanine-tRNA charging activity is reduced, and some
  variants also destabilize the protein or abolish editing. Dominant AARS1
  axonal neuropathy (Charcot-Marie-Tooth disease type 2N) is a separate
  allelic disorder curated in Charcot-Marie-Tooth_Disease_Type_2. There is no
  disease-modifying therapy.
disease_term:
  preferred_term: AARS1-related leukoencephalopathy
  term:
    id: MONDO:1010132
    label: AARS1-related leukoencephalopathy
synonyms:
- AARS1-related white matter disease
- AARS-related leukoencephalopathy
parents:
- leukodystrophy
- aminoacyl-tRNA synthetase disorder
has_subtypes:
- name: DEE29
  display_name: Developmental and epileptic encephalopathy 29 (infantile-onset, recessive)
  description: >-
    The predominant presentation of biallelic AARS1 variants: infantile-onset
    refractory epileptic encephalopathy with persistently deficient myelination,
    progressive microcephaly, spasticity and peripheral neuropathy.
  subtype_term:
    preferred_term: developmental and epileptic encephalopathy 29
    term:
      id: MONDO:0014593
      label: developmental and epileptic encephalopathy, 29
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
    explanation: Index description of the recessive infantile-onset presentation.
- name: Later-onset recessive
  display_name: Later-onset recessive AARS1 leukoencephalopathy
  description: >-
    Biallelic AARS1 disease with onset after the first year of life and a
    progressive, posterior-predominant leukoencephalopathy that extends to the
    frontal white matter, with rapid clinical decline. No separate MONDO term.
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Defines the later-onset recessive group in an 11-patient cohort.
- name: HDLS2
  display_name: Hereditary diffuse leukoencephalopathy with spheroids 2 (adult-onset)
  description: >-
    Adult-onset, rapidly progressive leukoencephalopathy with neuroaxonal
    spheroids, described as dominant in the Swedish HDLS kindred carrying the
    heterozygous p.Cys152Phe aminoacylation-domain variant. This rests on a
    single family, and the authors call the variant the probable cause. Distinct from
    the CSF1R-related disorder curated in
    Hereditary_Diffuse_Leukoencephalopathy_with_Spheroids.
  subtype_term:
    preferred_term: hereditary diffuse leukoencephalopathy with spheroids 2
    term:
      id: MONDO:0030634
      label: leukoencephalopathy, hereditary diffuse, with spheroids 2
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease."
    explanation: Assigns the Swedish HDLS kindred to AARS1.
- name: Adult-onset recessive ALSP
  display_name: Adult-onset recessive AARS1 leukoencephalopathy with spheroids and pigmented glia
  description: >-
    One consanguineous family with a homozygous p.Thr606Ile variant and
    heterozygous unaffected relatives: onset in the early twenties with gait
    difficulty, then dysarthria, visual loss and cognitive decline, with axonal
    spheroids on biopsy. The authors treat it as a recessive entity separate
    from the dominant Swedish kindred. No separate MONDO term; single family.
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we associated a recessive AARS1 variant with ALSP (AARS1-AR-ALSP)."
    explanation: Defines the recessive adult-onset spheroid presentation.
- name: TTD8
  display_name: Trichothiodystrophy 8, nonphotosensitive
  curated_in: Trichothiodystrophy
  description: >-
    Biallelic AARS1 variants that destabilize AlaRS cause non-photosensitive
    trichothiodystrophy. MONDO places TTD8 under AARS1-related
    leukoencephalopathy, so the row is kept here for discoverability, but its
    hair, skin and developmental phenotypes are curated with the other
    non-photosensitive TTD genes in Trichothiodystrophy.
  subtype_term:
    preferred_term: trichothiodystrophy 8, nonphotosensitive
    term:
      id: MONDO:0030517
      label: trichothiodystrophy 8, nonphotosensitive
  evidence:
  - reference: PMID:33909043
    reference_title: "Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD."
    explanation: Establishes AARS1 as a non-photosensitive TTD gene.
inheritance:
- name: Autosomal Recessive
  description: >-
    Biallelic AARS1 variants cause the infantile-onset epileptic encephalopathy,
    the later-onset recessive leukoencephalopathy, the adult-onset recessive
    ALSP family and TTD8.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS."
    explanation: Compound heterozygous and homozygous probands establish recessive inheritance.
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His parents and brother carried the same heterozygous variant"
    explanation: Heterozygous relatives of the homozygous adult-onset proband.
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His parents and younger brother had no neurological symptoms, as confirmed by electromyogram and magnetic resonance imaging (MRI)."
    explanation: The heterozygous carriers are unaffected, consistent with recessive inheritance in this family.
- name: Autosomal Dominant
  description: >-
    Applies only to the HDLS2 presentation. The Swedish HDLS kindred shows
    dominant segregation of a heterozygous AARS1 variant; this rests on a
    single family.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern."
    explanation: Dominant segregation of the disease in the HDLS-S kindred.
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease."
    explanation: The heterozygous variant is named only as the probable cause in this one family.
pathophysiology:
- name: Biallelic AARS1 Loss of Function
  description: >-
    Recessive AARS1 variants reduce alanyl-tRNA synthetase function, through
    reduced aminoacylation activity, reduced protein abundance, or both.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: AARS1
    term:
      id: hgnc:20
      label: AARS1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: alanine-tRNA ligase activity
    modifier: DECREASED
    term:
      id: GO:0004813
      label: alanine-tRNA ligase activity
  downstream:
  - target: Reduced Alanyl-tRNA Charging
  - target: Defective tRNA-Ala Editing
  - target: Neuroaxonal Degeneration with Spheroids
    description: >-
      Applies to the adult-onset recessive ALSP family. The intermediate steps
      between the homozygous variant and spheroid formation are not known.
    evidence:
    - reference: PMID:37106376
      reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this study, we associated a recessive AARS1 variant with ALSP (AARS1-AR-ALSP)."
      explanation: The authors assign the recessive spheroid leukoencephalopathy to AARS1.
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two identified mutations were found to result in a significant reduction in function."
    explanation: Functional testing of the index recessive variants shows loss of function.
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance."
    explanation: Patient cells show reduced AlaRS protein.
- name: Heterozygous AARS1 p.Cys152Phe Variant
  description: >-
    The heterozygous aminoacylation-domain variant segregating in the Swedish
    HDLS kindred, named by the authors as the probable cause. It does not alter
    splicing or brain expression, and its effect on AlaRS activity has not been
    reported, so no functional impact category is assigned.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: AARS1
    term:
      id: hgnc:20
      label: AARS1
  genetic_context:
    variant_origin: GERMLINE
  downstream:
  - target: Neuroaxonal Degeneration with Spheroids
    description: Applies to HDLS2; the mechanism linking the variant to spheroids is unknown.
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain."
    explanation: Locates the variant and excludes splicing or expression effects; its consequence for the enzyme is not tested.
- name: Reduced Alanyl-tRNA Charging
  description: >-
    Reduced aminoacylation of tRNA-Ala lowers the supply of charged tRNA-Ala
    for cytoplasmic translation.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: cytoplasmic alanyl-tRNA aminoacylation
    modifier: DECREASED
    term:
      id: GO:0006419
      label: alanyl-tRNA aminoacylation
  downstream:
  - target: Deficient CNS Myelination
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutations decrease aminoacylation efficiency by 70%-90%."
    explanation: Direct measurement of reduced aminoacylation by the recessive variants.
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes."
    explanation: Reduced activity measured in patient fibroblasts across both recessive presentations.
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In aminoacylation and misaminoacylation assays, the AlaRS T606I variant showed deficient aminoacylation efficiency"
    explanation: The adult-onset recessive variant also reduces aminoacylation.
- name: Defective tRNA-Ala Editing
  description: >-
    AlaRS hydrolyses mischarged tRNA-Ala (for example Ser-tRNA-Ala). Loss of
    editing raises mistranslation at alanine codons. In the reported human
    case this applies to one variant only; the downstream consequence comes
    from the sticky mouse.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: aminoacyl-tRNA metabolism involved in translational fidelity
    modifier: DECREASED
    term:
      id: GO:0106074
      label: aminoacyl-tRNA metabolism involved in translational fidelity
  downstream:
  - target: Neuronal Misfolded Protein Accumulation
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation."
    explanation: One patient variant abolishes editing.
- name: Neuronal Misfolded Protein Accumulation
  description: >-
    In the sticky mouse, an editing-domain Aars missense variant causes
    accumulation of misfolded proteins, chaperone upregulation and the unfolded
    protein response in Purkinje cells, followed by their death. Whether this
    occurs in human AARS1 disease has not been shown.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: response to unfolded protein
    modifier: INCREASED
    term:
      id: GO:0006986
      label: response to unfolded protein
  evidence:
  - reference: PMID:16906134
    reference_title: "Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response."
    explanation: Mouse evidence that an AlaRS editing defect causes neuronal protein misfolding.
- name: Deficient CNS Myelination
  description: >-
    Recessive AARS1 disease shows persistently deficient myelination on MRI,
    or a progressive leukoencephalopathy in later-onset cases. Oligodendrocytes
    are bound because CNS myelination is their function; no oligodendrocyte-level
    data exist, and the cellular step between reduced charging and the myelin
    defect has not been established.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: central nervous system myelination
    modifier: DECREASED
    term:
      id: GO:0022010
      label: central nervous system myelination
  locations:
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002316
      label: white matter
  downstream:
  - target: CNS hypomyelination
  - target: Leukoencephalopathy
  - target: Thin corpus callosum
  - target: Spasticity
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations."
    explanation: >-
      The authors attribute the central myelin defect to reduced alanyl-tRNA
      charging; this is an inference from genetics and enzyme activity, not a
      measurement in oligodendrocytes.
- name: Neuroaxonal Degeneration with Spheroids
  description: >-
    Applies to the adult-onset HDLS2 and recessive ALSP presentations. They are marked by
    neuroaxonal degeneration with spheroids, ending in white matter
    liquefaction in the Swedish kindred. How AARS1 variants produce it is
    unknown.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002316
      label: white matter
  downstream:
  - target: Central nervous system axonal spheroid
  - target: Central nervous system axonal spheroid (recessive adult-onset)
  - target: Extrapyramidal signs
    evidence:
    - reference: PMID:31775912
      reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
      explanation: Extrapyramidal symptoms are part of the advancing HDLS-S encephalopathy.
  - target: Visual impairment
    evidence:
    - reference: PMID:31775912
      reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
      explanation: Optic tract symptoms are part of the advancing HDLS-S encephalopathy.
  - target: Personality changes
    evidence:
    - reference: PMID:31775912
      reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
      explanation: Frontal-lobe symptoms open the HDLS-S encephalopathy.
  - target: Cognitive decline
  - target: Dysarthria
  - target: Hyperreflexia
  - target: Visual impairment (recessive adult-onset)
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front."
    explanation: Neuropathology of end-stage HDLS-S.
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern."
    explanation: Neuraxonal degeneration with spheroids is the defining lesion.
phenotypes:
- name: CNS hypomyelination
  category: Neurological
  description: Persistently deficient myelination on MRI in infantile-onset disease.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity."
    explanation: Hypomyelination in recessive siblings.
- name: Epileptic encephalopathy
  category: Neurological
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  subtype: DEE29
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination."
    explanation: Epileptic encephalopathy is the predominant presentation.
- name: Progressive microcephaly
  category: Neurological
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  subtype: DEE29
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity."
    explanation: Progressive microcephaly in recessive siblings.
- name: Spasticity
  category: Neurological
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity."
    explanation: Spasticity in recessive siblings.
- name: Talipes equinovarus
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Clubfoot
    term:
      id: HP:0001762
      label: Talipes equinovarus
  subtype: DEE29
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
    explanation: Clubfoot in the index cases.
- name: Areflexia
  category: Neurological
  phenotype_term:
    preferred_term: Absent deep tendon reflexes
    term:
      id: HP:0001284
      label: Areflexia
  subtype: DEE29
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
    explanation: Absent reflexes in the index cases.
- name: Peripheral neuropathy
  category: Neurological
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations."
    explanation: Peripheral neuropathy accompanies the central disease.
- name: Leukoencephalopathy
  category: Neurological
  description: Progressive posterior-predominant leukoencephalopathy in later-onset recessive disease.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  subtype: Later-onset recessive
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Imaging hallmark of the later-onset group.
- name: Central nervous system axonal spheroid
  category: Neurological
  phenotype_term:
    preferred_term: Central nervous system axonal spheroid
    term:
      id: HP:0034381
      label: Central nervous system axonal spheroid
  subtype: HDLS2
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern."
    explanation: Axonal spheroids are the histopathological hallmark.
- name: Infantile spasms
  category: Neurological
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  subtype: DEE29
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to the previously reported autosomal recessive cases, the affected individuals demonstrated congenital and progressive microcephaly, central hypomyelination and severe early-onset epilepsy, including infantile spasms and Lennox-Gastaut syndrome."
    explanation: Infantile spasms in both recessive siblings.
- name: Thin corpus callosum
  category: Neurological
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  subtype: DEE29
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The corpus callosum was fully formed but very thin."
    explanation: MRI finding in one of the recessive siblings (a single case).
- name: Failure to thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  subtype: DEE29
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had failure to thrive, microcephaly and generalized hypotonia at birth, and spent 6 days in the Neonatal Intensive Care Unit because of apnea and poor feeding."
    explanation: Neonatal failure to thrive in a recessive sibling.
- name: Generalized hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  subtype: DEE29
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had failure to thrive, microcephaly and generalized hypotonia at birth, and spent 6 days in the Neonatal Intensive Care Unit because of apnea and poor feeding."
    explanation: Neonatal hypotonia in a recessive sibling.
- name: Cognitive decline
  category: Neurological
  description: Progressive cognitive decline in adult-onset recessive disease.
  phenotype_term:
    preferred_term: Cognitive decline
    term:
      id: HP:0001268
      label: Mental deterioration
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 25, he was wheelchair-dependent with progressive dysarthria, blurred vision and cognitive decline."
    explanation: Cognitive decline in the recessive AARS1 ALSP proband.
- name: Basal ganglia calcification
  category: Neurological
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CT scan (Fig. 1e-1) revealed symmetric patchy calcifications in the basal ganglia."
    explanation: CT finding in a single proband.
- name: Extrapyramidal signs
  category: Neurological
  phenotype_term:
    preferred_term: Extrapyramidal symptoms
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI."
    explanation: Extrapyramidal symptoms in the infantile index cases.
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
    explanation: Extrapyramidal involvement in adult-onset HDLS-S.
- name: Visual impairment
  category: Neurological
  description: Optic tract involvement in adult-onset disease.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  subtype: HDLS2
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
    explanation: Optic tract symptoms in HDLS-S.
- name: Dysarthria
  category: Neurological
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 25, he was wheelchair-dependent with progressive dysarthria, blurred vision and cognitive decline."
    explanation: Progressive dysarthria in a single adult proband.
- name: Visual impairment (recessive adult-onset)
  category: Neurological
  phenotype_term:
    preferred_term: Blurred vision
    term:
      id: HP:0000505
      label: Visual impairment
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 25, he was wheelchair-dependent with progressive dysarthria, blurred vision and cognitive decline."
    explanation: Blurred vision in the recessive AARS1 ALSP proband.
- name: Central nervous system axonal spheroid (recessive adult-onset)
  category: Neurological
  phenotype_term:
    preferred_term: Axonal spheroids on brain biopsy
    term:
      id: HP:0034381
      label: Central nervous system axonal spheroid
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsy showed mild loss of neurofilaments (Fig. 1h-1, i-1), swollen neurons (Fig. 1h-1), and sporadic spheroids (Fig. 1i-1)."
    explanation: Spheroids on the proband's brain biopsy.
- name: Personality changes
  category: Behavioral
  description: >-
    Frontal-lobe symptoms, including personality change and passivity, open
    the disease in the Swedish kindred.
  phenotype_term:
    preferred_term: Personality changes
    term:
      id: HP:0000751
      label: Personality changes
  subtype: HDLS2
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Briefly, at age 46 this previously healthy manual worker suffered a progressive personality change with striking passivity and loss of responsibility at work and at home."
    explanation: Personality change at onset in one HDLS-S family member.
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms."
    explanation: Frontal-lobe symptoms dominate the initial stage of HDLS-S.
- name: Hyperreflexia
  category: Neurological
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination showed marasmus (1.73 m height, 40 kg weight, body mass index 13.36), hypertonia, hyperreflexia and decreased muscle strength."
    explanation: Hyperreflexia in a single adult proband; the infantile index cases instead had absent reflexes.
- name: Cachexia
  category: Metabolic
  phenotype_term:
    preferred_term: Marasmus
    term:
      id: HP:0004326
      label: Cachexia
  subtype: Adult-onset recessive ALSP
  evidence:
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination showed marasmus (1.73 m height, 40 kg weight, body mass index 13.36), hypertonia, hyperreflexia and decreased muscle strength."
    explanation: Severe wasting (BMI 13.4) in a single adult proband.
- name: Global developmental delay
  category: Neurological
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  subtype: DEE29
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The younger sister (MC32501) had a similar clinical course with congenital microcephaly and global developmental delay."
    explanation: Global developmental delay in a recessive sibling.
genetic:
- name: AARS1
  gene_term:
    preferred_term: AARS1
    term:
      id: hgnc:20
      label: AARS1
  relationship_type: CAUSATIVE
  notes: >-
    AARS1 encodes cytoplasmic alanyl-tRNA synthetase. Dominant AARS1 variants
    also cause Charcot-Marie-Tooth disease type 2N, which is outside this entry.
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families"
    explanation: Identifies AARS1 as the causal gene.
  variants:
  - name: p.Lys81Thr
    description: Compound heterozygous with p.Arg751Gly in two siblings with DEE29.
    evidence:
    - reference: PMID:25817015
      reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS."
      explanation: Reports the variant and its zygosity.
  - name: p.Arg751Gly
    description: Homozygous in one DEE29 patient and compound heterozygous with p.Lys81Thr in two siblings.
    evidence:
    - reference: PMID:25817015
      reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS."
      explanation: Reports the variant and its zygosity.
  - name: c.2067dupC (p.Tyr690Leufs*3)
    description: >-
      Compound heterozygous with p.Gly913Asp in two siblings; abolishes editing
      and reduces protein abundance.
    evidence:
    - reference: PMID:28493438
      reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp)."
      explanation: Reports the variant and its zygosity.
  - name: c.2738G>A (p.Gly913Asp)
    description: Compound heterozygous with p.Tyr690Leufs*3 in two siblings.
    evidence:
    - reference: PMID:28493438
      reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp)."
      explanation: Reports the variant and its zygosity.
  - name: p.Cys152Phe
    description: Heterozygous in the dominant Swedish HDLS kindred; the probable cause, single family.
    evidence:
    - reference: PMID:31775912
      reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease."
      explanation: Reports the variant.
  - name: c.1817C>T (p.Thr606Ile)
    description: Homozygous in the recessive adult-onset ALSP family; reduces aminoacylation.
    evidence:
    - reference: PMID:37106376
      reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "revealed a homozygous nonsynonymous variant AARS1:NM_001605:exon14:c.1817C > T:p.Thr606Ile"
      explanation: Reports the variant and its zygosity.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. The largest series has 11 individuals with
    biallelic variants; the adult-onset forms are each known from one family.
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 11 affected individuals."
    explanation: The largest reported cohort.
diagnosis:
- name: Brain MRI
  description: >-
    MRI shows persistently deficient myelination in infantile-onset disease, a
    posterior-predominant leukoencephalopathy that spreads frontally in
    later-onset recessive disease, and periventricular and corpus callosum
    hyperintensity in adult-onset disease.
  diagnosis_term:
    preferred_term: brain MRI
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: The later-onset recessive MRI pattern.
  - reference: PMID:37106376
    reference_title: "An AARS1 variant identified to cause adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to patients with CSF1R-ALSP and AARS2-ALSP from our ALSP cohort, brain MRI of the patient revealed predominant symmetric hyperintensity of periventricular white matter and the corpus callosum in FLAIR"
    explanation: The adult-onset recessive MRI pattern, which resembles CSF1R- and AARS2-related ALSP.
- name: Exome sequencing
  description: >-
    Every reported case was identified by exome or genome sequencing. In adults
    with spheroid leukoencephalopathy and no CSF1R variant, AARS1 and AARS2
    should both be tested.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:25817015
    reference_title: "Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families"
    explanation: Exome sequencing identified the index recessive families.
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies."
    explanation: Supports testing AARS1 in CSF1R-negative adult spheroid leukoencephalopathy.
progression:
- phase: Infantile onset (recessive)
  age_range: Neonatal period to early infancy
  notes: >-
    Refractory epilepsy, deficient myelination and progressive microcephaly
    begin in early infancy; clubfoot can be present at birth.
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination."
    explanation: Onset of the predominant recessive form.
- phase: Later-onset progressive leukoencephalopathy (recessive)
  age_range: After the first year of life
  notes: >-
    Posterior-predominant white matter disease that extends frontally, with
    rapid clinical decline.
  evidence:
  - reference: PMID:34446925
    reference_title: "Expanded phenotype of AARS1-related white matter disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline."
    explanation: Course of the later-onset recessive form.
- phase: Adult-onset spheroid leukoencephalopathy
  age_range: Adulthood
  notes: >-
    Frontal-lobe symptoms followed by rapidly advancing encephalopathy, ending
    in white matter liquefaction. Median survival in the Swedish kindred was
    under ten years.
  evidence:
  - reference: PMID:31775912
    reference_title: "An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median survival is less than 10 years."
    explanation: Survival in HDLS-S, a single family.
treatments:
- name: ACTH for infantile spasms
  description: >-
    Infantile spasms in one recessive patient responded to ACTH only
    transiently before seizures recurred. This is a single-patient observation,
    and seizure control is otherwise reported as refractory.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticotropin
      term:
        id: CHEBI:3892
        label: corticotropin
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:28493438
    reference_title: "Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The infantile spasms transiently responded to adrenocorticotropic hormone (ACTH) therapy but then she had recurrent spasms and seizures, as well as occasional atypical absence seizures."
    explanation: A transient response in one patient; does not establish lasting benefit.
discussions:
- discussion_id: aars1_dominant_hdls_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Heterozygous AARS1 p.Cys152Phe Variant
  - pathophysiology#Neuroaxonal Degeneration with Spheroids
  prompt: >-
    How does a single heterozygous aminoacylation-domain variant (p.Cys152Phe)
    cause adult-onset spheroid leukoencephalopathy, when heterozygous carriers
    in the recessive adult-onset family are unaffected?
  rationale: >-
    The variant did not change splicing or brain expression, its effect on
    AlaRS activity has not been reported, and the dominant presentation rests
    on one family. In the recessive ALSP family the parents and brother carry
    the variant heterozygously (PMID:37106376). A dominant-negative effect on
    the AlaRS dimer is possible but untested.
- discussion_id: aars1_sticky_mouse_fidelity
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Neuronal Misfolded Protein Accumulation
  - pathophysiology#Deficient CNS Myelination
  prompt: >-
    Does the editing-defect mechanism shown in the sticky mouse operate in
    human AARS1 leukoencephalopathy, which is a white matter disease and is
    mainly caused by loss of aminoacylation?
  rationale: >-
    The sticky mouse shows Purkinje cell death from mistranslation, not
    hypomyelination, and only one human variant has been shown to abolish
    editing. No model carrying a recessive human variant, and no
    oligodendrocyte-specific model, has been reported.
animal_models:
- name: Sticky mouse (Aars editing-domain missense)
  species: Mouse
  genotype: Aars sti/sti (editing-domain missense)
  publication: PMID:16906134
  description: >-
    The sticky mouse carries an editing-domain Aars missense variant and
    develops Purkinje cell loss and ataxia. It models the editing defect, not
    the hypomyelination of the human disease.
  modeled_mechanisms:
  - target: Neuronal Misfolded Protein Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    limitations: >-
      Models an editing defect in cerebellar neurons; human AARS1
      leukoencephalopathy is mainly an aminoacylation defect with white-matter
      disease, and only one human variant has been shown to abolish editing.
    evidence:
    - reference: PMID:16906134
      reference_title: "Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs."
      explanation: Defines the model and its editing defect.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: AARS1-related_Leukoencephalopathy · 2026-10-14T17:51:16Z · View source

New gene-level entry for MONDO:1010132 with four subtypes curated here (DEE29; a later-onset recessive group and an adult-onset recessive ALSP family, neither with its own MONDO term; and HDLS2) and a TTD8 pointer row (curated_in: Trichothiodystrophy), since that entry already curates the AARS1 TTD form with the other non-photosensitive TTD genes. Falcon was the requested provider but failed authentication (503 'Failed to authenticate'; deep-research-client providers --check reported it UNREACHABLE), and this checkout's justfile has no dr_fallback option, so the claude_code provider was run directly: research/AARS1-related_Leukoencephalopathy-deep-research-claude_code.md. Its validation block shows 15/15 references resolved and 0 off topic; the one unmatched quote (PMID:34446925) differs from the abstract by one word and was not reused, and the correct abstract sentence is cited instead. preflight-dr PASS (AARS1 mentioned 34 times). PMID:38689878 (heterozygous AARS1 p.Arg695* with a CACNA1A variant) was read and deliberately not cited, because it shows neither biallelic AARS1 disease nor leukoencephalopathy. The lactylation papers the report mentions (PMID:38653238, PMID:39322678) were not used: they have no shown link to this disease. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER). A pre-PR review by a separate agent found the homozygous p.Thr606Ile ALSP family (PMID:37106376) filed under the dominant HDLS2 subtype; it now has its own recessive subtype, and its single-proband phenotypes moved with it. The same review regraded the fibroblast AlaRS activity item to IN_VITRO, marked the charging-to-myelination and variant-causality items INDIRECT, and added global developmental delay, personality change, hyperreflexia and cachexia. Uncited references the report cached (PMID:35168888, 38689878, 42650065, 38653238, 39322678, 40847183, and an EPRS1 DOI) were not committed. The PR review (#14175) found only 2 of 23 phenotypes causally connected and no diagnosis section. Added a root node for the dominant p.Cys152Phe variant (no functional impact category, since its effect on AlaRS is unreported), an edge from biallelic loss of function to the spheroid node for the recessive ALSP family, and edges from the spheroid and myelination nodes to the adult-onset and imaging phenotypes. Connectivity is now 13 of 24; the remaining links (epilepsy, microcephaly, clubfoot, areflexia) have no sourced mechanism and were left unconnected. Also added diagnosis (brain MRI, NCIT:C16809; exome sequencing, NCIT:C101295), a CASES_IN_LITERATURE / ULTRA_RARE prevalence record, the six reported variants with zygosity, and an ALSP-scoped axonal spheroid phenotype from the proband's biopsy. Validation: just validate-disorders passed; count-verified-snippets 68/68; entity refs, causal targets, enum values, duplicate keys and block-scalar checks all clean; check-granularity reports only the expected advisory POINTER_TERM_MISMATCH on the TTD8 pointer.

Claude Code ▸
AARS1-related Leukoencephalopathy (MONDO:1010132): Research Report
claude-haiku-5-5, claude-opus-5-5 13 citations 2026-10-14T13:45:18.979567

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

Resource ID Notes
MONDO (umbrella) MONDO:1010132 AARS1-related leukoencephalopathy Label confirmed in cache/mondo/terms.csv
MONDO (DEE29) MONDO:0014593 developmental and epileptic encephalopathy, 29 Cached
MONDO (HDLS-S) MONDO:0030634 leukoencephalopathy, hereditary diffuse, with spheroids 2 Used in the draft entry
OMIM 616339 (DEE29) [web, not cached]; LOVD, ClinVar RCV000995470
Orphanet ORPHA:442835 (DEE29) [web, not cached]: seen only as a ClinVar cross-reference. Check with just fetch-reference ORPHA:442835
MedGen C4225361 [web, not cached]
DOID DOID:0080451 [web, not cached]; glycosmos
Gene AARS1, hgnc:20, chromosome 16q22 Draft binding

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).

Phenotype Suggested HPO Onset Course Frequency / notes Source
Epileptic encephalopathy, refractory seizures (often myoclonic) HP:0200134 Epileptic encephalopathy Neonatal/early infancy Refractory Very frequent in the infantile form; less defined in the late form PMID:25817015, 28493438
Deficient / delayed myelination HP:0003429 CNS hypomyelination Infancy Persistent All index cases ("persistently deficient myelination on MRI") PMID:25817015
Progressive microcephaly HP:0000253 Infancy Progressive Index siblings PMID:28493438
Spasticity / hypertonia, hyperreflexia HP:0001257 Infancy (late form: childhood or adult) Progressive Frequent PMID:28493438, 37106376
Clubfoot HP:0001762 Talipes equinovarus Congenital Static Index cases PMID:25817015
Absent deep tendon reflexes HP:0001284 Areflexia Infancy n/a Index cases. Note this conflicts with the hyperreflexia seen in others. PMID:25817015
Peripheral neuropathy HP:0009830 Infancy/adult Progressive Index cases; axonal and demyelinating changes in the adult ALSP case PMID:25817015, 37106376
Extrapyramidal signs HP:0002071 Abnormality of extrapyramidal motor function Infancy n/a Index cases PMID:25817015
Global developmental delay HP:0001263 Infancy n/a Frequent PMID:28493438
Posterior-predominant leukoencephalopathy evolving frontally HP:0002352 Leukoencephalopathy >1 year Rapidly progressive 4/11 in the Helman cohort PMID:34446925
Frontal-lobe/behavioral syndrome, then cognitive decline HP:0000751 Personality changes; HP:0001268 Mental deterioration Adult Rapid HDLS-S family PMID:31775912
Cognitive impairment (MMSE 12/30, MoCA 3/30) HP:0100543 Cognitive impairment Adult Progressive ALSP case PMID:37106376
Dysarthria HP:0001260 Adult Progressive ALSP case PMID:37106376
Visual impairment / optic tract involvement HP:0000505 Visual impairment Infant (poor fixation) / adult Progressive DEE29 (OMIM summary); HDLS-S; ALSP case PMID:31775912, 37106376
Axonal spheroids (neuropathology) HP:0034381 Central nervous system axonal spheroid Adult n/a HDLS-S autopsies PMID:31775912
Cachexia, very low BMI (13.4) HP:0004326 Cachexia Adult n/a Single ALSP case PMID:37106376
Poor growth HP:0001510 Growth delay Infancy n/a DEE29 summary (OMIM, [web]) —

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)

Variant (NM_001605) Zygosity Domain Functional consequence Phenotype PMID
p.Lys81Thr compound heterozygous with p.Arg751Gly aminoacylation Reduced function Infantile DEE 25817015
p.Arg751Gly homozygous; compound heterozygous editing region / C-terminal half Reduced function Infantile DEE 25817015
c.2067dupC p.Tyr690Leufs*3 compound heterozygous editing Protein loss, editing abolished Progressive microcephaly, hypomyelination, DEE 28493438
c.2738G>A p.Gly913Asp compound heterozygous C-Ala Reduced aminoacylation same 28493438
c.455G>T p.Cys152Phe (HGVS c. as reported; verify) heterozygous (AD) aminoacylation Not established; no splicing or brain expression change HDLS-S 31775912
c.1817C>T p.Thr606Ile homozygous tRNA recognition/editing boundary Deficient aminoacylation (reported) Adult ALSP 37106376
Further variants in 11 individuals biallelic various AlaRS activity reduced in 5 tested Infantile and late forms 34446925

"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

Level Structure Suggested term
Primary organ Brain, cerebral white matter UBERON:0002316 white matter (draft); UBERON:0011299 white matter of telencephalon (verify)
Regional pattern Posterior-first (parieto-occipital), then frontal (late form); periventricular and corpus callosum (ALSP) UBERON:0002336 corpus callosum (verify)
Secondary Peripheral nerves; optic pathway/retina (thin RNFL on OCT in the ALSP case); cerebellum (mouse) UBERON:0001021 nerve; UBERON:0000941 cranial nerve II (verify); UBERON:0002037 cerebellum
Cells oligodendrocytes, neurons/axons, microglia/macrophages see §6
Subcellular cytosol (translation); ER (UPR); axon (spheroids) GO:0005829 cytosol; GO:0005783 endoplasmic reticulum; GO:0030424 axon
Lateralization Bilateral, symmetric —

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:

Treatment Suggested NCIT therapeutic_modality
Antiseizure pharmacotherapy (refractory epilepsy) NCIT:C15986 Pharmacotherapy SMALL_MOLECULE (agent-specific)
Physical therapy for spasticity and contractures NCIT:C15302 Physical Therapy BEHAVIORAL
Orthopedic management of clubfoot NCIT:C16186 Orthopedic Surgical Procedure SURGERY
Nutritional support or gastrostomy NCIT:C15433 Nutritional Support (check the actual intervention before tagging a modality) —
Genetic counseling NCIT:C15240 Genetic Counseling —
Supportive and palliative care NCIT:C15747 Supportive Care —

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

Model Genotype Recapitulates Limitations PMID
Mouse sticky (sti) Homozygous Aars p.Ala734Glu, editing-domain missense Purkinje cell loss, ataxia, neuronal misfolded-protein accumulation, UPR Editing-specific. It does not model the hypomyelination or epilepsy of the human disease. It shows cerebellar rather than white matter disease. 16906134
Patient LCL / fibroblasts Biallelic patient variants Low AlaRS abundance and activity No CNS context 28493438, 34446925
Yeast complementation Patient alleles Functional loss (as used in AARS-CMT and recessive studies) Single-cell, not neural 25817015 (full text; verify)

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.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 7
Quoted claims found in source 6
Quoted claims not found in source 1
References weighed for topical relevance 15
On topic 7
Off topic 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.

Outcome Count
Terms checked 54
Resolved 52
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 9
Terms named correctly 5
Terms named as a different term 2
Terms whose name is worth a second look 2

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.