Mevalonic aciduria

Summary

Mevalonic aciduria (MONDO:0012481) is a disease caused by MVK (GenCC Definitive), with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include givinostat.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MVK (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 620
• Phenotypes (HPO): 17
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000268	Dolichocephaly	Very frequent (80-99%)
HP:0000325	Triangular face	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000592	Blue sclerae	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mevalonic aciduria
Mondo ID	MONDO:0012481
OMIM	610377
Orphanet	29
DOID	DOID:0050452
ICD-11	572875152
NCIT	C84890
SNOMED CT	718558008
UMLS	C1959626
MedGen	368373
GARD	0003588
MedDRA	10072219
Is cancer (heuristic)	no

Also known as: complete mevalonate kinase deficiency · HIDS · hyperimmunoglobulin D with periodic fever syndrome · MEVA · mevalonic aciduria · Mevalonicaciduria · MKD · MVA

Data availability: 620 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › mevalonic aciduria

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

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

600 retrieved; paginated sample, class counts are floors:

244 likely benign, 203 uncertain significance, 48 conflicting classifications of pathogenicity, 45 pathogenic, 27 likely pathogenic, 14 pathogenic/likely pathogenic, 11 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071478	NM_000431.4(MVK):c.605dup (p.Val203fs)	MVK	Pathogenic	criteria provided, single submitter
1075609	NC_000012.11:g.(?110032813)(110034402_?)del	MVK	Pathogenic	criteria provided, single submitter
11928	NM_000431.4(MVK):c.902A>C (p.Asn301Thr)	MVK	Pathogenic	no assertion criteria provided
11929	NM_000431.4(MVK):c.1129G>A (p.Val377Ile)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11930	NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11931	NM_000431.4(MVK):c.59A>C (p.His20Pro)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11932	NM_000431.4(MVK):c.803T>C (p.Ile268Thr)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11934	NM_000431.4(MVK):c.928G>A (p.Val310Met)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
11935	NM_000431.4(MVK):c.16_34del (p.Leu6fs)	MVK	Pathogenic	no assertion criteria provided
1460450	NC_000012.11:g.(?110013783)(110013970_?)del	MVK	Pathogenic	criteria provided, single submitter
2024803	NM_000431.4(MVK):c.1090_1091del (p.Gly364fs)	MVK	Pathogenic	criteria provided, single submitter
2090149	NM_000431.4(MVK):c.671T>G (p.Leu224Ter)	MVK	Pathogenic	criteria provided, single submitter
2137420	NM_000431.4(MVK):c.481_482del (p.Cys161fs)	MVK	Pathogenic	criteria provided, single submitter
2142782	NM_000431.4(MVK):c.345dup (p.Tyr116fs)	MVK	Pathogenic	criteria provided, single submitter
2196384	NM_000431.4(MVK):c.790dup (p.Leu264fs)	MVK	Pathogenic	criteria provided, single submitter
234379	NM_000431.4(MVK):c.643C>T (p.Arg215Ter)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
2423080	NC_000012.11:g.(?110032813)(110034382_?)del	MVK	Pathogenic	criteria provided, single submitter
2635502	NM_000431.4(MVK):c.560_561del (p.Lys187fs)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
2921862	NM_000431.4(MVK):c.621_630del (p.Ser208fs)	MVK	Pathogenic	criteria provided, single submitter
2925505	NM_000431.4(MVK):c.1A>C (p.Met1Leu)	MVK	Pathogenic	criteria provided, single submitter
2925507	NM_000431.4(MVK):c.395del (p.Val132fs)	MVK	Pathogenic	criteria provided, single submitter
2931188	NM_000431.4(MVK):c.417del (p.Ala141fs)	MVK	Pathogenic	criteria provided, single submitter
2938110	NM_000431.4(MVK):c.207_208del (p.Leu70fs)	MVK	Pathogenic	criteria provided, single submitter
2943228	NM_000431.4(MVK):c.46_49del (p.Leu16fs)	MVK	Pathogenic	criteria provided, single submitter
2944926	NM_000431.4(MVK):c.661_668dup (p.Leu224fs)	MVK	Pathogenic	criteria provided, single submitter
2947497	NM_000431.4(MVK):c.976G>T (p.Gly326Ter)	MVK	Pathogenic	criteria provided, single submitter
2948422	NM_000431.4(MVK):c.664del (p.Ser222fs)	MVK	Pathogenic	criteria provided, single submitter
2949233	NM_000431.4(MVK):c.712A>T (p.Lys238Ter)	MVK	Pathogenic	criteria provided, single submitter
2952122	NM_000431.4(MVK):c.629G>A (p.Trp210Ter)	MVK	Pathogenic	criteria provided, single submitter
2953001	NM_000431.4(MVK):c.386_422del (p.Leu129fs)	MVK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
MVK	Definitive	Autosomal recessive	mevalonic aciduria	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis
MMAB	Orphanet:79311	Vitamin B12-responsive methylmalonic acidemia type cblB

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
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	gencc,clinvar
MMAB	HGNC:19331	ENSG00000139428	Q96EY8	Corrinoid adenosyltransferase MMAB	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.
MMAB	Corrinoid adenosyltransferase MMAB	Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion.

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin
MMAB	Enzyme (other)	yes	2.5.1.17	CblAdoTrfase-like, PduO-typ, CblAdoTrfase-like_sf

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
right lobe of liver	2
lower esophagus mucosa	1
metanephros cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex
MMAB	235	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424
MMAB	1,121

Intra-cohort edges

A	B	Sources
MMAB	MVK	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMAB	Q96EY8	6
MVK	Q03426	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Defective MMAB causes MMA, cblB type	1	2855.0×	0.006	MMAB
Cobalamin (Cbl) metabolism	1	634.4×	0.008	MMAB
Cholesterol biosynthesis	1	571.0×	0.008	MVK
Defects in cobalamin (B12) metabolism	1	407.9×	0.008	MMAB
Lanosterol biosynthesis	1	380.7×	0.008	MVK
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.008	MMAB
Defects in vitamin and cofactor metabolism	1	300.5×	0.008	MMAB
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.012	MVK
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.012	MVK
Metabolism	2	11.6×	0.012	MVK, MMAB
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.016	MMAB
Metabolism of steroids	1	68.8×	0.019	MVK
Metabolism of vitamins and cofactors	1	58.3×	0.021	MMAB
Diseases of metabolism	1	40.2×	0.028	MMAB
Metabolism of lipids	1	15.8×	0.067	MVK
Disease	1	6.5×	0.147	MMAB

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
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	2808.7×	0.002	MVK
isoprenoid biosynthetic process	1	842.6×	0.002	MVK
cobalamin metabolic process	1	766.0×	0.002	MMAB
cholesterol biosynthetic process	1	210.7×	0.006	MVK
negative regulation of inflammatory response	1	68.5×	0.015	MVK

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
MVK	0	0
MMAB	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
MMAB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MVK	2.7.1.36	mevalonate kinase
MMAB	2.5.1.17	corrinoid adenosyltransferase

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	MVK, MMAB
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)
MVK	0	—
MMAB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT05292768	Not specified	NOT_YET_RECRUITING	Are Mast Cells Involved in Autoinflammatory Diseases
NCT00260299	Not specified	TERMINATED	Dietary Cholesterol and Defects in Cholesterol Synthesis in Mevalonate Kinase Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GIVINOSTAT	4	1