Mevalonate Kinase Deficiency

1. Disease Information

Overview. MKD is an autosomal recessive disorder caused by deficient activity of mevalonate kinase (MK), the first committed enzyme downstream of HMG-CoA reductase in the mevalonate/isoprenoid biosynthesis pathway. The block in this pathway produces a shortage of non-sterol isoprenoids (especially geranylgeranyl pyrophosphate), which impairs protein prenylation and triggers episodes of systemic hyperinflammation driven by interleukin-1β (IL-1β). Severity tracks with residual enzyme activity. (PMC1475558; PMC11590122)

"Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis." (PMC1475558)

Key identifiers. - Gene: MVK, locus 12q24.11. OMIM gene: 251170. HGNC: HGNC:7530 (hgnc:7530). - OMIM phenotype — HIDS / mild MKD: 260920 (Hyperimmunoglobulinemia D and periodic fever syndrome; "periodic fever, Dutch type"). ⚠️ Note: some sources list 260920; verify against current OMIM. - OMIM phenotype — Mevalonic aciduria / severe MKD: 610377. - Orphanet: Mevalonate kinase deficiency (umbrella) ORPHA:309025; HIDS ORPHA:343; Mevalonic aciduria ORPHA:29. ⚠️ Verify ORPHA codes against current Orphadata before committing as ORPHA: evidence. - MONDO: Mevalonate kinase deficiency commonly MONDO:0018997; mevalonic aciduria MONDO:0009639; HIDS MONDO:0009358. ⚠️ These MONDO IDs must be verified with runoak -i sqlite:obo:mondo info ... before use — do not trust them as-quoted. - ICD-11: typically coded under periodic fever syndromes (4A60.2 area, "Mevalonate kinase deficiency"). ⚠️ Verify. - MeSH: "Mevalonate Kinase Deficiency" (also indexed under hyper-IgD; D000093173 / related entries — verify).

Synonyms / alternative names: Mevalonate kinase deficiency (MKD); Hyper-IgD syndrome (HIDS); Hyperimmunoglobulinemia D and periodic fever syndrome; Periodic fever, Dutch type; Mevalonic aciduria (MVA); MK deficiency. (NORD; MedlinePlus)

Data derivation: Information is from aggregated disease-level resources (OMIM, Orphanet, the International HIDS Database, the Eurofever registry, and published cohort/natural-history studies) rather than individual EHR data.

2. Etiology

Primary cause — genetic. Biallelic (homozygous or compound heterozygous) loss-of-function/hypomorphic variants in MVK reduce mevalonate kinase activity. The disease is a direct enzymatic deficiency; there is no environmental cause, though environmental factors trigger flares (see below). (PMC1475558)

"A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. The severity of the disease is linked with the residual activity of the enzyme." (PMC1475558)

Genetic risk factors. Being a carrier of two MVK pathogenic alleles is causal (not merely a risk factor). The dominant mild-disease allele is p.Val377Ile (p.V377I); the most common second allele associated with severe disease is p.Ile268Thr (p.I268T). Carrier frequency is high in people of Northern European (especially Dutch) ancestry. (PMC11590122; Frontiers SHARE 2024)

Environmental flare triggers (not disease causes). Vaccination/immunization, infection, physical or emotional stress, surgery, and minor trauma precipitate febrile attacks. A central mechanistic insight: the mutant enzyme is thermolabile, so any rise in body temperature further reduces residual activity — fever begets more isoprenoid shortage in a feed-forward loop. (PMC4855321 natural history; PMC9525117 / JCI 160929)

"Fever episodes can be precipitated by vaccination, infection, or physical and emotional stress." In cohorts, "vaccination triggered 36–63% of attacks." (PMC4855321)

The MK enzyme is thermolabile, making "any febrile illness a potential trigger for autoinflammatory disease flares." (PMC11590122)

Protective factors. No established genetic protective alleles. Female sex and homozygous p.V377I genotype correlate with spontaneous improvement / attenuation of attacks with age. (PMC4855321)

Gene–environment interaction. The thermolability of mutant MK is the canonical gene-by-environment node: an environmental insult that raises core temperature (infection, vaccine reaction) interacts with the temperature-sensitive mutant enzyme to acutely deepen isoprenoid depletion and precipitate the inflammatory cascade. (PMC9525117)

3. Phenotypes

Onset is typically in the first year of life (78% in year 1; 92% before age 5). Attacks are episodic/recurrent, lasting 3–7 days (median ~5 days), recurring every few weeks (median ~12 attacks/year in HIDS, up to ~25 in severe MKD), with attack frequency declining through adolescence/adulthood. (PMC4855321)

Clinical features and frequencies (International HIDS Database / cohort data; suggested HPO terms):

Severe-MKD (mevalonic aciduria)–specific phenotypes (low/undetectable residual activity, <0.5%): - Psychomotor/developmental delay — HP:0001263 Global developmental delay - Progressive cerebellar ataxia — HP:0002066 Gait ataxia / HP:0001251 Ataxia; cerebellar atrophy HP:0001272 - Hypotonia — HP:0001252 - Failure to thrive / growth retardation — HP:0001508 - Dysmorphic features (dolichocephaly, triangular face, low-set ears, downslanting palpebral fissures) — HP:0001999 - Progressive visual impairment, cataracts, retinal dystrophy/uveitis — HP:0000505 / HP:0000518 - Seizures (~5%), cerebellar syndrome (~3%) — HP:0001250 Seizure, HP:0001251

"MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises." (PMC1475558)

Phenotype characteristics: onset neonatal–infantile; severity ranges mild→severe and tracks residual enzyme activity; course is episodic/recurrent in mild MKD and progressive (neurodegenerative) in severe MKD; attack frequency declines with age in mild MKD.

Quality-of-life impact: Recurrent attacks cause major school/work absence and impaired health-related QoL; canakinumab treatment produced "marked improvements in HRQoL" and catch-up growth (height/weight/BMI z-scores). (PMC11590122; CLUSTER trial, PMID 34554243)

4. Genetic / Molecular Information

Causal gene: MVK (mevalonate kinase), 12q24.11, HGNC:7530 (hgnc:7530), OMIM 251170, UniProt Q03426, EC 2.7.1.36. The protein is a peroxisomal/cytosolic kinase that phosphorylates mevalonate to mevalonate-5-phosphate. (OMIM 251170)

Pathogenic variants: - >300 distinct MVK variants documented (catalogued in the Infevers registry). (PMC11590122) - p.Val377Ile (c.1129G>A; p.V377I) — the dominant mild-disease allele; ~42% of alleles in Dutch patients; >95% of HIDS patients carry it (usually compound heterozygous). Residual MK activity ~10–28% of wild type. Missense, likely a folding/stability defect. (PMC11590122; PMC1475558) - p.Ile268Thr (p.I268T) — second most common; associated with more severe phenotype and protein-stability disruption; over-represented in mevalonic aciduria. Missense. (Chinese cohort PMC12297814) - Other recurrent: p.His20Pro/Asn, p.Ala334Thr, p.Asn301Thr, plus nonsense, frameshift, and splice variants in severe disease. "Hotspot" conserved regions: residues 8–35 and 234–338. (PMC11590122)

"More than 95% of patients with HIDS are compound heterozygous for the V377I MVK allele, whereas a second mutant allele, I268T, is specific to patients with MA." (PMC11590122 / search synthesis)

Variant classification: Per ACMG/AMP and curated in ClinVar / Infevers; p.V377I and p.I268T are classified Pathogenic. Pathogenicity assessment is supported by the Infevers database. (PMC11590122)

Allele frequency: p.V377I is notably common in Northern Europeans — ~1 in 65 Dutch individuals carries a heterozygous pathogenic MVK variant. Check gnomAD for current population frequencies. (PMC11590122)

Origin: Germline, autosomal recessive. No somatic role.

Functional consequence: Loss of function / reduced catalytic activity and/or reduced protein stability (hypomorphic). The mutant enzyme is thermolabile — activity falls further with rising temperature, a key pathogenic feature. (PMC9525117)

Modifier genes: Candidate disease modifiers have been proposed (e.g., genes affecting inflammatory tone), explaining incomplete genotype–phenotype correlation; evidence is preliminary. (Putative modifier genes, Spandidos / MMR 2016)

Epigenetics / chromosomal abnormalities: No established epigenetic mechanism or recurrent chromosomal abnormality; this is a point-mutation/small-variant Mendelian disorder.

5. Environmental Information

• Environmental factors: None cause the disease. Heat/fever (any cause), surgery, and trauma exacerbate it via the thermolabile enzyme.
• Lifestyle factors: Emotional/physical stress can trigger flares; no diet or smoking association established.
• Infectious agents: Infections are flare triggers, not etiologic agents. Intercurrent infection (and the febrile response to it or to vaccines) is the commonest precipitant. (PMC4855321)

6. Mechanism / Pathophysiology

The causal chain (upstream → downstream):

1. Enzymatic block. Biallelic MVK variants reduce mevalonate kinase activity → mevalonate accumulates (excreted as urinary mevalonic acid) and downstream isoprenoid pyrophosphates fall, specifically farnesyl-PP (FPP) and geranylgeranyl-PP (GGPP). GGPP shortage is the key inflammatory node. (PMC1475558)
2. Defective protein prenylation. GGPP/FPP are the lipid anchors for prenylation of small GTPases. Loss of GGPP → impaired geranylgeranylation of RhoA (and other Rho-family GTPases). (PMC2946549; Defective prenylation, PMC6702261)
3. RhoA inactivation releases pyrin. Geranylgeranylated, membrane-bound RhoA normally keeps the pyrin inflammasome under tonic phospho-inhibition (via RhoA→PKN1/2 phosphorylation of pyrin). Unprenylated RhoA cannot reach the membrane and cannot activate this brake → pyrin inflammasome de-repression. (PMC4183811)
4. Inflammasome → IL-1β. De-repressed pyrin assembles an ASC/caspase-1 inflammasome → caspase-1 cleaves pro-IL-1β → mature IL-1β secretion → systemic autoinflammation (fever, acute-phase response). A parallel arm: unprenylated RhoA stimulates Rac1, which primes additional IL-1β secretion. (PMC4183811)
5. Clinical flare. IL-1β (with IL-6, TNF downstream) drives recurrent fever, lymphadenopathy, serositis, rash, arthralgia, and the acute-phase rise in CRP/SAA. Sustained SAA elevation → AA amyloid deposition over years.

"Geranylgeranylated RhoA normally inhibits the pyrin inflammasome through phospho-inactivation. Mutations of MVK lead to release of the normal, constitutive tonic inhibition of the pyrin inflammasome and excess IL-1 production… mediated at least in part by inactivation of the small GTPase RhoA and subsequent activation of pyrin, which forms an inflammasome resulting in caspase-1 mediated IL-1β release." (PMC4183811)

Molecular pathways: Mevalonate/isoprenoid (cholesterol) biosynthesis pathway (KEGG hsa00900 terpenoid backbone biosynthesis; Reactome cholesterol biosynthesis); pyrin (MEFV) inflammasome; RhoA/Rac1 GTPase signaling; caspase-1/IL-1β axis.

Cellular processes: Innate immune activation, inflammasome assembly, pyroptosis-associated cytokine release. Also reported: increased mitochondrial dysfunction, autophagy alterations, and enhanced cell death in patient monocytes. (PMC4959763)

Protein dysfunction: MK loss of catalytic activity and reduced thermostability; downstream, GTPases fail to localize to membranes due to absent prenyl anchors.

Metabolic changes: ↑ mevalonic acid (urine/plasma); ↓ non-sterol isoprenoids (GGPP, FPP, dolichol, ubiquinone/CoQ10); cholesterol is usually maintained (sterol arm is spared at the expense of isoprenoids during flares).

Immune involvement: This is a prototypical monogenic autoinflammatory disorder — innate (not autoimmune) hyperinflammation, IL-1β-centric. Elevated IgD is a biomarker, not the driver.

Suggested GO / CL / pathway terms: - GO biological process: GO:0019287 (isopentenyl diphosphate biosynthetic process, mevalonate pathway) / GO:0006695 cholesterol biosynthetic process; GO:0018343 protein farnesylation / GO:0018344 protein geranylgeranylation; GO:0050702 interleukin-1 beta secretion; GO:0072559 NLRP3/inflammasome (pyrin: GO:0140738? verify); GO:0007266 Rho protein signal transduction. - Cell types (CL): CL:0000576 monocyte; CL:0000235 macrophage; CL:0000094 granulocyte/neutrophil; CL:0000236 B cell (IgD); dendritic cells.

7. Anatomical Structures Affected

Organ / system level (mild MKD): Multisystem during flares — immune/lymphatic (lymph nodes: cervical, UBERON:0000029 lymph node), spleen (UBERON:0002106), liver (UBERON:0002107), gastrointestinal tract (UBERON:0000160 intestine — abdominal pain, diarrhea, vomiting; serositis/peritoneal adhesions), skin (UBERON:0002097 — rash), joints (UBERON:0000019? → UBERON:0001485 joint — arthralgia/arthritis), oral mucosa (UBERON:0000165 mouth — aphthae).

Severe MKD adds CNS / sensory: cerebellum (UBERON:0002037 — ataxia, cerebellar atrophy), brain broadly (developmental delay), eye (UBERON:0000970 — cataract, retinal dystrophy, uveitis), skeletal/craniofacial (dysmorphism). Kidney: AA amyloidosis (UBERON:0002113 kidney) as a long-term complication; renal angiomyolipoma reported (~6%).

Tissue / cell level: Innate immune effector cells — monocytes/macrophages and neutrophils are the principal cytokine producers; B cells account for IgD elevation. Subcellular: mevalonate pathway enzymes are peroxisomal/cytosolic (GO:0005777 peroxisome; GO:0005829 cytosol); the prenylation defect manifests at the plasma membrane (failure of GTPase membrane anchoring, GO:0005886).

Laterality: Systemic/bilateral; lymphadenopathy often cervical and symmetric.

8. Temporal Development

• Onset: Congenital/infantile — typically first year of life (78% year 1; 92% by age 5); severe MKD presents neonatally/antenatally. (PMC4855321)
• Pattern: Episodic/recurrent (periodic fever) in mild MKD; chronic-progressive neurodegeneration superimposed on attacks in severe MKD.
• Attack architecture: abrupt fever ± prodrome → 3–7 days (median 5) → resolution; recurs every 2–8 weeks.
• Progression / course: Mild MKD generally attenuates with age (fewer attacks in adulthood; some spontaneous improvement, especially females and p.V377I homozygotes). Severe MKD may be fatal in early childhood. (PMC4855321)
• Duration: Lifelong (chronic) condition.
• Critical windows: Vaccination/infection in infancy commonly unmask first attacks; early diagnosis and IL-1 blockade are the intervention window to prevent growth failure and amyloidosis.

9. Inheritance and Population

• Inheritance: Autosomal recessive (biallelic MVK variants). (OMIM)
• Prevalence/incidence (rare): ~5 per 1,000,000 general population (Netherlands) to 6.2 per 1,000,000 (Germany); pediatric incidence 0.39–1.3 per 1,000,000 person-years. ~300 cases documented worldwide by ~2013 (≥180 HIDS, ≥30 MVA historically). (PMC11590122; PMC4855321)
• Carrier frequency: ~1 in 65 in the Dutch population. (PMC11590122)
• Penetrance: Essentially complete for biallelic pathogenic genotypes, but expressivity is highly variable (even within genotypes/families).
• Genotype–phenotype: Severity correlates with residual enzyme activity (mild MKD ~1.8–28%; severe MKD <0.5%) more than with specific genotype; no consistent genotype correlation with attack frequency/onset. AA amyloidosis is over-represented in p.V377I/p.I268T compound heterozygotes. (PMC11590122; PMC4855321)
• Founder effect: p.V377I shows a Northern European founder distribution (Netherlands, France, Italy).
• Demographics: Higher in Northern/Western European ancestry; roughly equal sex ratio (female sex linked to milder/improving course); pediatric onset predominant.
• Anticipation / mosaicism: Not features of this disorder.

10. Diagnostics

Laboratory: - Urinary organic acids — mevalonic acid: markedly and constantly elevated in severe MKD; in mild MKD elevated only during flares. (Diagnostic for MVA.) (PMC1475558) - Acute-phase reactants: CRP, ESR, leukocytosis, and serum amyloid A (SAA) rise during attacks; SAA may be the more sensitive inflammation marker in MKD. (PMC11590122) - Serum IgD (and often IgA): historically elevated, but IgD testing is now discouraged — poor sensitivity/specificity (often normal in young children). (PMC11590122) - Enzyme assay: Reduced mevalonate kinase activity in leukocytes/fibroblasts (confirmatory). LOINC codes apply for organic acid and CRP/SAA assays (verify specific LOINC).

Genetic testing (definitive): MVK sequencing — single-gene test or autoinflammatory/periodic-fever gene panel (alongside MEFV, TNFRSF1A, NLRP3); WES/WGS in undifferentiated cases. Pathogenicity referenced against Infevers and ClinVar. "MVK gene testing is prioritized as the definitive diagnostic approach." (PMC11590122)

Clinical criteria: 2015 Eurofever/PRINTO classification (onset <2 yr, aphthous stomatitis, painful lymph nodes, diarrhea, absence of chest pain) — ~93% sensitivity, ~89% specificity. (PMC11590122)

Differential diagnosis: Other hereditary periodic fevers — FMF (MEFV), TRAPS (TNFRSF1A), CAPS (NLRP3), PFAPA syndrome, systemic JIA, cyclic neutropenia, and infections. Distinguishing features: very early onset, vaccine-triggered attacks, prominent cervical adenopathy + GI symptoms + aphthae point to MKD.

Imaging/neuro (severe MKD): Brain MRI shows cerebellar atrophy; ophthalmologic exam for cataract/retinopathy.

Screening: Not part of routine newborn screening in most regions, though MVA is detectable by urinary organic-acid analysis. Carrier/cascade screening offered in affected families (high Dutch carrier rate); prenatal diagnosis possible by MVK genotyping or enzyme assay.

11. Outcome / Prognosis

• Mild MKD (HIDS): generally normal life expectancy; morbidity from recurrent attacks, growth impairment, school/work disruption; attacks tend to lessen with age. (PMC4855321)
• Severe MKD (MVA): guarded — can be fatal in early childhood (e.g., 4 deaths among 11 MVA children aged 6 months–4 years in one European cohort); survivors have permanent neurodevelopmental disability. (PMC4855321)
• Key long-term complication — AA (secondary) amyloidosis: ~3–5%, after 20+ years of chronically elevated SAA, leading to renal failure; over-represented in p.V377I/p.I268T compound heterozygotes. Other complications: abdominal adhesions (~10%), joint contractures (~4%), renal angiomyolipoma (~6%), severe (e.g., pneumococcal) infections (1–6%), chronic multi-organ involvement (~55%). (PMC4855321)
• Prognostic factors: Residual enzyme activity (the dominant determinant), genotype (amyloidosis risk), sustained SAA control on therapy, female sex (better), age (improvement over time in mild disease).

12. Treatment

The therapeutic logic follows the mechanism: block IL-1β.

Pharmacotherapy — IL-1 blockade (first-line biologics): - Canakinumab (anti-IL-1β monoclonal antibody) — only agent with regulatory approval/RCT evidence for MKD. In the Phase 3 CLUSTER trial (NCT02059291): 35% complete response at week 16 vs 6% placebo; over the 72-week extension, 64% of patients had no flares and >90% reported minimal/no disease activity (vs median 12 flares/year at baseline). Often needs higher doses (150–300 mg q4–8 wk) than for CAPS. (CLUSTER, PMID 34554243; PMC11590122) — MAXO: pharmacotherapy / NCIT:C15986 + therapeutic agent canakinumab (NCIT). - Anakinra (recombinant IL-1 receptor antagonist) — effective for on-demand or continuous therapy; "rational alternative" when canakinumab unavailable; high response in pediatric HIDS. (PMC11590122)

Second-line / alternative biologics: - Tocilizumab (anti-IL-6R) — option for IL-1-inhibitor-refractory cases (limited evidence). (Tocilizumab, PMC6129367) - Etanercept / TNF inhibitors — partial/variable benefit; second-line.

Acute flare management: NSAIDs and short-course corticosteroids for symptom control. MAXO: supportive care / pharmacotherapy.

Not recommended: Statins and bisphosphonates are not recommended — statins (HMG-CoA reductase inhibitors) may worsen isoprenoid depletion; earlier simvastatin reports were not borne out. (PMC11590122)

Curative / advanced: Allogeneic hematopoietic stem cell transplantation (HSCT) for severe, biologic-refractory MKD — in a multicenter series, 7/9 achieved complete remission but 2 died of transplant-related complications; reserved for severe cases. MAXO: MAXO:0010039 organ/cell transplantation (HSCT). (PMC11590122) Liver transplantation has been used in select severe MVA cases.

Experimental: Geranylgeraniol (GGOH) supplementation — replenishes the depleted isoprenoid; a 2024 study reported "improvement in inflammatory parameters and reversal of the disease-specific protein signature in patients with hyper-IgD syndrome." (medRxiv 2024)

Pharmacogenomics: No established PGx guidance; therapy is genotype-informed mainly via severity (residual activity) rather than drug metabolism.

Supportive/preventive within treatment: judicious vaccination (benefits outweigh transient flare risk; consider IL-1 cover), antipyretics, growth monitoring, SAA monitoring to pre-empt amyloidosis.

13. Prevention

• Primary prevention: Not possible (Mendelian). Genetic counseling (autosomal recessive; 25% recurrence risk) and carrier/cascade screening in families — especially relevant given the high Dutch carrier frequency. Preimplantation/prenatal genetic diagnosis available. MAXO: MAXO:0000079 genetic counseling.
• Secondary prevention: Early MVK genetic diagnosis to start IL-1 blockade promptly, preventing growth failure and chronic inflammation.
• Tertiary prevention: SAA/CRP monitoring and sustained IL-1 inhibition to prevent AA amyloidosis and renal failure; manage triggers; consider prophylactic IL-1 cover around vaccinations/surgery.
• Trigger avoidance: managing infections promptly and minimizing avoidable febrile/stress triggers (with the caveat that vaccines remain recommended).

14. Other Species / Natural Disease

• Taxonomy: Human disease (NCBITaxon:9606). The MVK gene and mevalonate pathway are deeply evolutionarily conserved (yeast→plants→mammals), as is protein prenylation.
• Orthologs: Mvk in mouse (NCBI Gene mouse Mvk), rat, zebrafish; ERG12 in S. cerevisiae. (Check Alliance of Genome Resources / HomoloGene for IDs.)
• Natural disease in animals: No well-described spontaneous naturally occurring MKD in companion animals/wildlife (OMIA — verify); the disease is essentially studied via engineered models.
• Comparative biology: The RhoA-prenylation → pyrin-inflammasome axis is conserved in mammals, supporting cross-species mechanistic study.
• Zoonosis: Not applicable (non-infectious genetic disorder).

15. Model Organisms

• Mouse — complete knockout is embryonic lethal (mevalonate pathway is essential), limiting full-null models. Heterozygous Mvk+/− mice have reduced MK activity and immune dysfunction (↑ serum IgD, ↑ TNF-α). (search synthesis; PMC4959763)
• "Mouse avatar" / knock-in & temperature studies: Models recapitulating patient genotypes show that increased core body temperature exacerbates the protein-prenylation defect — directly modeling the thermolabile-enzyme/fever-trigger mechanism. (JCI 160929 / PMC9525117; bioRxiv preprint)
• Pharmacologic models: Mevalonate-pathway blockade with statins, bisphosphonates (aminobisphosphonates), and prenyltransferase inhibitors in cells/animals reproduces the prenylation defect and IL-1β hypersecretion. (PMC4183811)
• In vitro / cellular models: Patient PBMCs/monocytes, fibroblasts, and PBMC + statin/inhibitor systems demonstrate the RhoA→pyrin→caspase-1→IL-1β cascade and Rac1 priming. (PMC4183811; PMC2946549)
• Model strengths: Heterozygous and pharmacologic models reproduce inflammatory cytokine phenotype and the temperature-dependence; limitation: no single model fully captures the severe neurodegenerative MVA phenotype, and full-null lethality precludes a true KO. Zebrafish mvk models are referenced but less characterized (verify).
• Resources: MGI/IMPC (mouse), ZFIN (zebrafish), Alliance of Genome Resources.

Key Evidence Citations (for KB population)

⚠️ Curation cautions (per dismech anti-hallucination SOP)

Before committing any of this to a KB entry: 1. Verify all ontology IDs — the MONDO/ORPHA/ICD-11/HPO/GO/CL/UBERON IDs above are suggestions; several (especially MONDO IDs, the SAA/IgD HPO terms, and lymphadenopathy HP) are flagged and must be confirmed with OAK (runoak ... info <ID>) and just validate-terms-file. 2. All evidence snippets must be exact abstract substrings — the quoted sentences here are drawn from WebFetch summaries of PMC pages, not verified against the real PubMed abstract. Run just fetch-reference PMID:XXXX and just validate-references for each before use. 3. Confirm OMIM 260920 vs alternative HIDS OMIM coding and the exact ORPHA umbrella code (309025) against current Orphadata — given the NEC risk in spectrum disorders with multiple historical names (HIDS vs MVA vs MKD).

Sources: - Houten et al., Orphanet J Rare Dis 2006 (PMC1475558) - Politiek & Waterham, SHARE revision, Front Immunol 2024 (PMC11590122) - Natural history of MKD, Pediatr Rheumatol 2016 (PMC4855321) - Unprenylated RhoA & IL-1β, JBC 2014 (PMC4183811) - Compromised RhoA/Rac1 geranylgeranylation (PMC2946549) - CLUSTER trial, PMID 34554243 - Temperature & prenylation, JCI 2022 (PMC9525117) - Defective prenylation spectrum (PMC6702261) - MKD current perspectives (PMC4959763) - OMIM 251170 (MVK) - MedlinePlus Genetics: MKD - NORD: Hyper-IgD/MKD - Geranylgeraniol supplementation, medRxiv 2024