Hydrops–Lactic Acidosis–Sideroblastic Anemia–Multisystemic Failure Syndrome (HLASA)

Comprehensive Disease Characterization Report

MONDO:0014869 · Gene: LARS2 · Category: Mendelian (autosomal recessive mitochondrial disorder)

Evidence base: This is an ultra-rare disorder with fewer than ~10 reported patients worldwide. The knowledge base derives almost entirely from individual patient case reports (not aggregated registries): the index proband (Riley et al., 2016, 26537577) and three additional cases from two families (Riley et al., 2020, 32442335), supplemented by the wider LARS2/Perrault-syndrome and congenital sideroblastic anemia literature. Where disease-level facts are unavailable, this is stated explicitly.

1. Disease Information

Overview. HLASA is an infantile-lethal, autosomal-recessive mitochondrial multisystem metabolic disorder caused by biallelic pathogenic variants in LARS2, the nuclear gene encoding mitochondrial leucyl-tRNA synthetase. It represents the most severe end of the LARS2 phenotypic spectrum, which ranges (mild → severe) from Perrault syndrome (deafness + primary ovarian insufficiency), through deafness with (ovario-)leukodystrophy and reversible mitochondrial myopathy, to lethal neonatal HLASA. The cardinal features are non-immune hydrops fetalis, severe lactic acidosis, and sideroblastic anemia, accompanied by multiorgan (cardiac, pulmonary, renal, hepatic) failure.

"In this study, we report variants in LARS2 that are associated with a severe multisystem metabolic disorder. The proband was born prematurely with severe lactic acidosis, hydrops, and sideroblastic anemia." — 26537577

Key identifiers. - MONDO: MONDO:0014869 - Gene: LARS2, HGNC:21353, OMIM *604544, locus 3p21.3, UniProt Q15031 - Related OMIM phenotype: Perrault syndrome 4, #615300 (allelic series) - Orphanet: Perrault syndrome (ORPHA:2855) is the closest catalogued entity; HLASA is described as a LARS2-related severe variant. - ICD-11: best fit 5C53 / 5C50.4 (mitochondrial/metabolic disorders); ICD-10: E88.8 (other specified metabolic disorders) / D64.0 (hereditary sideroblastic anemia) — no dedicated code. - MeSH: no specific term; indexed under "Anemia, Sideroblastic," "Mitochondrial Diseases," "Hydrops Fetalis."

Synonyms / alternative names. HLASA; Hydrops, Lactic Acidosis, and Sideroblastic Anemia; LARS2-related hydrops-lactic acidosis-sideroblastic anemia and multisystem failure.

2. Etiology

Primary cause — genetic. Biallelic (compound heterozygous in all reported families) pathogenic variants in LARS2. Index proband: c.1289C>T (p.Ala430Val) and c.1565C>A (p.Thr522Asn); both predicted damaging (SIFT, PolyPhen). p.Thr522Asn was previously reported in Perrault syndrome.

"Whole exome sequencing of patient DNA revealed compound heterozygous variants in LARS2 (c.1289C>T; p.Ala430Val and c.1565C>A; p.Thr522Asn)." — 26537577

Genetic risk factors. The disease is monogenic/Mendelian; the only "risk factor" is inheriting two damaging LARS2 alleles. Being a carrier (heterozygote) is not associated with disease. Consanguinity/shared ancestry increases recurrence risk (as for all AR disorders). No validated modifier genes are established, though residual aminoacylation activity of the specific allele combination is the principal determinant of severity (genotype–phenotype correlation, see §4/§6).

Environmental / infectious factors. None. HLASA is not caused or triggered by toxins, infection, or lifestyle. Intercurrent illness and physiologic stress (e.g., prematurity, pregnancy in milder LARS2/YARS2-related disease) can precipitate metabolic decompensation but are not causal.

Protective factors. None described genetically or environmentally. (Not applicable for an ultra-rare Mendelian lethal disorder.)

Gene–environment interactions. Not established. Metabolic stress may unmask/aggravate mitochondrial insufficiency (inferred from the broader mt-aaRS literature), but no specific GxE data exist for HLASA.

3. Phenotypes

All are congenital/neonatal onset, severe, and rapidly progressive in classic HLASA; two of four reported patients survived the neonatal period with residual chronic morbidity (developmental delay, deafness). Frequencies below are from the ≤4 reported HLASA cases (small-N; qualitative).

"She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease and succumbed at 5 days of age." — 26537577

"All were males with genital anomalies. Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss." — 32442335

Quality of life. In lethal cases QoL assessment is not applicable (death at ~5 days). Survivors face lifelong burden from deafness and neurodevelopmental disability requiring multidisciplinary support. No formal EQ-5D/SF-36/PROMIS data exist for HLASA.

4. Genetic / Molecular Information

Causal gene. LARS2 (mitochondrial leucyl-tRNA synthetase). HGNC:21353; OMIM *604544; 3p21.3; UniProt Q15031; a class I aminoacyl-tRNA synthetase that charges L-leucine onto mt-tRNA^Leu (two isoacceptors, UUR and CUN).

Pathogenic variants (reported/HLASA-relevant). - c.1289C>T (p.Ala430Val) — missense; loss-of-function (severely reduced aminoacylation, ~18-fold decreased efficiency in vitro); HLASA index allele. - c.1565C>A (p.Thr522Asn) — missense; previously Perrault-associated; HLASA index allele. - Additional HLASA-associated LARS2 missense alleles in the 2020 series produced the most severe aminoacylation deficit of all LARS2 variants tested.

Variant class: predominantly missense; germline; ACMG classification pathogenic/likely pathogenic (supported by functional aminoacylation assays, in-silico prediction, segregation, rarity). No somatic contribution (contrast SF3B1 in acquired MDS-RS).

Allele frequency. Reported HLASA alleles are rare/absent in gnomAD (consistent with a severe recessive disorder); exact per-variant frequencies not reported in the primary papers. Carrier frequency in the general population is not established.

Functional consequence: loss of function (hypomorphic reduction of leucyl-tRNA aminoacylation). Not gain-of-function or dominant-negative. Genotype–phenotype rule: severity is inversely proportional to residual aminoacylation activity.

"Analysis of recombinant LARS2 variant proteins showed they had reduced aminoacylation efficiency, with HLASA-associated variants having the most severe effect." — 32442335

Modifier genes / epigenetics / chromosomal abnormalities. None established. No epigenetic mechanism or large-scale chromosomal rearrangement is implicated; the disorder is a point-mutation, single-gene condition.

5. Environmental Information

Not applicable. HLASA is a purely genetic Mendelian disorder. No environmental toxins, radiation, occupational exposures, lifestyle factors, or infectious agents cause or trigger it. (For completeness: acquired/secondary sideroblastic anemias can be caused by alcohol, isoniazid, chloramphenicol, linezolid, zinc-induced copper deficiency — but these are not relevant to LARS2-HLASA.)

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

1. Biallelic loss-of-function LARS2 variants are inherited → results in a hypomorphic mitochondrial leucyl-tRNA synthetase enzyme.
2. Reduced enzyme activity leads to deficient aminoacylation (leucine-charging) of mitochondrial tRNA^Leu (demonstrated in vitro; ~18-fold reduced for p.Ala430Val).
3. Deficient charged mt-tRNA^Leu impairs mitochondrial translation of the 13 mtDNA-encoded oxidative-phosphorylation (OXPHOS) subunits (inferred from enzyme role; supported by protein data).
4. Impaired mitochondrial translation results in reduced assembly/levels of respiratory-chain complexes, especially Complex I (demonstrated: reduced Complex I protein in patient muscle and liver).
5. Reduced OXPHOS leads to an energy (ATP) deficit and a compensatory shift to anaerobic glycolysis → systemic lactic acidosis (CHEBI:16113 lactate).
6. Branch A — erythroid lineage: OXPHOS/mitochondrial dysfunction in erythroblasts disrupts mitochondrial heme biosynthesis and iron-sulfur cluster metabolism → mitochondrial iron accumulation in perinuclear mitochondria → ring sideroblasts and ineffective erythropoiesis → sideroblastic anemia and fetal anemia (inferred by analogy to congenital sideroblastic anemia mechanisms).
7. Fetal anemia + high-output cardiac strain + generalized energy failure results in fluid extravasation and serous effusions → non-immune hydrops fetalis (inferred).
8. Branch B — high-energy organs: OXPHOS deficiency in heart, lung vasculature, kidney, and liver leads to impaired cardiac function, pulmonary hypertension, progressive renal disease, hepatic dysfunction, and coagulopathy → multiorgan failure and neonatal death (demonstrated clinically).
9. Branch C — survivors / milder spectrum: partial mitochondrial translation deficiency in cochlea and CNS leads to sensorineural hearing loss, developmental delay (and, at the milder Perrault end, leukodystrophy and ovarian dysfunction); in gonads it impacts development (male undervirilization; C. elegans lars-2 loss abolishes germ-cell production).

Supporting detail by category

• Molecular pathways: mitochondrial translation / OXPHOS (KEGG hsa00190 oxidative phosphorylation; Reactome "Mitochondrial translation," "Metabolism of amino acids"). Aminoacyl-tRNA biosynthesis (KEGG hsa00970).
• Cellular processes: ineffective erythropoiesis, cellular energy failure, apoptosis of energy-starved cells (inferred), impaired erythroid maturation.
• Protein dysfunction: loss of function of a class-I aaRS via missense substitutions reducing catalytic aminoacylation efficiency (not aggregation/misfolding-driven per se).
• Metabolic changes: lactic acidemia; disrupted heme/iron handling; energy-metabolism failure.
• Biochemical abnormality: enzyme deficiency — mitochondrial leucyl-tRNA ligase (EC 6.1.1.4); secondary Complex I (NADH:ubiquinone oxidoreductase) deficiency.
• Tissue damage mechanism: bioenergetic insufficiency / ischemic-type energy starvation in high-demand tissues; mitochondrial iron toxicity in erythroblasts.
• Immune involvement: none (hydrops is non-immune).
• Molecular profiling: patient-tissue immunoblot showed reduced LARS2 (liver) and reduced Complex I (muscle, liver); notably RC enzyme activities were not markedly deficient in the index proband's muscle/liver, indicating a partial/tissue-variable biochemical lesion.

"Muscle and liver samples from the proband did not display marked mitochondrial respiratory chain enzyme deficiency... complex I protein levels were reduced in patient muscle and liver." — 26537577

GO / CL suggestions. BP: GO:0070127 (mitochondrial translation), GO:0006783 (heme biosynthetic process), GO:0032543 (mitochondrial translation), GO:0006418 (tRNA aminoacylation for protein translation), GO:0045333 (cellular respiration). MF: GO:0004823 (leucine-tRNA ligase activity). CC: GO:0005739 (mitochondrion), GO:0005759 (mitochondrial matrix). Cells: CL:0000764 (erythroblast), CL:0000232 (erythrocyte), CL:0000746 (cardiac muscle cell).

7. Anatomical Structures Affected

• Primary organs / systems: hematopoietic–erythroid (bone marrow, UBERON:0002371), cardiovascular (heart UBERON:0000948; pulmonary vasculature → pulmonary hypertension), respiratory (lung UBERON:0002048), renal (kidney UBERON:0002113), hepatic (liver UBERON:0002107).
• Secondary / spectrum: skeletal muscle (UBERON:0001134; reduced Complex I, degeneration), auditory system (cochlea/inner ear UBERON:0001846), CNS/white matter (brain UBERON:0000955; leukodystrophy at milder end), reproductive organs (testis UBERON:0000473; ovary UBERON:0000992). Generalized serosal cavities (hydrops).
• Tissue/cell level: erythroid precursors (CL:0000764 erythroblast), cardiomyocytes, cochlear hair cells, oocytes/germ cells; connective/serous tissue edema in hydrops.
• Subcellular: mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759) — the primary locus of the molecular defect.
• Lateralization: systemic/bilateral (hearing loss bilateral; multiorgan involvement generalized).

8. Temporal Development

• Onset: congenital — prenatal (hydrops detectable in utero) to immediate neonatal; acute presentation at/shortly after birth.
• Progression: rapidly progressive in classic HLASA → death typically within days (index proband died at day 5). Survivors stabilize after the neonatal crisis and follow a chronic, static-to-slowly-evolving course dominated by deafness and developmental delay.
• Disease course pattern: neonatal catastrophic (lethal) or neonatal crisis followed by chronic residual disability.
• Duration: self-limited by early death, or lifelong chronic in survivors.
• Remission: none spontaneous; note the broader LARS2 spectrum includes a reversible infantile mitochondrial myopathy phenotype (distinct from HLASA).
• Critical period: the perinatal/neonatal window is both the period of maximal vulnerability and the only window for life-saving intensive support.

9. Inheritance and Population

• Inheritance: autosomal recessive (biallelic; compound heterozygous in reported families). Reflects the Perrault-syndrome gene family.
• Penetrance/expressivity: presumed high penetrance for the biallelic severe genotype; highly variable expressivity/allelic heterogeneity across the LARS2 spectrum (same gene → Perrault vs leukodystrophy vs reversible myopathy vs HLASA), governed by residual enzyme activity.
• Anticipation / mosaicism / founder effects: none described (not a repeat-expansion disorder). Consanguinity increases recurrence risk generally.
• Carrier frequency: not established; alleles are individually very rare in gnomAD.
• Epidemiology: ultra-rare — HLASA reported in only ~4 individuals (2016 + 2020). Perrault syndrome overall (~15 causal genes) has ~100 reported cases. No prevalence/incidence estimate is available for HLASA specifically (Orphanet lists Perrault syndrome as <1/1,000,000).
• Sex ratio: all reported HLASA survivors are male with genital anomalies; the original lethal proband was female. Small-N precludes a true ratio. (In Perrault, ovarian phenotype is female-specific.)
• Geographic/ethnic distribution: no predilection identified; reported families are of varied ancestry.

10. Diagnostics

Laboratory / biochemical. - Blood gas & metabolic: elevated blood lactate, metabolic (lactic) acidosis, elevated lactate:pyruvate ratio (LOINC 2524-7 lactate); CSF lactate if CNS involved. - CBC: anemia; peripheral smear. - Bone marrow aspirate with Perls' (Prussian blue) iron stain: ring sideroblasts (≥15%, type 3) — diagnostic of sideroblastic anemia. - Coagulation studies (coagulopathy), renal function, cardiac enzymes/BNP.

Biomarkers. Lactate (CHEBI:16113); ring sideroblasts; reduced Complex I protein on muscle/liver immunoblot; reduced LARS2 protein. No validated circulating molecular biomarker specific to HLASA.

Imaging / functional. Fetal/neonatal ultrasound (hydrops, effusions); echocardiography (cardiac dysfunction, pulmonary hypertension); brain MRI (leukodystrophy in milder spectrum). Audiology (ABR/OAE) for hearing loss in survivors.

Biopsy / pathology. Bone marrow (ring sideroblasts). Muscle histology may show an "unusual form of degeneration" (2020 myopathy case). Respiratory chain enzymology may be normal or only mildly reduced — a diagnostic pitfall.

Genetic testing (definitive). - First-line: trio/proband whole-exome (WES) or whole-genome sequencing (WGS) — how all reported cases were diagnosed. - Targeted gene panels: mitochondrial disease panels, Perrault-syndrome panels (incl. LARS2, HARS2, CLPP, TWNK, ERAL1, HSD17B4), and congenital sideroblastic anemia panels (ALAS2, SLC25A38, GLRX5, YARS2, PUS1, ABCB7, SF3B1). - Single-gene LARS2 testing for cascade/known familial variants; confirm biallelic status and phase (parental testing). - mtDNA testing / karyotype / CMA / FISH / repeat-expansion testing: used to exclude differentials (e.g., Pearson syndrome mtDNA deletion, MT-ATP6 variants), not to diagnose HLASA.

Clinical criteria / differential diagnosis. No formal consensus criteria (too rare). Diagnosis = characteristic triad (hydrops + lactic acidosis + sideroblastic anemia) + biallelic LARS2 variants. Differential: MLASA (MLASA1 PUS1, MLASA2 YARS2, MT-ATP6); other congenital sideroblastic anemias (ALAS2 X-linked, SLC25A38 AR, GLRX5, ABCB7); Pearson marrow-pancreas syndrome (mtDNA deletion); other causes of non-immune hydrops; other mt-aaRS disorders.

"Our study confirms that MLASA must be considered in patients with congenital sideroblastic anemia and underlines the importance of early diagnosis and supportive therapy." — 25638461

Screening. No newborn-screening assay detects HLASA. Carrier and cascade screening is possible once a familial variant is known; prenatal diagnosis / PGT feasible for at-risk couples.

11. Outcome / Prognosis

• Survival / mortality: poor. Classic HLASA is infantile-lethal (index proband died day 5). However, 2 of 4 reported patients survived the neonatal multisystem crisis with intensive support — so the phenotype is not uniformly lethal.
• Life expectancy: days in classic lethal presentation; survivors have undefined long-term expectancy with chronic morbidity.
• Morbidity in survivors: developmental delay and sensorineural hearing loss (lifelong disability); genital anomalies requiring surgery.
• Complications: respiratory failure (hyaline membrane disease), cardiac failure, pulmonary hypertension, coagulopathy, renal failure, transfusion-dependent anemia and iron overload.
• Recovery potential: no reversal of the underlying enzyme defect; survivors do not "recover" but can stabilize.
• Prognostic factors: degree of residual LARS2 aminoacylation activity (genotype), severity of neonatal acidosis and multiorgan involvement, and availability of intensive neonatal support. Prognostic biomarker: persistently high lactate reflects ongoing bioenergetic failure.

12. Treatment

No approved disease-specific/curative therapy exists. Management is supportive and multidisciplinary (NCIT: Supportive Care; Palliative Care).

• Sideroblastic anemia: empiric pyridoxine (vitamin B6) trial (NCIT Pyridoxine; CHEBI:27306) — responsiveness variable and generally limited in mitochondrial-translation forms; packed red-cell transfusion (NCIT Red Blood Cell Transfusion) for transfusion dependence; iron chelation (deferasirox/deferoxamine; NCIT Iron Chelation Therapy) for iron overload. Fetal anemia/hydrops from mitochondrial disease has been managed with intrauterine transfusion in related cases.
• Metabolic/acidosis: correction of acidosis, glucose/energy support, avoidance of mitochondrial toxins.
• Organ support: mechanical ventilation (RDS), inotropes and pulmonary-hypertension therapy, renal support, correction of coagulopathy.
• Mitochondrial "cocktails": empiric antioxidants/cofactors/vitamins (CoQ10, riboflavin, thiamine, L-carnitine, etc.) are used without validated efficacy. A preclinical study showed synergistic rescue with glucose + nicotinic acid + N-acetylcysteine in C. elegans and zebrafish Complex I disease models — mechanistically relevant but not clinically validated.
• Survivor care: hearing habilitation (hearing aids/cochlear implants), developmental/rehabilitation therapies (PT/OT/speech), urologic surgery for genital anomalies.
• Advanced therapeutics (gene/cell/RNA/targeted/immuno): none available; no HLASA-specific clinical trials (ClinicalTrials.gov). HSCT is curative only for select other congenital sideroblastic anemias (e.g., SLC25A38), not for LARS2-HLASA.
• Pharmacogenomics: not applicable.

"Synergistic rescue occurred only with glucose, nicotinic acid and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential..." — 33640978 (preclinical)

13. Prevention

• Primary prevention: not possible (genetic). Genetic counseling for at-risk couples; carrier screening where a familial variant is known.
• Reproductive options: prenatal diagnosis and preimplantation genetic testing (PGT-M) for couples with two known LARS2 variants; prenatal ultrasound surveillance for hydrops in at-risk pregnancies.
• Secondary prevention: early molecular diagnosis to guide anticipatory management (transfusion, acidosis control) and prognostic counseling.
• Tertiary prevention: prevent complications in survivors — iron-overload monitoring/chelation, audiologic and developmental surveillance, cardiac/renal monitoring.
• Immunization / public health / behavioral / environmental interventions: not applicable (no environmental etiology).

14. Other Species / Natural Disease

• Taxonomy / orthologs: LARS2 is evolutionarily conserved. Orthologs: mouse Lars2 (NCBITaxon:10090), zebrafish lars2 (NCBITaxon:7955), Caenorhabditis elegans lars-2 (NCBITaxon:6239), S. cerevisiae mitochondrial LeuRS NAM2 (NCBITaxon:4932).
• Natural disease in animals: no naturally occurring HLASA-equivalent disease reported in companion animals or wildlife (OMIA: none catalogued). No veterinary or zoonotic relevance.
• Comparative biology: the requirement of mitochondrial LeuRS for OXPHOS translation is conserved across eukaryotes; C. elegans lars-2 loss abolishes germ-cell production, mirroring the gonadal/reproductive phenotype seen in human LARS2 disease.

"...complete infertility due to failure to produce germ cells in Caenorhabditis elegans (C. elegans), indicating that LARS2 is expressed in gonadal tissue and can impact gonadal development." — 40119736

15. Model Organisms

• Invertebrate: C. elegans lars-2 — informative for gonadal/germ-cell role; general mitochondrial Complex I disease worm models (e.g., gas-1(fc21)/ndufs2) used for therapeutic screening (33640978).
• Vertebrate: zebrafish Complex I disease/inhibition models (rotenone; 33640978) recapitulate lactate elevation, reduced activity, and neuro-metabolic failure — a platform for testing metabolic rescue.
• In vitro / biochemical: recombinant LARS2 aminoacylation assays (the key functional model establishing variant pathogenicity and genotype–severity correlation; PMIDs 26537577, 32442335); patient-derived muscle/liver samples.
• Genetic models available: knockdown/knockout in worm and fish; no published Lars2 HLASA-specific mouse knock-in recapitulating the full syndrome.
• Phenotype recapitulation & limitations: cellular/invertebrate models capture the bioenergetic (Complex I/OXPHOS) deficit and enable drug screening but do not reproduce the full multisystem neonatal HLASA phenotype (hydrops, sideroblastic anemia, human-specific developmental features). This is the principal gap for mechanistic and preclinical therapeutic work.
• Resources: WormBase (lars-2), ZFIN (lars2), MGI (Lars2), Alliance of Genome Resources.

Evidence Summary & Source Types

• Human clinical (case reports): 26537577 (index proband, functional assays), 32442335 (spectrum incl. 3 HLASA cases + recombinant protein assays), 40119736 (LARS2 Perrault + gonadal/undervirilization + C. elegans), 42283975 (Perrault gene family/AR inheritance), 35334505 (mitochondrial fetal anemia/IUT), 35393742 & 25638461 (YARS2/MLASA differential).
• In vitro / biochemical: recombinant aminoacylation assays (26537577, 32442335).
• Model organism / preclinical: 33640978 (C. elegans + zebrafish Complex I therapy).
• Reviews: 31839000 (mt-aaRS disorders), 32759564 / 39358290 / 40769913 (sideroblastic anemia pathophysiology), 26637696 (SA diagnosis/treatment).

Limitations

• Extremely small evidence base (≤4 HLASA patients); frequencies, prevalence, sex ratio, and prognosis are imprecise.
• No HLASA-specific animal model; branch-point mechanisms for sideroblastic anemia and hydrops are inferred from congenital sideroblastic anemia biology, not directly demonstrated in HLASA tissue.
• No clinical trials or disease-modifying therapies.

Future Directions

• Generate a faithful Lars2 knock-in/erythroid-conditional mammalian model to test the erythroid heme/Fe-S branch and candidate therapies.
• Systematic genotype–residual-activity–phenotype mapping across LARS2 alleles.
• Evaluate mitochondrial cofactor combinations (e.g., Glu+NA+NAC) and mt-tRNA-directed strategies in HLASA-relevant systems.