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Molecular Genetics and Metabolism Jun 2022Mevalonate kinase deficiency (MKD) is a monogenic auto-inflammatory disease. Its manifestations range from partial MKD to mevalonic aciduria (MVA). All patients display... (Review)
Review
INTRODUCTION
Mevalonate kinase deficiency (MKD) is a monogenic auto-inflammatory disease. Its manifestations range from partial MKD to mevalonic aciduria (MVA). All patients display a periodic fever, and MVA patients additionally exhibit severe neurological involvement. The objective of this work was to describe neurological manifestations of MKD.
METHODS
A systematic literature review was performed from January 1990 to January 2022. Forty-five patients from 18 case reports and five cohort studies were included in the analysis.
RESULTS
In cohort studies, the most-reported manifestations were headaches (41%) and fatigue (31%). Serious involvements including ataxia and developmental delay were described less than 1% of patients but 22-31% of case reports. They consistently appeared in the first years of life. Retinal dystrophy was frequently reported (31%) in case reports. Other manifestations, including uveitis, aseptic meningitis, and stroke remained rare.
DISCUSSION
Severe neurological manifestations are rare in MKD but are responsible for major functional disabilities. They are present at onset and never appear at follow-up of patients with mild MKD. Conversely, headaches and fatigue are frequent symptoms that should be investigated. Visual examinations should be performed on the appearance of visual symptoms. The efficacy of anti-IL-1β therapy on neurological manifestations should be further investigated.
Topics: Fatigue; Headache; Humans; Mevalonate Kinase Deficiency
PubMed: 35525811
DOI: 10.1016/j.ymgme.2022.04.006 -
Journal of Cell Science May 2020Peroxisomes are single-membrane organelles present in eukaryotes. The functional importance of peroxisomes in humans is represented by peroxisome-deficient peroxisome... (Review)
Review
Peroxisomes are single-membrane organelles present in eukaryotes. The functional importance of peroxisomes in humans is represented by peroxisome-deficient peroxisome biogenesis disorders (PBDs), including Zellweger syndrome. Defects in the genes that encode the 14 peroxins that are required for peroxisomal membrane assembly, matrix protein import and division have been identified in PBDs. A number of recent findings have advanced our understanding of the biology, physiology and consequences of functional defects in peroxisomes. In this Review, we discuss a cooperative cell defense mechanisms against oxidative stress that involves the localization of BAK (also known as BAK1) to peroxisomes, which alters peroxisomal membrane permeability, resulting in the export of catalase, a peroxisomal enzyme. Another important recent finding is the discovery of a nucleoside diphosphate kinase-like protein that has been shown to be essential for how the energy GTP is generated and provided for the fission of peroxisomes. With regard to PBDs, we newly identified a mild mutation, Pex26-F51L that causes only hearing loss. We will also discuss findings from a new PBD model mouse defective in Pex14, which manifested dysregulation of the BDNF-TrkB pathway, an essential signaling pathway in cerebellar morphogenesis. Here, we thus aim to provide a current view of peroxisome biogenesis and the molecular pathogenesis of PBDs.
Topics: Animals; Intracellular Membranes; Mice; Peroxins; Peroxisomal Disorders; Peroxisomes; Protein Transport
PubMed: 32393673
DOI: 10.1242/jcs.236943 -
Neurotoxicity Research Jun 2021Peroxisomes are versatile cell organelles that exhibit a repertoire of organism and cell-type dependent functions. The presence of oxidases and antioxidant enzymes is a... (Review)
Review
Peroxisomes are versatile cell organelles that exhibit a repertoire of organism and cell-type dependent functions. The presence of oxidases and antioxidant enzymes is a characteristic feature of these organelles. The role of peroxisomes in various cell types in human health and disease is under investigation. Defects in the biogenesis of the organelle and its function lead to severe debilitating disorders. In this manuscript, we discuss the distribution and functions of peroxisomes in the nervous system and especially in the brain cells. The important peroxisomal functions in these cells and their role in the pathology of associated disorders such as neurodegeneration are highlighted in recent studies. Although the cause of the pathogenesis of these disorders is still not clearly understood, emerging evidence supports a crucial role of peroxisomes. In this review, we discuss research highlighting the role of peroxisomes in brain development and its function. We also provide an overview of the major findings in recent years that highlight the role of peroxisome dysfunction in various associated diseases.
Topics: Animals; Brain; Brain Diseases; Humans; Peroxisomal Disorders; Peroxisomes; Reactive Oxygen Species
PubMed: 33400183
DOI: 10.1007/s12640-020-00323-9 -
International Journal of Molecular... Apr 2021Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases... (Review)
Review
Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or β-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors.
Topics: Animals; Disease Models, Animal; Metabolome; Peroxisomes; Phospholipids; Retina; Retinal Diseases
PubMed: 33921065
DOI: 10.3390/ijms22084101 -
Biomedicine & Pharmacotherapy =... Nov 2021X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with mutations of the ABCD1 gene that encodes a peroxisomal transmembrane... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with mutations of the ABCD1 gene that encodes a peroxisomal transmembrane protein. It results in accumulation of very long chain fatty acids in tissues and body fluid. Along with other factors such as epigenetic and environmental involvement, ABCD1 mutation-provoked disorders can present different phenotypes including cerebral adrenoleukodystrophy (cALD), adrenomyeloneuropathy (AMN), and peripheral neuropathy. cALD is the most severe form that causes death in young childhood. Bone marrow transplantation and hematopoietic stem cell gene therapy are only effective when performed at an early stage of onsets in cALD. Nonetheless, current research and development of novel therapies are hampered by a lack of in-depth understanding disease pathophysiology and a lack of reliable cALD models. The Abcd1 and Abcd1/Abcd2 knock-out mouse models as well as the deficiency of Abcd1 rabbit models created in our lab, do not develop cALD phenotypes observed in human beings. In this review, we summarize the clinical and biochemical features of X-ALD, the progress of pre-clinical and clinical studies. Challenges and perspectives for future X-ALD studies are also discussed.
Topics: ATP Binding Cassette Transporter, Subfamily D; ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Animals; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Mice, Knockout; Mutation; Phenotype; Prognosis; Rabbits; Species Specificity; Mice
PubMed: 34560537
DOI: 10.1016/j.biopha.2021.112214 -
Advances in Experimental Medicine and... 2020Peroxisomopathies are qualitative or quantitative deficiencies in peroxisomes which lead to increases in the level of very-long-chain fatty acids (VLCFA) and can be... (Review)
Review
7-Ketocholesterol- and 7β-Hydroxycholesterol-Induced Peroxisomal Disorders in Glial, Microglial and Neuronal Cells: Potential Role in Neurodegeneration : 7-ketocholesterol and 7β-hydroxycholesterol-Induced Peroxisomal Disorders and Neurodegeneration.
Peroxisomopathies are qualitative or quantitative deficiencies in peroxisomes which lead to increases in the level of very-long-chain fatty acids (VLCFA) and can be associated with more or less pronounced dysfunction of central nervous system cells: glial and microglial cells. Currently, in frequent neurodegenerative diseases, Alzheimer's disease (AD) and multiple sclerosis (MS), peroxisomal dysfunction is also suspected due to an increase in VLCFA, which can be associated with a decrease of plasmalogens, in these patients. Moreover, in patients suffering from peroxisomopathies, such as X-linked adrenoleukodystrophy (X-ALD), AD, or MS, the increase in oxidative stress observed leads to the formation of cytotoxic oxysterols: 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-OHC). These observations led to the demonstration that 7KC and 7β-OHC alter the biogenesis and activity of peroxisomes in glial and microglial cells. In X-ALD, AD, and MS, it is suggested that 7KC and 7β-OHC affecting the peroxisome, and which also induce mitochondrial dysfunctions, oxidative stress, and inflammation, could promote neurodegeneration. Consequently, the study of oxisome in peroxisomopathies, AD and MS, could help to better understand the pathophysiology of these diseases to identify therapeutic targets for effective treatments.
Topics: Humans; Hydroxycholesterols; Ketocholesterols; Microglia; Neurodegenerative Diseases; Neuroglia; Neurons; Peroxisomal Disorders
PubMed: 33417205
DOI: 10.1007/978-3-030-60204-8_3 -
Archives de Pediatrie : Organe Officiel... Jul 2017
Topics: Brain; Humans; Infant, Newborn; Magnetic Resonance Imaging; Male; Zellweger Syndrome
PubMed: 28576584
DOI: 10.1016/j.arcped.2017.04.015 -
Endocrine Development 2016X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease. It is often lethal and currently lacks a satisfactory therapy. The... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease. It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of very-long-chain fatty acids (VLCFA) in organs and plasma. Recent findings on pathomechanisms of the peroxisomal neurometabolic disease X-ALD have provided important clues on therapeutic targets. Here we describe the impact of chronic redox imbalance caused by the excess VLCFA on mitochondrial biogenesis and respiration, and explore the consequences on the protein quality control systems essential for cell survival, such as the proteasome and autophagic flux. Defective proteostasis, together with mitochondrial malfunction, is a hallmark of the most prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and of the aging process. Thus, we discuss molecular targets and emerging treatment options that may be common to both multifactorial neurodegenerative disorders and X-ALD. New-generation antioxidants, some of them mitochondrial targeted, mitochondrial biogenesis boosters such as pioglitazone and resveratrol, and the mTOR inhibitor temsirolimus hold promise as disease-modifying therapies.
Topics: Adrenoleukodystrophy; Disease Progression; Humans
PubMed: 26684655
DOI: 10.1159/000439340 -
Orvosi Hetilap Mar 2015The catalase enzyme decomposes the toxic concentrations of hydrogen peroxide into oxygen and water. Hydrogen peroxide is a highly reactive small molecule and its... (Review)
Review
The catalase enzyme decomposes the toxic concentrations of hydrogen peroxide into oxygen and water. Hydrogen peroxide is a highly reactive small molecule and its excessive concentration may cause significant damages to proteins, deoxyribonucleic acid, ribonucleic acid and lipids. Acatalasemia refers to inherited deficiency of the catalase enzyme. In this review the authors discuss the possible role of the human catalase enzyme, the metabolism of hydrogen peroxide, and the phenomenon of hydrogen peroxide paradox. In addition, they review data obtained from Hungarian acatalasemic patients indicating an increased frequency of type 2 diabetes mellitus, especially in female patients, and an early onset of type 2 diabetes in these patients. There are 10 catalase gene variants which appear to be responsible for decreased blood catalase activity in acatalasemic patients with type 2 diabetes. It is assumed that low levels of blood catalase may cause an increased concentration of hydrogen peroxide which may contribute to the pathogenesis of type 2 diabetes mellitus.
Topics: Acatalasia; Catalase; Diabetes Mellitus, Type 2; Genetic Variation; Heterozygote; Humans; Hungary; Hydrogen Peroxide; Mutation; Oxidative Stress; Sex Factors
PubMed: 25726767
DOI: 10.1556/OH.2015.30095 -
Journal of Inherited Metabolic Disease Mar 2022Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease... (Observational Study)
Observational Study
Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. The study aim was to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration, and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were carried out by sex and for the full dataset. Sixty-one men and 87 women participated. Average age, 46 ± 12 years; Expanded Disability Status Scale, 3 (1-6.5); symptom duration, 10.8 ± 9.4 years. The cohort showed significant worsening in all standing conditions (P < .001), sensation (P = .0223) and strength (P = .001); but more stability in walking with only velocity (P < .0337) significantly declining. For each sex, postural sway declines significantly in all conditions (P < .01) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (P < .03). Sex-specific significant decline is seen in walking (velocity P = .0276; distance P = .0072) for men only. Quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.
Topics: Adrenoleukodystrophy; Adult; Disease Progression; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Postural Balance; Prospective Studies
PubMed: 34796974
DOI: 10.1002/jimd.12457