Mevalonate Kinase Deficiency

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Inheritance

1

Autosomal recessive inheritance HP:0000007

MKD is caused by biallelic (homozygous or compound heterozygous) pathogenic MVK variants and follows autosomal recessive inheritance.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders."

Establishes biallelic MVK pathogenic variants / reduced MVK activity as the shared genetic basis of HIDS and mevalonic aciduria.

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Subtypes

2

Hyperimmunoglobulinemia D Syndrome (HIDS / mild MKD)

The milder, more common end of the MKD spectrum, with substantial residual mevalonate kinase activity. Characterized by recurrent febrile attacks beginning in infancy with cervical lymphadenopathy, abdominal symptoms, arthralgia, aphthous ulcers, and skin rash, generally without the severe neurologic and dysmorphic features of mevalonic aciduria. Most patients carry the p.Val377Ile MVK allele. Attacks tend to attenuate with age.

Mevalonic Aciduria (MA / severe MKD)

The severe end of the MKD spectrum, with near-absent mevalonate kinase activity and markedly, constantly elevated urinary mevalonic acid. In addition to the autoinflammatory features, patients have psychomotor/developmental delay, progressive cerebellar ataxia, dysmorphic features, cataracts and progressive visual impairment, and failure to thrive, with a high rate of early-childhood mortality.

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Discussions and Knowledge Gaps

1

Why does the same isoprenoid/prenylation defect produce a purely autoinflammatory phenotype at the mild end (HIDS) but progressive neurodegeneration (ataxia, developmental delay, cataract) in severe mevalonic aciduria, and is this neurodegeneration IL-1-driven or prenylation-intrinsic?

KNOWLEDGE GAP OPEN gap_mkd_severe_neuro_mechanism

Attached to

pathophysiology#Defective Protein Prenylation and Pyrin Inflammasome Activation

Severity tracks residual enzyme activity, but the mechanism by which near-absent activity additionally causes progressive CNS and ocular degeneration (versus the episodic IL-1-mediated inflammation that IL-1 blockade controls) is not established; IL-1 inhibition controls the inflammatory attacks but is not known to halt the neurodegenerative course of mevalonic aciduria.

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"There is no established successful treatment for MVA."

The absence of established treatment for the severe (neurodegenerative) end underscores the open mechanistic question of MVA-specific CNS injury.

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Pathophysiology

3

Mevalonate Kinase Deficiency and Isoprenoid Shortage

Biallelic MVK variants reduce mevalonate kinase enzyme activity, impairing flux through the mevalonate pathway. Mevalonate accumulates (and is excreted as urinary mevalonic acid) while downstream non-sterol isoprenoid pyrophosphates, especially geranylgeranyl pyrophosphate (GGPP), fall. The shortage of GGPP is the key node linking the metabolic defect to inflammation. Disease severity tracks inversely with residual enzyme activity.

isoprenoid biosynthetic process GO:0008299 ↓ DECREASED cholesterol biosynthetic process GO:0006695 ↓ DECREASED

mevalonate kinase activity GO:0004496 ↓ DECREASED

Downstream

Defective Protein Prenylation and Pyrin Inflammasome Activation The fall in geranylgeranyl pyrophosphate deprives small GTPases of their prenyl lipid anchor, triggering the downstream prenylation/inflammasome defect.

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis."

Identifies mevalonate kinase deficiency in the cholesterol/isoprenoid biosynthesis pathway as the cause spanning the MKD spectrum.

Defective Protein Prenylation and Pyrin Inflammasome Activation

Geranylgeranyl pyrophosphate is the lipid anchor for prenylation (geranylgeranylation) of small GTPases including RhoA. With GGPP depleted, RhoA is not geranylgeranylated, cannot localize to the membrane, and loses its GTPase activity. Geranylgeranylated RhoA normally keeps the pyrin inflammasome under tonic phospho-inhibition; unprenylated RhoA releases this brake, allowing pyrin inflammasome assembly, caspase-1 activation, and excessive interleukin-1 beta secretion in monocytes. Unprenylated RhoA also boosts Rac1 activity, further priming IL-1 beta production. The IL-1 beta-centric mechanism is inferred from human cell-culture and pharmacologic models.

monocyte CL:0000576 macrophage CL:0000235

protein geranylgeranylation GO:0018344 ↓ DECREASED Rho protein signal transduction GO:0007266 ↓ DECREASED interleukin-1 beta production GO:0032611 ↑ INCREASED

Downstream

Systemic Autoinflammation Excess IL-1 beta from the de-repressed pyrin inflammasome drives the systemic autoinflammatory clinical picture.

Show evidence (2 references)

PMID:25107911 SUPPORT In Vitro

"our data show that RhoA plays a pivotal role in MKD pathogenesis through Rac1/PKB signaling toward interleukin 1β production and elucidate the effects of protein prenylation in monocytes."

Demonstrates in human cells that unprenylated RhoA drives IL-1 beta production through Rac1/PKB signaling in monocytes.

PMID:27270401 SUPPORT In Vitro

"Defects in prenylation, seen in HIDS, led to RhoA inactivation and consequent pyrin inflammasome activation."

Shows that the prenylation defect in HIDS inactivates RhoA and activates the pyrin inflammasome.

Systemic Autoinflammation

Sustained IL-1 beta-driven inflammation produces recurrent febrile attacks with an acute-phase response (elevated CRP and serum amyloid A) and the systemic manifestations of MKD: lymphadenopathy, abdominal symptoms, arthralgia, rash, and aphthous ulcers. Chronic elevation of serum amyloid A over years can lead to AA (secondary) amyloidosis.

inflammatory response GO:0006954 ↑ INCREASED positive regulation of inflammatory response GO:0050729 ↑ INCREASED

Show evidence (1 reference)

PMID:27213830 SUPPORT Human Clinical

"Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes."

Characterizes MKD clinically as a disease of recurrent inflammatory episodes, the readout of the autoinflammatory cascade.

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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

18

Cardiovascular 3

Cervical Lymphadenopathy Cervical lymphadenopathy HP:0025289

Show evidence (1 reference)

PMID:22038276 SUPPORT Human Clinical

"Fever was accompanied by abdominal pain, vomiting, diarrhea, cervical lymphadenopathy"

Cervical lymphadenopathy accompanies the febrile attacks in HIDS.

Lymphadenopathy VERY_FREQUENT Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:27213830 SUPPORT Human Clinical

"lymphadenopathy (n = 102)"

Lymphadenopathy was present in 102 of 114 patients (very frequent).

Splenomegaly Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes."

Hepatosplenomegaly commonly accompanies the febrile episodes in MKD.

Digestive 2

Vomiting Vomiting HP:0002013

Show evidence (1 reference)

PMID:22038276 SUPPORT Human Clinical

"Fever was accompanied by abdominal pain, vomiting, diarrhea"

Vomiting accompanies the febrile attacks in HIDS.

Diarrhea Diarrhea HP:0002014

Show evidence (1 reference)

PMID:22038276 SUPPORT Human Clinical

"Fever was accompanied by abdominal pain, vomiting, diarrhea"

Diarrhea accompanies the febrile attacks in HIDS.

Eye 1

Cataract Cataract HP:0000518

Show evidence (1 reference)

PMID:12563048 SUPPORT Human Clinical

"the development of retinal dystrophy and cataracts in both of them."

Retinal dystrophy and cataracts developed in mevalonic aciduria patients.

Head and Neck 1

Dysmorphic Features Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

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

Mevalonic aciduria is characterized by dysmorphic features.

Immune 1

Skin Rash Skin rash HP:0000988

Show evidence (1 reference)

PMID:27213830 SUPPORT Human Clinical

"mucocutaneous involvement (n = 99)"

Mucocutaneous involvement (including skin rash and aphthae) was present in 99 of 114 patients.

Metabolism 1

Recurrent Fever Recurrent fever HP:0001954

Temporal: RECURRENT

Show evidence (1 reference)

PMID:22038276 SUPPORT Human Clinical

"HIDS symptoms generally started in infancy with recurrent fever episodes lasting 3-12 (median, 4.5) days and recurring every 1-12 weeks."

Documents recurrent febrile episodes beginning in infancy as the hallmark of HIDS/MKD.

Nervous System 2

Global Developmental Delay Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:12563048 SUPPORT Human Clinical

"Mevalonic aciduria as a result of mevalonate kinase deficiency is an inborn error of cholesterol biosynthesis characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises"

Mevalonic aciduria is characterized by psychomotor retardation (developmental delay).

Cerebellar Ataxia Ataxia HP:0001251

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:12563048 SUPPORT Human Clinical

"Ataxia has become the predominant clinical manifestation"

Progressive cerebellar ataxia becomes the predominant manifestation in adolescent mevalonic aciduria patients.

Constitutional 2

Abdominal Pain VERY_FREQUENT Abdominal pain HP:0002027

Show evidence (2 references)

PMID:27213830 SUPPORT Human Clinical

"Most patients had gastrointestinal symptoms (n = 112)"

Gastrointestinal symptoms (including abdominal pain) were present in 112 of 114 patients (very frequent).

PMID:22038276 SUPPORT Human Clinical

"Fever was accompanied by abdominal pain, vomiting, diarrhea"

Abdominal pain accompanies febrile attacks in HIDS.

Arthralgia Arthralgia HP:0002829

Show evidence (1 reference)

PMID:27213830 SUPPORT Human Clinical

"or musculoskeletal symptoms (n = 89)"

Musculoskeletal symptoms (including arthralgia) were present in 89 of 114 patients.

Growth 1

Failure to Thrive Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

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

Mevalonic aciduria is characterized by failure to thrive.

Other 4

Aphthous Ulcers Aphthous ulcer HP:0032154

Show evidence (1 reference)

PMID:27213830 SUPPORT Human Clinical

"mucocutaneous involvement (n = 99)"

Aphthous ulcers fall within the mucocutaneous involvement present in 99 of 114 patients.

Elevated Serum IgD Increased circulating immunoglobulin concentration HP:0010702

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA)"

Increased IgD and, in most patients, IgA are characteristic laboratory findings in HIDS.

Elevated Urinary Mevalonic Acid Elevated urine mevalonic acid level HP:0032638

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine."

Highly elevated urinary mevalonic acid establishes the diagnosis of mevalonic aciduria.

Reduced Mevalonate Kinase Activity Reduced mevalonate kinase activity HP:0033168

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations."

Low mevalonate kinase activity confirms the diagnosis of MKD.

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Genetic Associations

1

MVK (Primary causal gene)

Gene: MVK hgnc:7530

Show evidence (2 references)

PMID:16722536 SUPPORT Human Clinical

"A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders."

Identifies MVK pathogenic variants / reduced MVK activity as the cause of both HIDS and mevalonic aciduria.

PMID:22038276 SUPPORT Human Clinical

"The most frequent mutation was p.Val377Ile (81%, 13 out of 16)."

Confirms p.Val377Ile as the most frequent MVK allele in a HIDS cohort.

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Medical Actions

5

Canakinumab (Anti-IL-1beta Monoclonal Antibody)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: canakinumab NCIT:C80971

Canakinumab is a selective human anti-interleukin-1 beta monoclonal antibody and the only agent with randomized controlled trial evidence and regulatory approval for MKD. In the Phase 3 CLUSTER trial it controlled disease activity and prevented flares, with most patients flare-free during long-term treatment; higher doses are often required than for other periodic fever syndromes.

Mechanism Target:

INHIBITS Defective Protein Prenylation and Pyrin Inflammasome Activation — Canakinumab neutralizes IL-1 beta, the effector cytokine downstream of pyrin inflammasome de-repression.

Show evidence (2 references)

PMID:34554243 SUPPORT Human Clinical

"During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline."

In the Phase 3 CLUSTER trial, long-term canakinumab rendered most MKD patients flare-free versus a baseline median of 12 flares per year.

PMID:29768139 SUPPORT Human Clinical

"57% of those with mevalonate kinase deficiency"

In the randomized trial, up-titrated canakinumab achieved a complete response in 57% of MKD patients.

Anakinra (IL-1 Receptor Antagonist)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: anakinra NCIT:C38717

Anakinra is a recombinant IL-1 receptor antagonist that blocks IL-1 signaling. It is effective for on-demand or continuous treatment of MKD attacks and is a rational alternative when canakinumab is unavailable.

Mechanism Target:

INHIBITS Defective Protein Prenylation and Pyrin Inflammasome Activation — Anakinra blocks the IL-1 receptor, interrupting signaling by the excess IL-1 beta produced downstream of pyrin inflammasome activation.

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS."

Anakinra has shown beneficial effect in HIDS (IL-1 blockade).

Etanercept (TNF Inhibitor)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: etanercept CHEBI:4875

Etanercept, a TNF inhibitor, can improve symptoms and induce remission in some MKD patients and is used as a second-line biologic, with variable/partial benefit relative to IL-1 blockade.

Show evidence (1 reference)

PMID:27213830 PARTIAL Human Clinical

"Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD."

Etanercept (with steroids and anakinra) appeared to improve symptoms and could induce remission in MKD, supporting second-line use.

NSAIDs and Corticosteroids (Acute Attack Management)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Nonsteroidal anti-inflammatory drugs relieve attack symptoms, and short-course corticosteroids given during attacks can improve symptoms. These are supportive measures for acute flares rather than disease-modifying therapy.

Show evidence (1 reference)

PMID:27213830 SUPPORT Human Clinical

"Treatment with nonsteroidal antiinflammatory drugs relieved symptoms."

NSAIDs relieved symptoms in MKD patients, supporting their role in acute attack management.

Allogeneic Hematopoietic Stem Cell Transplantation

Category: Therapeutic Action: organ transplantation MAXO:0010039

Allogeneic HSCT can be curative for severe, biologic-refractory MKD (including mevalonic aciduria) by replacing the hematopoietic compartment, but it carries significant transplant-related mortality and is reserved for severe cases.

Show evidence (2 references)

PMID:35906690 SUPPORT Human Clinical

"Seven patients went into complete remission after stem cell transplantation."

In a multicenter series of 9 transplanted MKD patients, seven achieved complete remission after allogeneic HSCT, supporting HSCT as a potentially curative option in severe disease.

PMID:16722536 PARTIAL Human Clinical

"There is no established successful treatment for MVA."

Underscores the lack of established pharmacologic therapy for severe MKD (mevalonic aciduria), the unmet need that motivates HSCT in refractory severe disease.

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Biochemical Markers

2

Elevated Serum IgD and IgA

Show evidence (2 references)

PMID:16722536 SUPPORT Human Clinical

"Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS."

Documents elevated IgD and IgA, with enhanced mevalonic acid excretion, as laboratory evidence for HIDS.

PMID:12563048 PARTIAL Human Clinical

"Elevation of IgD is most likely a secondary phenomenon that seems to be linked to recurrent febrile crises."

Supports that IgD elevation is a secondary marker linked to febrile crises, not the primary mechanism.

Urinary Mevalonic Acid

Show evidence (1 reference)

PMID:16722536 SUPPORT Human Clinical

"In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine."

Highly elevated urinary mevalonic acid is the diagnostic biochemical marker of mevalonic aciduria.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Mevalonate Kinase Deficiency:

Familial Mediterranean Fever (FMF)

Overlapping Features FMF (MEFV) is the other pyrin-inflammasome periodic fever syndrome and is the principal differential. It shares IL-1-mediated autoinflammation but differs in genetics, ethnic distribution, attack features, and colchicine responsiveness.

Distinguishing Features

MEFV mutations (gain-of-function pyrin) rather than MVK enzyme deficiency
Colchicine-responsive, whereas MKD attacks are not reliably colchicine-responsive
No elevation of urinary mevalonic acid in FMF

Show evidence (1 reference)

PMID:27270401 SUPPORT Human Clinical

"Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS)."

FMF (MEFV/pyrin) and HIDS (MVK) are distinct IL-1-mediated autoinflammatory diseases that must be distinguished.

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Clinical Trials

1

NCT02059291 PHASE_III COMPLETED

The CLUSTER trial: a randomized, double-blind, placebo-controlled study of canakinumab in patients with hereditary periodic fevers (TRAPS, HIDS/MKD, or colchicine-resistant FMF), with subsequent randomized withdrawal/dose-reduction and an open-label long-term treatment epoch.

Target Phenotypes: Recurrent fever HP:0001954

Show evidence (1 reference)

clinicaltrials:NCT02059291 SUPPORT Human Clinical

"This study is to determine whether canakinumab is able to induce and maintain a clinically meaningful reduction of disease activity in participants with Hereditary Periodic Fevers (HPF) compared to placebo."

The CLUSTER trial evaluated canakinumab in hereditary periodic fevers including HIDS/MKD.

{ }

Source YAML

click to show

name: Mevalonate Kinase Deficiency
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: mevalonate kinase deficiency
  term:
    id: MONDO:0017708
    label: mevalonate kinase deficiency
parents:
  - hereditary periodic fever syndrome
  - autoinflammatory syndrome
  - inborn error of metabolism
synonyms:
  - MKD
  - hyperimmunoglobulinemia D syndrome
  - hyper-IgD syndrome
  - HIDS
  - mevalonic aciduria
  - periodic fever, Dutch type
description: >
  Mevalonate kinase deficiency (MKD) is an autosomal recessive systemic
  autoinflammatory disorder caused by biallelic loss-of-function variants in MVK,
  which encodes mevalonate kinase, an early enzyme of the mevalonate/isoprenoid
  (cholesterol) biosynthetic pathway. MKD is a continuous clinical spectrum: the
  milder end is hyperimmunoglobulinemia D syndrome (HIDS, hyper-IgD with periodic
  fever) and the severe end is mevalonic aciduria (MA), which adds developmental
  delay, cerebellar ataxia, dysmorphism, cataracts, and failure to thrive. Disease
  severity tracks inversely with residual enzyme activity. Patients have recurrent
  febrile attacks beginning in infancy, accompanied by cervical lymphadenopathy,
  abdominal pain, vomiting, diarrhea, arthralgia, aphthous/oral ulcers,
  splenomegaly, and skin rash, often with elevated serum IgD and IgA.
  Mechanistically, reduced mevalonate kinase activity lowers downstream non-sterol
  isoprenoids (notably geranylgeranyl pyrophosphate, GGPP), causing defective
  protein prenylation of small GTPases such as RhoA; unprenylated RhoA fails to
  keep the pyrin inflammasome under tonic inhibition, leading to caspase-1
  activation and excessive interleukin-1 beta secretion that drives the
  autoinflammatory phenotype.
has_subtypes:
- name: HIDS
  display_name: Hyperimmunoglobulinemia D Syndrome (HIDS / mild MKD)
  description: >
    The milder, more common end of the MKD spectrum, with substantial residual
    mevalonate kinase activity. Characterized by recurrent febrile attacks
    beginning in infancy with cervical lymphadenopathy, abdominal symptoms,
    arthralgia, aphthous ulcers, and skin rash, generally without the severe
    neurologic and dysmorphic features of mevalonic aciduria. Most patients carry
    the p.Val377Ile MVK allele. Attacks tend to attenuate with age.
- name: Mevalonic Aciduria
  display_name: Mevalonic Aciduria (MA / severe MKD)
  description: >
    The severe end of the MKD spectrum, with near-absent mevalonate kinase
    activity and markedly, constantly elevated urinary mevalonic acid. In addition
    to the autoinflammatory features, patients have psychomotor/developmental
    delay, progressive cerebellar ataxia, dysmorphic features, cataracts and
    progressive visual impairment, and failure to thrive, with a high rate of
    early-childhood mortality.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    MKD is caused by biallelic (homozygous or compound heterozygous) pathogenic
    MVK variants and follows autosomal recessive inheritance.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A reduced activity of MVK and pathogenic mutations \nin the MVK gene have been demonstrated as the common genetic basis in both \ndisorders."
    explanation: >-
      Establishes biallelic MVK pathogenic variants / reduced MVK activity as the
      shared genetic basis of HIDS and mevalonic aciduria.
pathophysiology:
- name: Mevalonate Kinase Deficiency and Isoprenoid Shortage
  description: >
    Biallelic MVK variants reduce mevalonate kinase enzyme activity, impairing
    flux through the mevalonate pathway. Mevalonate accumulates (and is excreted as
    urinary mevalonic acid) while downstream non-sterol isoprenoid pyrophosphates,
    especially geranylgeranyl pyrophosphate (GGPP), fall. The shortage of GGPP is
    the key node linking the metabolic defect to inflammation. Disease severity
    tracks inversely with residual enzyme activity.
  molecular_functions:
  - preferred_term: mevalonate kinase activity
    term:
      id: GO:0004496
      label: mevalonate kinase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: isoprenoid biosynthetic process
    term:
      id: GO:0008299
      label: isoprenoid biosynthetic process
    modifier: DECREASED
  - preferred_term: cholesterol biosynthetic process
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the two ends of a clinical spectrum of disease caused by deficiency of \nmevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis."
    explanation: >-
      Identifies mevalonate kinase deficiency in the cholesterol/isoprenoid
      biosynthesis pathway as the cause spanning the MKD spectrum.
  downstream:
  - target: Defective Protein Prenylation and Pyrin Inflammasome Activation
    causal_link_type: DIRECT
    description: >-
      The fall in geranylgeranyl pyrophosphate deprives small GTPases of their
      prenyl lipid anchor, triggering the downstream prenylation/inflammasome
      defect.
    evidence:
    - reference: PMID:25107911
      reference_title: "Unprenylated RhoA contributes to IL-1β hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The autoinflammatory disease mevalonate kinase \ndeficiency (MKD) is characterized by a severe reduction in protein prenylation."
      explanation: >-
        Links reduced isoprenoid availability in MKD to a severe reduction in
        protein prenylation of small GTPases.
- name: Defective Protein Prenylation and Pyrin Inflammasome Activation
  description: >
    Geranylgeranyl pyrophosphate is the lipid anchor for prenylation
    (geranylgeranylation) of small GTPases including RhoA. With GGPP depleted, RhoA
    is not geranylgeranylated, cannot localize to the membrane, and loses its
    GTPase activity. Geranylgeranylated RhoA normally keeps the pyrin inflammasome
    under tonic phospho-inhibition; unprenylated RhoA releases this brake, allowing
    pyrin inflammasome assembly, caspase-1 activation, and excessive interleukin-1
    beta secretion in monocytes. Unprenylated RhoA also boosts Rac1 activity,
    further priming IL-1 beta production. The IL-1 beta-centric mechanism is
    inferred from human cell-culture and pharmacologic models.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: protein geranylgeranylation
    term:
      id: GO:0018344
      label: protein geranylgeranylation
    modifier: DECREASED
  - preferred_term: Rho protein signal transduction
    term:
      id: GO:0007266
      label: Rho protein signal transduction
    modifier: DECREASED
  - preferred_term: interleukin-1 beta production
    term:
      id: GO:0032611
      label: interleukin-1 beta production
    modifier: INCREASED
  evidence:
  - reference: PMID:25107911
    reference_title: "Unprenylated RhoA contributes to IL-1β hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our data show that RhoA plays a pivotal role in MKD pathogenesis through \nRac1/PKB signaling toward interleukin 1β production and elucidate the effects of \nprotein prenylation in monocytes."
    explanation: >-
      Demonstrates in human cells that unprenylated RhoA drives IL-1 beta
      production through Rac1/PKB signaling in monocytes.
  - reference: PMID:27270401
    reference_title: "Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Defects in prenylation, seen in HIDS, led to RhoA \ninactivation and consequent pyrin inflammasome activation."
    explanation: >-
      Shows that the prenylation defect in HIDS inactivates RhoA and activates the
      pyrin inflammasome.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: DIRECT
    description: >-
      Excess IL-1 beta from the de-repressed pyrin inflammasome drives the
      systemic autoinflammatory clinical picture.
    evidence:
    - reference: PMID:27270401
      reference_title: "Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings indicate an essential role for the pyrin inflammasome in the pathogenesis of HIDS"
      explanation: >-
        Ex vivo studies of HIDS patient cells establish an essential role for the
        pyrin inflammasome (the source of excess IL-1 beta) in driving HIDS, the
        link to the systemic autoinflammatory phenotype.
- name: Systemic Autoinflammation
  description: >
    Sustained IL-1 beta-driven inflammation produces recurrent febrile attacks with
    an acute-phase response (elevated CRP and serum amyloid A) and the systemic
    manifestations of MKD: lymphadenopathy, abdominal symptoms, arthralgia, rash,
    and aphthous ulcers. Chronic elevation of serum amyloid A over years can lead
    to AA (secondary) amyloidosis.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: positive regulation of inflammatory response
    term:
      id: GO:0050729
      label: positive regulation of inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mevalonate kinase deficiency (MKD) is a rare metabolic disease \ncharacterized by recurrent inflammatory episodes."
    explanation: >-
      Characterizes MKD clinically as a disease of recurrent inflammatory
      episodes, the readout of the autoinflammatory cascade.
phenotypes:
- category: Constitutional
  name: Recurrent Fever
  description: >
    Recurrent febrile attacks, typically beginning in the first year of life, are
    the defining manifestation of MKD. Attacks last several days and recur every
    few weeks, with frequency declining through adolescence in milder disease.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  evidence:
  - reference: PMID:22038276
    reference_title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HIDS symptoms generally started in infancy \nwith recurrent fever episodes lasting 3-12 (median, 4.5) days and recurring \nevery 1-12 weeks."
    explanation: >-
      Documents recurrent febrile episodes beginning in infancy as the hallmark of
      HIDS/MKD.
- category: Hematologic
  name: Cervical Lymphadenopathy
  description: >
    Tender cervical lymphadenopathy is characteristically present during febrile
    attacks and is one of the most discriminating features of MKD among the
    periodic fever syndromes.
  subtype: HIDS
  phenotype_term:
    preferred_term: Cervical lymphadenopathy
    term:
      id: HP:0025289
      label: Cervical lymphadenopathy
  evidence:
  - reference: PMID:22038276
    reference_title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fever was accompanied by abdominal pain, vomiting, diarrhea, \ncervical lymphadenopathy"
    explanation: >-
      Cervical lymphadenopathy accompanies the febrile attacks in HIDS.
- category: Gastrointestinal
  name: Abdominal Pain
  description: >
    Abdominal pain is a near-universal feature of attacks; gastrointestinal
    symptoms were present in almost all patients in the Eurofever cohort.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had \ngastrointestinal symptoms (n = 112)"
    explanation: >-
      Gastrointestinal symptoms (including abdominal pain) were present in 112 of
      114 patients (very frequent).
  - reference: PMID:22038276
    reference_title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fever was accompanied by abdominal pain, vomiting, diarrhea"
    explanation: >-
      Abdominal pain accompanies febrile attacks in HIDS.
- category: Gastrointestinal
  name: Vomiting
  description: >
    Vomiting is a common gastrointestinal symptom during MKD attacks.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:22038276
    reference_title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fever was accompanied by abdominal pain, vomiting, diarrhea"
    explanation: >-
      Vomiting accompanies the febrile attacks in HIDS.
- category: Gastrointestinal
  name: Diarrhea
  description: >
    Diarrhea is a frequent gastrointestinal manifestation during attacks.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:22038276
    reference_title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fever was accompanied by abdominal pain, vomiting, diarrhea"
    explanation: >-
      Diarrhea accompanies the febrile attacks in HIDS.
- category: Musculoskeletal
  name: Arthralgia
  description: >
    Joint pain (arthralgia), with or without arthritis, is among the most frequent
    musculoskeletal manifestations of MKD.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "or musculoskeletal symptoms (n = 89)"
    explanation: >-
      Musculoskeletal symptoms (including arthralgia) were present in 89 of 114
      patients.
- category: Dermatologic
  name: Skin Rash
  description: >
    A maculopapular or urticarial skin rash occurs during attacks; mucocutaneous
    involvement was present in the large majority of the Eurofever cohort.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mucocutaneous involvement (n = 99)"
    explanation: >-
      Mucocutaneous involvement (including skin rash and aphthae) was present in 99
      of 114 patients.
- category: Dermatologic
  name: Aphthous Ulcers
  description: >
    Recurrent aphthous (oral, sometimes genital) ulcers are a characteristic
    mucocutaneous feature and part of the MKD classification criteria.
  phenotype_term:
    preferred_term: Aphthous ulcer
    term:
      id: HP:0032154
      label: Aphthous ulcer
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mucocutaneous involvement (n = 99)"
    explanation: >-
      Aphthous ulcers fall within the mucocutaneous involvement present in 99 of
      114 patients.
- category: Hematologic
  name: Lymphadenopathy
  description: >
    Generalized lymphadenopathy (beyond the cervical region) is very frequent in
    MKD attacks.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphadenopathy (n = 102)"
    explanation: >-
      Lymphadenopathy was present in 102 of 114 patients (very frequent).
- category: Abdominal
  name: Splenomegaly
  description: >
    Splenomegaly (often with hepatomegaly) reflects reticuloendothelial activation
    during febrile crises, particularly prominent in mevalonic aciduria.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The febrile episodes are commonly \naccompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, \narthralgia and skin rashes."
    explanation: >-
      Hepatosplenomegaly commonly accompanies the febrile episodes in MKD.
- category: Neurologic
  name: Global Developmental Delay
  description: >
    Psychomotor/developmental delay is a defining feature of mevalonic aciduria
    (severe MKD) and reflects the neurodegenerative component absent in mild
    disease.
  subtype: Mevalonic Aciduria
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:12563048
    reference_title: "Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mevalonic aciduria as a result of mevalonate kinase deficiency is an \ninborn error of cholesterol biosynthesis characterized by dysmorphology, \npsychomotor retardation, progressive cerebellar ataxia, and recurrent febrile \ncrises"
    explanation: >-
      Mevalonic aciduria is characterized by psychomotor retardation
      (developmental delay).
- category: Neurologic
  name: Cerebellar Ataxia
  description: >
    Progressive cerebellar ataxia (with cerebellar atrophy on imaging) is a
    hallmark of mevalonic aciduria and can become the predominant manifestation
    with age in survivors.
  subtype: Mevalonic Aciduria
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:12563048
    reference_title: "Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxia has become the \npredominant clinical manifestation"
    explanation: >-
      Progressive cerebellar ataxia becomes the predominant manifestation in
      adolescent mevalonic aciduria patients.
- category: Ophthalmologic
  name: Cataract
  description: >
    Cataracts (with retinal dystrophy and progressive visual impairment) develop
    in mevalonic aciduria.
  subtype: Mevalonic Aciduria
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:12563048
    reference_title: "Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the development of retinal dystrophy and cataracts in both of them."
    explanation: >-
      Retinal dystrophy and cataracts developed in mevalonic aciduria patients.
- category: Constitutional
  name: Failure to Thrive
  description: >
    Failure to thrive / growth retardation (short stature) is characteristic of
    mevalonic aciduria.
  subtype: Mevalonic Aciduria
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MVA is characterized by psychomotor retardation, failure to thrive, \nprogressive cerebellar ataxia, dysmorphic features, progressive visual \nimpairment and recurrent febrile crises."
    explanation: >-
      Mevalonic aciduria is characterized by failure to thrive.
- category: Craniofacial
  name: Dysmorphic Features
  description: >
    Dysmorphic facial features (e.g., dolichocephaly, triangular face, low-set
    ears, downslanting palpebral fissures) are part of the mevalonic aciduria
    phenotype.
  subtype: Mevalonic Aciduria
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MVA is characterized by psychomotor retardation, failure to thrive, \nprogressive cerebellar ataxia, dysmorphic features, progressive visual \nimpairment and recurrent febrile crises."
    explanation: >-
      Mevalonic aciduria is characterized by dysmorphic features.
- category: Laboratory
  name: Elevated Serum IgD
  description: >
    Elevated serum immunoglobulin D (often with elevated IgA) gave HIDS its name.
    It is a biomarker rather than the disease driver, is most evident in milder
    disease, and may be normal in young children, so IgD testing is no longer
    relied upon for diagnosis.
  phenotype_term:
    preferred_term: Elevated serum IgD
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased levels of immunoglobulin D \n(IgD) and, in most patients of immunoglobulin A (IgA)"
    explanation: >-
      Increased IgD and, in most patients, IgA are characteristic laboratory
      findings in HIDS.
- category: Laboratory
  name: Elevated Urinary Mevalonic Acid
  description: >
    Markedly elevated urinary mevalonic acid is the direct biochemical signature of
    the enzyme block. It is constantly elevated in mevalonic aciduria and elevated
    only during flares in milder disease.
  phenotype_term:
    preferred_term: Elevated urine mevalonic acid level
    term:
      id: HP:0032638
      label: Elevated urine mevalonic acid level
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In MVA, the diagnosis is established by detection of highly elevated \nlevels of mevalonic acid excreted in urine."
    explanation: >-
      Highly elevated urinary mevalonic acid establishes the diagnosis of
      mevalonic aciduria.
- category: Laboratory
  name: Reduced Mevalonate Kinase Activity
  description: >
    Reduced mevalonate kinase enzyme activity in leukocytes or fibroblasts is the
    confirmatory enzymatic defect; residual activity correlates inversely with
    disease severity.
  phenotype_term:
    preferred_term: Reduced mevalonate kinase activity
    term:
      id: HP:0033168
      label: Reduced mevalonate kinase activity
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The \ndiagnosis is confirmed by low activity of mevalonate kinase or by demonstration \nof disease-causing mutations."
    explanation: >-
      Low mevalonate kinase activity confirms the diagnosis of MKD.
biochemical:
- name: Elevated Serum IgD and IgA
  notes: >-
    Increased serum immunoglobulin D, and in most patients immunoglobulin A, are
    the classic (though imperfectly sensitive) laboratory markers of HIDS. IgD is
    considered a secondary phenomenon linked to recurrent febrile crises rather
    than a driver of disease.
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased levels of immunoglobulin D \n(IgD) and, in most patients of immunoglobulin A (IgA), in combination with \nenhanced excretion of mevalonic acid provide strong evidence for HIDS."
    explanation: >-
      Documents elevated IgD and IgA, with enhanced mevalonic acid excretion, as
      laboratory evidence for HIDS.
  - reference: PMID:12563048
    reference_title: "Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevation of IgD is most likely a secondary phenomenon that \nseems to be linked to recurrent febrile crises."
    explanation: >-
      Supports that IgD elevation is a secondary marker linked to febrile crises,
      not the primary mechanism.
- name: Urinary Mevalonic Acid
  notes: >-
    Mevalonic acid accumulates upstream of the enzyme block and is excreted in
    urine; it is markedly and constantly elevated in mevalonic aciduria and rises
    during flares in milder disease.
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In MVA, the diagnosis is established by detection of highly elevated \nlevels of mevalonic acid excreted in urine."
    explanation: >-
      Highly elevated urinary mevalonic acid is the diagnostic biochemical marker
      of mevalonic aciduria.
genetic:
- name: MVK
  association: Primary causal gene
  gene_term:
    preferred_term: MVK
    term:
      id: hgnc:7530
      label: MVK
  notes: >-
    MVK encodes mevalonate kinase. Biallelic loss-of-function/hypomorphic variants
    reduce enzyme activity. The dominant mild-disease allele is p.Val377Ile, most
    frequent in HIDS and common in Northern European (Dutch) ancestry; the
    p.Ile268Thr allele is associated with more severe disease. The mutant enzyme is
    thermolabile, so febrile illness further reduces residual activity.
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A reduced activity of MVK and pathogenic mutations \nin the MVK gene have been demonstrated as the common genetic basis in both \ndisorders."
    explanation: >-
      Identifies MVK pathogenic variants / reduced MVK activity as the cause of
      both HIDS and mevalonic aciduria.
  - reference: PMID:22038276
    reference_title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent mutation was p.Val377Ile \n(81%, 13 out of 16)."
    explanation: >-
      Confirms p.Val377Ile as the most frequent MVK allele in a HIDS cohort.
treatments:
- name: Canakinumab (Anti-IL-1beta Monoclonal Antibody)
  description: >
    Canakinumab is a selective human anti-interleukin-1 beta monoclonal antibody
    and the only agent with randomized controlled trial evidence and regulatory
    approval for MKD. In the Phase 3 CLUSTER trial it controlled disease activity
    and prevented flares, with most patients flare-free during long-term treatment;
    higher doses are often required than for other periodic fever syndromes.
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  target_mechanisms:
  - target: Defective Protein Prenylation and Pyrin Inflammasome Activation
    treatment_effect: INHIBITS
    description: >-
      Canakinumab neutralizes IL-1 beta, the effector cytokine downstream of pyrin
      inflammasome de-repression.
  evidence:
  - reference: PMID:34554243
    reference_title: "Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the 72-week period, 42 (64%) patients experienced no \nflares, while 13 (20%) had one flare, as compared with a median of 12 flares per \nyear reported at baseline."
    explanation: >-
      In the Phase 3 CLUSTER trial, long-term canakinumab rendered most MKD
      patients flare-free versus a baseline median of 12 flares per year.
  - reference: PMID:29768139
    reference_title: "Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "57% of those with mevalonate \nkinase deficiency"
    explanation: >-
      In the randomized trial, up-titrated canakinumab achieved a complete
      response in 57% of MKD patients.
- name: Anakinra (IL-1 Receptor Antagonist)
  description: >
    Anakinra is a recombinant IL-1 receptor antagonist that blocks IL-1 signaling.
    It is effective for on-demand or continuous treatment of MKD attacks and is a
    rational alternative when canakinumab is unavailable.
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_mechanisms:
  - target: Defective Protein Prenylation and Pyrin Inflammasome Activation
    treatment_effect: INHIBITS
    description: >-
      Anakinra blocks the IL-1 receptor, interrupting signaling by the excess IL-1
      beta produced downstream of pyrin inflammasome activation.
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Simvastatin, an \ninhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial \neffect in HIDS."
    explanation: >-
      Anakinra has shown beneficial effect in HIDS (IL-1 blockade).
- name: Etanercept (TNF Inhibitor)
  description: >
    Etanercept, a TNF inhibitor, can improve symptoms and induce remission in some
    MKD patients and is used as a second-line biologic, with variable/partial
    benefit relative to IL-1 blockade.
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: etanercept
      term:
        id: CHEBI:4875
        label: etanercept
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Steroids given during attacks, \nanakinra, and etanercept appeared to improve symptoms and could induce complete \nremission in patients with MKD."
    explanation: >-
      Etanercept (with steroids and anakinra) appeared to improve symptoms and
      could induce remission in MKD, supporting second-line use.
- name: NSAIDs and Corticosteroids (Acute Attack Management)
  description: >
    Nonsteroidal anti-inflammatory drugs relieve attack symptoms, and short-course
    corticosteroids given during attacks can improve symptoms. These are supportive
    measures for acute flares rather than disease-modifying therapy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:27213830
    reference_title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with nonsteroidal \nantiinflammatory drugs relieved symptoms."
    explanation: >-
      NSAIDs relieved symptoms in MKD patients, supporting their role in acute
      attack management.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >
    Allogeneic HSCT can be curative for severe, biologic-refractory MKD (including
    mevalonic aciduria) by replacing the hematopoietic compartment, but it carries
    significant transplant-related mortality and is reserved for severe cases.
  action_category: THERAPEUTIC
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:35906690
    reference_title: "The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven \npatients went into complete remission after stem cell transplantation."
    explanation: >-
      In a multicenter series of 9 transplanted MKD patients, seven achieved
      complete remission after allogeneic HSCT, supporting HSCT as a potentially
      curative option in severe disease.
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no established successful treatment for MVA."
    explanation: >-
      Underscores the lack of established pharmacologic therapy for severe MKD
      (mevalonic aciduria), the unmet need that motivates HSCT in refractory
      severe disease.
diagnosis:
- name: MVK Genetic Testing and Biochemical Confirmation
  description: >
    Diagnosis combines clinical recognition (early-onset recurrent fever with
    cervical adenopathy, abdominal symptoms, and aphthae) with biochemical findings
    (elevated urinary mevalonic acid, acute-phase reactants) and is confirmed by
    demonstrating reduced mevalonate kinase activity or biallelic pathogenic MVK
    variants.
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The \ndiagnosis is confirmed by low activity of mevalonate kinase or by demonstration \nof disease-causing mutations."
    explanation: >-
      Diagnosis is confirmed by low mevalonate kinase activity or by demonstration
      of disease-causing MVK mutations.
differential_diagnoses:
- name: Familial Mediterranean Fever (FMF)
  description: >
    FMF (MEFV) is the other pyrin-inflammasome periodic fever syndrome and is the
    principal differential. It shares IL-1-mediated autoinflammation but differs in
    genetics, ethnic distribution, attack features, and colchicine responsiveness.
  distinguishing_features:
  - MEFV mutations (gain-of-function pyrin) rather than MVK enzyme deficiency
  - Colchicine-responsive, whereas MKD attacks are not reliably colchicine-responsive
  - No elevation of urinary mevalonic acid in FMF
  evidence:
  - reference: PMID:27270401
    reference_title: "Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct \ninterleukin-1β (IL-1β)-mediated autoinflammatory diseases: familial \nMediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS)."
    explanation: >-
      FMF (MEFV/pyrin) and HIDS (MVK) are distinct IL-1-mediated autoinflammatory
      diseases that must be distinguished.
clinical_trials:
- name: NCT02059291
  phase: PHASE_III
  status: COMPLETED
  description: >
    The CLUSTER trial: a randomized, double-blind, placebo-controlled study of
    canakinumab in patients with hereditary periodic fevers (TRAPS, HIDS/MKD, or
    colchicine-resistant FMF), with subsequent randomized withdrawal/dose-reduction
    and an open-label long-term treatment epoch.
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: clinicaltrials:NCT02059291
    reference_title: "A Randomized, Double-blind, Placebo Controlled Study of Canakinumab in Patients With Hereditary Periodic Fevers (TRAPS, HIDS, or crFMF), With Subsequent Randomized Withdrawal/Dosing Frequency Reduction and Open-label Long-term Treatment Epochs"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study is to determine whether canakinumab is able to induce and maintain a clinically meaningful reduction of disease activity in participants with Hereditary Periodic Fevers (HPF) compared to placebo."
    explanation: >-
      The CLUSTER trial evaluated canakinumab in hereditary periodic fevers
      including HIDS/MKD.
discussions:
- discussion_id: gap_mkd_severe_neuro_mechanism
  prompt: >-
    Why does the same isoprenoid/prenylation defect produce a purely
    autoinflammatory phenotype at the mild end (HIDS) but progressive
    neurodegeneration (ataxia, developmental delay, cataract) in severe mevalonic
    aciduria, and is this neurodegeneration IL-1-driven or prenylation-intrinsic?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Defective Protein Prenylation and Pyrin Inflammasome Activation
  rationale: >-
    Severity tracks residual enzyme activity, but the mechanism by which
    near-absent activity additionally causes progressive CNS and ocular
    degeneration (versus the episodic IL-1-mediated inflammation that IL-1 blockade
    controls) is not established; IL-1 inhibition controls the inflammatory attacks
    but is not known to halt the neurodegenerative course of mevalonic aciduria.
  evidence:
  - reference: PMID:16722536
    reference_title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no established successful treatment for MVA."
    explanation: >-
      The absence of established treatment for the severe (neurodegenerative) end
      underscores the open mechanistic question of MVA-specific CNS injury.
references:
- reference: PMID:16722536
  title: "Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome."
- reference: PMID:12563048
  title: "Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum."
- reference: PMID:27213830
  title: "The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry."
- reference: PMID:27270401
  title: "Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS."
- reference: PMID:25107911
  title: "Unprenylated RhoA contributes to IL-1β hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity."
- reference: PMID:22038276
  title: "Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children."
- reference: PMID:34554243
  title: "Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial."
- reference: PMID:29768139
  title: "Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes."
- reference: PMID:40717084
  title: "Mevalonate kinase deficiency: genetic and clinical characteristics of a Chinese pediatric cohort."
- reference: PMID:35906690
  title: "The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency."

📚

References & Deep Research

References

10

PMID:16722536

Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome.

No top-level findings curated for this source.

PMID:12563048

Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum.

No top-level findings curated for this source.

PMID:27213830

The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry.

No top-level findings curated for this source.

PMID:27270401

Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.

No top-level findings curated for this source.

PMID:25107911

Unprenylated RhoA contributes to IL-1β hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity.

No top-level findings curated for this source.

PMID:22038276

Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children.

No top-level findings curated for this source.

PMID:34554243

Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial.

No top-level findings curated for this source.

PMID:29768139

Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.

No top-level findings curated for this source.

PMID:40717084

Mevalonate kinase deficiency: genetic and clinical characteristics of a Chinese pediatric cohort.

No top-level findings curated for this source.

PMID:35906690

The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-4-8[1m] 18 citations 2026-06-29T22:16:14.279367

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):

Phenotype	Frequency	Type	Suggested HPO
Recurrent fever (often >40°C), episodic	~100% (defining)	Symptom	HP:0001954 Episodic fever / HP:0001945 Fever
Cervical lymphadenopathy	84–87%	Sign	HP:0002721? → HP:0002716 Lymphadenopathy
Abdominal pain	85–88%	Symptom	HP:0002027 Abdominal pain
Diarrhea	69–84%	Symptom	HP:0002014 Diarrhea
Vomiting	69–71%	Symptom	HP:0002013 Vomiting
Arthralgia	71–84%	Symptom	HP:0002829 Arthralgia
Skin rash (maculopapular/urticarial)	39–69%	Sign	HP:0000988 Skin rash
Aphthous ulcers (oral/genital)	43–60%	Sign	HP:0010783? → HP:0000155 Oral ulcer / HP:0011110 Recurrent aphthous stomatitis
Splenomegaly	32–63%	Sign	HP:0001744 Splenomegaly
Hepatomegaly	22–37%	Sign	HP:0002240 Hepatomegaly
Headache	38–63%	Symptom	HP:0002315 Headache
Myalgia	22–57%	Symptom	HP:0003326 Myalgia
Arthritis	variable	Sign	HP:0001369 Arthritis
Elevated acute-phase reactants (CRP, SAA, leukocytosis) during flares	~all flares	Lab	HP:0011227 Elevated CRP; HP:0011966 Elevated SAA (verify)
Elevated serum IgD (and often IgA)	majority (mild MKD)	Lab	HP:0003498? Increased IgD (verify)
Elevated urinary mevalonic acid	severe MKD constant; mild MKD only during flares	Lab	— (HP for mevalonic aciduria, verify)

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):

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)
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)
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)
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)
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)

PMID / source	Use
PMC1475558 (Houten et al., 2006, Orphanet J Rare Dis)	Disease overview, spectrum, biochemistry, diagnosis
PMC11590122 / PMID 39600705 (2024 SHARE revision, Front Immunol)	Terminology, epidemiology, diagnostics, treatment recs, amyloidosis
PMC4855321 (Natural history review, 2016, Pediatr Rheumatol)	Phenotype frequencies, onset, triggers, complications
PMC4183811 / JBC 2014	RhoA/Rac1 → pyrin inflammasome → IL-1β mechanism
PMC2946549	Compromised RhoA/Rac1 geranylgeranylation in MKD
PMID 34554243 (CLUSTER trial, Rheumatology 2022)	Canakinumab long-term efficacy/safety; NCT02059291
PMC9525117 / JCI 160929 (2022)	Temperature exacerbates prenylation defect (mouse models)
PMC6702261	Defective protein prenylation across MKD severity spectrum
OMIM 251170 / 260920 / 610377	Gene + phenotype identifiers, inheritance
medRxiv 2024.07.17.24309492	Geranylgeraniol supplementation (experimental)

⚠️ 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

Mevalonate Kinase Deficiency

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15. Model Organisms

Key Evidence Citations (for KB population)

⚠️ Curation cautions (per dismech anti-hallucination SOP)