Myopathy, lactic acidosis, and sideroblastic anemia

Summary

Myopathy, lactic acidosis, and sideroblastic anemia (MONDO:0000863) is a disease with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include ampreloxetine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 68
• Phenotypes (HPO): 19
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0003737	Mitochondrial myopathy	Very frequent (80-99%)
HP:0009055	Generalized limb muscle atrophy	Very frequent (80-99%)
HP:0009743	Distichiasis	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, lactic acidosis, and sideroblastic anemia
Mondo ID	MONDO:0000863
MeSH	C536101
OMIM	600462
Orphanet	2598
DOID	DOID:0080099
ICD-11	678852156
SNOMED CT	724138007
UMLS	C1838103
MedGen	373888
GARD	0003885
Is cancer (heuristic)	no

Also known as: mitochondrial myopathy and sideroblastic anaemia · mitochondrial myopathy and sideroblastic anemia · MLASA · MSA · myopathy with lactic acidosis and sideroblastic anaemia · myopathy with lactic acidosis and sideroblastic anemia · myopathy, lactic acidosis and sideroblastic anaemia · myopathy, lactic acidosis and sideroblastic anemia · myopathy, lactic acidosis, and siderblastic anaemia · myopathy, lactic acidosis, and siderblastic anemia · sideroblastic anaemia and mitochondrial myopathy · sideroblastic anemia and mitochondrial myopathy

Data availability: 68 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › myopathy, lactic acidosis, and sideroblastic anemia

Related subtypes (7): congenital nonspherocytic hemolytic anemia, congenital dyserythropoietic anemia type 3, congenital dyserythropoietic anemia type 2, congenital dyserythropoietic anemia type 4, severe congenital hypochromic anemia with ringed sideroblasts, Fanconi anemia, congenital dyserythropoietic anemia type 1

Subtypes (3): myopathy, lactic acidosis, and sideroblastic anemia 3, myopathy, lactic acidosis, and sideroblastic anemia 2, myopathy, lactic acidosis, and sideroblastic anemia 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

68 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 15 likely pathogenic, 14 likely benign, 5 pathogenic/likely pathogenic, 2 benign/likely benign, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2137450	NM_025215.6(PUS1):c.460C>T (p.Gln154Ter)	PUS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2536	NM_025215.6(PUS1):c.430C>T (p.Arg144Trp)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2810732	NM_025215.6(PUS1):c.505_506del (p.Lys169fs)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423712	NM_025215.6(PUS1):c.454dup (p.Ala152fs)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
846145	NM_025215.6(PUS1):c.837_838del (p.Ala280fs)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
970678	NM_025215.6(PUS1):c.301C>T (p.Gln101Ter)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4060561	NM_025215.6(PUS1):c.109_115del (p.Pro37fs)	LOC130009240	Likely pathogenic	criteria provided, single submitter
4816250	NM_025215.6(PUS1):c.130del (p.Gln44fs)	LOC130009240	Likely pathogenic	criteria provided, single submitter
4816251	NM_025215.6(PUS1):c.139_142delinsGG (p.Arg47fs)	LOC130009240	Likely pathogenic	criteria provided, single submitter
4816252	NM_025215.6(PUS1):c.147del (p.Ser48_Cys49insTer)	LOC130009240	Likely pathogenic	criteria provided, single submitter
4060577	NM_025215.6(PUS1):c.364_365insTG (p.Arg122fs)	LOC132090059	Likely pathogenic	criteria provided, single submitter
4060585	NM_025215.6(PUS1):c.430dup (p.Arg144fs)	LOC132090059	Likely pathogenic	criteria provided, single submitter
4816255	NM_025215.6(PUS1):c.431G>A (p.Arg144Gln)	LOC132090059	Likely pathogenic	criteria provided, single submitter
4816256	NM_025215.6(PUS1):c.436_439del (p.Asp146fs)	LOC132090059	Likely pathogenic	criteria provided, single submitter
4060572	NM_025215.6(PUS1):c.823del (p.Glu275fs)	PUS1	Likely pathogenic	criteria provided, single submitter
4816247	NM_025215.6(PUS1):c.1033C>T (p.Gln345Ter)	PUS1	Likely pathogenic	criteria provided, single submitter
4816248	NM_025215.6(PUS1):c.1033del (p.Gln345fs)	PUS1	Likely pathogenic	criteria provided, single submitter
4816249	NM_025215.6(PUS1):c.1128_1131del (p.Ile377fs)	PUS1	Likely pathogenic	criteria provided, single submitter
4816253	NM_025215.6(PUS1):c.187G>T (p.Glu63Ter)	PUS1	Likely pathogenic	criteria provided, single submitter
4816254	NM_025215.6(PUS1):c.291_295del (p.Tyr97_Gly99delinsTer)	PUS1	Likely pathogenic	criteria provided, single submitter
4816257	NM_025215.6(PUS1):c.853A>T (p.Lys285Ter)	PUS1	Likely pathogenic	criteria provided, single submitter
378450	NM_025215.6(PUS1):c.545-7C>T	PUS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1254575	NM_025215.6(PUS1):c.127C>T (p.Pro43Ser)	LOC130009240	Uncertain significance	criteria provided, multiple submitters, no conflicts
4060562	NM_025215.6(PUS1):c.113C>G (p.Ala38Gly)	LOC130009240	Uncertain significance	no assertion criteria provided
4060576	NM_025215.6(PUS1):c.155G>C (p.Arg52Pro)	LOC130009240	Uncertain significance	no assertion criteria provided
4060584	NM_025215.6(PUS1):c.82C>T (p.Arg28Cys)	LOC130009240	Uncertain significance	no assertion criteria provided
4060586	NM_025215.6(PUS1):c.107C>A (p.Pro36Gln)	LOC130009240	Uncertain significance	no assertion criteria provided
2187061	NM_025215.6(PUS1):c.430C>G (p.Arg144Gly)	LOC132090059	Uncertain significance	criteria provided, single submitter
1197754	NM_025215.6(PUS1):c.41G>A (p.Arg14Gln)	PUS1	Uncertain significance	criteria provided, single submitter
215046	NM_025215.6(PUS1):c.789C>G (p.Ile263Met)	PUS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PUS1	Definitive	Autosomal recessive	myopathy, lactic acidosis, and sideroblastic anemia 1	5
YARS2	Definitive	Autosomal recessive	myopathy, lactic acidosis, and sideroblastic anemia 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PUS1	Orphanet:2598	Mitochondrial myopathy and sideroblastic anemia
YARS2	Orphanet:2598	Mitochondrial myopathy and sideroblastic anemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PUS1	HGNC:15508	ENSG00000177192	Q9Y606	Pseudouridylate synthase 1 homolog	gencc,clinvar
YARS2	HGNC:24249	ENSG00000139131	Q9Y2Z4	Tyrosine–tRNA ligase, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PUS1	Pseudouridylate synthase 1 homolog	Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs.
YARS2	Tyrosine–tRNA ligase, mitochondrial	Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PUS1	Enzyme (other)	yes	5.4.99.B22	PsdUridine_synth_TruA, TruA/RsuA/RluB/E/F_N, PsdUridine_synth_TruA_C
YARS2	Enzyme (other)	yes	6.1.1.1	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ic, Tyr-tRNA-ligase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
lower esophagus mucosa	1
mucosa of transverse colon	1
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PUS1	229	ubiquitous	marker	granulocyte, mucosa of transverse colon, lower esophagus mucosa
YARS2	276	ubiquitous	marker	oocyte, secondary oocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YARS2	3,284
PUS1	2,688

Intra-cohort edges

A	B	Sources
PUS1	YARS2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PUS1	Q9Y606	6
YARS2	Q9Y2Z4	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA modification in the mitochondrion	1	519.1×	0.010	PUS1
Mitochondrial tRNA aminoacylation	1	259.6×	0.010	YARS2
tRNA modification in the nucleus and cytosol	1	146.4×	0.010	PUS1
tRNA Aminoacylation	1	142.8×	0.010	YARS2
Translation	1	31.0×	0.038	YARS2
Metabolism of proteins	1	6.2×	0.155	YARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial tyrosyl-tRNA aminoacylation	1	8426.0×	0.001	YARS2
tRNA aminoacylation	1	4213.0×	0.001	YARS2
mitochondrial tRNA pseudouridine synthesis	1	2808.7×	0.001	PUS1
tRNA pseudouridine synthesis	1	1404.3×	0.002	PUS1
mRNA pseudouridine synthesis	1	842.6×	0.002	PUS1
translation	1	51.4×	0.028	YARS2
RNA splicing	1	44.1×	0.028	PUS1
mRNA processing	1	39.4×	0.028	PUS1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	PUS1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PUS1	0	0
YARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PUS1	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PUS1	5.4.99.B22
YARS2	6.1.1.1	tyrosine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	PUS1, YARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PUS1	6	—
YARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
PHASE3	1
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03829657	PHASE3	TERMINATED	Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
NCT02315027	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Mesenchymal Stem Cell Therapy in Multiple System Atrophy
NCT07465198	PHASE2	NOT_YET_RECRUITING	Autologous Stem Cell Therapy in Patients With Multiple System Atrophy
NCT03033680	PHASE1/PHASE2	COMPLETED	Establishing 18F-PBR06 PET Imaging as a Viable Pharmacodynamic Endpoint in MSA
NCT06647641	Not specified	RECRUITING	The CurePSP Genetics Program

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMPRELOXETINE	3	1