Hypotonia with lactic acidemia and hyperammonemia

Summary

Hypotonia with lactic acidemia and hyperammonemia (MONDO:0012718) is a disease caused by MRPS22 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MRPS22 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hypotonia with lactic acidemia and hyperammonemia
Mondo ID	MONDO:0012718
MeSH	C567126
OMIM	611719
Orphanet	137908
DOID	DOID:0111473
SNOMED CT	724279004
UMLS	C2673642
MedGen	435972
GARD	0016950
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation defect type 5 · combined oxidative phosphorylation deficiency 5 · combined oxidative phosphorylation deficiency caused by mutation in MRPS22 · combined oxidative phosphorylation deficiency type 5 · COXPD5 · MRPS22 combined oxidative phosphorylation deficiency

Data availability: 36 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › hypotonia with lactic acidemia and hyperammonemia

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

36 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 10 conflicting classifications of pathogenicity, 5 pathogenic, 2 benign/likely benign, 2 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033933	NM_020191.4(MRPS22):c.874_875del (p.Asp292fs)	MRPS22	Pathogenic	criteria provided, single submitter
2691748	NM_020191.4(MRPS22):c.648+1G>T	MRPS22	Pathogenic	no assertion criteria provided
30524	NM_020191.4(MRPS22):c.644T>C (p.Leu215Pro)	MRPS22	Pathogenic	no assertion criteria provided
4279693	NM_020191.4(MRPS22):c.948_949del (p.Ala317fs)	MRPS22	Pathogenic	criteria provided, single submitter
432184	NM_020191.4(MRPS22):c.878+1G>T	MRPS22	Pathogenic	criteria provided, multiple submitters, no conflicts
4753	NM_020191.4(MRPS22):c.509G>A (p.Arg170His)	MRPS22	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806198	NM_020191.4(MRPS22):c.992_993del (p.Phe331fs)	MRPS22	Likely pathogenic	criteria provided, single submitter
2445204	NM_020191.4(MRPS22):c.481dup (p.Ile161fs)	MRPS22	Likely pathogenic	criteria provided, single submitter
343484	NM_020191.4(MRPS22):c.172+11T>C	LOC112903839	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138252	NM_020191.4(MRPS22):c.6G>A (p.Ala2=)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214681	NM_020191.4(MRPS22):c.938C>T (p.Ser313Leu)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214683	NM_020191.4(MRPS22):c.617C>T (p.Thr206Ile)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214686	NM_020191.4(MRPS22):c.502C>T (p.Arg168Trp)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343483	NM_020191.4(MRPS22):c.90G>A (p.Gln30=)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343485	NM_020191.4(MRPS22):c.327A>G (p.Ala109=)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343486	NM_020191.4(MRPS22):c.340-14T>A	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
631909	NM_020191.4(MRPS22):c.1032_1035dup (p.Leu346fs)	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
743755	NM_020191.4(MRPS22):c.172+7G>T	MRPS22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902377	NM_020191.4(MRPS22):c.64C>G (p.Arg22Gly)	LOC112903839	Uncertain significance	criteria provided, single submitter
902378	NM_020191.4(MRPS22):c.166G>A (p.Glu56Lys)	LOC112903839	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029741	NM_020191.4(MRPS22):c.137T>C (p.Met46Thr)	MRPS22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029744	NM_020191.4(MRPS22):c.318G>A (p.Met106Ile)	MRPS22	Uncertain significance	criteria provided, single submitter
1065493	NM_020191.4(MRPS22):c.600A>C (p.Glu200Asp)	MRPS22	Uncertain significance	criteria provided, single submitter
1477449	NM_020191.4(MRPS22):c.758T>C (p.Ile253Thr)	MRPS22	Uncertain significance	criteria provided, multiple submitters, no conflicts
214684	NM_020191.4(MRPS22):c.787C>T (p.Arg263Cys)	MRPS22	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585582	NM_020191.4(MRPS22):c.943C>T (p.Gln315Ter)	MRPS22	Uncertain significance	criteria provided, single submitter
2585583	NM_020191.4(MRPS22):c.433G>T (p.Asp145Tyr)	MRPS22	Uncertain significance	criteria provided, single submitter
343488	NM_020191.4(MRPS22):c.652A>G (p.Met218Val)	MRPS22	Uncertain significance	criteria provided, multiple submitters, no conflicts
343489	NM_020191.4(MRPS22):c.732G>A (p.Lys244=)	MRPS22	Uncertain significance	criteria provided, multiple submitters, no conflicts
343492	NM_020191.4(MRPS22):c.1045T>A (p.Tyr349Asn)	MRPS22	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
MRPS22	Strong	Autosomal recessive	hypotonia with lactic acidemia and hyperammonemia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MRPS22	Orphanet:137908	Hypotonia with lactic acidemia and hyperammonemia
MRPS22	Orphanet:243	46,XX gonadal dysgenesis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MRPS22	HGNC:14508	ENSG00000175110	P82650	Small ribosomal subunit protein mS22	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MRPS22	Other/Unknown	no		Ribosomal_mS22

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRPS22	289	ubiquitous	marker	adrenal tissue, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPS22	2,985

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPS22	P82650	77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation	1	137.6×	0.013	MRPS22
Mitochondrial translation initiation	1	126.9×	0.013	MRPS22
Mitochondrial translation elongation	1	126.9×	0.013	MRPS22
Mitochondrial ribosome-associated quality control	1	122.8×	0.013	MRPS22
Mitochondrial translation termination	1	109.8×	0.013	MRPS22
Translation	1	62.1×	0.019	MRPS22
Metabolism of proteins	1	12.4×	0.081	MRPS22

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial translation	1	173.7×	0.006	MRPS22

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MRPS22	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MRPS22	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MRPS22

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MRPS22	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.