ABSTRACT
Mevalonate kinase deficiency (MKD) an orphan drug rare disease affecting humans with different clinical presentations, is still lacking information about its pathogenesis; no animal or cell model mimicking the genetic defect, mutations at MVK gene, and its consequences on the mevalonate pathway is available. Trying to clarify the effects of MVK gene impairment on the mevalonate pathway we used a yeast model, the erg12-d mutant strain Saccharomyces cerevisiae (orthologous of MKV) retaining only 10% of mevalonate kinase (MK) activity, to describe the effects of reduced MK activity on the mevalonate pathway. Since shortage of isoprenoids has been described in MKD, we checked this observation using a physiologic approach: while normally growing on glucose, erg12-d showed growth deficiency in glycerol, a respirable carbon source, that was not rescued by supplementation with non-sterol isoprenoids, such as farnesol, geraniol nor geranylgeraniol, produced by the mevalonate pathway. Erg12-d whole genome expression analysis revealed specific downregulation of RSF2 gene encoding general transcription factor for respiratory genes, explaining the absence of growth on glycerol. Moreover, we observed the upregulation of genes involved in sulphur amino acids biosynthesis that coincided with the increasing in the amount of proteins containing sulfhydryl groups; upregulation of ubiquinone biosynthesis genes was also detected. Our findings demonstrated that the shortage of isoprenoids is not the main mechanism involved in the respiratory deficit and mitochondrial malfunctioning of MK-defective cells, while the scarcity of ubiquinone plays an important role, as already observed in MKD patients.
Subject(s)
Mevalonate Kinase Deficiency/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Respiration/genetics , Saccharomyces cerevisiae/genetics , Gene Expression Regulation, Fungal , Genome, Fungal , Humans , Mevalonate Kinase Deficiency/metabolism , Mevalonate Kinase Deficiency/pathology , Mutation , Phosphotransferases (Alcohol Group Acceptor)/deficiency , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae Proteins/genetics , Terpenes/metabolism , Transcription Factors/genetics , Ubiquinone/genetics , Ubiquinone/metabolismABSTRACT
We previously described a girl with recurrent episodes of pneumococcal pneumonia with septicemia and other infections,(1) found to have interleukin-1 receptor-associated kinase 4 deficiency (IRAK-4) deficiency.(2) In this report, we show that our patient is unable to sustain antibody responses either to polysaccharide or protein antigens or to a neoantigen-bacteriophage.
Subject(s)
Antibodies, Bacterial/analysis , Bacterial Infections/immunology , Phosphotransferases (Alcohol Group Acceptor)/deficiency , Blotting, Northern , Blotting, Western , Child , Consanguinity , Female , Humans , Immunologic Deficiency Syndromes/genetics , Interleukin-1 Receptor-Associated Kinases , Interleukin-6/biosynthesis , Membrane Glycoproteins/immunology , Phosphotransferases (Alcohol Group Acceptor)/genetics , Receptors, Cell Surface/immunology , Signal Transduction , Toll-Like ReceptorsABSTRACT
INTRODUCTION: Pantothenate kinase deficiency (Hallervorden-Spatz syndrome, HSS) triggers cerebral neurodegeneration with iron deposition in the basal ganglia. The classical form has an early onset in infancy, a progressive course, the presence of extrapyramidal symptoms (dystonia, chorea, rigidity) and pigmentary retinitis. There are atypical late onset forms with predominance of symptoms of Parkinsonism and dementia, which progress slowly and course somewhat less progressively. CASE REPORT: We describe three patients with HSS and an atypical presentation, with onset during the second decade of life. In all cases magnetic resonance imaging showed areas of hyposignal in T2 sequences in medial globus pallidus, with central hypersignal, which gave rise to a tiger's eye image. Other aetiologies, such as Wilson's disease, gangliosidosis GM1, hypoprebetalipoproteinemia, hexosaminidase A deficiency, aminoacidurias and infantile Huntingdon's chorea, were precluded. In the 20-year-old male the initial manifestations at the age of 17 were superposed over Gilles de la Tourette syndrome, with complex motor and vocal tics, palilalia, behavioural disorders and postural instability. The 13-year-old patient presented symptoms of chorea, hemiballic movements and dystonia in the lower limbs, which limited walking at the age of 12. The 28-year-old female patient presented a progressive rigid akinetic syndrome, with dementia and partial response to levodopa. CONCLUSIONS: The clinical spectrum of HSS is broad and its differential diagnosis must include hemiballism, Tourette syndrome and juvenile Parkinsonism.