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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 -
Neuropediatrics Feb 2022
Topics: Humans; Neuroimaging; Peroxisomal Disorders
PubMed: 34298577
DOI: 10.1055/s-0041-1732312 -
Orphanet Journal of Rare Diseases Dec 2015Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a... (Review)
Review
Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients.
Topics: Disease Management; Humans; Mutation; Peroxisomes; Zellweger Syndrome
PubMed: 26627182
DOI: 10.1186/s13023-015-0368-9 -
Pediatric Rheumatology Online Journal May 2016Mevalonate kinase deficiency (MKD), a very rare autosomal recessive autoinflammatory disease with multiple organ involvement, presents clinically as... (Review)
Review
Mevalonate kinase deficiency (MKD), a very rare autosomal recessive autoinflammatory disease with multiple organ involvement, presents clinically as hyperimmunoglobulinemia D syndrome (HIDS), a less severe phenotype and more common form, and mevalonic aciduria (MVA), a more severe phenotype and rare form. MKD is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. Patients with MVA also have intrauterine growth retardation, congenital defects (cataracts, shortened limbs, and dysmorphic craniofacial features), neurological disease, and failure to thrive. Mean age at onset of symptoms is within the first year of life. There is a delay by several years between symptom onset and diagnosis, which is in part attributable to the initial misdiagnosis due to the rarity and nonspecific clinical manifestations of disease. The frequency of recurrent febrile attacks is highest in childhood and gradually decreases after adolescence. MKD is associated with rare long-term complications such as type AA amyloidosis, joint contractures, abdominal adhesions, renal angiomyolipoma, and severe pneumococcal infections. Frequent febrile attacks significantly impair several aspects of patients' and caregivers' quality of life, with an adverse impact on patients' daily activities, education, and employment. Lifespan is generally normal for HIDS whereas MVA can be fatal in early childhood.
Topics: Age of Onset; Child; Diagnostic Errors; Disease Management; Humans; Mevalonate Kinase Deficiency; Prognosis; Symptom Assessment
PubMed: 27142780
DOI: 10.1186/s12969-016-0091-7 -
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 -
Biomolecules Jul 2021Premature termination codon (PTC) mutations account for approximately 10% of pathogenic variants in monogenic diseases. Stimulation of translational readthrough, also...
Premature termination codon (PTC) mutations account for approximately 10% of pathogenic variants in monogenic diseases. Stimulation of translational readthrough, also known as stop codon suppression, using translational readthrough-inducing drugs (TRIDs) may serve as a possible therapeutic strategy for the treatment of genetic PTC diseases. One important parameter governing readthrough is the stop codon context (SCC)-the stop codon itself and the nucleotides in the vicinity of the stop codon on the mRNA. However, the quantitative influence of the SCC on treatment outcome and on appropriate drug concentrations are largely unknown. Here, we analyze the readthrough-stimulatory effect of various readthrough-inducing drugs on the SCCs of five common premature termination codon mutations of in a sensitive dual reporter system. Mutations in , encoding the peroxisomal targeting signal 1 receptor, can cause peroxisomal biogenesis disorders of the Zellweger spectrum. We show that the stop context has a strong influence on the levels of readthrough stimulation and impacts the choice of the most effective drug and its concentration. These results highlight potential advantages and the personalized medicine nature of an SCC-based strategy in the therapy of rare diseases.
Topics: Codon, Nonsense; HeLa Cells; Humans; Peroxisomal Disorders; Peroxisome-Targeting Signal 1 Receptor; Protein Biosynthesis; RNA, Messenger
PubMed: 34356630
DOI: 10.3390/biom11071006 -
European Journal of Pediatrics Apr 2015Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning.... (Review)
Review
Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning. We report on an 8-month-old female infant and a 6-month-old female infant with typical clinical, radiological and laboratory features of Zellweger syndrome; light microscopic and ultrastructural evidence of mitochondrial pathology in their muscle biopsies; and homozygous pathogenic mutations of the PEX16 gene (c.460 + 5G > A) and the PEX 12 gene (c.888_889 del p.Leu297Thrfs*12), respectively. Additionally, mitochondrial respiratory chain enzymology analysis in the first girl showed a mildly low activity in complexes II-III and IV. We also review five children previously reported in the literature with a presumptive diagnosis of ZS and additional mitochondrial findings in their muscle biopsies. In conclusion, this is the first study of patients with a molecularly confirmed peroxisomal disorder with features of a concomitant mitochondrial myopathy and underscores the role of secondary mitochondrial dysfunction in Zellweger syndrome, potentially contributing to the clinical phenotype.
Topics: Female; Homozygote; Humans; Infant; Magnetic Resonance Imaging; Mitochondria; Mitochondrial Myopathies; Mutation; Zellweger Syndrome
PubMed: 25287621
DOI: 10.1007/s00431-014-2431-2 -
Journal of Child Neurology Apr 2022Cerebral X-linked adrenoleukodystrophy (cALD) is an inflammatory demyelination of the brain that can lead to death unless treated by hematopoietic stem cell...
OBJECTIVES
Cerebral X-linked adrenoleukodystrophy (cALD) is an inflammatory demyelination of the brain that can lead to death unless treated by hematopoietic stem cell transplantation. Survival and improved outcomes for cerebral adrenoleukodystrophy are associated with hematopoietic stem cell transplantation at earliest evidence of disease on magnetic resonance imaging (MRI). Our goal was to determine average duration between diagnosis of cALD and hematopoietic stem cell transplantation.
METHODS
This was a retrospective review of data of patients aged 18 years or younger, using a nationwide administrative health care database (Pediatric Health Information System), with an () diagnosis of adrenoleukodystrophy. Time range was October 1, 2015, through June 30, 2021. We determined time to hematopoietic stem cell transplantation by duration between index brain MRI and a code for hematopoietic stem cell transplantation.
RESULTS
We identified 27 patients with cerebral adrenoleukodystrophy. Total charges for the cohort was $53 million. Time to transplant averaged 97 days. For Hispanic patients, time to transplant was 117 days, compared with 80 days for White, non-Hispanic patients. Comparison of different hospitals showed significant variability in time to hematopoietic stem cell transplantation.
DISCUSSION
We found that time to hematopoietic stem cell transplantation was >3 months for patients with cerebral adrenoleukodystrophy in the hospitals we evaluated. We noted differences in average time by race/ethnicity and by hospital. Our findings suggest opportunity to reduce time to transplant in cerebral adrenoleukodystrophy.
Topics: Adrenoleukodystrophy; Child; Hematopoietic Stem Cell Transplantation; Humans; Magnetic Resonance Imaging; Retrospective Studies
PubMed: 35238239
DOI: 10.1177/08830738221081141 -
BMJ Case Reports Apr 2022Hyperimmunoglobulinaemia D syndrome (HIDS) is a rare autosomal recessive disorder caused by mutations in the mevalonate kinase (MVK) gene, located on chromosome 12. The...
Hyperimmunoglobulinaemia D syndrome (HIDS) is a rare autosomal recessive disorder caused by mutations in the mevalonate kinase (MVK) gene, located on chromosome 12. The most common mutation identified in MVK gene so far is V377I. Compound heterozygotes that include this variant may exhibit a more severe phenotype of the disease and homozygotes are rarely found in clinical practice probably they express a milder phenotype. HIDS is a chronic autoinflammatory disease characterised by recurrent febrile episodes, associated with lymphadenopathies, abdominal pain, rash and arthritis. These flares can be triggered by vaccination, minor trauma, surgery and stress.We report a case of a 2-year-old girl who had recurrent attacks of fever associated with cervical lymphadenopathy, macular erythematous skin rash, abdominal pain and aphthous ulcers in the mouth. The patient was found to excrete elevated amounts of urinary mevalonic acid and a homozygous V337I mutation in the MVK gene was identified.
Topics: Abdominal Pain; Child, Preschool; Female; Fever; Homozygote; Humans; Immunoglobulin D; Mevalonate Kinase Deficiency; Mutation; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 35387795
DOI: 10.1136/bcr-2022-249135 -
Methods in Molecular Biology (Clifton,... 2023During the last three decades many mouse lines were created or identified that are deficient in one or more peroxisomal functions. Different methodologies were applied...
During the last three decades many mouse lines were created or identified that are deficient in one or more peroxisomal functions. Different methodologies were applied to obtain global, hypomorph, cell type selective, inducible, and knockin mice. Whereas some models closely mimic pathologies in patients, others strongly deviate or no human counterpart has been reported. Often, mice, apparently endowed with a stronger transcriptional adaptation, have to be challenged with dietary additions or restrictions in order to trigger phenotypic changes. Depending on the inactivated peroxisomal protein, several approaches can be taken to validate the loss-of-function. Here, an overview is given of the available mouse models and their most important characteristics.
Topics: Animals; Mice; Fatty Acids; Peroxisomes; Peroxisomal Disorders
PubMed: 36952207
DOI: 10.1007/978-1-0716-3048-8_34