Hydrops-Lactic Acidosis-Sideroblastic Anemia-Multisystemic Failure Syndrome

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Classifications

Harrison's Part

Mechanistic Nosology

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic and compound heterozygous in every published family. In the index case the mother carried one allele and the father the other, which is the segregation that establishes recessive inheritance; the parents were non-consanguineous and of Pakistani origin. The 2020 HLASA cases come from two unrelated families. LARS2 is nuclear and autosomal, so despite the mitochondrial biochemistry there is no maternal transmission and the sibling recurrence risk is 25 percent.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mother was heterozygous for the c.1289C>T variant and the father heterozygous for the c.1565C>A variant, consistent with the expectation of recessive inheritance."

Biparental transmission of the two alleles, which is what makes this recessive rather than de novo.

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Discussions and Knowledge Gaps

3

How does a mitochondrial leucyl-tRNA synthetase defect produce ring sideroblasts, and is the route the same one that operates in the heme-synthesis and iron-sulfur-cluster sideroblastic anaemias?

KNOWLEDGE GAP OPEN hlasa_sideroblast_mechanism

Attached to

pathophysiology#Erythroblast Mitochondrial Iron Accumulation phenotypes#Sideroblastic Anaemia

Sideroblastic anaemia is one of the three features this entity is named for, and it is the one with no mechanism measured in it. The accepted account — mitochondrial protein synthesis failure impairing heme synthesis and iron-sulfur cluster assembly, stranding iron inside the mitochondrion — is imported from the congenital sideroblastic anaemia group as a whole. No one has measured erythroblast iron, heme intermediates, ALAS2 function or iron-sulfur cluster assembly in a LARS2 patient. The gap is not academic. Whether the erythroid phenotype follows from the general translation defect or from something specific about leucine supply in erythroblasts decides whether it should be expected in the milder LARS2 phenotypes, where nobody looks for it. The 2020 series reports HLASA and Perrault syndrome in the same paper without reporting marrow findings for the Perrault patients. Erythroblasts are accessible. A marrow sample from a surviving patient, or a differentiated CD34-positive culture carrying the alleles, would answer it.

Why did one patient die at five days while two others survived the same neonatal multisystem illness?

OPEN QUESTION OPEN hlasa_severity_determinant

Attached to

progression#Neonatal crisis, with two outcomes pathophysiology#Biallelic Hypomorphic LARS2 Variants

Across the LARS2 spectrum, severity tracks residual aminoacylation activity, and the 2020 series shows the HLASA alleles are the most severely impaired of all LARS2 variants tested. That explains why HLASA is worse than Perrault syndrome. It does not explain the fork inside HLASA. Nothing published separates the fatal from the surviving cases. The index proband was born at 29 weeks weighing 1010 g, so prematurity is an obvious confounder and might be the whole answer; the 2020 abstract does not give gestations. Nor is there an allele-by-allele comparison across the four patients — the 2020 aminoacylation data are reported as a group statement rather than per patient. With four patients this may not be answerable. It is recorded because an entity described in the literature as infantile-lethal has a 50 percent survival rate in its published series, and anyone using this entry for counselling needs to know that both the survival and its unexplained variability are real.

Is the glucose, nicotinic acid and N-acetylcysteine combination that rescues complex I dysfunction in worm and fish models worth testing in a mitochondrial aminoacyl-tRNA synthetase disease?

OPEN QUESTION OPEN hlasa_metabolic_rescue_lead

Attached to

treatments#Neonatal Intensive Supportive Care pathophysiology#Reduced Respiratory Chain Complex I in Liver and Muscle

The openscientist report committed with this entry raises a preclinical combination that produced synergistic rescue of mitochondrial membrane potential in C. elegans and zebrafish complex I models. It is deliberately not curated as a treatment in this entry: that work is not about LARS2, was not done in this disease, and has never been given to a patient with it. It is recorded as a lead rather than dropped because the logic is not absurd — the endpoint in HLASA is a complex I deficiency, which is what those models have. The reasons to be cautious are specific rather than general. The models are chemically or genetically induced complex I lesions, not translation defects, so the step this disease actually fails is upstream of what they model. And the therapeutic window in HLASA is antenatal or the first days of life, which is not where a nutritional combination is easy to deploy. Anyone acting on this should note that the chain from the cited preclinical work to this disease runs through two inferences, and that this entry has made neither of them.

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Pathophysiology

7

Biallelic Hypomorphic LARS2 Variants

Mechanism confidence: Established

The index proband carries c.1289C>T, p.Ala430Val in trans with c.1565C>A, p.Thr522Asn. The second allele is the same one reported homozygously in Perrault syndrome, which is the single most informative fact about this entity: the severe and the mild phenotype share an allele, so severity is a property of the allele combination rather than of the variant. The two residues sit in different parts of the enzyme. Thr522 is in the catalytic domain where the 3-prime end of the tRNA binds, and Ala430 is in the CP1 connective-peptide domain, which in cytosolic synthetases is an editing domain. LARS2's editing domain is present but not functional, and the authors tested that directly — no mischarging with isoleucine was detectable for wild-type or variant enzyme. So the Ala430Val effect is on aminoacylation rather than on proofreading, which is worth recording because the domain's name invites the opposite inference.

LARS2 hgnc:17095

Genetic context LARS2 hgnc:17095 allele_type: two missense variants in trans, one of which also occurs in Perrault syndrome variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Compound heterozygosity is the reported configuration in every HLASA family, index case and 2020 series alike.

PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION is the measured position: recombinant p.Ala430Val retains about a eighteenth of wild-type catalytic efficiency and p.Thr522Asn about a ninth, so neither allele is a null. A complete loss of mitochondrial leucyl-tRNA synthetase is presumed incompatible with life, and the residual activity is what the genotype-phenotype relationship in this gene is built on.

Downstream

Reduced Leucyl-tRNA Aminoacylation Both substitutions reduce the rate at which the enzyme charges leucine onto tRNA-Leu, measured on purified recombinant protein rather than inferred from the residue position.

Show evidence (2 references)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

The two alleles and the configuration they are in.

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging (SIFT, PolyPhen)."

The allele shared with the milder disease. This is the observation that makes HLASA and Perrault syndrome 4 one allelic series rather than two diseases.

Reduced Leucyl-tRNA Aminoacylation

Mechanism confidence: Established

Less charged mitochondrial tRNA-Leu is available to the mitoribosome. The kinetics show the loss is in catalytic rate rather than in substrate affinity: k-cat falls roughly fourteen-fold for p.Ala430Val and ninefold for p.Thr522Asn while K-m barely moves. An enzyme that binds its substrate normally and turns it over slowly is a hypomorph whose output scales with how much of it there is, which is the basis for expecting tissue-dependent severity. Across the 2020 series the HLASA alleles were the most severely impaired of all LARS2 variants assayed, which extends the relationship from one family to the spectrum.

leucyl-tRNA aminoacylation GO:0006429 ↓ DECREASED

leucine-tRNA ligase activity GO:0004823 ↓ DECREASED

Experimental models

Recombinant LARS2 aminoacylation assay OTHER Quantifies the catalytic consequence of each allele: 18-fold and 9-fold losses of efficiency, driven by k-cat rather than K-m.

Downstream

Impaired Mitochondrial Translation in High-Demand Tissues

Show evidence (1 reference)

PMID:32442335 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

The spectrum-level relationship: within one gene, the alleles that produce this phenotype are the ones with the least residual activity.

Impaired Mitochondrial Translation in High-Demand Tissues

Mechanism confidence: Provisional

Translation of the thirteen mtDNA-encoded respiratory-chain subunits depends on a supply of charged tRNA-Leu, and a hypomorphic synthetase restricts it. The tissue qualifier is not decoration: in the index proband's fibroblasts and induced myotubes, LARS2 protein was normal, respiratory-chain proteins were normal, and an in vitro mitochondrial protein synthesis assay found no defect at all. The authors conclude the variants affect only tissues with higher energy demands. Graded PROVISIONAL because the translation defect itself was never demonstrated in an affected tissue. What was demonstrated in liver and muscle is reduced LARS2 protein and reduced complex I protein; the translation step between them is inferred from the enzyme's known function. The one assay that could have shown it was run in the tissue where the disease is absent.

mitochondrial translation GO:0032543 ↓ DECREASED

Downstream

Reduced Respiratory Chain Complex I in Liver and Muscle

Show evidence (1 reference)

PMID:26537577 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"no defect in mitochondrial protein synthesis was detected in an in vitro assay in patient fibroblasts or induced myotubes (results not shown), indicating the LARS2 variants most likely only affect tissues with higher energy demands"

A negative result, and the tissue restriction the authors draw from it. Graded INDIRECT because it supports this node's scope qualifier rather than the translation defect itself — the assay found nothing, in the wrong tissue.

Reduced Respiratory Chain Complex I in Liver and Muscle

Mechanism confidence: Established

Complex I protein was about 57 percent of a gestational-age-matched fetal control in muscle and about 25 percent of control in liver, with LARS2 itself at about 50 percent in liver. Complex I is the complex with the most mtDNA-encoded subunits, which is why a general translation restriction shows up there first. The enzymology tells a different story from the immunoblot and the difference is the diagnostic point of this entry. Measured activities for complexes I and IV were low in muscle and complex IV low in liver, but in each case the authors judged them not low enough to be diagnostic of a respiratory-chain disorder, and consistent with what premature infants show anyway. Citrate synthase was raised in both tissues. A service laboratory reporting that panel would not call it a mitochondrial disease.

oxidative phosphorylation GO:0006119 ↓ DECREASED

mitochondrial respiratory chain complex I GO:0045271

Downstream

Bioenergetic Failure in High-Demand Organs

Erythroblast Mitochondrial Iron Accumulation Ring sideroblasts are the shared endpoint of the congenital sideroblastic anaemias, which are caused by defects in heme biosynthesis, iron-sulfur cluster biosynthesis and mitochondrial protein synthesis alike. LARS2 sits in the third of those groups, so the edge is drawn by class membership. No measurement of erythroblast iron, heme synthesis or iron-sulfur cluster assembly exists in any LARS2 patient.

Show evidence (2 references)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Levels of the RC complexes were also reduced in patient liver with complex I being the most markedly reduced at ~25% of the control level."

The magnitude of the complex I reduction in liver.

PMID:26537577 REFUTE DIRECT PRIMARY RESULT Human Clinical

"RC enzyme activities for complexes I and IV were low in muscle (Table 1), consistent with levels typically found in premature infants and not sufficiently low to be diagnostic for a mitochondrial RC disorder."

Recorded as REFUTE against this node deliberately. Enzymology is the assay a reader would expect to confirm a respiratory-chain deficiency, and in this patient it did not; the node stands on immunoblot instead. Burying that under a supporting quote would misrepresent what the source found.

Bioenergetic Failure in High-Demand Organs

Mechanism confidence: Established

A respiratory chain that cannot keep up forces glycolysis, and in this patient the result was among the most extreme recorded: arterial pH fell to 6.8 with lactate at 16 mmol/L against a reference of 0.7 to 2.0, and lactate stayed at 13 despite bicarbonate infusion, normal blood pressure and adequate perfusion. That last clause is the one that matters clinically. Lactate at 16 in a sick premature neonate is usually read as tissue hypoperfusion; here the haemodynamics were normal, so the lactate is metabolic rather than circulatory. The distinction is what should prompt mitochondrial investigation rather than escalating inotropes.

oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Severe Lactic Acidosis

Lactic Aciduria

Multi-Organ Failure

Sensorineural Hearing Loss Hearing loss is the feature that unites the whole LARS2 spectrum, from this entity's survivors to Perrault syndrome. No cochlear measurement exists in any LARS2 patient, so the edge is the organ-vulnerability argument rather than a finding.

Global Developmental Delay Present in both 2020 survivors. Whether it reflects ongoing central energy failure or residual injury from the neonatal crisis is not separable from the published data.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The acidosis continued with lactate of 13 mmol/L, despite management with sodium bicarbonate infusions and despite normal mean blood pressures and presumed adequate perfusion."

The observation that separates a metabolic lactataemia from a circulatory one, and the failure of buffering to correct it.

Erythroblast Mitochondrial Iron Accumulation

Mechanism confidence: Hypothetical

Ring sideroblasts are erythroblasts whose perinuclear mitochondria are loaded with iron, and the proband had them on Perls staining of her marrow, alongside vacuolated proerythroblasts and, in the liver, dyserythropoietic extramedullary haematopoiesis with irregular crenated nuclei and binucleate forms. The node is graded HYPOTHETICAL because everything above the histology is borrowed. The accepted account of ring sideroblast formation — mitochondrial protein synthesis failure impairing heme synthesis and iron-sulfur cluster assembly, leaving iron that entered the mitochondrion with nowhere to go — comes from the congenital sideroblastic anaemias as a group. Nobody has measured any of it in a LARS2 erythroblast. What is observed here is the endpoint; the mechanism is the group's.

erythroblast CL:0000765

heme biosynthetic process GO:0006783 ↓ DECREASED iron-sulfur cluster assembly GO:0016226 ↓ DECREASED

Downstream

Sideroblastic Anaemia

Non-Immune Hydrops Fetalis Fetal anaemia is an established cause of non-immune hydrops through high-output cardiac strain and loss of oncotic pressure, and this fetus was anaemic in utero. No one has shown the sequence in a LARS2 pregnancy, and the proband also had cardiac dysfunction and hypoalbuminaemia, each of which could contribute independently, so the edge is one plausible route among several rather than the established one.

Show evidence (1 reference)

PMID:32759564 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Ring sideroblasts show abnormal mitochondrial iron accumulation, and their emergence in the bone marrow is a characteristic of sideroblastic anemias"

Defines what the observed histology means at the subcellular level. It is a review's definition applied to this disease, which is why the node is HYPOTHETICAL rather than established.

Multi-Organ Failure

Mechanism confidence: Established

The proband's course was simultaneous rather than sequential failure: hyaline membrane disease, impaired cardiac function, coagulopathy with low albumin requiring plasma, cryoprecipitate and albumin, pulmonary hypertension, rising creatinine with haematuria on structurally normal kidneys, and clinical and electrical seizures on a diffusely abnormal EEG with normal cranial ultrasound. Normal structure with abnormal function, repeated across kidney and brain, is the signature of an energetic rather than a structural lesion, and it is what makes the multi-organ picture one disease rather than a list of complications of prematurity.

Downstream

Impaired Cardiac Function

Pulmonary Arterial Hypertension

Coagulopathy

Progressive Renal Disease

Neonatal Respiratory Distress

Neonatal Seizures

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"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."

The organs involved and the outcome, in the index patient.

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Pathograph

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Phenotypes

14

Blood 2

Sideroblastic Anaemia VERY_FREQUENT Sideroblastic anemia HP:0001924

Named in the entity. In the index case the finding is documented histologically; the 2020 abstract does not report marrow findings for its three cases individually.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Perl’s iron stain of bone marrow aspirate showing ringed sideroblasts (arrows). (b) May–Grunwald–Giemsa stain of bone marrow aspirate showing vacuolation of proerythroblasts."

The two marrow findings, with the stains that produced them. Quoted from the figure legend because that is where the paper states what was seen.

Coagulopathy OCCASIONAL Abnormality of coagulation HP:0001928

1 of 1 patient described in detail.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"There was no liver enlargement but liver dysfunction with disordered coagulation was treated with fresh-frozen plasma and cryoprecipitate, and a low albumin level required albumin infusion."

The coagulopathy, its attribution to the liver, the absent hepatomegaly, and the products used — all in one sentence.

Cardiovascular 2

Impaired Cardiac Function OCCASIONAL Congestive heart failure HP:0001635

Course: PROGRESSIVE

1 of 1 patient described in detail. The HPO term names congestive failure where the source says impaired cardiac function with hypotension; that is the nearest available term for a functional cardiac deficit and preferred_term keeps the source's wording rather than upgrading it to a diagnosis the paper does not make.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Worsening cardiac function and hypotension led to a decision by the family for withdrawal of active intensive care management and she succumbed at 5 days of age."

The cardiac trajectory and its role in the fatal outcome.

Pulmonary Arterial Hypertension OCCASIONAL HP:0002092

1 of 1 patient described in detail. The source says "pulmonary hypertension" without specifying the arterial subtype that the HPO label names; in a ventilated neonate this is almost always persistent pulmonary hypertension of the newborn, and the binding is the nearest term rather than a claim about subtype.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease"

The list of organ involvements including this one.

Ear 1

Sensorineural Hearing Loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407

2 of 2 survivors in the 2020 series. It cannot be assessed in a patient who dies at five days, so the denominator is survivors rather than all patients — which is a real ascertainment limit, not a rounding of the figure.

Show evidence (1 reference)

PMID:32442335 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss."

The outcome in both survivors, covering this phenotype and the developmental one.

Genitourinary 3

Lactic Aciduria OCCASIONAL HP:0003648

1 of 1 patient for whom a urine screen is reported. Recorded separately from the blood lactate because the urine screen is a different test with a different access route, and in a neonate it may be the first abnormal result available.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A urine metabolic screen showed gross lactic aciduria."

The urine finding in the index case.

Progressive Renal Disease OCCASIONAL Nephropathy HP:0000112

Course: PROGRESSIVE

1 of 1 patient described in detail.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her renal function showed rising creatinine levels with hematuria, although her kidneys were found to be structurally normal on ultrasound."

The functional impairment set against normal structure.

Male Genital Anomalies VERY_FREQUENT Abnormality of the genital system HP:0000078

Coarse binding: variable spectrum

3 of 3 male HLASA patients in the 2020 series. Bound to the organ-system root deliberately: the 2020 abstract says "genital anomalies" without naming them, and the specific anomalies that are named — cryptorchidism and hypospadias — come from Perrault-syndrome siblings rather than from HLASA patients. Binding HP:0000028 or HP:0000047 here would import a specific anomaly from a different phenotype in the same gene.

Show evidence (2 references)

PMID:32442335 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Three HLASA cases from two unrelated families were identified. All were males with genital anomalies."

The observation in the only series that reports it, with its denominator.

PMID:40119736 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"In addition to bilateral profound sensorineural hearing loss, both brothers had bilateral undescended testes that required surgical intervention. In addition, the younger affected brother had hypospadias with chordee."

The specific anomalies documented in LARS2 disease. Graded INDIRECT because these are Perrault-syndrome patients, not HLASA patients — they establish that the gene affects male genital development, not what the HLASA anomalies were.

Metabolism 2

Non-Immune Hydrops Fetalis VERY_FREQUENT HP:0001789

Reported in the index proband. The 2020 abstract describes three further HLASA cases without listing their individual prenatal findings, so the denominator that can be quoted from a source is one of one rather than four of four. The name of the entity implies it is general; the abstract does not say so.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The pregnancy was complicated by oligohydramnios and fetal growth restriction, hydrops, and anemia, with antenatal scans showing fetal pericardial effusion, ascites, and scalp edema."

The prenatal picture in full, including the two components — effusions and oedema — that make the finding hydrops rather than isolated ascites.

Severe Lactic Acidosis VERY_FREQUENT HP:0003128

Named in the entity and reported with numbers in the index case. Bound to HP:0003128 rather than to the circulating-lactate term because a pH of 6.8 is measured acidosis and not merely a raised lactate.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"an arterial blood gas showed acidosis with pH to 6.8 and lactate to 16 mmol/L (reference range 0.7–2.0 mmol/L)"

The measured pH and lactate with the laboratory's reference range.

Nervous System 2

Neonatal Seizures OCCASIONAL HP:0001250

1 of 1 patient described in detail. The absence of MRI is worth recording: a normal cranial ultrasound excludes gross structural lesions and haemorrhage but not the white-matter change that the milder end of the LARS2 spectrum produces, so this patient's brain was never examined for leukodystrophy.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"An electroencephalogram showed an abnormal background consistent with diffuse cerebral dysfunction, despite normal structures apparent on head ultrasound. No neuroimaging was performed."

The electrophysiological abnormality, the normal structural screen, and the authors' own statement that imaging was not done.

Global Developmental Delay VERY_FREQUENT HP:0001263

2 of 2 survivors in the 2020 series, same ascertainment limit as the hearing loss. Whether the delay is a continuing consequence of the translation defect or residual injury from the neonatal crisis cannot be separated from the published data.

Show evidence (1 reference)

PMID:32442335 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"both have developmental delay and hearing loss"

The neurodevelopmental outcome in both survivors.

Prenatal and Birth 1

Premature Birth with Growth Restriction OCCASIONAL HP:0001622

1 of 1 patient described in detail. In a hydropic fetus, preterm delivery is partly a consequence of the hydrops and partly an obstetric decision, so it is a feature of the presentation rather than an independent phenotype.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Fetal cardiotocography at 29 weeks’ gestation was abnormal and led to an emergency caesarean section."

The gestation and the indication.

Respiratory 1

Neonatal Respiratory Distress OCCASIONAL HP:0002643

1 of 1 patient described in detail, and confounded by 29-week prematurity. Recorded with the confound stated rather than omitted, because a reader assembling a phenotype list from this entity should know which features carry an alternative explanation.

Show evidence (1 reference)

PMID:26537577 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"She was intubated and ventilated from birth."

The respiratory support required. Graded INDIRECT because ventilation at 29 weeks does not by itself attribute the respiratory failure to this disease.

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Genetic Associations

1

LARS2

Gene: LARS2 hgnc:17095 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:32442335 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we describe five patients with a range of phenotypes, in whom we identified biallelic LARS2 variants: three patients with a HLASA-like phenotype, an individual with Perrault syndrome whose affected siblings also had leukodystrophy, and an individual with a reversible mitochondrial myopathy,..."

The full allelic series in one sentence, and the basis for treating this entity as one end of a spectrum rather than as an isolated disease.

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Medical Actions

1

Neonatal Intensive Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

What was given to the index proband: ventilation from birth, sodium bicarbonate for the acidosis, fresh-frozen plasma and cryoprecipitate for the coagulopathy, albumin for the low albumin, and multiple anticonvulsants for the seizures. None of it altered the lactate, which stayed at 13 mmol/L through bicarbonate infusion. Two of the three 2020 patients survived the neonatal period on comparable support, so supportive care is not futile in this entity even though it is not disease-modifying. What decides the outcome is not known.

Mechanism Target:

Severe Lactic Acidosis — Bicarbonate buffers the acidosis without touching its cause, and in this patient did not lower the lactate. Recorded against the phenotype rather than a mechanism node for exactly that reason.

Show evidence (1 reference)

PMID:26537577 REFUTE DIRECT PRIMARY RESULT Human Clinical

"The acidosis continued with lactate of 13 mmol/L, despite management with sodium bicarbonate infusions"

Graded REFUTE against the claim that this treatment controls the acidosis. It is the only treatment-outcome observation in this literature and it is a negative one; recording it as support would invert what the source says.

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Diagnosis

4

Respiratory chain enzymology in muscle and liver (ABSENT)

Recorded as a negative because it is the trap. In the index proband, complexes I and IV were low in muscle and complex IV low in liver, and the authors judged none of it low enough to diagnose a respiratory-chain disorder — the muscle values being what premature infants show anyway. Citrate synthase was raised in both tissues, with no premature-infant normative data to compare against. An entity caused by a mitochondrial translation defect can therefore have a non-diagnostic respiratory-chain panel. Immunoblotting of the same tissues is what showed the lesion.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Complex IV activity was also reduced in liver (Table 1), but again, not to a level that would support the diagnosis of a mitochondrial RC disorder."

The authors' own judgement that their enzymology was not diagnostic.

Fibroblast studies (ABSENT)

Also a negative, and a stronger one. The proband's fibroblasts showed normal LARS2 protein, normal respiratory-chain complex protein, and no defect in mitochondrial protein synthesis. Fibroblasts are the standard cell for functional confirmation of a suspected mitochondrial disease, and in this disease they are uninformative.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Immunoblotting of patient fibroblasts showed no change in LARS2 protein level and no effect on mitochondrial RC complex protein levels relative to pediatric control fibroblasts"

The negative fibroblast result, which is what makes the tissue restriction of this disease a practical diagnostic problem rather than a curiosity.

Bone marrow aspirate with Perls iron stain

Ring sideroblasts are the finding that names the entity and, in the index case, the finding that steered the exome analysis: the authors prioritised genes previously implicated in sideroblastic anaemia alongside MitoCarta mitochondrial genes, and that filter is what surfaced LARS2.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Due to the severity of the phenotype and the presence of ringed sideroblasts, we prioritized variants that were: (1) rare, with less than 1% frequency"

How the marrow finding was used to constrain the genomic analysis.

Whole exome sequencing

The diagnostic route in every published case. In the index patient it followed a negative targeted screen of YARS2, the gene whose MLASA2 phenotype the presentation most resembled, and mitochondrial DNA sequencing and copy-number testing of liver, both normal.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient DNA was then analyzed by whole exome sequencing, identifying two heterozygous variants in a related gene, LARS2."

The diagnostic step that found the gene, and that it came after the targeted screen failed.

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Progression

2

Antenatal

Hydrops, fetal anaemia, growth restriction and oligohydramnios are present before birth, and the cord blood gas already shows metabolic acidosis. The disease is therefore established in utero, which bears on what any postnatal intervention could hope to achieve.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her arterial cord pH was 7.27 and base excess was −6.7 mEq/L, indicative of metabolic acidosis."

Metabolic acidosis at the moment of delivery, which places the onset before birth rather than in the neonatal course.

Neonatal crisis, with two outcomes

The index proband deteriorated over five days to withdrawal of care. Two of the three 2020 patients survived the same neonatal multisystem illness. So the entity is not uniformly lethal despite being described as infantile-lethal, and the fork happens within the first days. What separates the two outcomes is not established. With four patients and no published allele-by-allele comparison across them, the obvious candidate — residual aminoacylation activity of the specific allele pair — is untested for this fork specifically, even though it is the established explanation for severity across the wider LARS2 spectrum.

Show evidence (1 reference)

PMID:32442335 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two survived multisystem disease in the neonatal period"

That survival is possible, which is the fact most likely to be lost if this entity is summarised as lethal.

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Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Four patients: the index proband reported in 2015 and three from two unrelated families in 2020. No population estimate exists. All four were ascertained through diagnostic sequencing of a severe neonatal phenotype, so the denominator is unknown by construction and rate_per_100000 is left unset rather than computed from four cases. One figure worth recording as a negative: the founding group screened LARS2 by Sanger sequencing in fourteen further probands with syndromic sideroblastic anaemia and found no variants. That is a small but real upper bound on how much of the syndromic sideroblastic anaemia population this gene accounts for.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We did not identify LARS2 variants in fourteen other probands with syndromic sideroblastic anemia."

The negative screen, which is the only quantitative statement anyone has made about how common this gene is in the phenotype it presents as.

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Experimental Models

1

Recombinant LARS2 aminoacylation assay OTHER

Purified recombinant human LARS2, wild-type and each patient variant, assayed for leucylation of an E. coli tRNA-Leu transcript with carbon-14 leucine, with kinetic parameters from Lineweaver-Burk plots. Deacylation and misacylation controls were run in the same system. This is the only functional model of the disease that exists, and it is a purified-enzyme assay rather than a cell or animal model.

Pathograph links

Reduced Leucyl-tRNA Aminoacylation measures fidelity: moderate observes: molecular Quantifies the catalytic consequence of each allele: 18-fold and 9-fold losses of efficiency, driven by k-cat rather than K-m.

Limitations: The tRNA substrate is bacterial, not human mitochondrial tRNA-Leu, and the authors note that their wild-type kinetic values differ from previously published ones for exactly this reason — a different tRNA substrate was used. So the fold-changes are internally comparable and the absolute constants are not transferable. The assay also tests each variant enzyme alone, where the patient is compound heterozygous and carries both.

Divergences from the human mechanism

proxy quantity qualifying

The measured quantity is leucylation of an E. coli tRNA-Leu transcript. The quantity that matters in the patient is leucylation of human mitochondrial tRNA-Leu, which has two isoacceptors and a different structure.

boundary omission qualifying

The mitochondrial matrix, the import machinery that delivers LARS2 there, and the mitoribosome that consumes the charged tRNA are all outside the assay. The model reports catalysis and nothing about supply.

Readouts

Catalytic efficiency of leucylation

Direction: DECREASED

Interpretation: Both patient alleles retain measurable activity, which is the observation that makes this a hypomorphic rather than a null genotype.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT In Vitro

"LARS2 p.Ala430Val demonstrated an 18-fold loss of catalytic efficiency and LARS2 p.Thr522Asn showed a 9-fold reduction compared to WT LARS2, essentially due to decreased catalytic rates"

The two fold-changes and the kinetic parameter they come from, which is what distinguishes a slow enzyme from one that cannot find its substrate.

Show evidence (1 reference)

PMID:26537577 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Kinetic parameters were determined from Lineweaver–Burk plots in the presence of 3–30 nM WT or variant LARS2 and concentrations of E. coli tRNALeu transcript ranging from 0.3 to 5.6 μM."

The assay design, quoted so a reader can see what the model does and does not contain.

Notes

The editing controls matter for interpreting the Ala430Val allele. Ala430 sits in the CP1 connective-peptide domain, which in cytosolic synthetases edits mischarged tRNA, so a reader might expect an editing defect. The authors tested it: no isoleucine-charged tRNA-Leu was detectable with wild-type or variant enzyme, and all three enzymes were inactive in deacylation. LARS2's editing domain is present but not functional, so the allele's effect is on aminoacylation.

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Source YAML

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name: Hydrops-Lactic Acidosis-Sideroblastic Anemia-Multisystemic Failure Syndrome
category: Mendelian
creation_date: "2026-09-22T00:00:00Z"
synonyms:
- HLASA
- hydrops, lactic acidosis, and sideroblastic anemia
- hydrops, lactic acidosis, and sideroblastic anaemia
- LARS2-related hydrops-lactic acidosis-sideroblastic anemia
disease_term:
  preferred_term: hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
  term:
    id: MONDO:0014869
    label: hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
description: >-
  HLASA is the severe end of the LARS2 allelic spectrum: a perinatal presentation of non-immune
  hydrops, extreme lactic acidosis and sideroblastic anaemia with multi-organ failure, caused by
  biallelic variants in the mitochondrial leucyl-tRNA synthetase. Four patients have been
  published — the index proband in 2015, who died at five days, and three further males from two
  families in 2020, two of whom survived the neonatal crisis.

  LARS2 charges leucine onto mitochondrial tRNA-Leu, so a hypomorphic enzyme starves
  mitochondrial translation of a charged substrate and the thirteen mtDNA-encoded
  respiratory-chain subunits are made less well. The aminoacylation defect is measured rather
  than assumed: recombinant enzyme carrying the index proband's two alleles loses 18-fold and
  9-fold of its catalytic efficiency, and in the 2020 series the HLASA-associated alleles were
  the most severely affected of all LARS2 variants tested. That is the quantitative basis for
  treating this entity as the same disease as Perrault syndrome 4 at a lower residual activity,
  rather than as a separate mechanism.

  The diagnostic trap is that the respiratory chain looks nearly normal. The index proband's
  muscle and liver enzymology was reduced but not to a level anyone would call diagnostic, her
  fibroblasts showed no LARS2 reduction, no respiratory-chain protein reduction and no
  mitochondrial protein-synthesis defect at all, and the authors conclude the variants affect
  only tissues with high energy demand. An entity defined by a mitochondrial translation defect
  can therefore be missed by the two assays a mitochondrial service would run first. What did
  show the lesion was immunoblotting of the affected tissues — LARS2 at about half of control in
  liver, complex I at about a quarter.

  The relationship between the anaemia and the hydrops is the part that is inferred rather than
  shown. Ring sideroblasts were seen on the proband's marrow and dyserythropoiesis in her liver,
  and mitochondrial iron accumulation is the shared mechanism across the congenital sideroblastic
  anaemias, but nobody has measured erythroblast iron handling, heme synthesis or iron-sulfur
  cluster assembly in a LARS2 patient. The chain from fetal anaemia to hydrops is likewise the
  standard reading of non-immune hydrops rather than a finding in this disease, and both are
  carried here as indirect edges with the gap recorded.
parents:
- Mitochondrial Disease
- Perrault Syndrome
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian, mechanism-defined mitochondrial disorder. Its haematological presentation
      would put it in front of a haematologist first, but it is diagnosed and understood as an
      inherited mitochondrial translation defect.
  mechanistic_category:
  - classification_value: mitochondrial disease
  icimd_category:
  - classification_value: mitochondrial_aminoacyl_trna_synthetases
    notes: >-
      The lesion is in a mitochondrial aminoacyl-tRNA synthetase rather than in the mitoribosome,
      a respiratory-chain subunit or an assembly factor. That places it beside the AARS2, YARS2
      and HARS2 disorders, which is the comparison the founding paper draws.
references:
- reference: PMID:26537577
  title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
- reference: PMID:32442335
  title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
- reference: PMID:40119736
  title: "LARS2-Related Perrault Syndrome in Siblings With 46,XY Differences of Sex Development."
- reference: PMID:32759564
  title: "[Ring sideroblasts and iron metabolism]."
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic and compound heterozygous in every published family. In the index case the mother
    carried one allele and the father the other, which is the segregation that establishes
    recessive inheritance; the parents were non-consanguineous and of Pakistani origin. The 2020
    HLASA cases come from two unrelated families. LARS2 is nuclear and autosomal, so despite the
    mitochondrial biochemistry there is no maternal transmission and the sibling recurrence risk
    is 25 percent.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The mother was heterozygous for the c.1289C>T variant and the father heterozygous for the c.1565C>A variant, consistent with the expectation of recessive inheritance."
    explanation: Biparental transmission of the two alleles, which is what makes this recessive rather than de novo.
pathophysiology:
- name: Biallelic Hypomorphic LARS2 Variants
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The index proband carries c.1289C>T, p.Ala430Val in trans with c.1565C>A, p.Thr522Asn. The
    second allele is the same one reported homozygously in Perrault syndrome, which is the
    single most informative fact about this entity: the severe and the mild phenotype share an
    allele, so severity is a property of the allele combination rather than of the variant.

    The two residues sit in different parts of the enzyme. Thr522 is in the catalytic domain
    where the 3-prime end of the tRNA binds, and Ala430 is in the CP1 connective-peptide domain,
    which in cytosolic synthetases is an editing domain. LARS2's editing domain is present but
    not functional, and the authors tested that directly — no mischarging with isoleucine was
    detectable for wild-type or variant enzyme. So the Ala430Val effect is on aminoacylation
    rather than on proofreading, which is worth recording because the domain's name invites the
    opposite inference.
  genes:
  - preferred_term: LARS2
    term:
      id: hgnc:17095
      label: LARS2
  genetic_context:
    genes:
    - preferred_term: LARS2
      term:
        id: hgnc:17095
        label: LARS2
    allele_type: two missense variants in trans, one of which also occurs in Perrault syndrome
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Compound heterozygosity is the reported configuration in every HLASA family, index case and
      2020 series alike.
    notes: >-
      PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION is the measured position: recombinant
      p.Ala430Val retains about a eighteenth of wild-type catalytic efficiency and p.Thr522Asn
      about a ninth, so neither allele is a null. A complete loss of mitochondrial leucyl-tRNA
      synthetase is presumed incompatible with life, and the residual activity is what the
      genotype-phenotype relationship in this gene is built on.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Whole exome sequencing of patient DNA revealed compound heterozygous variants in LARS2 (c.1289C>T; p.Ala430Val and c.1565C>A; p.Thr522Asn)."
    explanation: The two alleles and the configuration they are in.
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging (SIFT, PolyPhen)."
    explanation: >-
      The allele shared with the milder disease. This is the observation that makes HLASA and
      Perrault syndrome 4 one allelic series rather than two diseases.
  downstream:
  - target: Reduced Leucyl-tRNA Aminoacylation
    causal_link_type: DIRECT
    description: >-
      Both substitutions reduce the rate at which the enzyme charges leucine onto tRNA-Leu,
      measured on purified recombinant protein rather than inferred from the residue position.
    evidence:
    - reference: PMID:26537577
      reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Aminoacylation assays revealed p.Ala430Val LARS2 had an 18-fold loss of catalytic efficiency and p.Thr522Asn a 9-fold loss compared to wild-type LARS2."
      explanation: >-
        The quantified enzymatic consequence of each allele — the measurement the whole
        genotype-phenotype argument in this gene rests on.
- name: Reduced Leucyl-tRNA Aminoacylation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Less charged mitochondrial tRNA-Leu is available to the mitoribosome. The kinetics show the
    loss is in catalytic rate rather than in substrate affinity: k-cat falls roughly fourteen-fold
    for p.Ala430Val and ninefold for p.Thr522Asn while K-m barely moves. An enzyme that binds its
    substrate normally and turns it over slowly is a hypomorph whose output scales with how much
    of it there is, which is the basis for expecting tissue-dependent severity.

    Across the 2020 series the HLASA alleles were the most severely impaired of all LARS2
    variants assayed, which extends the relationship from one family to the spectrum.
  molecular_functions:
  - preferred_term: leucine-tRNA ligase activity
    term:
      id: GO:0004823
      label: leucine-tRNA ligase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: leucyl-tRNA aminoacylation
    term:
      id: GO:0006429
      label: leucyl-tRNA aminoacylation
    modifier: DECREASED
  evidence:
  - reference: PMID:32442335
    reference_title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Analysis of recombinant LARS2 variant proteins showed they had reduced aminoacylation efficiency, with HLASA-associated variants having the most severe effect."
    explanation: >-
      The spectrum-level relationship: within one gene, the alleles that produce this phenotype
      are the ones with the least residual activity.
  downstream:
  - target: Impaired Mitochondrial Translation in High-Demand Tissues
    causal_link_type: DIRECT
- name: Impaired Mitochondrial Translation in High-Demand Tissues
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Translation of the thirteen mtDNA-encoded respiratory-chain subunits depends on a supply of
    charged tRNA-Leu, and a hypomorphic synthetase restricts it. The tissue qualifier is not
    decoration: in the index proband's fibroblasts and induced myotubes, LARS2 protein was
    normal, respiratory-chain proteins were normal, and an in vitro mitochondrial protein
    synthesis assay found no defect at all. The authors conclude the variants affect only tissues
    with higher energy demands.

    Graded PROVISIONAL because the translation defect itself was never demonstrated in an
    affected tissue. What was demonstrated in liver and muscle is reduced LARS2 protein and
    reduced complex I protein; the translation step between them is inferred from the enzyme's
    known function. The one assay that could have shown it was run in the tissue where the
    disease is absent.
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "no defect in mitochondrial protein synthesis was detected in an in vitro assay in patient fibroblasts or induced myotubes (results not shown), indicating the LARS2 variants most likely only affect tissues with higher energy demands"
    explanation: >-
      A negative result, and the tissue restriction the authors draw from it. Graded INDIRECT
      because it supports this node's scope qualifier rather than the translation defect itself —
      the assay found nothing, in the wrong tissue.
  downstream:
  - target: Reduced Respiratory Chain Complex I in Liver and Muscle
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26537577
      reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Immunoblotting of patient muscle and liver showed LARS2 levels were reduced in liver and complex I protein levels were reduced in patient muscle and liver."
      explanation: >-
        The two protein measurements in affected tissue — the endpoints of the step this edge
        draws.
- name: Reduced Respiratory Chain Complex I in Liver and Muscle
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Complex I protein was about 57 percent of a gestational-age-matched fetal control in muscle
    and about 25 percent of control in liver, with LARS2 itself at about 50 percent in liver.
    Complex I is the complex with the most mtDNA-encoded subunits, which is why a general
    translation restriction shows up there first.

    The enzymology tells a different story from the immunoblot and the difference is the
    diagnostic point of this entry. Measured activities for complexes I and IV were low in muscle
    and complex IV low in liver, but in each case the authors judged them not low enough to be
    diagnostic of a respiratory-chain disorder, and consistent with what premature infants show
    anyway. Citrate synthase was raised in both tissues. A service laboratory reporting that
    panel would not call it a mitochondrial disease.
  cellular_components:
  - preferred_term: mitochondrial respiratory chain complex I
    term:
      id: GO:0045271
      label: respiratory chain complex I
    modifier: DECREASED
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Levels of the RC complexes were also reduced in patient liver with complex I being the most markedly reduced at ~25% of the control level."
    explanation: The magnitude of the complex I reduction in liver.
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "RC enzyme activities for complexes I and IV were low in muscle (Table 1), consistent with levels typically found in premature infants and not sufficiently low to be diagnostic for a mitochondrial RC disorder."
    explanation: >-
      Recorded as REFUTE against this node deliberately. Enzymology is the assay a reader would
      expect to confirm a respiratory-chain deficiency, and in this patient it did not; the node
      stands on immunoblot instead. Burying that under a supporting quote would misrepresent what
      the source found.
  downstream:
  - target: Bioenergetic Failure in High-Demand Organs
    causal_link_type: DIRECT
  - target: Erythroblast Mitochondrial Iron Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ring sideroblasts are the shared endpoint of the congenital sideroblastic anaemias, which
      are caused by defects in heme biosynthesis, iron-sulfur cluster biosynthesis and
      mitochondrial protein synthesis alike. LARS2 sits in the third of those groups, so the
      edge is drawn by class membership. No measurement of erythroblast iron, heme synthesis or
      iron-sulfur cluster assembly exists in any LARS2 patient.
    evidence:
    - reference: PMID:32759564
      reference_title: "[Ring sideroblasts and iron metabolism]."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Congenital SA is a rare disease caused by gene mutations involved in heme biosynthesis, iron-sulfur cluster biosynthesis, and mitochondrial protein synthesis."
      explanation: >-
        Places mitochondrial protein synthesis defects among the causes of congenital
        sideroblastic anaemia, which is the class argument this edge makes. Graded
        REVIEW_SYNTHESIS and INDIRECT because it is a review's statement about the disease group
        and says nothing about LARS2.
- name: Bioenergetic Failure in High-Demand Organs
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    A respiratory chain that cannot keep up forces glycolysis, and in this patient the result was
    among the most extreme recorded: arterial pH fell to 6.8 with lactate at 16 mmol/L against a
    reference of 0.7 to 2.0, and lactate stayed at 13 despite bicarbonate infusion, normal blood
    pressure and adequate perfusion.

    That last clause is the one that matters clinically. Lactate at 16 in a sick premature
    neonate is usually read as tissue hypoperfusion; here the haemodynamics were normal, so the
    lactate is metabolic rather than circulatory. The distinction is what should prompt
    mitochondrial investigation rather than escalating inotropes.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
    modifier: INCREASED
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The acidosis continued with lactate of 13 mmol/L, despite management with sodium bicarbonate infusions and despite normal mean blood pressures and presumed adequate perfusion."
    explanation: >-
      The observation that separates a metabolic lactataemia from a circulatory one, and the
      failure of buffering to correct it.
  downstream:
  - target: Severe Lactic Acidosis
    causal_link_type: DIRECT
  - target: Lactic Aciduria
    causal_link_type: DIRECT
  - target: Multi-Organ Failure
    causal_link_type: DIRECT
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hearing loss is the feature that unites the whole LARS2 spectrum, from this entity's
      survivors to Perrault syndrome. No cochlear measurement exists in any LARS2 patient, so the
      edge is the organ-vulnerability argument rather than a finding.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Present in both 2020 survivors. Whether it reflects ongoing central energy failure or
      residual injury from the neonatal crisis is not separable from the published data.
- name: Erythroblast Mitochondrial Iron Accumulation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Ring sideroblasts are erythroblasts whose perinuclear mitochondria are loaded with iron, and
    the proband had them on Perls staining of her marrow, alongside vacuolated proerythroblasts
    and, in the liver, dyserythropoietic extramedullary haematopoiesis with irregular crenated
    nuclei and binucleate forms.

    The node is graded HYPOTHETICAL because everything above the histology is borrowed. The
    accepted account of ring sideroblast formation — mitochondrial protein synthesis failure
    impairing heme synthesis and iron-sulfur cluster assembly, leaving iron that entered the
    mitochondrion with nowhere to go — comes from the congenital sideroblastic anaemias as a
    group. Nobody has measured any of it in a LARS2 erythroblast. What is observed here is the
    endpoint; the mechanism is the group's.
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  biological_processes:
  - preferred_term: heme biosynthetic process
    term:
      id: GO:0006783
      label: heme biosynthetic process
    modifier: DECREASED
  - preferred_term: iron-sulfur cluster assembly
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:32759564
    reference_title: "[Ring sideroblasts and iron metabolism]."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ring sideroblasts show abnormal mitochondrial iron accumulation, and their emergence in the bone marrow is a characteristic of sideroblastic anemias"
    explanation: >-
      Defines what the observed histology means at the subcellular level. It is a review's
      definition applied to this disease, which is why the node is HYPOTHETICAL rather than
      established.
  downstream:
  - target: Sideroblastic Anaemia
    causal_link_type: DIRECT
  - target: Non-Immune Hydrops Fetalis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Fetal anaemia is an established cause of non-immune hydrops through high-output cardiac
      strain and loss of oncotic pressure, and this fetus was anaemic in utero. No one has shown
      the sequence in a LARS2 pregnancy, and the proband also had cardiac dysfunction and
      hypoalbuminaemia, each of which could contribute independently, so the edge is one
      plausible route among several rather than the established one.
- name: Multi-Organ Failure
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The proband's course was simultaneous rather than sequential failure: hyaline membrane
    disease, impaired cardiac function, coagulopathy with low albumin requiring plasma,
    cryoprecipitate and albumin, pulmonary hypertension, rising creatinine with haematuria on
    structurally normal kidneys, and clinical and electrical seizures on a diffusely abnormal
    EEG with normal cranial ultrasound.

    Normal structure with abnormal function, repeated across kidney and brain, is the signature
    of an energetic rather than a structural lesion, and it is what makes the multi-organ picture
    one disease rather than a list of complications of prematurity.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "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."
    explanation: The organs involved and the outcome, in the index patient.
  downstream:
  - target: Impaired Cardiac Function
    causal_link_type: DIRECT
  - target: Pulmonary Arterial Hypertension
    causal_link_type: DIRECT
  - target: Coagulopathy
    causal_link_type: DIRECT
  - target: Progressive Renal Disease
    causal_link_type: DIRECT
  - target: Neonatal Respiratory Distress
    causal_link_type: DIRECT
  - target: Neonatal Seizures
    causal_link_type: DIRECT
phenotypes:
- name: Non-Immune Hydrops Fetalis
  category: Prenatal
  description: >-
    Detected antenatally in the index pregnancy, with pericardial effusion, ascites and scalp
    oedema on scan, alongside oligohydramnios, fetal growth restriction and fetal anaemia. It is
    one of the three features the entity is named for.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Non-immune hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  notes: >-
    Reported in the index proband. The 2020 abstract describes three further HLASA cases without
    listing their individual prenatal findings, so the denominator that can be quoted from a
    source is one of one rather than four of four. The name of the entity implies it is general;
    the abstract does not say so.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The pregnancy was complicated by oligohydramnios and fetal growth restriction, hydrops, and anemia, with antenatal scans showing fetal pericardial effusion, ascites, and scalp edema."
    explanation: >-
      The prenatal picture in full, including the two components — effusions and oedema — that
      make the finding hydrops rather than isolated ascites.
- name: Severe Lactic Acidosis
  category: Metabolism
  description: >-
    Arterial pH to 6.8 with lactate to 16 mmol/L against a reference range of 0.7 to 2.0 shortly
    after birth, persisting at 13 mmol/L despite bicarbonate. Cord pH was 7.27 with a base excess
    of minus 6.7, so the metabolic acidosis was present before delivery and worsened after it.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  notes: >-
    Named in the entity and reported with numbers in the index case. Bound to HP:0003128 rather
    than to the circulating-lactate term because a pH of 6.8 is measured acidosis and not merely
    a raised lactate.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "an arterial blood gas showed acidosis with pH to 6.8 and lactate to 16 mmol/L (reference range 0.7–2.0 mmol/L)"
    explanation: The measured pH and lactate with the laboratory's reference range.
- name: Sideroblastic Anaemia
  category: Hematologic
  description: >-
    Ring sideroblasts on Perls iron staining of the marrow, with vacuolated proerythroblasts on
    May-Grunwald-Giemsa, and dyserythropoietic extramedullary haematopoiesis in the liver showing
    irregular crenated nuclei and binucleate forms. The fetus was already anaemic in utero.

    This is the feature that sends the patient to haematology rather than to metabolic medicine,
    and it is why the differential runs through the congenital sideroblastic anaemia panel —
    ALAS2, SLC25A38, GLRX5, YARS2, PUS1, ABCB7 — rather than through a mitochondrial panel.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sideroblastic anaemia with ring sideroblasts
    term:
      id: HP:0001924
      label: Sideroblastic anemia
  notes: >-
    Named in the entity. In the index case the finding is documented histologically; the 2020
    abstract does not report marrow findings for its three cases individually.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Perl’s iron stain of bone marrow aspirate showing ringed sideroblasts (arrows). (b) May–Grunwald–Giemsa stain of bone marrow aspirate showing vacuolation of proerythroblasts."
    explanation: >-
      The two marrow findings, with the stains that produced them. Quoted from the figure legend
      because that is where the paper states what was seen.
- name: Lactic Aciduria
  category: Metabolism
  description: Gross lactic aciduria on urine metabolic screen in the index case.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Gross lactic aciduria
    term:
      id: HP:0003648
      label: Lacticaciduria
  notes: >-
    1 of 1 patient for whom a urine screen is reported. Recorded separately from the blood
    lactate because the urine screen is a different test with a different access route, and in a
    neonate it may be the first abnormal result available.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A urine metabolic screen showed gross lactic aciduria."
    explanation: The urine finding in the index case.
- name: Impaired Cardiac Function
  category: Cardiovascular
  description: >-
    Impaired cardiac function from the first days, worsening to hypotension that precipitated the
    decision to withdraw intensive care.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Impaired cardiac function
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  notes: >-
    1 of 1 patient described in detail. The HPO term names congestive failure where the source
    says impaired cardiac function with hypotension; that is the nearest available term for a
    functional cardiac deficit and preferred_term keeps the source's wording rather than
    upgrading it to a diagnosis the paper does not make.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Worsening cardiac function and hypotension led to a decision by the family for withdrawal of active intensive care management and she succumbed at 5 days of age."
    explanation: The cardiac trajectory and its role in the fatal outcome.
- name: Pulmonary Arterial Hypertension
  category: Cardiovascular
  description: Pulmonary hypertension as part of the index patient's multisystem course.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  notes: >-
    1 of 1 patient described in detail. The source says "pulmonary hypertension" without
    specifying the arterial subtype that the HPO label names; in a ventilated neonate this is
    almost always persistent pulmonary hypertension of the newborn, and the binding is the
    nearest term rather than a claim about subtype.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease"
    explanation: The list of organ involvements including this one.
- name: Coagulopathy
  category: Hematologic
  description: >-
    Disordered coagulation with hypoalbuminaemia, attributed by the authors to liver dysfunction
    and treated with fresh-frozen plasma, cryoprecipitate and albumin. The liver was not enlarged.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Coagulopathy from hepatic dysfunction
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  notes: 1 of 1 patient described in detail.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "There was no liver enlargement but liver dysfunction with disordered coagulation was treated with fresh-frozen plasma and cryoprecipitate, and a low albumin level required albumin infusion."
    explanation: >-
      The coagulopathy, its attribution to the liver, the absent hepatomegaly, and the products
      used — all in one sentence.
- name: Progressive Renal Disease
  category: Renal
  description: >-
    Rising creatinine with haematuria on structurally normal kidneys. Normal structure with
    failing function is the pattern that points at an energetic lesion rather than a
    malformation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Progressive renal impairment with haematuria
    term:
      id: HP:0000112
      label: Nephropathy
    clinical_course: PROGRESSIVE
  notes: 1 of 1 patient described in detail.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Her renal function showed rising creatinine levels with hematuria, although her kidneys were found to be structurally normal on ultrasound."
    explanation: The functional impairment set against normal structure.
- name: Neonatal Respiratory Distress
  category: Respiratory
  description: >-
    Hyaline membrane disease requiring intubation and ventilation from birth, in an infant born
    at 29 weeks. Prematurity alone would explain it, so its attribution to the disease is not
    separable here.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyaline membrane disease
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  notes: >-
    1 of 1 patient described in detail, and confounded by 29-week prematurity. Recorded with the
    confound stated rather than omitted, because a reader assembling a phenotype list from this
    entity should know which features carry an alternative explanation.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She was intubated and ventilated from birth."
    explanation: >-
      The respiratory support required. Graded INDIRECT because ventilation at 29 weeks does not
      by itself attribute the respiratory failure to this disease.
- name: Neonatal Seizures
  category: Nervous System
  description: >-
    Clinical and electrical seizures requiring multiple anticonvulsants, with an EEG showing a
    diffusely abnormal background and a normal head ultrasound. No neuroimaging beyond ultrasound
    was performed.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Clinical and electrical neonatal seizures
    term:
      id: HP:0001250
      label: Seizure
  notes: >-
    1 of 1 patient described in detail. The absence of MRI is worth recording: a normal cranial
    ultrasound excludes gross structural lesions and haemorrhage but not the white-matter change
    that the milder end of the LARS2 spectrum produces, so this patient's brain was never
    examined for leukodystrophy.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "An electroencephalogram showed an abnormal background consistent with diffuse cerebral dysfunction, despite normal structures apparent on head ultrasound. No neuroimaging was performed."
    explanation: >-
      The electrophysiological abnormality, the normal structural screen, and the authors' own
      statement that imaging was not done.
- name: Premature Birth with Growth Restriction
  category: Prenatal
  description: >-
    Emergency caesarean at 29 weeks for an abnormal cardiotocograph, birth weight 1010 g, with
    antenatal growth restriction and oligohydramnios.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Preterm delivery at 29 weeks
    term:
      id: HP:0001622
      label: Premature birth
  notes: >-
    1 of 1 patient described in detail. In a hydropic fetus, preterm delivery is partly a
    consequence of the hydrops and partly an obstetric decision, so it is a feature of the
    presentation rather than an independent phenotype.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Fetal cardiotocography at 29 weeks’ gestation was abnormal and led to an emergency caesarean section."
    explanation: The gestation and the indication.
- name: Male Genital Anomalies
  category: Genitourinary
  description: >-
    All three 2020 HLASA patients were male with genital anomalies. The founding female proband
    had none reported. Undervirilization is separately documented in LARS2-related Perrault
    syndrome — two 46,XY brothers with bilateral undescended testes and, in one, hypospadias with
    chordee — and those authors argue it is an underrecognised component of LARS2 disease rather
    than a coincidence, pointing to ovarian dysgenesis in 46,XX individuals and complete failure
    of germ-cell production in the C. elegans orthologue as evidence that the gene acts in
    gonadal development.

    That makes this the one feature of HLASA with an independent mechanistic argument behind it,
    and the one most likely to be missed, since a neonate in multi-organ failure is not examined
    for undervirilization.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Genital anomalies with undervirilization in 46,XY individuals
    term:
      id: HP:0000078
      label: Abnormality of the genital system
    coarse_binding_basis: VARIABLE_SPECTRUM
  notes: >-
    3 of 3 male HLASA patients in the 2020 series. Bound to the organ-system root deliberately:
    the 2020 abstract says "genital anomalies" without naming them, and the specific anomalies
    that are named — cryptorchidism and hypospadias — come from Perrault-syndrome siblings rather
    than from HLASA patients. Binding HP:0000028 or HP:0000047 here would import a specific
    anomaly from a different phenotype in the same gene.
  evidence:
  - reference: PMID:32442335
    reference_title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Three HLASA cases from two unrelated families were identified. All were males with genital anomalies."
    explanation: The observation in the only series that reports it, with its denominator.
  - reference: PMID:40119736
    reference_title: "LARS2-Related Perrault Syndrome in Siblings With 46,XY Differences of Sex Development."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In addition to bilateral profound sensorineural hearing loss, both brothers had bilateral undescended testes that required surgical intervention. In addition, the younger affected brother had hypospadias with chordee."
    explanation: >-
      The specific anomalies documented in LARS2 disease. Graded INDIRECT because these are
      Perrault-syndrome patients, not HLASA patients — they establish that the gene affects male
      genital development, not what the HLASA anomalies were.
- name: Sensorineural Hearing Loss
  category: Nervous System
  description: >-
    Present in both 2020 HLASA survivors, and the feature that runs through the entire LARS2
    spectrum from here to Perrault syndrome. It is the reason survivors of the neonatal crisis
    need audiology rather than only metabolic follow-up.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    2 of 2 survivors in the 2020 series. It cannot be assessed in a patient who dies at five
    days, so the denominator is survivors rather than all patients — which is a real
    ascertainment limit, not a rounding of the figure.
  evidence:
  - reference: PMID:32442335
    reference_title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss."
    explanation: The outcome in both survivors, covering this phenotype and the developmental one.
- name: Global Developmental Delay
  category: Nervous System
  description: Present in both 2020 HLASA survivors.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    2 of 2 survivors in the 2020 series, same ascertainment limit as the hearing loss. Whether
    the delay is a continuing consequence of the translation defect or residual injury from the
    neonatal crisis cannot be separated from the published data.
  evidence:
  - reference: PMID:32442335
    reference_title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "both have developmental delay and hearing loss"
    explanation: The neurodevelopmental outcome in both survivors.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Four patients: the index proband reported in 2015 and three from two unrelated families in
    2020. No population estimate exists. All four were ascertained through diagnostic sequencing
    of a severe neonatal phenotype, so the denominator is unknown by construction and
    rate_per_100000 is left unset rather than computed from four cases.

    One figure worth recording as a negative: the founding group screened LARS2 by Sanger
    sequencing in fourteen further probands with syndromic sideroblastic anaemia and found no
    variants. That is a small but real upper bound on how much of the syndromic sideroblastic
    anaemia population this gene accounts for.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We did not identify LARS2 variants in fourteen other probands with syndromic sideroblastic anemia."
    explanation: >-
      The negative screen, which is the only quantitative statement anyone has made about how
      common this gene is in the phenotype it presents as.
progression:
- phase: Antenatal
  notes: >-
    Hydrops, fetal anaemia, growth restriction and oligohydramnios are present before birth, and
    the cord blood gas already shows metabolic acidosis. The disease is therefore established in
    utero, which bears on what any postnatal intervention could hope to achieve.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Her arterial cord pH was 7.27 and base excess was −6.7 mEq/L, indicative of metabolic acidosis."
    explanation: >-
      Metabolic acidosis at the moment of delivery, which places the onset before birth rather
      than in the neonatal course.
- phase: Neonatal crisis, with two outcomes
  notes: >-
    The index proband deteriorated over five days to withdrawal of care. Two of the three 2020
    patients survived the same neonatal multisystem illness. So the entity is not uniformly
    lethal despite being described as infantile-lethal, and the fork happens within the first
    days.

    What separates the two outcomes is not established. With four patients and no published
    allele-by-allele comparison across them, the obvious candidate — residual aminoacylation
    activity of the specific allele pair — is untested for this fork specifically, even though
    it is the established explanation for severity across the wider LARS2 spectrum.
  evidence:
  - reference: PMID:32442335
    reference_title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Two survived multisystem disease in the neonatal period"
    explanation: >-
      That survival is possible, which is the fact most likely to be lost if this entity is
      summarised as lethal.
genetic:
- name: LARS2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: LARS2
    term:
      id: hgnc:17095
      label: LARS2
  notes: >-
    The single causal gene, and one whose phenotypes span an unusually wide range: Perrault
    syndrome 4 at the mild end, deafness with ovarioleukodystrophy, a reversible infantile
    mitochondrial myopathy, and HLASA at the severe end. The unifying variable is residual
    aminoacylation activity.

    A note on the identifier. The deep-research report committed alongside this entry gives
    LARS2 as HGNC:21353, which is KLHL31, an unrelated kelch-family gene. The correct identifier
    is hgnc:17095. The report's own term-validation step could not catch it because the research
    recipe passes --term-skip-prefix HGNC, and the KB-side check compares a CURIE against its own
    label rather than against the gene the entry names — the failure mode recorded in dismech
    issue #10948. It was caught here only because this entry writes the label out and the label
    disagreed.
  evidence:
  - reference: PMID:32442335
    reference_title: "The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Here we describe five patients with a range of phenotypes, in whom we identified biallelic LARS2 variants: three patients with a HLASA-like phenotype, an individual with Perrault syndrome whose affected siblings also had leukodystrophy, and an individual with a reversible mitochondrial myopathy, lactic acidosis, and developmental delay."
    explanation: >-
      The full allelic series in one sentence, and the basis for treating this entity as one end
      of a spectrum rather than as an isolated disease.
diagnosis:
- name: Respiratory chain enzymology in muscle and liver
  presence: ABSENT
  description: >-
    Recorded as a negative because it is the trap. In the index proband, complexes I and IV were
    low in muscle and complex IV low in liver, and the authors judged none of it low enough to
    diagnose a respiratory-chain disorder — the muscle values being what premature infants show
    anyway. Citrate synthase was raised in both tissues, with no premature-infant normative data
    to compare against.

    An entity caused by a mitochondrial translation defect can therefore have a non-diagnostic
    respiratory-chain panel. Immunoblotting of the same tissues is what showed the lesion.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Complex IV activity was also reduced in liver (Table 1), but again, not to a level that would support the diagnosis of a mitochondrial RC disorder."
    explanation: The authors' own judgement that their enzymology was not diagnostic.
- name: Fibroblast studies
  presence: ABSENT
  description: >-
    Also a negative, and a stronger one. The proband's fibroblasts showed normal LARS2 protein,
    normal respiratory-chain complex protein, and no defect in mitochondrial protein synthesis.
    Fibroblasts are the standard cell for functional confirmation of a suspected mitochondrial
    disease, and in this disease they are uninformative.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Immunoblotting of patient fibroblasts showed no change in LARS2 protein level and no effect on mitochondrial RC complex protein levels relative to pediatric control fibroblasts"
    explanation: >-
      The negative fibroblast result, which is what makes the tissue restriction of this disease
      a practical diagnostic problem rather than a curiosity.
- name: Bone marrow aspirate with Perls iron stain
  description: >-
    Ring sideroblasts are the finding that names the entity and, in the index case, the finding
    that steered the exome analysis: the authors prioritised genes previously implicated in
    sideroblastic anaemia alongside MitoCarta mitochondrial genes, and that filter is what
    surfaced LARS2.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Due to the severity of the phenotype and the presence of ringed sideroblasts, we prioritized variants that were: (1) rare, with less than 1% frequency"
    explanation: How the marrow finding was used to constrain the genomic analysis.
- name: Whole exome sequencing
  description: >-
    The diagnostic route in every published case. In the index patient it followed a negative
    targeted screen of YARS2, the gene whose MLASA2 phenotype the presentation most resembled,
    and mitochondrial DNA sequencing and copy-number testing of liver, both normal.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patient DNA was then analyzed by whole exome sequencing, identifying two heterozygous variants in a related gene, LARS2."
    explanation: The diagnostic step that found the gene, and that it came after the targeted screen failed.
experimental_models:
- name: Recombinant LARS2 aminoacylation assay
  experimental_model_type: OTHER
  description: >-
    Purified recombinant human LARS2, wild-type and each patient variant, assayed for leucylation
    of an E. coli tRNA-Leu transcript with carbon-14 leucine, with kinetic parameters from
    Lineweaver-Burk plots. Deacylation and misacylation controls were run in the same system.

    This is the only functional model of the disease that exists, and it is a purified-enzyme
    assay rather than a cell or animal model.
  modeled_mechanisms:
  - target: Reduced Leucyl-tRNA Aminoacylation
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Quantifies the catalytic consequence of each allele: 18-fold and 9-fold losses of
      efficiency, driven by k-cat rather than K-m.
    limitations: >-
      The tRNA substrate is bacterial, not human mitochondrial tRNA-Leu, and the authors note
      that their wild-type kinetic values differ from previously published ones for exactly this
      reason — a different tRNA substrate was used. So the fold-changes are internally comparable
      and the absolute constants are not transferable. The assay also tests each variant enzyme
      alone, where the patient is compound heterozygous and carries both.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantity is leucylation of an E. coli tRNA-Leu transcript. The quantity that
        matters in the patient is leucylation of human mitochondrial tRNA-Leu, which has two
        isoacceptors and a different structure.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The mitochondrial matrix, the import machinery that delivers LARS2 there, and the
        mitoribosome that consumes the charged tRNA are all outside the assay. The model reports
        catalysis and nothing about supply.
    readouts:
    - name: Catalytic efficiency of leucylation
      target: Reduced Leucyl-tRNA Aminoacylation
      direction: DECREASED
      interpretation: >-
        Both patient alleles retain measurable activity, which is the observation that makes this
        a hypomorphic rather than a null genotype.
      evidence:
      - reference: PMID:26537577
        reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: "LARS2 p.Ala430Val demonstrated an 18-fold loss of catalytic efficiency and LARS2 p.Thr522Asn showed a 9-fold reduction compared to WT LARS2, essentially due to decreased catalytic rates"
        explanation: >-
          The two fold-changes and the kinetic parameter they come from, which is what
          distinguishes a slow enzyme from one that cannot find its substrate.
    evidence:
    - reference: PMID:26537577
      reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Kinetic parameters were determined from Lineweaver–Burk plots in the presence of 3–30 nM WT or variant LARS2 and concentrations of E. coli tRNALeu transcript ranging from 0.3 to 5.6 μM."
      explanation: The assay design, quoted so a reader can see what the model does and does not contain.
  notes: >-
    The editing controls matter for interpreting the Ala430Val allele. Ala430 sits in the CP1
    connective-peptide domain, which in cytosolic synthetases edits mischarged tRNA, so a reader
    might expect an editing defect. The authors tested it: no isoleucine-charged tRNA-Leu was
    detectable with wild-type or variant enzyme, and all three enzymes were inactive in
    deacylation. LARS2's editing domain is present but not functional, so the allele's effect is
    on aminoacylation.
treatments:
- name: Neonatal Intensive Supportive Care
  therapeutic_modality: OTHER
  description: >-
    What was given to the index proband: ventilation from birth, sodium bicarbonate for the
    acidosis, fresh-frozen plasma and cryoprecipitate for the coagulopathy, albumin for the low
    albumin, and multiple anticonvulsants for the seizures. None of it altered the lactate, which
    stayed at 13 mmol/L through bicarbonate infusion.

    Two of the three 2020 patients survived the neonatal period on comparable support, so
    supportive care is not futile in this entity even though it is not disease-modifying. What
    decides the outcome is not known.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Severe Lactic Acidosis
    description: >-
      Bicarbonate buffers the acidosis without touching its cause, and in this patient did not
      lower the lactate. Recorded against the phenotype rather than a mechanism node for exactly
      that reason.
  evidence:
  - reference: PMID:26537577
    reference_title: "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The acidosis continued with lactate of 13 mmol/L, despite management with sodium bicarbonate infusions"
    explanation: >-
      Graded REFUTE against the claim that this treatment controls the acidosis. It is the only
      treatment-outcome observation in this literature and it is a negative one; recording it as
      support would invert what the source says.
  notes: >-
    No disease-modifying therapy exists and none has been trialled. The deep-research report
    committed alongside this entry discusses a metabolic rescue combination — glucose, nicotinic
    acid and N-acetylcysteine — from a C. elegans and zebrafish complex I screen. That work is
    not about LARS2, was not done in this disease, and has never been given to a patient with it,
    so it is deliberately not curated here as a treatment. It is recorded in the discussions
    section as what it is: a lead.
discussions:
- discussion_id: hlasa_sideroblast_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does a mitochondrial leucyl-tRNA synthetase defect produce ring sideroblasts, and is the
    route the same one that operates in the heme-synthesis and iron-sulfur-cluster sideroblastic
    anaemias?
  rationale: >-
    Sideroblastic anaemia is one of the three features this entity is named for, and it is the
    one with no mechanism measured in it. The accepted account — mitochondrial protein synthesis
    failure impairing heme synthesis and iron-sulfur cluster assembly, stranding iron inside the
    mitochondrion — is imported from the congenital sideroblastic anaemia group as a whole. No
    one has measured erythroblast iron, heme intermediates, ALAS2 function or iron-sulfur cluster
    assembly in a LARS2 patient.

    The gap is not academic. Whether the erythroid phenotype follows from the general translation
    defect or from something specific about leucine supply in erythroblasts decides whether it
    should be expected in the milder LARS2 phenotypes, where nobody looks for it. The 2020 series
    reports HLASA and Perrault syndrome in the same paper without reporting marrow findings for
    the Perrault patients.

    Erythroblasts are accessible. A marrow sample from a surviving patient, or a differentiated
    CD34-positive culture carrying the alleles, would answer it.
  attaches_to:
  - pathophysiology#Erythroblast Mitochondrial Iron Accumulation
  - phenotypes#Sideroblastic Anaemia
- discussion_id: hlasa_severity_determinant
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Why did one patient die at five days while two others survived the same neonatal multisystem
    illness?
  rationale: >-
    Across the LARS2 spectrum, severity tracks residual aminoacylation activity, and the 2020
    series shows the HLASA alleles are the most severely impaired of all LARS2 variants tested.
    That explains why HLASA is worse than Perrault syndrome. It does not explain the fork inside
    HLASA.

    Nothing published separates the fatal from the surviving cases. The index proband was born
    at 29 weeks weighing 1010 g, so prematurity is an obvious confounder and might be the whole
    answer; the 2020 abstract does not give gestations. Nor is there an allele-by-allele
    comparison across the four patients — the 2020 aminoacylation data are reported as a group
    statement rather than per patient.

    With four patients this may not be answerable. It is recorded because an entity described in
    the literature as infantile-lethal has a 50 percent survival rate in its published series,
    and anyone using this entry for counselling needs to know that both the survival and its
    unexplained variability are real.
  attaches_to:
  - progression#Neonatal crisis, with two outcomes
  - pathophysiology#Biallelic Hypomorphic LARS2 Variants
- discussion_id: hlasa_metabolic_rescue_lead
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the glucose, nicotinic acid and N-acetylcysteine combination that rescues complex I
    dysfunction in worm and fish models worth testing in a mitochondrial aminoacyl-tRNA
    synthetase disease?
  rationale: >-
    The openscientist report committed with this entry raises a preclinical combination that
    produced synergistic rescue of mitochondrial membrane potential in C. elegans and zebrafish
    complex I models. It is deliberately not curated as a treatment in this entry: that work is
    not about LARS2, was not done in this disease, and has never been given to a patient with it.

    It is recorded as a lead rather than dropped because the logic is not absurd — the endpoint
    in HLASA is a complex I deficiency, which is what those models have. The reasons to be
    cautious are specific rather than general. The models are chemically or genetically induced
    complex I lesions, not translation defects, so the step this disease actually fails is
    upstream of what they model. And the therapeutic window in HLASA is antenatal or the first
    days of life, which is not where a nutritional combination is easy to deploy.

    Anyone acting on this should note that the chain from the cited preclinical work to this
    disease runs through two inferences, and that this entry has made neither of them.
  attaches_to:
  - treatments#Neonatal Intensive Supportive Care
  - pathophysiology#Reduced Respiratory Chain Complex I in Liver and Muscle
notes: >-
  Naming and scope. This entry covers HLASA specifically — the severe, perinatal end of the
  LARS2 allelic series. Perrault syndrome 4, LARS2 deafness with ovarioleukodystrophy and the
  reversible infantile mitochondrial myopathy are separate entities in the same series, and the
  2020 paper reports all of them together. The entity is kept separate because its presentation,
  its differential and its timing share almost nothing with the others, while the gene and the
  mechanism are identical — which is the lump-versus-split case that `has_subtypes` handles badly
  and a grouping handles well. `Perrault Syndrome` is listed as a parent to make the relationship
  navigable.

  Patient count and denominators. Four published patients: the index proband in PMID:26537577
  (2015) and three from two unrelated families in PMID:32442335 (2020). Only the index case is
  described clinically in any detail; the 2020 report is available here as an abstract, which
  reports its three cases as a group. That is why most phenotype denominators in this entry read
  "1 of 1 patient described in detail" rather than a fraction of four. It is a limit of what can
  be quoted, not a claim that the features are rare.

  The gene identifier, and how it was nearly wrong. The openscientist report committed alongside
  this entry gives LARS2 as HGNC:21353. That identifier is KLHL31, an unrelated kelch-family
  gene. The correct one is hgnc:17095. Neither validation lane catches this by itself: the
  research recipe passes `--term-skip-prefix HGNC`, so gene CURIEs are unchecked where they are
  emitted, and `just validate-terms` compares a CURIE against its own canonical label rather than
  against the gene the surrounding text names — the failure mode recorded in dismech issue
  #10948. It surfaced only because this entry writes `label:` out, and the label disagreed with
  the CURIE. A curator who had copied the identifier and left the label blank, or filled it in
  from the ontology, would have committed a binding that validates cleanly and names the wrong
  gene.

  GeneReviews baseline: `just check-genereviews` reports NO_CHAPTER for both GeneReviews and
  StatPearls against the committed Bookshelf index (snapshot 2026-09-10). There is a GeneReviews
  chapter for Perrault syndrome, which is a different entity in this gene's series and does not
  name this one.

  What the enzymology negative means for anyone reading a report. Two standard confirmatory
  assays are recorded here under `diagnosis` with `presence: ABSENT`: respiratory-chain
  enzymology, which the authors judged non-diagnostic, and fibroblast studies, which were
  entirely normal. Both are recorded as negatives rather than omitted because a service
  laboratory running either one on a future patient will get the same answer, and an entry that
  listed only the assays that worked would be teaching the wrong lesson.

📚

References & Deep Research

References

4

PMID:26537577

LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure.

No top-level findings curated for this source.

PMID:32442335

The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.

No top-level findings curated for this source.

PMID:40119736

LARS2-Related Perrault Syndrome in Siblings With 46,XY Differences of Sex Development.

No top-level findings curated for this source.

PMID:32759564

[Ring sideroblasts and iron metabolism].

No top-level findings curated for this source.

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: HLASA (LARS2) · 2026-09-22T17:40:10Z · View source

De novo curation of HLASA (LARS2, MONDO:0014869) from the 2015 index report and the 2020 spectrum paper, with a LARS2 Perrault DSD case report and a ring-sideroblast review for the two edges the primary literature does not cover. Deep research: one openscientist run, committed at research/Hydrops-Lactic_Acidosis-Sideroblastic_Anemia-Multisystemic_Failure_Syndrome-deep-research-openscientist.md (11 references, 11/11 resolved, 5/11 judged on topic, needs_review true; 13 of 25 label checks reported as mismatches, all of which are the validator reading the report's markdown table Type column rather than real mis-bindings). The report gave LARS2 as HGNC:21353, which is KLHL31; the correct identifier hgnc:17095 was substituted and the error recorded in genetic.notes, since neither the research lane (--term-skip-prefix HGNC) nor just validate-terms (CURIE-versus-own-label only) catches it. Pathograph is a seven-node chain with two branches from the complex I deficiency, one to bioenergetic failure and one to erythroblast iron accumulation; the erythroid branch is graded HYPOTHETICAL because its mechanism is imported from the congenital sideroblastic anaemia group and nothing has been measured in a LARS2 erythroblast. Two evidence items are REFUTE on purpose: the non-diagnostic respiratory-chain enzymology against the complex I node, and the failure of bicarbonate to lower the lactate against supportive care. Three discussions record the sideroblast mechanism gap, the unexplained survival fork, and a preclinical metabolic-rescue lead deliberately not curated as a treatment. Validation on the final tree: just validate, validate-terms, validate-disorders, count-verified-snippets 39/39, check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-enum-values, check-coarse-phenotypes, check-reference-titles, check-case-collisions, check-genereviews (NO_CHAPTER), list-disconnected-phenotypes 12/14.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 2026-09-22T17:08:22.344448

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." — PMID 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)." — PMID 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).

Phenotype	Type	HPO term	Onset/severity	Frequency (reported cases)
Non-immune hydrops fetalis	physical/clinical sign	HP:0001789	prenatal/neonatal, severe	core feature
Lactic acidosis	lab abnormality	HP:0003128	neonatal, severe	core feature
Sideroblastic anemia (ring sideroblasts)	lab abnormality	HP:0001924	neonatal, severe	core feature
Pulmonary hypertension	clinical sign	HP:0002092	neonatal	index case
Hyaline membrane disease / RDS	clinical sign	HP:0002094 (resp. insufficiency)	neonatal	index case
Impaired cardiac function	clinical sign	HP:0001637 / HP:0001635	neonatal	index case
Coagulopathy	lab abnormality	HP:0001928	neonatal	index case
Progressive renal disease	clinical sign	HP:0000112	neonatal	index case
Prematurity	clinical	HP:0001622	perinatal	index case
Male genital anomalies / undervirilization (incl. hypospadias, cryptorchidism)	physical	HP:0000811 / HP:0000047 / HP:0000028	congenital	all survivors (males)
Sensorineural hearing loss	clinical sign	HP:0000407	infancy	survivors
Global developmental delay	clinical sign	HP:0001263	infancy	survivors

"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." — PMID 26537577

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

Biallelic loss-of-function LARS2 variants are inherited → results in a hypomorphic mitochondrial leucyl-tRNA synthetase enzyme.
Reduced enzyme activity leads to deficient aminoacylation (leucine-charging) of mitochondrial tRNA^Leu (demonstrated in vitro; ~18-fold reduced for p.Ala430Val).
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).
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).
Reduced OXPHOS leads to an energy (ATP) deficit and a compensatory shift to anaerobic glycolysis → systemic lactic acidosis (CHEBI:16113 lactate).
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).
Fetal anemia + high-output cardiac strain + generalized energy failure results in fluid extravasation and serous effusions → non-immune hydrops fetalis (inferred).
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).
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." — PMID 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." — PMID 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..." — PMID 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." — PMID 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 (PMID 33640978).
Vertebrate: zebrafish Complex I disease/inhibition models (rotenone; PMID 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): PMID 26537577 (index proband, functional assays), PMID 32442335 (spectrum incl. 3 HLASA cases + recombinant protein assays), PMID 40119736 (LARS2 Perrault + gonadal/undervirilization + C. elegans), PMID 42283975 (Perrault gene family/AR inheritance), PMID 35334505 (mitochondrial fetal anemia/IUT), PMID 35393742 & 25638461 (YARS2/MLASA differential).
In vitro / biochemical: recombinant aminoacylation assays (26537577, 32442335).
Model organism / preclinical: PMID 33640978 (C. elegans + zebrafish Complex I therapy).
Reviews: PMID 31839000 (mt-aaRS disorders), PMID 32759564 / 39358290 / 40769913 (sideroblastic anemia pathophysiology), PMID 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.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	45
Resolved	43
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	25
Terms named correctly	8
Terms named as a different term	13
Terms whose name is worth a second look	4

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:

HP:0001789 (1 mention) - the report calls it "physical/clinical sign"; HP calls it Hydrops fetalis
HP:0003128 (1 mention) - the report calls it "lab abnormality"; HP calls it Lactic acidosis
HP:0001924 (1 mention) - the report calls it "lab abnormality"; HP calls it Sideroblastic anemia
HP:0002092 (1 mention) - the report calls it "clinical sign"; HP calls it Pulmonary arterial hypertension
HP:0002094 (1 mention) - the report calls it "resp. insufficiency"; HP calls it Dyspnea
HP:0000112 (1 mention) - the report calls it "clinical sign"; HP calls it Nephropathy
HP:0001622 (1 mention) - the report calls it "clinical"; HP calls it Premature birth
HP:0000407 (1 mention) - the report calls it "clinical sign"; HP calls it Sensorineural hearing impairment
HP:0001263 (1 mention) - the report calls it "clinical sign"; HP calls it Global developmental delay
NCBITaxon:10090 (1 mention) - the report calls it "Lars2"; NCBITaxon calls it Mus musculus
NCBITaxon:7955 (1 mention) - the report calls it "lars2"; NCBITaxon calls it Danio rerio
NCBITaxon:6239 (1 mention) - the report calls it "lars-2"; NCBITaxon calls it Caenorhabditis elegans
NCBITaxon:4932 (1 mention) - the report calls it "NAM2"; NCBITaxon calls it Saccharomyces cerevisiae

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:0001928 (1 mention) - the report calls it "lab abnormality"; HP calls it Abnormality of coagulation, and lists "Coagulation abnormality" among its other names
GO:0070127 (1 mention) - the report calls it "mitochondrial translation"; GO calls it tRNA aminoacylation for mitochondrial protein translation
GO:0005739 (2 mentions) - the report calls it "mitochondrion", "Subcellular: mitochondrion"; GO calls it mitochondrion
CL:0000764 (2 mentions) - the report calls it "erythroblast"; CL calls it erythroid lineage cell

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0005739 - called "mitochondrion", "Subcellular: mitochondrion"

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.

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Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver