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leukoencephalopathy, progressive, with ovarian failure (LKENP) - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

leukoencephalopathy, progressive, with ovarian failure

MONDO:0014387

Also known as:LKENP

Overview

GeneticsAutosomal recessive · AARS2 (chr 6)

ResearchLimited published research (2 articles)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Periventricular leukomalacia, Cytochrome C oxidase-negative muscle fibers, Loss of previously acquired skills (developmental regression), and Leukoencephalopathy; and very common findings: Premature ovarian insufficiency, Shrinkage of the cerebellum (cerebellar atrophy), and Overactive reflexes (hyperreflexia). 23 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	14

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

AARS2 encodes alanyl-tRNA synthetase 2, mitochondrial (985 aa). Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Highest expression in Brain Cerebellar Hemisphere (22.0 TPM) and Cells EBV-transformed lymphocytes (21.9 TPM).

Leukoencephalopathy, progressive, with ovarian failure is associated with mutations in the AARS2 gene on chromosome 6.

AARS2 is classified as a druggable target (Enzyme category) with score 0.0.

46 pathogenic variants reported in AARS2 in ClinVar, including hotspot variants 235275 and 213968.

Variant

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Formal diagnostic criteria for AARS2-related disorder have not been established. AARS2-related disorder includes two distinct phenotypes: (1) infantile-onset cardiomyopathy and (2) neurodegeneration with or without leukoencephalopathy.

Suggestive Findings

AARS2-related disorder should be suspected in probands with the following clinical, laboratory, histopathology, and imaging findings and family history.

AARS2-Related Infantile-Onset Cardiomyopathy

Clinical findings

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for leukoencephalopathy, progressive, with ovarian failure. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for AARS2-related disorder have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with AARS2-related infantile-onset cardiomyopathy, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in and are recommended. Table 8a. AARS2-Related Infantile-Onset Cardiomyopathy: Surveillance

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for leukoencephalopathy, progressive, with ovarian failure.

2 publications have been identified in PubMed for leukoencephalopathy, progressive, with ovarian failure. Research spans Case Report / Case Series (100%).

Recent Publications

Green K (2024). [PMID: 38507676](https://pubmed.ncbi.nlm.nih.gov/38507676/). *Neurology*. [Case Report / Case Series]
Fernandes J (2024). [PMID: 39539319](https://pubmed.ncbi.nlm.nih.gov/39539319/). *Mol Genet Metab Rep*. [Case Report / Case Series]

Data assembled from 7 of 12 sources · Last updated Sep 18, 2026, 12:04 AM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:615889

GARD

Genetic and Rare Diseases Info Center

GARD:18252

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

Clinical Guidance

AARS2-related disorder includes two distinct phenotypes, infantile-onset cardiomyopathy and neurodegeneration with or without leukoencephalopathy. To date, about 60 individuals have been identified with biallelic pathogenic variants in AARS2 [, , , , ]. The following description of the phenotypic features associated with this condition is based on these reports. AARS2-Related Infantile-Onset Cardiomyopathy Table 2. AARS2-Related Infantile-Onset Cardiomyopathy: Frequency of Select Features

Feature	% of Persons w/Feature1	Comment
Hypertrophic cardiomyopathy	83%	A few instances of lethal primary pulmonary hypoplasia w/o cardiomyopathy have been reported; some authors suggest that this might represent a separate phenotype.1
Hypotonia	72%	—
Pulmonary hypoplasia	44%	—
Nonimmune hydrops	11%	—
Lactic acidosis	83%	Of those persons tested 1. Hypertrophic cardiomyopathy. Cardiac involvement is present in almost all reported infants. Cardiac dysfunction is present before or shortly after birth. Significant cardiac hypertrophy can lead to secondary lung hypoplasia . Hypotonia and myopathy.
AARS2-Related Neurodegeneration with or without Leukoencephalopathy: Frequency of Select Features Feature	% of Persons w/Feature1	Comment
Movement disorder	71%	Ataxia, dystonia, chorea, parkinsonism, tremor
Cognitive impairment/decline	67%	—
Spasticity hyperreflexia	64%	—
Premature ovarian failure	84% of females	—
Psychiatric manifestations	46%	Depression, psychosis, anxiety, behavioral changes
Ocular manifestations	38%	Nystagmus, ophthalmoplegia 1. Onset. The age of onset of AARS2-related neurodegeneration with or without leukoencephalopathy can range from childhood to adulthood. Cognitive decline is documented in most individuals. The onset of cognitive decline is often with disease onset.

Source: GeneReviews — "AARS2-Related Disorder"

GeneReviews

Differential Diagnosis

AARS2-Related Infantile-Onset Cardiomyopathy Table 4. Genes of Interest in the Differential Diagnosis of AARS2-Related Infantile-Onset Cardiomyopathy

Gene	Disorder	MOI	Features of Disorder
Pompe disease	AR	Hypertrophic CM; Muscle weakness; Respiratory deficiency	Macroglossia; Less severe manifestations GLA
Fabry disease	XL	Hypertrophic CM	Angiokeratomas; Hypohidrosis; Proteinuria; Kidney disease LAMP2
Danon disease	XL	Hypertrophic CM; Skeletal muscle weakness	Less severe manifestations w/later age of onset (teenage years)
MT-TI	MT-TI-related Leigh syndrome spectrum (See Mitochondrial DNA-Associated Leigh Syndrome Spectrum.)	MT	Fatal early-onset CM; Lactic acidosis
PRKAG2	Glycogen storage disease of the heart, lethal congenital (OMIM 261740)	AD	Hypertrophic CM
SCO2	SCO2-related Leigh syndrome spectrum (See Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.)	AR	Early-onset CM
Barth syndrome	XL	Infantile-onset CM, often fatal in childhood	Less severely affected persons can live to teenage years or early adulthood
TMEM70	Mitochondrial complex V deficiency (OMIM 614052)	AR	Hypertrophic CM; Hypotonia

Source: GeneReviews — "AARS2-Related Disorder"

Kisho

leukoencephalopathy, progressive, with ovarian failure

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Clinical Guidance

Laboratory findings. Lactic acidosis

Differential Diagnosis

Cardiac

Growth/Nutrition

Respiratory

Genetic counseling

Clinical Guidance

Therapies Under Investigation

Clinical Trials

leukoencephalopathy, progressive, with ovarian failure

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Clinical Guidance

Laboratory findings. Lactic acidosis

Differential Diagnosis

Cardiac

Growth/Nutrition

Respiratory

Genetic counseling

Clinical Guidance

Therapies Under Investigation

Clinical Trials