Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review

Touitou, Isabelle

doi:10.1016/j.gendis.2021.05.002

Cited by 11 publications

(16 citation statements)

References 69 publications

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“…On the other hand, shortage of CNS cholesterol causes myelination defects and neuronal impairments 4 . In addition, upstream accumulation of mevalonic acid may also be toxic for the CNS 2 . Statin therapy (which blocks HMG‐CoA reductase upstream of MK, thus reducing mevalonic acid levels) has been tried in some patients, with mixed but overall disappointing results and, in some patients, even aggravation of auto‐inflammation, although the effect on neurological symptoms is unknown 13 .…”

Section: Discussionmentioning

confidence: 99%

“…8 Autoinflammation in MK deficiency is driven by defective prenylation due to downstream reduced isoprenoid synthesis which results in reduced inflammasome inhibition, ultimately leading to excessive interleukin 1 (IL-1, a potent pro-inflammatory cytokine) secretion. 2,11 Following this, IL-1 blocking therapy is the standard of care treatment for auto-inflammatory symptoms in MK deficiency, either continuously or intermittently at the onset of flares. 12 Although the exact pathophysiological mechanism of neurological manifestations of MK deficiency is unknown, it is proposed that, on the one hand, downstream prenylation defects cause central nerve system (CNS) inflammation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is possible that inflammatory symptoms could arise later in life, periodic fever episodes usually start very young and tend to lessen with age 8 . Autoinflammation in MK deficiency is driven by defective prenylation due to downstream reduced isoprenoid synthesis which results in reduced inflammasome inhibition, ultimately leading to excessive interleukin 1 (IL‐1, a potent pro‐inflammatory cytokine) secretion 2,11 . Following this, IL‐1 blocking therapy is the standard of care treatment for auto‐inflammatory symptoms in MK deficiency, either continuously or intermittently at the onset of flares 12 .…”

Section: Discussionmentioning

confidence: 99%

“…1 The clinical spectrum of MK‐associated diseases is very broad, including autoinflammation and neurological symptoms caused by biallelic variants in the MVK gene, as well as the skin disorder porokeratosis, caused by dominant variants in the MVK gene. 2 …”

Section: Introductionmentioning

confidence: 99%

“…1 The clinical spectrum of MK-associated diseases is very broad, including autoinflammation and neurological symptoms caused by biallelic variants in the MVK gene, as well as the skin disorder porokeratosis, caused by dominant variants in the MVK gene. 2 Patients with severe MK deficiency develop symptoms early in life and present with massive urinary excretion of mevalonic acid. Classic symptoms include autoinflammation (recurrent fever, diverse skin rashes, elevated inflammation biomarkers) with additional neurological symptoms (developmental delay, hypotonia, ataxia).…”

Section: Introductionmentioning

confidence: 99%

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Isolated neurological presentations of mevalonate kinase deficiency

et al. 2022

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Mevalonate kinase (MK) deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the MVK gene with a broad phenotypic spectrum including autoinflammation, developmental delay and ataxia. Typically, neurological symptoms are considered to be part of the severe end of the phenotypical spectrum and are reported to be in addition to the autoinflammatory symptoms. Here, we describe a patient with MK deficiency with severe neurological symptoms but without autoinflammation and we found several similar patients in the literature. Possibly, the non‐inflammatory phenotype is related to a specific genotype: the MVK p.(His20Pro)/p.(Ala334Thr) variant. There is probably an underdetection of the neurological MK deficient phenotype without inflammatory symptoms as clinicians may not test for MK deficiency when patients present with only neurological symptoms. In conclusion, although rare, neurological symptoms without hyperinflammation might be more common than expected in MK deficiency. It seems relevant to consider MK deficiency in patients with psychomotor delay and ataxia, even if there are no inflammatory symptoms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Isolated neurological presentations of mevalonate kinase deficiency

et al. 2022

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Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel MvdF250S/+ Knock-In Mouse Model

Wong

Peng

et al. 2023

Inflammation

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Autoinflammatory Keratinization Diseases—The Concept, Pathophysiology, and Clinical Implications

Blicharz,

Czuwara,

Rudnicka

et al. 2023

Clinic Rev Allerg Immunol

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Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis, type V pityriasis rubra pilaris), IL36RN (generalized pustular psoriasis without concomitant psoriasis vulgaris, impetigo herpetiformis, acrodermatitis continua of Hallopeau), NLRP1 (familial forms of keratosis lichenoides chronica), and genes of the mevalonate pathway, i.e., MVK, PMVK, MVD, and FDPS (porokeratosis). Since then, endotypes underlying novel entities matching the concept of autoinflammatory keratinization diseases have been discovered (mutations of JAK1, POMP, and EGFR). This review describes the concept and pathophysiology of autoinflammatory keratinization diseases and outlines the characteristic clinical features of the associated entities. Furthermore, a novel term for NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) describing the spectrum of autoinflammatory keratinization diseases secondary to NLRP1 mutations is proposed.

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Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review

Cited by 11 publications

References 69 publications

Isolated neurological presentations of mevalonate kinase deficiency

Isolated neurological presentations of mevalonate kinase deficiency

Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel MvdF250S/+ Knock-In Mouse Model

Autoinflammatory Keratinization Diseases—The Concept, Pathophysiology, and Clinical Implications

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