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Mappings

MONDO

MONDO:0000863 myopathy, lactic acidosis, and sideroblastic anemia

Orphanet ORPHA:2598 lists MONDO:0000863 as an exact cross-reference for mitochondrial myopathy and sideroblastic anemia.

📘

Definitions

1

Orphanet MLASA definition

Orphanet defines MLASA as a metabolic myopathy with childhood progressive exercise intolerance, adolescent sideroblastic anemia, lactic acidemia, and mitochondrial myopathy.

OTHER

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"Mitochondrial myopathy and sideroblastic anemia belongs to the heterogeneous family of metabolic myopathies. It is characterised by progressive exercise intolerance manifesting in childhood, onset of sideroblastic anaemia around adolescence, lactic acidaemia, and mitochondrial myopathy."

Orphanet's definition captures the core clinical syndrome.

👪

Inheritance

2

Autosomal recessive HP:0000007

PUS1-related MLASA1 and YARS2-related MLASA2 are autosomal recessive disorders caused by biallelic pathogenic variants.

Autosomal recessive inheritance

Show evidence (2 references)

ORPHA:2598 SUPPORT Other

"Autosomal recessive"

Orphanet records autosomal recessive inheritance for the PUS1/YARS2 MLASA record.

PMID:15108122 SUPPORT Human Clinical

"Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow."

The PUS1 discovery paper explicitly describes autosomal recessive inheritance.

Mitochondrial/de novo inheritance HP:0001427

MLASA3 has been reported with a de novo heteroplasmic MT-ATP6 variant in mitochondrial DNA.

Mitochondrial inheritance

Show evidence (1 reference)

PMID:25037980 SUPPORT Human Clinical

"Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."

MT-ATP6-related MLASA-plus involves heteroplasmic mitochondrial DNA variation.

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Subtypes

3

Myopathy, lactic acidosis, and sideroblastic anemia 1 MONDO:0024553

PUS1-related autosomal recessive MLASA caused by deficient tRNA pseudouridylation.

Show evidence (1 reference)

PMID:15108122 SUPPORT Human Clinical

"identified a homozygous missense mutation in the pseudouridine synthase 1 gene (PUS1) in all patients with MLASA from these families."

The original linkage and sequencing study established PUS1-related MLASA.

Myopathy, lactic acidosis, and sideroblastic anemia 2 MONDO:0013307

YARS2-related autosomal recessive MLASA caused by impaired mitochondrial tyrosyl-tRNA aminoacylation.

Show evidence (1 reference)

PMID:20598274 SUPPORT Human Clinical

"MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA."

The YARS2 discovery paper identifies YARS2 as an alternative genetic cause of MLASA.

Myopathy, lactic acidosis, and sideroblastic anemia 3 MONDO:0010782

MT-ATP6-related MLASA-plus phenotype caused by de novo heteroplasmic mitochondrial DNA variants impairing ATP synthase complex V function.

Show evidence (1 reference)

PMID:25037980 SUPPORT Human Clinical

"Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."

The MLASA-plus report identifies de novo heteroplasmic MT-ATP6 variation as the genetic basis.

⚙

Pathophysiology

5

PUS1 tRNA pseudouridylation defect

Biallelic PUS1 variants impair Pus1p-mediated pseudouridylation of mitochondrial and cytoplasmic tRNAs.

PUS1 link

pseudouridine synthesis link ↓ DECREASED

mitochondrion link

Downstream

Mitochondrial translation defect Reduced tRNA pseudouridylation impairs mitochondrial tRNA function and mitochondrial translation.

Intellectual disability PUS1 is expressed in brain and modifies mitochondrial and cytoplasmic tRNAs; MLASA-associated neurodevelopmental involvement is modeled as an incompletely resolved downstream effect of impaired tRNA modification.

Microcephaly Microcephaly is modeled as a neurodevelopmental manifestation of PUS1-related tRNA modification deficiency.

Distichiasis Distichiasis is connected as part of the PUS1-associated developmental phenotype cluster recorded for MLASA.

High palate High palate is connected as part of the PUS1-associated craniofacial phenotype cluster recorded for MLASA.

Long philtrum Long philtrum is connected as part of the PUS1-associated craniofacial phenotype cluster recorded for MLASA.

Micrognathia Micrognathia is connected as part of the PUS1-associated craniofacial phenotype cluster recorded for MLASA.

Short nose Short nose is connected as part of the craniofacial phenotype cluster recorded for MLASA.

Show evidence (2 references)

PMID:15772074 SUPPORT In Vitro

"MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis."

Patient-derived cell studies directly show reduced tRNA pseudouridylation.

PMID:17056637 SUPPORT In Vitro

"The stop mutation in PUS1 is likely to determine the loss of function of the protein"

A PUS1 nonsense variant supports loss of PUS1 function in MLASA.

YARS2 mitochondrial tyrosyl-tRNA aminoacylation defect

Biallelic YARS2 variants reduce mitochondrial tyrosyl-tRNA synthetase catalytic efficiency and impair aminoacylation needed for mitochondrial protein synthesis.

YARS2 link

tRNA aminoacylation for mitochondrial protein translation link ↓ DECREASED

mitochondrion link

Downstream

Mitochondrial translation defect Defective YARS2 aminoacylation lowers mitochondrial protein synthesis.

Show evidence (3 references)

PMID:30026338 SUPPORT Other

"YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, YARS2, which is responsible for the ATP-dependent conjugation of tyrosine to its cognate tRNA, required to support mitochondrial protein synthesis."

Review and cohort paper defines the normal YARS2 function relevant to MLASA2.

PMID:30026338 SUPPORT In Vitro

"YARS2 p.(Ser203Ile) and p.(Gly244Ala) demonstrated a 17-fold loss in catalytic efficiency."

In vitro aminoacylation assays demonstrate reduced YARS2 catalytic activity for pathogenic variants.

PMID:20598274 SUPPORT In Vitro

"We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction."

Functional studies link YARS2 aminoacylation defects to mitochondrial protein synthesis and respiratory-chain dysfunction.

MT-ATP6 complex V respiratory defect

De novo heteroplasmic MT-ATP6 variants can produce an MLASA-plus phenotype through impaired oligomycin-sensitive ATP synthase respiration.

MT-ATP6 link

oxidative phosphorylation link ↓ DECREASED

mitochondrion link

Downstream

Mitochondrial respiratory-chain dysfunction Complex V respiratory dysfunction reduces oxidative phosphorylation capacity.

Show evidence (1 reference)

PMID:25037980 SUPPORT In Vitro

"Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect."

Patient fibroblast studies support an ATP synthase complex V respiratory defect.

Mitochondrial translation defect

PUS1 and YARS2 defects converge on impaired mitochondrial translation, reducing synthesis of respiratory-chain subunits.

mitochondrial translation link ↓ DECREASED

Downstream

Mitochondrial respiratory-chain dysfunction Reduced mitochondrial translation decreases respiratory-chain subunits.

Show evidence (2 references)

PMID:17056637 SUPPORT In Vitro

"combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria."

PUS1-related MLASA showed low mitochondrial translation products.

PMID:20598274 SUPPORT In Vitro

"A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines."

YARS2-related patient myotubes show reduced synthesis of respiratory-chain subunits.

Mitochondrial respiratory-chain dysfunction

Impaired mitochondrial translation or complex V function reduces oxidative phosphorylation in skeletal muscle and other high-energy tissues and disrupts erythroid maturation in bone marrow.

oxidative phosphorylation link ↓ DECREASED

skeletal muscle tissue link bone marrow link

Downstream

Mitochondrial myopathy Skeletal muscle oxidative phosphorylation failure causes mitochondrial myopathy.

Myopathy Skeletal muscle respiratory-chain dysfunction produces the generalized myopathy reported in YARS2-related MLASA.

Exercise intolerance Impaired mitochondrial ATP production in skeletal muscle limits exertional energy capacity.

Generalized limb muscle atrophy Chronic mitochondrial myopathy is modeled as the upstream context for generalized limb muscle atrophy.

Hypotonia Hypotonia is modeled as a neuromuscular manifestation of mitochondrial myopathy and energy failure.

Lactic acidosis Respiratory-chain dysfunction shifts metabolism toward lactate production.

Abnormality of metabolism/homeostasis The broad metabolism/homeostasis abnormality is grounded in impaired oxidative phosphorylation and lactic acidosis.

Elevated lactate Respiratory-chain dysfunction shifts pyruvate handling toward lactate accumulation.

Elevated pyruvate Disturbed lactate metabolism in MLASA can include elevated pyruvate on organic-acid analysis.

Respiratory chain complex activity Respiratory-chain enzyme deficiency is a biochemical tissue readout of the same mitochondrial dysfunction node.

EMG abnormality Myopathic muscle involvement can produce abnormal electromyography.

Sideroblastic anemia Bone marrow mitochondrial dysfunction disrupts erythroid maturation and iron handling.

Hypertrophic cardiomyopathy Cardiac energy stress can produce hypertrophic cardiomyopathy in YARS2-related disease.

Respiratory insufficiency Respiratory muscle weakness can lead to respiratory insufficiency.

Delayed puberty Delayed puberty is connected as a multisystem manifestation recorded in the MLASA Orphanet phenotype profile; the intermediate mechanism is unresolved.

Glaucoma Glaucoma is connected as an ophthalmologic manifestation recorded in the MLASA Orphanet phenotype profile; the intermediate mechanism is unresolved.

Show evidence (2 references)

PMID:28395030 SUPPORT Human Clinical

"Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies."

YARS2-related cases show respiratory-chain deficiencies in muscle.

PMID:15108122 SUPPORT Human Clinical

"Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow."

The original clinical genetic paper frames MLASA as a skeletal muscle and bone marrow oxidative phosphorylation disorder.

✶

Histopathology

2

Bone marrow ringed sideroblasts

Sideroblastic anemia is identified by bone marrow ringed sideroblasts, erythroblasts with pathologic intramitochondrial iron deposits.

Show evidence (2 references)

PMID:30026338 SUPPORT Human Clinical

"Sideroblastic anemia is defined by the presence of bone marrow ringed sideroblasts, which are erythroblasts containing pathological intramitochondrial iron deposits."

The YARS2 spectrum paper defines sideroblastic anemia by marrow ringed sideroblasts.

PMID:23918765 SUPPORT Human Clinical

"Bone marrow aspirate at 5 years revealed ringed sideroblasts"

YARS2-related MLASA case had ringed sideroblasts on marrow aspirate.

Ragged-red fiber mitochondrial myopathy

Muscle biopsy can show mitochondrial myopathy histopathology, including ragged-red fibers and ultrastructural mitochondrial abnormalities.

Show evidence (2 references)

PMID:30026338 SUPPORT Human Clinical

"muscle biopsy showed histopathological features typical of a mitochondrial myopathy, including ragged red fibers on trichrome stain"

YARS2 cohort paper documents ragged-red fiber mitochondrial myopathy in an affected patient.

PMID:23918765 SUPPORT Human Clinical

"global impairment of mitochondrial translation, manifest histologically by a ragged-red fiber myopathy with subsarcolemmal mitochondrial proliferation."

Full-text report links MLASA/Pearson translation defects to ragged-red fiber myopathy.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

22

Blood 1

Sideroblastic anemia VERY_FREQUENT Anemia (HP:0001903)

Show evidence (3 references)

ORPHA:2598 SUPPORT Other

"HP:0001903 | Anemia | Very frequent (99-80%)"

Orphanet lists anemia as very frequent in MLASA.

PMID:30026338 SUPPORT Human Clinical

"The 11 probands all had moderate to severe normocytic to macrocytic anemia."

YARS2 cohort documents anemia in all probands.

PMID:28395030 SUPPORT Human Clinical

"only 12 patients (71%) manifested with sideroblastic anemia."

YARS2-related mitochondrial myopathy case series documents sideroblastic anemia.

Cardiovascular 1

Hypertrophic cardiomyopathy OCCASIONAL Hypertrophic cardiomyopathy (HP:0001639)

Show evidence (1 reference)

PMID:23918765 SUPPORT Human Clinical

"Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support."

YARS2-related MLASA case report documents hypertrophic cardiomyopathy.

Endocrine 1

Delayed puberty FREQUENT Delayed puberty (HP:0000823)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0000823 | Delayed puberty | Frequent (79-30%)"

Orphanet lists delayed puberty as frequent.

Eye 1

Glaucoma FREQUENT Glaucoma (HP:0000501)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0000501 | Glaucoma | Frequent (79-30%)"

Orphanet lists glaucoma as frequent.

Head and Neck 5

Microcephaly FREQUENT Microcephaly (HP:0000252)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0000252 | Microcephaly | Frequent (79-30%)"

Orphanet lists microcephaly as frequent.

High palate VERY_FREQUENT High palate (HP:0000218)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0000218 | High palate | Very frequent (99-80%)"

Orphanet lists high palate as very frequent.

Long philtrum VERY_FREQUENT Long philtrum (HP:0000343)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0000343 | Long philtrum | Very frequent (99-80%)"

Orphanet lists long philtrum as very frequent.

Micrognathia VERY_FREQUENT Micrognathia (HP:0000347)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0000347 | Micrognathia | Very frequent (99-80%)"

Orphanet lists micrognathia as very frequent.

Short nose FREQUENT Short nose (HP:0003196)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0003196 | Short nose | Frequent (79-30%)"

Orphanet lists short nose as frequent.

Metabolism 1

Lactic acidosis VERY_FREQUENT Lactic acidosis (HP:0003128)

Show evidence (2 references)

ORPHA:2598 SUPPORT Other

"HP:0003128 | Lactic acidosis | Very frequent (99-80%)"

Orphanet lists lactic acidosis as very frequent.

PMID:28395030 SUPPORT Human Clinical

"Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"

YARS2-related case series supports elevated lactate as a common manifestation.

Musculoskeletal 4

Myopathy VERY_FREQUENT Myopathy (HP:0003198)

Sequelae: Scoliosis Kyphosis

Show evidence (2 references)

ORPHA:2598 SUPPORT Other

"HP:0003198 | Myopathy | Very frequent (99-80%)"

Orphanet lists myopathy as very frequent.

PMID:28395030 SUPPORT Human Clinical

"Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"

YARS2-related case series documents generalized myopathy in most patients.

Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0001252 | Hypotonia | Very frequent (99-80%)"

Orphanet lists hypotonia as very frequent.

Scoliosis FREQUENT Scoliosis (HP:0002650)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0002650 | Scoliosis | Frequent (79-30%)"

Orphanet lists scoliosis as frequent.

Kyphosis FREQUENT Kyphosis (HP:0002808)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0002808 | Kyphosis | Frequent (79-30%)"

Orphanet lists kyphosis as frequent.

Nervous System 1

Intellectual disability FREQUENT Intellectual disability (HP:0001249)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0001249 | Intellectual disability | Frequent (79-30%)"

Orphanet lists intellectual disability as frequent.

Respiratory 1

Respiratory insufficiency OCCASIONAL Respiratory insufficiency (HP:0002093)

Show evidence (1 reference)

PMID:23918765 SUPPORT Human Clinical

"Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support."

YARS2-related MLASA case report documents respiratory failure requiring ventilatory support.

Constitutional 1

Exercise intolerance FREQUENT Exercise intolerance (HP:0003546)

Show evidence (2 references)

ORPHA:2598 SUPPORT Other

"progressive exercise intolerance manifesting in childhood"

Orphanet definition explicitly states progressive childhood exercise intolerance.

PMID:28395030 SUPPORT Human Clinical

"Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity."

YARS2 case-series conclusion identifies exercise intolerance as a key presentation.

Other 5

Mitochondrial myopathy VERY_FREQUENT Mitochondrial myopathy (HP:0003737)

Show evidence (2 references)

ORPHA:2598 SUPPORT Other

"HP:0003737 | Mitochondrial myopathy | Very frequent (99-80%)"

Orphanet lists mitochondrial myopathy as very frequent in MLASA.

PMID:28395030 SUPPORT Human Clinical

"Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"

YARS2-related case series documents generalized myopathy in most patients.

Generalized limb muscle atrophy VERY_FREQUENT Generalized limb muscle atrophy (HP:0009055)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0009055 | Generalized limb muscle atrophy | Very frequent (99-80%)"

Orphanet lists generalized limb muscle atrophy as very frequent.

Abnormality of metabolism/homeostasis VERY_FREQUENT Abnormality of metabolism/homeostasis (HP:0001939)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0001939 | Abnormality of metabolism/homeostasis | Very frequent (99-80%)"

Orphanet lists abnormality of metabolism/homeostasis as very frequent.

Distichiasis VERY_FREQUENT Distichiasis (HP:0009743)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0009743 | Distichiasis | Very frequent (99-80%)"

Orphanet lists distichiasis as very frequent.

EMG abnormality VERY_FREQUENT EMG abnormality (HP:0003457)

Show evidence (1 reference)

ORPHA:2598 SUPPORT Other

"HP:0003457 | EMG abnormality | Very frequent (99-80%)"

Orphanet lists abnormal EMG as very frequent.

🧬

Genetic Associations

3

PUS1 pathogenic variants (Causative)

Show evidence (2 references)

PMID:15108122 SUPPORT Human Clinical

"identified a homozygous missense mutation in the pseudouridine synthase 1 gene (PUS1) in all patients with MLASA from these families."

Sequencing identified homozygous PUS1 variants segregating with MLASA.

PMID:15772074 SUPPORT In Vitro

"MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis."

Functional assays support PUS1 molecular causality.

YARS2 pathogenic variants (Causative)

Show evidence (2 references)

PMID:20598274 SUPPORT Human Clinical

"We subsequently identified the same mutation in another unrelated MLASA patient."

The YARS2 discovery paper replicated the YARS2 variant in an unrelated MLASA patient.

PMID:30026338 SUPPORT Human Clinical

"biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype."

The expanded YARS2 cohort supports causality across MLASA and sideroblastic anemia presentations.

MT-ATP6 de novo heteroplasmic variants (Causative)

Show evidence (2 references)

PMID:25037980 SUPPORT Human Clinical

"Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."

The MLASA-plus case report identifies a de novo heteroplasmic MT-ATP6 variant.

PMID:25037980 SUPPORT In Vitro

"Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect."

Patient fibroblast assays support pathogenic ATP synthase dysfunction.

💊

Treatments

4

Supportive care and complication surveillance

Action: supportive care MAXO:0000950

No curative treatment is established for MLASA overall. Management is supportive, with early genetic diagnosis enabling monitoring and treatment of cardiomyopathy, respiratory muscle weakness, anemia, nutrition, and other complications.

Mechanism Target:

Mitochondrial respiratory-chain dysfunction — Supportive care and surveillance are directed at complications of mitochondrial respiratory-chain dysfunction.

Mitochondrial translation defect — Early diagnosis of mitochondrial translation disorders guides complication surveillance and supportive management.

Target Phenotypes: Lactic acidosis ↗ Mitochondrial myopathy ↗ Anemia ↗ Hypertrophic cardiomyopathy ↗ Respiratory insufficiency ↗

Show evidence (2 references)

PMID:23918765 SUPPORT Human Clinical

"Although no specific curative therapies are available, early diagnosis and initiation of appropriate supportive therapy is likely to be important in the prevention of the longterm complications of this disorder."

Full-text MLASA report supports supportive therapy in the absence of curative treatment.

PMID:28395030 SUPPORT Human Clinical

"Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder."

YARS2 cohort recommends surveillance and early treatment for major complications.

Noninvasive ventilation for respiratory insufficiency

Action: noninvasive ventilation MAXO:0000506

Noninvasive ventilatory support may be needed when respiratory muscle weakness causes hypoventilation or respiratory failure.

Target Phenotypes: Respiratory insufficiency ↗

Show evidence (1 reference)

PMID:23918765 SUPPORT Human Clinical

"Sleep study revealed severe hypoventilation with evidence of CO2 retention and he was commenced on nocturnal BiPAP ventilation."

A YARS2-related MLASA case required nocturnal BiPAP for hypoventilation.

Pyridoxine supplementation non-response

Action: Pharmacotherapy NCIT:C15986

Agent: pyridoxine ↗

Pyridoxine is not supported as an anemia-improving therapy for YARS2-related MLASA in the cached cohort evidence, helping distinguish this disorder from pyridoxine-responsive sideroblastic anemia.

Target Phenotypes: Anemia ↗

Show evidence (1 reference)

PMID:30026338 REFUTE Human Clinical

"Four patients were treated with pyridoxine with no improvement in their anemia"

The YARS2 cohort directly refutes pyridoxine responsiveness for anemia in treated patients.

Genetic counseling

Action: genetic counseling MAXO:0000079

Molecular diagnosis enables counseling about autosomal recessive PUS1/YARS2 MLASA and the rare de novo heteroplasmic MT-ATP6 MLASA-plus presentation.

Mechanism Target:

PUS1 tRNA pseudouridylation defect — Counseling addresses autosomal recessive PUS1-related MLASA1 recurrence risk.

YARS2 mitochondrial tyrosyl-tRNA aminoacylation defect — Counseling addresses autosomal recessive YARS2-related MLASA2 recurrence risk.

MT-ATP6 complex V respiratory defect — Counseling also covers the rare heteroplasmic mitochondrial MT-ATP6 MLASA-plus mechanism.

Show evidence (2 references)

PMID:23918765 SUPPORT Human Clinical

"Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy."

The YARS2-related MLASA report explicitly supports counseling after early genetic diagnosis.

PMID:25037980 SUPPORT Human Clinical

"Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."

The MT-ATP6 MLASA-plus case supports including mitochondrial de novo heteroplasmy in genetic counseling.

🔬

Biochemical Markers

5

Elevated lactate (INCREASED)

Context: Blood lactate and/or urine lactate can be elevated due to impaired mitochondrial energy metabolism.

Pathograph Readouts

Readout Of Mitochondrial respiratory-chain dysfunction Positive Diagnostic

Elevated lactate reports impaired oxidative phosphorylation with compensatory lactate production.

Readout Of Lactic acidosis Positive Diagnostic

Elevated lactate is the biochemical basis of the lactic acidosis phenotype.

Show evidence (2 references)

PMID:28395030 SUPPORT Human Clinical

"Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"

YARS2-related case series quantifies elevated blood lactate.

PMID:23918765 SUPPORT Human Clinical

"Urine organic acid analysis demonstrated strongly raised lactate and pyruvate with moderately raised 2-hydroxybutyrate and mildly raised 2-hydroxyisovalerate, secondary to disturbed lactate metabolism."

A YARS2-related MLASA case showed raised lactate and pyruvate on urine organic acid analysis.

Elevated pyruvate (INCREASED)

Context: Urine organic-acid analysis can show elevated pyruvate alongside lactate in YARS2-related MLASA.

Pathograph Readouts

Readout Of Mitochondrial respiratory-chain dysfunction Positive Diagnostic

Elevated pyruvate with lactate reflects disturbed mitochondrial energy metabolism.

Show evidence (1 reference)

PMID:23918765 SUPPORT Human Clinical

"Urine organic acid analysis demonstrated strongly raised lactate and pyruvate with moderately raised 2-hydroxybutyrate and mildly raised 2-hydroxyisovalerate, secondary to disturbed lactate metabolism."

A YARS2-related MLASA case showed raised urinary pyruvate together with lactate.

Respiratory chain complex activity (DECREASED)

Context: Skeletal muscle and patient-derived cells may show combined respiratory-chain defects.

Pathograph Readouts

Readout Of Mitochondrial respiratory-chain dysfunction Negative Diagnostic

Lower respiratory-chain complex activity reports greater mitochondrial respiratory-chain dysfunction.

Show evidence (2 references)

PMID:28395030 SUPPORT Human Clinical

"Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies."

Clinical muscle studies document reduced respiratory-chain activity.

PMID:17056637 SUPPORT In Vitro

"combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria."

PUS1-related patient material showed combined respiratory-chain defects and low mtDNA translation products.

tRNA pseudouridylation (DECREASED)

Context: PUS1-related MLASA shows deficient tRNA pseudouridylation at Pus1p-dependent sites.

Pathograph Readouts

Readout Of PUS1 tRNA pseudouridylation defect Negative Diagnostic

Reduced Pus1p-dependent tRNA pseudouridylation is the biochemical readout of PUS1 loss of function.

Show evidence (1 reference)

PMID:15772074 SUPPORT In Vitro

"MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis."

Patient-derived cell assays support decreased tRNA pseudouridylation.

YARS2 aminoacylation activity (DECREASED)

Context: Pathogenic YARS2 variants can reduce mitochondrial tyrosyl-tRNA synthetase catalytic efficiency.

Pathograph Readouts

Readout Of YARS2 mitochondrial tyrosyl-tRNA aminoacylation defect Negative Diagnostic

Lower catalytic efficiency reports impaired YARS2 mitochondrial tyrosyl-tRNA aminoacylation.

Show evidence (1 reference)

PMID:30026338 SUPPORT In Vitro

"YARS2 p.(Ser203Ile) and p.(Gly244Ala) demonstrated a 17-fold loss in catalytic efficiency."

In vitro aminoacylation assays show reduced YARS2 activity for pathogenic variants.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Myopathy, Lactic Acidosis, and Sideroblastic Anemia:

Pearson marrow-pancreas syndrome Not Yet Curated MONDO:0010797

Overlapping Features Pearson syndrome also causes infantile sideroblastic anemia and lactic acidosis, but typically involves large-scale mitochondrial DNA rearrangements and multisystem pancreatic, renal, and neurologic features.

Distinguishing Features

Large-scale mitochondrial DNA deletion/rearrangement
Pancreatic insufficiency and broader multisystem infantile presentation

Show evidence (1 reference)

PMID:23918765 SUPPORT Human Clinical

"Finally, Pearson syndrome was definitively excluded in our patient by the absence of mtDNA rearrangements in leukocyte DNA."

MLASA differential work-up includes excluding Pearson syndrome by mitochondrial DNA rearrangement testing.

X-linked sideroblastic anemia Not Yet Curated MONDO:0020721

Overlapping Features X-linked sideroblastic anemia can present as a pure sideroblastic anemia phenotype and is distinguished from MLASA by the absence of the mitochondrial myopathy and lactic acidosis syndrome.

Distinguishing Features

ALAS2-related pure sideroblastic anemia without mitochondrial myopathy

Show evidence (1 reference)

PMID:23918765 SUPPORT Human Clinical

"XLSA and Pearson syndrome can be easily distinguished clinically since the former causes a pure sideroblastic anemia phenotype"

The MLASA report contrasts X-linked sideroblastic anemia with syndromic MLASA/Pearson presentations.

{ }

Source YAML

click to show

name: Myopathy, Lactic Acidosis, and Sideroblastic Anemia
creation_date: '2026-05-07T15:30:00Z'
updated_date: '2026-05-18T09:59:03Z'
category: Mendelian
synonyms:
- MLASA
- Mitochondrial myopathy and sideroblastic anemia
- Myopathy, lactic acidosis and sideroblastic anemia
description: >-
  Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is an ultra-rare
  mitochondrial disorder centered on impaired mitochondrial translation or ATP
  synthase function. Biallelic PUS1 variants cause MLASA1 through deficient
  tRNA pseudouridylation, biallelic YARS2 variants cause MLASA2 through
  impaired mitochondrial tyrosyl-tRNA aminoacylation, and rare de novo
  heteroplasmic MT-ATP6 variants cause an MLASA-plus phenotype through complex V
  dysfunction. Core manifestations include mitochondrial myopathy, exercise
  intolerance or muscle weakness, lactic acidosis, and sideroblastic anemia with
  bone marrow ringed sideroblasts; YARS2-related disease may also include
  cardiomyopathy and respiratory insufficiency.
disease_term:
  preferred_term: myopathy, lactic acidosis, and sideroblastic anemia
  term:
    id: MONDO:0000863
    label: myopathy, lactic acidosis, and sideroblastic anemia
references:
- reference: ORPHA:2598
  title: Mitochondrial myopathy and sideroblastic anemia
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
- reference: PMID:15108122
  title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
- reference: PMID:20598274
  title: Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
- reference: PMID:28395030
  title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
- reference: PMID:30026338
  title: "The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2."
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
- reference: PMID:23918765
  title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
- reference: PMID:25037980
  title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
  found_in:
  - Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia-deep-research-fallback.md
parents:
- Mitochondrial disease
- Inherited sideroblastic anemia
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000863
      label: myopathy, lactic acidosis, and sideroblastic anemia
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:2598
    mapping_justification: >-
      Orphanet ORPHA:2598 lists MONDO:0000863 as an exact cross-reference for
      mitochondrial myopathy and sideroblastic anemia.
external_assertions:
- name: Orphanet mitochondrial myopathy and sideroblastic anemia record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:2598
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2598
  description: >-
    Orphanet's structured ORPHA:2598 record provides the exact MONDO mapping,
    synonyms, definition, inheritance, epidemiology, natural-history ages of
    onset, PUS1/YARS2 gene associations, and HPO phenotype annotations used in
    this entry.
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000863 | Exact"
    explanation: Orphanet maps ORPHA:2598 to the MONDO identifier used by this entry.
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PUS1 | pseudouridine synthase 1 | hgnc:15508 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PUS1 as a disease-causing gene for MLASA.
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "YARS2 | tyrosyl-tRNA synthetase 2 | hgnc:24249 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists YARS2 as a disease-causing gene for MLASA.
definitions:
- name: Orphanet MLASA definition
  definition_type: OTHER
  description: >-
    Orphanet defines MLASA as a metabolic myopathy with childhood progressive
    exercise intolerance, adolescent sideroblastic anemia, lactic acidemia, and
    mitochondrial myopathy.
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mitochondrial myopathy and sideroblastic anemia belongs to the heterogeneous family of metabolic myopathies. It is characterised by progressive exercise intolerance manifesting in childhood, onset of sideroblastic anaemia around adolescence, lactic acidaemia, and mitochondrial myopathy."
    explanation: Orphanet's definition captures the core clinical syndrome.
has_subtypes:
- name: MLASA1
  display_name: Myopathy, lactic acidosis, and sideroblastic anemia 1
  subtype_term:
    preferred_term: myopathy, lactic acidosis, and sideroblastic anemia 1
    term:
      id: MONDO:0024553
      label: myopathy, lactic acidosis, and sideroblastic anemia 1
  description: >-
    PUS1-related autosomal recessive MLASA caused by deficient tRNA
    pseudouridylation.
  evidence:
  - reference: PMID:15108122
    reference_title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a homozygous missense mutation in the pseudouridine synthase 1 gene (PUS1) in all patients with MLASA from these families."
    explanation: The original linkage and sequencing study established PUS1-related MLASA.
- name: MLASA2
  display_name: Myopathy, lactic acidosis, and sideroblastic anemia 2
  subtype_term:
    preferred_term: myopathy, lactic acidosis, and sideroblastic anemia 2
    term:
      id: MONDO:0013307
      label: myopathy, lactic acidosis, and sideroblastic anemia 2
  description: >-
    YARS2-related autosomal recessive MLASA caused by impaired mitochondrial
    tyrosyl-tRNA aminoacylation.
  evidence:
  - reference: PMID:20598274
    reference_title: Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA."
    explanation: The YARS2 discovery paper identifies YARS2 as an alternative genetic cause of MLASA.
- name: MLASA3
  display_name: Myopathy, lactic acidosis, and sideroblastic anemia 3
  subtype_term:
    preferred_term: myopathy, lactic acidosis, and sideroblastic anemia 3
    term:
      id: MONDO:0010782
      label: myopathy, lactic acidosis, and sideroblastic anemia 3
  description: >-
    MT-ATP6-related MLASA-plus phenotype caused by de novo heteroplasmic
    mitochondrial DNA variants impairing ATP synthase complex V function.
  evidence:
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."
    explanation: The MLASA-plus report identifies de novo heteroplasmic MT-ATP6 variation as the genetic basis.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    PUS1-related MLASA1 and YARS2-related MLASA2 are autosomal recessive
    disorders caused by biallelic pathogenic variants.
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for the PUS1/YARS2 MLASA record.
  - reference: PMID:15108122
    reference_title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow."
    explanation: The PUS1 discovery paper explicitly describes autosomal recessive inheritance.
- name: Mitochondrial/de novo inheritance
  inheritance_term:
    preferred_term: Mitochondrial inheritance
    term:
      id: HP:0001427
      label: Mitochondrial inheritance
  description: >-
    MLASA3 has been reported with a de novo heteroplasmic MT-ATP6 variant in
    mitochondrial DNA.
  evidence:
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."
    explanation: MT-ATP6-related MLASA-plus involves heteroplasmic mitochondrial DNA variation.
prevalence:
- population: Worldwide
  percentage: <1 / 1,000,000
  notes: >-
    Orphanet classifies MLASA as ultra-rare with point prevalence below one per
    million; published series consist of small families and case series.
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet reports worldwide point prevalence below one per million.
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "- | Worldwide | Cases/families | PMID:15971356"
    explanation: Orphanet also records epidemiology at the cases/families level.
pathophysiology:
- name: PUS1 tRNA pseudouridylation defect
  description: >-
    Biallelic PUS1 variants impair Pus1p-mediated pseudouridylation of
    mitochondrial and cytoplasmic tRNAs.
  genes:
  - preferred_term: PUS1
    term:
      id: hgnc:15508
      label: PUS1
  biological_processes:
  - preferred_term: pseudouridine synthesis
    modifier: DECREASED
    term:
      id: GO:0001522
      label: pseudouridine synthesis
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  chemical_entities:
  - preferred_term: pseudouridine
    term:
      id: CHEBI:17802
      label: pseudouridine
    modifier: DECREASED
  evidence:
  - reference: PMID:15772074
    reference_title: 'Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis."
    explanation: Patient-derived cell studies directly show reduced tRNA pseudouridylation.
  - reference: PMID:17056637
    reference_title: Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The stop mutation in PUS1 is likely to determine the loss of function of the protein"
    explanation: A PUS1 nonsense variant supports loss of PUS1 function in MLASA.
  downstream:
  - target: Mitochondrial translation defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced tRNA pseudouridylation impairs mitochondrial tRNA function and
      mitochondrial translation.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      PUS1 is expressed in brain and modifies mitochondrial and cytoplasmic
      tRNAs; MLASA-associated neurodevelopmental involvement is modeled as an
      incompletely resolved downstream effect of impaired tRNA modification.
    evidence:
    - reference: PMID:15108122
      reference_title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "PUS1 is widely expressed, and quantitative expression analysis of RNAs from liver, brain, heart, bone marrow, and skeletal muscle showed elevated levels of expression in skeletal muscle and brain."
      explanation: PUS1 brain expression provides tissue-context support for neurodevelopmental involvement, while the direct intermediate mechanism remains unresolved.
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
      explanation: Orphanet records intellectual disability as a frequent MLASA phenotype.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Microcephaly is modeled as a neurodevelopmental manifestation of PUS1-related tRNA modification deficiency.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000252 | Microcephaly | Frequent (79-30%)"
      explanation: Orphanet records microcephaly as a frequent MLASA phenotype.
  - target: Distichiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Distichiasis is connected as part of the PUS1-associated developmental phenotype cluster recorded for MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0009743 | Distichiasis | Very frequent (99-80%)"
      explanation: Orphanet records distichiasis as very frequent in MLASA.
  - target: High palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: High palate is connected as part of the PUS1-associated craniofacial phenotype cluster recorded for MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000218 | High palate | Very frequent (99-80%)"
      explanation: Orphanet records high palate as very frequent in MLASA.
  - target: Long philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Long philtrum is connected as part of the PUS1-associated craniofacial phenotype cluster recorded for MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000343 | Long philtrum | Very frequent (99-80%)"
      explanation: Orphanet records long philtrum as very frequent in MLASA.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Micrognathia is connected as part of the PUS1-associated craniofacial phenotype cluster recorded for MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
      explanation: Orphanet records micrognathia as very frequent in MLASA.
  - target: Short nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Short nose is connected as part of the craniofacial phenotype cluster recorded for MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003196 | Short nose | Frequent (79-30%)"
      explanation: Orphanet records short nose as frequent in MLASA.
- name: YARS2 mitochondrial tyrosyl-tRNA aminoacylation defect
  description: >-
    Biallelic YARS2 variants reduce mitochondrial tyrosyl-tRNA synthetase
    catalytic efficiency and impair aminoacylation needed for mitochondrial
    protein synthesis.
  genes:
  - preferred_term: YARS2
    term:
      id: hgnc:24249
      label: YARS2
  biological_processes:
  - preferred_term: tRNA aminoacylation for mitochondrial protein translation
    modifier: DECREASED
    term:
      id: GO:0070127
      label: tRNA aminoacylation for mitochondrial protein translation
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, YARS2, which is responsible for the ATP-dependent conjugation of tyrosine to its cognate tRNA, required to support mitochondrial protein synthesis."
    explanation: Review and cohort paper defines the normal YARS2 function relevant to MLASA2.
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "YARS2 p.(Ser203Ile) and p.(Gly244Ala) demonstrated a 17-fold loss in catalytic efficiency."
    explanation: In vitro aminoacylation assays demonstrate reduced YARS2 catalytic activity for pathogenic variants.
  - reference: PMID:20598274
    reference_title: Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction."
    explanation: Functional studies link YARS2 aminoacylation defects to mitochondrial protein synthesis and respiratory-chain dysfunction.
  downstream:
  - target: Mitochondrial translation defect
    causal_link_type: DIRECT
    description: Defective YARS2 aminoacylation lowers mitochondrial protein synthesis.
- name: MT-ATP6 complex V respiratory defect
  description: >-
    De novo heteroplasmic MT-ATP6 variants can produce an MLASA-plus phenotype
    through impaired oligomycin-sensitive ATP synthase respiration.
  genes:
  - preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect."
    explanation: Patient fibroblast studies support an ATP synthase complex V respiratory defect.
  downstream:
  - target: Mitochondrial respiratory-chain dysfunction
    causal_link_type: DIRECT
    description: Complex V respiratory dysfunction reduces oxidative phosphorylation capacity.
- name: Mitochondrial translation defect
  description: >-
    PUS1 and YARS2 defects converge on impaired mitochondrial translation,
    reducing synthesis of respiratory-chain subunits.
  biological_processes:
  - preferred_term: mitochondrial translation
    modifier: DECREASED
    term:
      id: GO:0032543
      label: mitochondrial translation
  evidence:
  - reference: PMID:17056637
    reference_title: Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria."
    explanation: PUS1-related MLASA showed low mitochondrial translation products.
  - reference: PMID:20598274
    reference_title: Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines."
    explanation: YARS2-related patient myotubes show reduced synthesis of respiratory-chain subunits.
  downstream:
  - target: Mitochondrial respiratory-chain dysfunction
    causal_link_type: DIRECT
    description: Reduced mitochondrial translation decreases respiratory-chain subunits.
- name: Mitochondrial respiratory-chain dysfunction
  description: >-
    Impaired mitochondrial translation or complex V function reduces oxidative
    phosphorylation in skeletal muscle and other high-energy tissues and
    disrupts erythroid maturation in bone marrow.
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  chemical_entities:
  - preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
    modifier: INCREASED
  - preferred_term: pyruvate
    term:
      id: CHEBI:15361
      label: pyruvate
    modifier: INCREASED
  evidence:
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies."
    explanation: YARS2-related cases show respiratory-chain deficiencies in muscle.
  - reference: PMID:15108122
    reference_title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow."
    explanation: The original clinical genetic paper frames MLASA as a skeletal muscle and bone marrow oxidative phosphorylation disorder.
  downstream:
  - target: Mitochondrial myopathy
    causal_link_type: DIRECT
    description: Skeletal muscle oxidative phosphorylation failure causes mitochondrial myopathy.
  - target: Myopathy
    causal_link_type: DIRECT
    description: Skeletal muscle respiratory-chain dysfunction produces the generalized myopathy reported in YARS2-related MLASA.
    evidence:
    - reference: PMID:28395030
      reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"
      explanation: The YARS2-related case series links elevated lactate with generalized myopathy in most patients.
  - target: Exercise intolerance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired mitochondrial ATP production in skeletal muscle limits exertional energy capacity.
    evidence:
    - reference: PMID:28395030
      reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity."
      explanation: YARS2-related mitochondrial myopathy is characterized by exercise intolerance and weakness.
  - target: Generalized limb muscle atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic mitochondrial myopathy is modeled as the upstream context for generalized limb muscle atrophy.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0009055 | Generalized limb muscle atrophy | Very frequent (99-80%)"
      explanation: Orphanet records generalized limb muscle atrophy as very frequent in MLASA.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypotonia is modeled as a neuromuscular manifestation of mitochondrial myopathy and energy failure.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001252 | Hypotonia | Very frequent (99-80%)"
      explanation: Orphanet records hypotonia as very frequent in MLASA.
  - target: Lactic acidosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Respiratory-chain dysfunction shifts metabolism toward lactate production.
  - target: Abnormality of metabolism/homeostasis
    causal_link_type: DIRECT
    description: The broad metabolism/homeostasis abnormality is grounded in impaired oxidative phosphorylation and lactic acidosis.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001939 | Abnormality of metabolism/homeostasis | Very frequent (99-80%)"
      explanation: Orphanet records abnormality of metabolism/homeostasis as very frequent in MLASA.
  - target: Elevated lactate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Respiratory-chain dysfunction shifts pyruvate handling toward lactate accumulation.
    evidence:
    - reference: PMID:28395030
      reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"
      explanation: Human YARS2-related MLASA series documents elevated blood lactate in most patients.
  - target: Elevated pyruvate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Disturbed lactate metabolism in MLASA can include elevated pyruvate on organic-acid analysis.
    evidence:
    - reference: PMID:23918765
      reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Urine organic acid analysis demonstrated strongly raised lactate and pyruvate with moderately raised 2-hydroxybutyrate and mildly raised 2-hydroxyisovalerate, secondary to disturbed lactate metabolism."
      explanation: A YARS2-related MLASA case showed raised urinary lactate and pyruvate.
  - target: Respiratory chain complex activity
    causal_link_type: DIRECT
    description: Respiratory-chain enzyme deficiency is a biochemical tissue readout of the same mitochondrial dysfunction node.
    evidence:
    - reference: PMID:28395030
      reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies."
      explanation: Clinical muscle studies document combined respiratory-chain complex activity deficiencies.
  - target: EMG abnormality
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Myopathic muscle involvement can produce abnormal electromyography.
    evidence:
    - reference: PMID:23918765
      reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electromyography demonstrated severe myopathic changes."
      explanation: A YARS2-related MLASA case showed severe myopathic EMG changes.
  - target: Sideroblastic anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bone marrow mitochondrial dysfunction disrupts erythroid maturation and iron handling.
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Cardiac energy stress can produce hypertrophic cardiomyopathy in YARS2-related disease.
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Respiratory muscle weakness can lead to respiratory insufficiency.
  - target: Delayed puberty
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Delayed puberty is connected as a multisystem manifestation recorded in the MLASA Orphanet phenotype profile; the intermediate mechanism is unresolved.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000823 | Delayed puberty | Frequent (79-30%)"
      explanation: Orphanet records delayed puberty as frequent in MLASA.
  - target: Glaucoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Glaucoma is connected as an ophthalmologic manifestation recorded in the MLASA Orphanet phenotype profile; the intermediate mechanism is unresolved.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000501 | Glaucoma | Frequent (79-30%)"
      explanation: Orphanet records glaucoma as frequent in MLASA.
phenotypes:
- category: Neuromuscular
  name: Mitochondrial myopathy
  frequency: VERY_FREQUENT
  description: >-
    Mitochondrial myopathy is a defining feature, with muscle weakness, exercise
    intolerance, abnormal EMG, and mitochondrial histopathology.
  phenotype_term:
    preferred_term: Mitochondrial myopathy
    term:
      id: HP:0003737
      label: Mitochondrial myopathy
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003737 | Mitochondrial myopathy | Very frequent (99-80%)"
    explanation: Orphanet lists mitochondrial myopathy as very frequent in MLASA.
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"
    explanation: YARS2-related case series documents generalized myopathy in most patients.
- category: Neuromuscular
  name: Myopathy
  frequency: VERY_FREQUENT
  description: >-
    Orphanet also records the broader myopathy HPO annotation, consistent with
    the generalized myopathy described in YARS2-related cohorts.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003198 | Myopathy | Very frequent (99-80%)"
    explanation: Orphanet lists myopathy as very frequent.
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"
    explanation: YARS2-related case series documents generalized myopathy in most patients.
  sequelae:
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic myopathy and axial weakness are modeled as contributing context for scoliosis in MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
      explanation: Orphanet records scoliosis as a frequent MLASA phenotype.
  - target: Kyphosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic myopathy and axial weakness are modeled as contributing context for kyphosis in MLASA.
    evidence:
    - reference: ORPHA:2598
      reference_title: Mitochondrial myopathy and sideroblastic anemia
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002808 | Kyphosis | Frequent (79-30%)"
      explanation: Orphanet records kyphosis as a frequent MLASA phenotype.
- category: Neuromuscular
  name: Exercise intolerance
  frequency: FREQUENT
  description: Progressive exercise intolerance is part of the Orphanet definition and reflects skeletal muscle energy failure.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive exercise intolerance manifesting in childhood"
    explanation: Orphanet definition explicitly states progressive childhood exercise intolerance.
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity."
    explanation: YARS2 case-series conclusion identifies exercise intolerance as a key presentation.
- category: Neuromuscular
  name: Generalized limb muscle atrophy
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Generalized limb muscle atrophy
    term:
      id: HP:0009055
      label: Generalized limb muscle atrophy
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009055 | Generalized limb muscle atrophy | Very frequent (99-80%)"
    explanation: Orphanet lists generalized limb muscle atrophy as very frequent.
- category: Neuromuscular
  name: Hypotonia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Very frequent (99-80%)"
    explanation: Orphanet lists hypotonia as very frequent.
- category: Metabolic
  name: Lactic acidosis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003128 | Lactic acidosis | Very frequent (99-80%)"
    explanation: Orphanet lists lactic acidosis as very frequent.
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"
    explanation: YARS2-related case series supports elevated lactate as a common manifestation.
- category: Metabolic
  name: Abnormality of metabolism/homeostasis
  frequency: VERY_FREQUENT
  description: >-
    Orphanet records this broad metabolism/homeostasis HPO annotation; in MLASA,
    the specific evidence-backed metabolic manifestation is lactic acidosis.
  phenotype_term:
    preferred_term: Abnormality of metabolism/homeostasis
    term:
      id: HP:0001939
      label: Abnormality of metabolism/homeostasis
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001939 | Abnormality of metabolism/homeostasis | Very frequent (99-80%)"
    explanation: Orphanet lists abnormality of metabolism/homeostasis as very frequent.
- category: Hematologic
  name: Sideroblastic anemia
  frequency: VERY_FREQUENT
  description: >-
    MLASA includes sideroblastic anemia, often normocytic or macrocytic in
    YARS2-related disease, with ringed sideroblasts on marrow examination.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Very frequent (99-80%)"
    explanation: Orphanet lists anemia as very frequent in MLASA.
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 11 probands all had moderate to severe normocytic to macrocytic anemia."
    explanation: YARS2 cohort documents anemia in all probands.
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only 12 patients (71%) manifested with sideroblastic anemia."
    explanation: YARS2-related mitochondrial myopathy case series documents sideroblastic anemia.
- category: Cardiac
  name: Hypertrophic cardiomyopathy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support."
    explanation: YARS2-related MLASA case report documents hypertrophic cardiomyopathy.
- category: Respiratory
  name: Respiratory insufficiency
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support."
    explanation: YARS2-related MLASA case report documents respiratory failure requiring ventilatory support.
- category: Neurologic
  name: Intellectual disability
  subtype: MLASA1
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
    explanation: Orphanet lists intellectual disability as frequent.
- category: Neurologic
  name: Microcephaly
  subtype: MLASA1
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Frequent (79-30%)"
    explanation: Orphanet lists microcephaly as frequent.
- category: Ophthalmologic
  name: Distichiasis
  subtype: MLASA1
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Distichiasis
    term:
      id: HP:0009743
      label: Distichiasis
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009743 | Distichiasis | Very frequent (99-80%)"
    explanation: Orphanet lists distichiasis as very frequent.
- category: Ophthalmologic
  name: Glaucoma
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000501 | Glaucoma | Frequent (79-30%)"
    explanation: Orphanet lists glaucoma as frequent.
- category: Craniofacial
  name: High palate
  subtype: MLASA1
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000218 | High palate | Very frequent (99-80%)"
    explanation: Orphanet lists high palate as very frequent.
- category: Craniofacial
  name: Long philtrum
  subtype: MLASA1
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000343 | Long philtrum | Very frequent (99-80%)"
    explanation: Orphanet lists long philtrum as very frequent.
- category: Craniofacial
  name: Micrognathia
  subtype: MLASA1
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
    explanation: Orphanet lists micrognathia as very frequent.
- category: Craniofacial
  name: Short nose
  subtype: MLASA1
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003196 | Short nose | Frequent (79-30%)"
    explanation: Orphanet lists short nose as frequent.
- category: Skeletal
  name: Scoliosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
    explanation: Orphanet lists scoliosis as frequent.
- category: Skeletal
  name: Kyphosis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002808 | Kyphosis | Frequent (79-30%)"
    explanation: Orphanet lists kyphosis as frequent.
- category: Endocrine
  name: Delayed puberty
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000823 | Delayed puberty | Frequent (79-30%)"
    explanation: Orphanet lists delayed puberty as frequent.
- category: Diagnostic
  name: EMG abnormality
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: EMG abnormality
    term:
      id: HP:0003457
      label: EMG abnormality
  evidence:
  - reference: ORPHA:2598
    reference_title: Mitochondrial myopathy and sideroblastic anemia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003457 | EMG abnormality | Very frequent (99-80%)"
    explanation: Orphanet lists abnormal EMG as very frequent.
biochemical:
- name: Elevated lactate
  presence: INCREASED
  context: Blood lactate and/or urine lactate can be elevated due to impaired mitochondrial energy metabolism.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  readouts:
  - target: Mitochondrial respiratory-chain dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated lactate reports impaired oxidative phosphorylation with compensatory lactate production.
  - target: Lactic acidosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated lactate is the biochemical basis of the lactic acidosis phenotype.
  evidence:
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy"
    explanation: YARS2-related case series quantifies elevated blood lactate.
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine organic acid analysis demonstrated strongly raised lactate and pyruvate with moderately raised 2-hydroxybutyrate and mildly raised 2-hydroxyisovalerate, secondary to disturbed lactate metabolism."
    explanation: A YARS2-related MLASA case showed raised lactate and pyruvate on urine organic acid analysis.
- name: Elevated pyruvate
  presence: INCREASED
  context: Urine organic-acid analysis can show elevated pyruvate alongside lactate in YARS2-related MLASA.
  biomarker_term:
    preferred_term: pyruvate
    term:
      id: CHEBI:15361
      label: pyruvate
  readouts:
  - target: Mitochondrial respiratory-chain dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated pyruvate with lactate reflects disturbed mitochondrial energy metabolism.
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine organic acid analysis demonstrated strongly raised lactate and pyruvate with moderately raised 2-hydroxybutyrate and mildly raised 2-hydroxyisovalerate, secondary to disturbed lactate metabolism."
    explanation: A YARS2-related MLASA case showed raised urinary pyruvate together with lactate.
- name: Respiratory chain complex activity
  presence: DECREASED
  context: Skeletal muscle and patient-derived cells may show combined respiratory-chain defects.
  readouts:
  - target: Mitochondrial respiratory-chain dysfunction
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower respiratory-chain complex activity reports greater mitochondrial respiratory-chain dysfunction.
  evidence:
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies."
    explanation: Clinical muscle studies document reduced respiratory-chain activity.
  - reference: PMID:17056637
    reference_title: Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria."
    explanation: PUS1-related patient material showed combined respiratory-chain defects and low mtDNA translation products.
- name: tRNA pseudouridylation
  presence: DECREASED
  context: PUS1-related MLASA shows deficient tRNA pseudouridylation at Pus1p-dependent sites.
  readouts:
  - target: PUS1 tRNA pseudouridylation defect
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced Pus1p-dependent tRNA pseudouridylation is the biochemical readout of PUS1 loss of function.
  evidence:
  - reference: PMID:15772074
    reference_title: 'Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis."
    explanation: Patient-derived cell assays support decreased tRNA pseudouridylation.
- name: YARS2 aminoacylation activity
  presence: DECREASED
  context: Pathogenic YARS2 variants can reduce mitochondrial tyrosyl-tRNA synthetase catalytic efficiency.
  readouts:
  - target: YARS2 mitochondrial tyrosyl-tRNA aminoacylation defect
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower catalytic efficiency reports impaired YARS2 mitochondrial tyrosyl-tRNA aminoacylation.
  evidence:
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "YARS2 p.(Ser203Ile) and p.(Gly244Ala) demonstrated a 17-fold loss in catalytic efficiency."
    explanation: In vitro aminoacylation assays show reduced YARS2 activity for pathogenic variants.
histopathology:
- name: Bone marrow ringed sideroblasts
  description: >-
    Sideroblastic anemia is identified by bone marrow ringed sideroblasts,
    erythroblasts with pathologic intramitochondrial iron deposits.
  context: Bone marrow aspirate
  evidence:
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sideroblastic anemia is defined by the presence of bone marrow ringed sideroblasts, which are erythroblasts containing pathological intramitochondrial iron deposits."
    explanation: The YARS2 spectrum paper defines sideroblastic anemia by marrow ringed sideroblasts.
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow aspirate at 5 years revealed ringed sideroblasts"
    explanation: YARS2-related MLASA case had ringed sideroblasts on marrow aspirate.
- name: Ragged-red fiber mitochondrial myopathy
  description: >-
    Muscle biopsy can show mitochondrial myopathy histopathology, including
    ragged-red fibers and ultrastructural mitochondrial abnormalities.
  context: Skeletal muscle biopsy
  evidence:
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle biopsy showed histopathological features typical of a mitochondrial myopathy, including ragged red fibers on trichrome stain"
    explanation: YARS2 cohort paper documents ragged-red fiber mitochondrial myopathy in an affected patient.
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "global impairment of mitochondrial translation, manifest histologically by a ragged-red fiber myopathy with subsarcolemmal mitochondrial proliferation."
    explanation: Full-text report links MLASA/Pearson translation defects to ragged-red fiber myopathy.
diagnosis:
- name: Molecular genetic testing of PUS1, YARS2, and MT-ATP6
  description: >-
    Molecular testing confirms MLASA by identifying biallelic PUS1 or YARS2
    variants, or by mitochondrial genome sequencing when an MT-ATP6
    MLASA-plus phenotype is suspected.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Pathogenic PUS1, YARS2, or MT-ATP6 variants support an MLASA diagnosis.
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy."
    explanation: YARS2/PUS1 sequencing is recommended as first-line investigation.
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."
    explanation: Mitochondrial genome sequencing identified an MT-ATP6 MLASA-plus case.
- name: Bone marrow evaluation for ringed sideroblasts
  description: >-
    Bone marrow aspirate can demonstrate ringed sideroblasts, supporting the
    sideroblastic anemia component of MLASA.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  results: Ringed sideroblasts support sideroblastic anemia in a compatible MLASA presentation.
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow aspirate at 5 years revealed ringed sideroblasts"
    explanation: A YARS2-related MLASA case was recognized through marrow ringed sideroblasts.
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In each case, CSA was ascertained by complete blood counts (CBCs), and peripheral blood or bone marrow morphology."
    explanation: The YARS2 cohort used blood counts and marrow/peripheral-blood morphology to ascertain congenital sideroblastic anemia.
- name: Muscle studies for mitochondrial respiratory-chain deficiency
  description: >-
    Muscle biopsy and respiratory-chain enzyme studies can document
    mitochondrial myopathy, although genetic testing can avoid invasive biopsy
    in the YARS2/PUS1 subgroup.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  results: Cytochrome-c oxidase deficiency or combined respiratory-chain complex deficiency supports mitochondrial myopathy.
  evidence:
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies."
    explanation: Muscle studies document the biochemical mitochondrial myopathy.
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct targeting of the YARS2 and PUS1 genes in MLASA patients can avoid invasive muscle biopsy for diagnosis of this subgroup of inborn errors of mitochondrial metabolism."
    explanation: This supports reserving muscle biopsy when direct gene testing can establish diagnosis.
genetic:
- name: PUS1 pathogenic variants
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PUS1
    term:
      id: hgnc:15508
      label: PUS1
  variant_origin: GERMLINE
  notes: >-
    Biallelic PUS1 variants cause MLASA1 through deficient tRNA
    pseudouridylation.
  evidence:
  - reference: PMID:15108122
    reference_title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a homozygous missense mutation in the pseudouridine synthase 1 gene (PUS1) in all patients with MLASA from these families."
    explanation: Sequencing identified homozygous PUS1 variants segregating with MLASA.
  - reference: PMID:15772074
    reference_title: 'Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis."
    explanation: Functional assays support PUS1 molecular causality.
- name: YARS2 pathogenic variants
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: YARS2
    term:
      id: hgnc:24249
      label: YARS2
  variant_origin: GERMLINE
  notes: >-
    Biallelic YARS2 variants cause MLASA2 and can also present as isolated or
    mild congenital sideroblastic anemia.
  evidence:
  - reference: PMID:20598274
    reference_title: Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently identified the same mutation in another unrelated MLASA patient."
    explanation: The YARS2 discovery paper replicated the YARS2 variant in an unrelated MLASA patient.
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype."
    explanation: The expanded YARS2 cohort supports causality across MLASA and sideroblastic anemia presentations.
- name: MT-ATP6 de novo heteroplasmic variants
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  variant_origin: DE_NOVO
  notes: >-
    MT-ATP6 variation has been reported in an MLASA-plus phenotype with complex
    V dysfunction.
  evidence:
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."
    explanation: The MLASA-plus case report identifies a de novo heteroplasmic MT-ATP6 variant.
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Studies of fibroblasts derived from the patient revealed a decrease in oligomycin-sensitive respiration, a finding which is consistent with a complex V defect."
    explanation: Patient fibroblast assays support pathogenic ATP synthase dysfunction.
treatments:
- name: Supportive care and complication surveillance
  description: >-
    No curative treatment is established for MLASA overall. Management is
    supportive, with early genetic diagnosis enabling monitoring and treatment of
    cardiomyopathy, respiratory muscle weakness, anemia, nutrition, and other
    complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  - preferred_term: Mitochondrial myopathy
    term:
      id: HP:0003737
      label: Mitochondrial myopathy
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  target_mechanisms:
  - target: Mitochondrial respiratory-chain dysfunction
    description: Supportive care and surveillance are directed at complications of mitochondrial respiratory-chain dysfunction.
  - target: Mitochondrial translation defect
    description: Early diagnosis of mitochondrial translation disorders guides complication surveillance and supportive management.
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although no specific curative therapies are available, early diagnosis and initiation of appropriate supportive therapy is likely to be important in the prevention of the longterm complications of this disorder."
    explanation: Full-text MLASA report supports supportive therapy in the absence of curative treatment.
  - reference: PMID:28395030
    reference_title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder."
    explanation: YARS2 cohort recommends surveillance and early treatment for major complications.
- name: Noninvasive ventilation for respiratory insufficiency
  description: >-
    Noninvasive ventilatory support may be needed when respiratory muscle
    weakness causes hypoventilation or respiratory failure.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: MAXO:0000506
      label: noninvasive ventilation
  target_phenotypes:
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sleep study revealed severe hypoventilation with evidence of CO2 retention and he was commenced on nocturnal BiPAP ventilation."
    explanation: A YARS2-related MLASA case required nocturnal BiPAP for hypoventilation.
- name: Pyridoxine supplementation non-response
  description: >-
    Pyridoxine is not supported as an anemia-improving therapy for
    YARS2-related MLASA in the cached cohort evidence, helping distinguish this
    disorder from pyridoxine-responsive sideroblastic anemia.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridoxine
      term:
        id: CHEBI:16709
        label: pyridoxine
  target_phenotypes:
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:30026338
    reference_title: 'The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients were treated with pyridoxine with no improvement in their anemia"
    explanation: The YARS2 cohort directly refutes pyridoxine responsiveness for anemia in treated patients.
- name: Genetic counseling
  description: >-
    Molecular diagnosis enables counseling about autosomal recessive PUS1/YARS2
    MLASA and the rare de novo heteroplasmic MT-ATP6 MLASA-plus presentation.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  target_mechanisms:
  - target: PUS1 tRNA pseudouridylation defect
    description: Counseling addresses autosomal recessive PUS1-related MLASA1 recurrence risk.
  - target: YARS2 mitochondrial tyrosyl-tRNA aminoacylation defect
    description: Counseling addresses autosomal recessive YARS2-related MLASA2 recurrence risk.
  - target: MT-ATP6 complex V respiratory defect
    description: Counseling also covers the rare heteroplasmic mitochondrial MT-ATP6 MLASA-plus mechanism.
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy."
    explanation: The YARS2-related MLASA report explicitly supports counseling after early genetic diagnosis.
  - reference: PMID:25037980
    reference_title: Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the mitochondrial genome identified a novel de novo, heteroplasmic mutation in the mitochondrial DNA (mtDNA) encoded ATP6 gene (m.8969G>A, p.S148N)."
    explanation: The MT-ATP6 MLASA-plus case supports including mitochondrial de novo heteroplasmy in genetic counseling.
differential_diagnoses:
- name: Pearson marrow-pancreas syndrome
  disease_term:
    preferred_term: Pearson syndrome
    term:
      id: MONDO:0010797
      label: Pearson syndrome
  description: >-
    Pearson syndrome also causes infantile sideroblastic anemia and lactic
    acidosis, but typically involves large-scale mitochondrial DNA rearrangements
    and multisystem pancreatic, renal, and neurologic features.
  distinguishing_features:
  - Large-scale mitochondrial DNA deletion/rearrangement
  - Pancreatic insufficiency and broader multisystem infantile presentation
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, Pearson syndrome was definitively excluded in our patient by the absence of mtDNA rearrangements in leukocyte DNA."
    explanation: MLASA differential work-up includes excluding Pearson syndrome by mitochondrial DNA rearrangement testing.
- name: X-linked sideroblastic anemia
  disease_term:
    preferred_term: X-linked sideroblastic anemia 1
    term:
      id: MONDO:0020721
      label: X-linked sideroblastic anemia 1
  description: >-
    X-linked sideroblastic anemia can present as a pure sideroblastic anemia
    phenotype and is distinguished from MLASA by the absence of the
    mitochondrial myopathy and lactic acidosis syndrome.
  distinguishing_features:
  - ALAS2-related pure sideroblastic anemia without mitochondrial myopathy
  evidence:
  - reference: PMID:23918765
    reference_title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "XLSA and Pearson syndrome can be easily distinguished clinically since the former causes a pure sideroblastic anemia phenotype"
    explanation: The MLASA report contrasts X-linked sideroblastic anemia with syndromic MLASA/Pearson presentations.
review_notes: >-
  GeneReviews baseline checked during this curation: PubMed search for "MLASA
  GeneReviews" returned no focal MLASA GeneReviews PMID, and the NCBI
  GeneReviews title search for MLASA returned no chapter. A broader PubMed query
  for myopathy, lactic acidosis, sideroblastic anemia, and GeneReviews returns
  the Single Large-Scale Mitochondrial DNA Deletion Syndromes chapter, which is
  relevant to Pearson syndrome in the differential diagnosis but is not a focal
  MLASA GeneReview.

📚

References & Deep Research

References

7

ORPHA:2598

Mitochondrial myopathy and sideroblastic anemia

No top-level findings curated for this source.

PMID:15108122

Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).

No top-level findings curated for this source.

PMID:20598274

Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.

No top-level findings curated for this source.

PMID:28395030

Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.

No top-level findings curated for this source.

PMID:30026338

The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.

No top-level findings curated for this source.

PMID:23918765

A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.

No top-level findings curated for this source.

PMID:25037980

Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene.

No top-level findings curated for this source.

Deep Research

1

Myopathy, Lactic Acidosis, and Sideroblastic Anemia Deep Research Fallback ▸

Myopathy, Lactic Acidosis, and Sideroblastic Anemia Deep Research Fallback

Provider Attempts

2026-05-07: timeout 90s just research-disorder falcon Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia timed out with exit code 124 after the provider command was terminated by timeout.
2026-05-07: timeout 90s just research-disorder openai Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia timed out with exit code 124 after the provider command was terminated by timeout.

No provider-generated deep-research artifact was available to integrate. Curation therefore proceeded from generated structured Orphanet evidence and fetched PubMed caches, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

ORPHA:2598 structured record for disease definition, MONDO and OMIM cross references, autosomal recessive inheritance, point prevalence, PUS1 and YARS2 gene associations, and HPO phenotype rows.
PMID:15108122 for the original PUS1-associated MLASA families and the framing of MLASA as an autosomal recessive oxidative phosphorylation disorder affecting skeletal muscle and bone marrow.
PMID:15772074 for absent or reduced PUS1-dependent mitochondrial tRNA pseudouridylation as a molecular pathogenesis mechanism.
PMID:17056637 for PUS1 loss-of-function evidence, reduced mitochondrial translation, and combined respiratory-chain defects.
PMID:20598274 for YARS2 as a cause of MLASA and the mechanism linking reduced mitochondrial tRNA aminoacylation to impaired mitochondrial protein synthesis and respiratory-chain dysfunction.
PMID:23918765 for YARS2/PUS1 sequencing as a diagnostic strategy, severe myopathy with respiratory failure requiring ventilatory support, and supportive clinical management.
PMID:25037980 for MT-ATP6-associated MLASA plus syndrome, including complex V dysfunction and impaired oligomycin-sensitive respiration.
PMID:28395030 for the broader YARS2 clinical cohort, elevated lactate, generalized myopathy, sideroblastic anemia, COX deficiency, and surveillance recommendations.
PMID:30026338 for the YARS2 phenotypic spectrum, YARS2 enzymatic function, ringed sideroblast pathology, ragged-red fiber myopathy, and pyridoxine treatment nonresponse.

Curation Conclusions

The curated graph models MLASA as genetically heterogeneous mitochondrial disease involving PUS1, YARS2, and MT-ATP6. PUS1 deficiency disrupts mitochondrial tRNA pseudouridylation, YARS2 deficiency disrupts mitochondrial tyrosyl-tRNA aminoacylation, and MT-ATP6 variation impairs ATP synthase complex V. These upstream defects converge on impaired mitochondrial translation and respiratory-chain dysfunction, supporting the clinical triad of mitochondrial myopathy, lactic acidosis, and sideroblastic anemia. The entry also records ORPHA-supported dysmorphic, skeletal, neurologic, endocrine, ocular, cardiorespiratory, biochemical, diagnostic, histopathologic, and supportive management features where exact cached snippets support them.

Myopathy, Lactic Acidosis, and Sideroblastic Anemia

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References & Deep Research

References

Deep Research

Myopathy, Lactic Acidosis, and Sideroblastic Anemia Deep Research Fallback

Provider Attempts

Evidence Scope Used For Curation

Curation Conclusions