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Implication of Mitochondrial Coenzyme Q10 (Ubiquinone) in Alzheimer’s Disease *
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Sayantan Maitra, Dibyendu Dutta
The precursor of the quinone ring is only 4-hydroxybenzoic acid (4-HB), which is derived from tyrosine. Mevalonate pathway is the main route to synthesize the isoprenoid tail, which is also common to cholesterol biosynthesis. The initial part of the mevalonate pathway involves the condensation of three acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA by HMG-CoA reductase, which is the main regulatory enzyme in cholesterol biosynthesis. Mevalonate is subsequently phosphorylated in two steps by mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK). Then, decarboxylation of mevalonate pyrophosphate yields isopentenyl pyrophosphate (IPP), which is the precursor of farnesyl pyrophosphate (FPP) and the building block for the biosynthesis of dolichol and the side chain of CoQ. Isomerization of IPP gives dimethylallyl pyrophosphate (DMAPP), and FPP synthase utilizes IPP and DMAPP to make FPP with the intermediary formation of geranyl pyrophosphate (GPP). FPP is further converted into cholesterol, dolichols, and CoQ [6]. Decalyprenyl diphosphate synthase (DPS) is a heterotetramer consisting of two different proteins, namely, PDSS1 and PDSS2. DPS catalyzes the condensation of IPP and FPP to produce ten units of prenyldiphosphate (decaprenyl diphosphate). 4-Hydroxybenzoic acid-decaprenyl diphosphate transferase (encoded by CoQ2 gene in humans) catalyzes the condensation of PHB with the isoprenoid tail to yield CoQ10 [7,8].
Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Mevalonic aciduria was discovered in 1986, the first inborn error in the biosynthesis of cholesterol and nonsterol isoprenoid compounds [1]. It results from a deficiency of the activity of mevalonate kinase (Figures 85.1 and 85.2). The disorder was recognized by organic acid analysis of the urine via gas chromatography/mass spectrometry (GCMS). This compound can easily be missed in GCMS analysis [2]. The development of a stable isotope dilution GCMS assay for Mevalonic acid has facilitated quantification of the compound in body fluids [2].
Phagocytic cells and their functions
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, John W. Sleasman
Mevalonate kinase deficiency, also known as hyper IgD syndrome, causes a less severe form of periodic fever syndrome associated with chronic adenopathy, oral aphthosis ulcers, chronic diarrhea, and mevalonate acidosis during attacks. Laboratory findings include leukocytosis and elevated IgD levels.
National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics
Published in Modern Rheumatology, 2019
Takayuki Tanaka, Kohei Yoshioka, Ryuta Nishikomori, Hidemasa Sakai, Junya Abe, Yuriko Yamashita, Ryugo Hiramoto, Akira Morimoto, Eiichi Ishii, Hirokazu Arakawa, Utako Kaneko, Yusei Ohshima, Nami Okamoto, Osamu Ohara, Ikue Hata, Yosuke Shigematsu, Tomoki Kawai, Takahiro Yasumi, Toshio Heike
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory syndrome caused by disease-causing variants of the gene encoding mevalonate kinase (MVK), an enzyme involved in biosynthesis of cholesterol and isoprenoids [1]. The disease manifests as a continuous spectrum of clinical signs ranging from recurrent febrile attacks, known as hyperimmunoglobulinemia D syndrome (HIDS, MIM no. 260920), to a more severe form known as mevalonic aciduria (MA, MIM no. 610377), which is also associated with psychomotor retardation, facial dysmorphia, cataract, and failure to thrive [2]. Low MVK activity reduces production of cholesterol and non-sterol isoprenoids. A shortage of isoprenoids, mainly geranyl-geranyl groups, leads to decreased geranylgeranylation of RhoA and increased production of IL-1β [3,4]. Currently, treatment of MKD is based on the severity of the symptoms shown by each patient; mild cases require NSAIDs or glucocorticoids, whereas more severe cases require biologics or hematopoietic stem cell transplantation [5,6].
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
Upregulated pyroptosis-induced inflammasomes as a result of a defect in Mevalonate kinase, increase the inflammatory response and subsequent platelet activation. Moreover, mevalonate kinase has a critical role in protein prenylation through isoprenyl production. Thus, some evidence has determined this syndrome leads to the decrement of protein prenylation and subsequently lowered endocytosis in cells. Endocytosis is one of the mechanisms involved in platelet adhesive capacity downregulation. Therefore, in this syndrome, thrombotic disease and thrombocytopenia may exhibit due to decreased endocytosis and increased platelet activation [207–210].
Hematopoietic stem cell transplantation in systemic autoinflammatory diseases - the first one hundred transplanted patients
Published in Expert Review of Clinical Immunology, 2022
Sara Signa, Gianluca Dell’Orso, Marco Gattorno, Maura Faraci
Mevalonic aciduria (MVA) is an autosomal recessive (AR) disease due to a severe deficiency (<1%) of MVK, an enzyme that plays a crucial role in the early stage of the isoprenoid biosynthesis. MVA is characterized by neurological involvement with psychomotor retardation, cerebellar ataxia, facial dysmorphism, with fever attacks lasting 4 to 7 days, cervical lymphadenopathy, abdominal pain with vomiting, and diarrhea. Biallelic mutations of MVK gene associated to a residual enzymatic activity are also responsible of hyper immunoglobulin D syndrome (HIDS), characterized by recurrent inflammatory episodes but without severe neurological impairment. The treatment of Mevalonate kinase deficiency (MKD) spectrum includes steroids and IL1-inhibitor as anakinra or canakinumab, reported as the most safe and efficacious drugs in this disease. However the most severe form of MKD, namely, MVA, is usually characterized by a persistent inflammation that generally is not completely controlled by anti-IL1 treatment. The first child with MVA who received an allo-HSCT was described in June 2007 by Neven et al [9]. The patient was a 3-year-old boy resistant to conventional treatments who received a related donor (RD) – HSCT. The child obtained a complete remission of inflammatory attacks 15 months after HSCT, while the neurological impairment and magnetic resonance imaging (MRI) findings remained stable as before the HSCT. To date, a total of 10 patients [9–17] with MKD receiving a transplant have been reported. Three patients required also IL-1 inhibition during HSCT period. Two patients died after HSCT for severe sepsis [10,14]. In another case, the underlying disease recurred 18 months after HSCT, requiring the use of anti IL-1β monoclonal antibodies, namely canakinumab [11]. Three patients received haploidentical (haplo) -HSCT with a negative selection of α/β T-cell and CD19 lymphocytes with a good engraftment (one after the second transplant). The conditioning regimens (CR) included Treosulfan (Treo)-Thiotepa (TT)- Fludarabine (Fluda) -antithymocyte globulin (ATG), and Rituximab. Two of them did not develop acute and chronic Graft versus host disease (GvHD) and had a satisfying immune reconstitution without infectious complications [12]. In the third patient, mild acute GvHD was reported [17]. A fourth patient received a haplo-HSCT as second transplant after graft failure and acute myeloid leukemia occurrence, but died few days later for sepsis [14] (Table 1).