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Children (Basel, Switzerland) Mar 2023The aim of this paper is to describe the temporal progression and clinical picture of a 2-year-old child with infantile Refsum disease, as well as the diagnostic...
The aim of this paper is to describe the temporal progression and clinical picture of a 2-year-old child with infantile Refsum disease, as well as the diagnostic procedures performed; this case presented multiple hematologic, metabolic, and developmental complications and progressive disabilities. Genetic testing revealed a mutation of the (Peroxisomal Biogenesis Factor 6) gene, and the metabolic profile was consistent with the diagnosis. Particularly, the child also presented altered coagulation factors and developed a spontaneous brain hemorrhage. The clinical picture includes several neurological, ophthalmological, digestive, cutaneous, and endocrine disorders as a result of the very long chain fatty acid accumulation as well as secondary oxidative anomalies. The study of metabolic disorders occurring because of genetic mutations is a subject of core importance in the pathology of children today. The PEX mutations, difficult to identify antepartum, are linked to an array of cell anomalies with severe consequences on the patient's status, afflicting multiple organs and systems. This is the reason for which our case history may be relevant, including a vast number of symptoms, as well as modified biological parameters.
PubMed: 36980088
DOI: 10.3390/children10030530 -
BMJ Open Gastroenterology May 2023To estimate the risk of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) in patients with inflammatory bowel disease (IBD).
OBJECTIVE
To estimate the risk of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) in patients with inflammatory bowel disease (IBD).
DESIGN
We undertook a two-country population cohort study with all patients diagnosed with IBD in Norway and Sweden from 1987 and 1993 through 2015 and 2016, respectively, and analysed the risk of NHL and HL. In Sweden, we also analysed prescriptions of thiopurines and anti-tumour necrosis factor (TNF)-α therapy from 2005. We calculated standardised incidence ratios (SIRs) with 95% CIs using the general populations as reference.
RESULTS
Among 131 492 patients with IBD with a medium follow-up of 9.6 years, we identified 369 cases of NHL and 44 cases of HL. The SIR of NHL was 1.3 (95% CI 1.1 to 1.5) in ulcerative colitis and 1.4 (95% CI 1.2 to 1.7) in Crohn's disease. We found no compelling heterogeneity in analyses stratified by patient characteristics. We found a similar pattern and magnitude of excess risks for HL. At 10 years, cumulative incidence was 0.26% (95% CI 0.23% to 0.30%) and 0.06% (95% CI 0.04% to 0.08%) for NHL and HL, respectively. Higher excess risks were found among patients with NHL with concomitant primary sclerosing cholangitis (SIR 3.4; 95% CI 2.1 to 5.2) and in those prescribed thiopurines alone (SIR 2.8; 95% CI 1.4 to 5.7) or with anti-TNF-α agents (SIR 5.7; 95% CI 2.7 to 11.9).
CONCLUSION
Patients with IBD have a statistically significant increased risk of malignant lymphomas compared with the general population, but the absolute risk remains low.
Topics: Humans; Cohort Studies; Tumor Necrosis Factor Inhibitors; Lymphoma; Inflammatory Bowel Diseases; Crohn Disease
PubMed: 37142293
DOI: 10.1136/bmjgast-2022-001037 -
Journal of Pediatric Genetics Mar 2018Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400... (Review)
Review
Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF.
PubMed: 29441214
DOI: 10.1055/s-0037-1617454 -
Proceedings of the National Academy of... Nov 2008Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation...
Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.
Topics: Animals; Ataxia; Automation; Behavior, Animal; Central Nervous System; Dietary Supplements; Disease Models, Animal; Gait; Gene Targeting; Genetic Vectors; Lipidoses; Male; Mice; Mixed Function Oxygenases; Peripheral Nervous System Diseases; Phenotype; Phytanic Acid; Phytol; Purkinje Cells; Refsum Disease; Spermatogonia
PubMed: 19004801
DOI: 10.1073/pnas.0806066105 -
Journal of Neurology, Neurosurgery, and... Dec 1982The author reports his experience on Refsum's disease and that gained after personally examining in detail 64 patients with Charcot-Marie-Tooth disease over the past ten...
The author reports his experience on Refsum's disease and that gained after personally examining in detail 64 patients with Charcot-Marie-Tooth disease over the past ten years. The "cerebellar" inco-ordination in Charcot-Marie-Tooth disease (with or without distal wasting) and in Refsum's disease is analysed. Some variations in the motor and sensory neuropathy of Charcot-Marie-Tooth disease and Refsum's disease are discussed. The adequacy of motor conduction velocity in genetically distinguishing types of the above mentioned familial peripheral neuropathies is reviewed. Data on the neuropathy assessed by modern techniques of three original patients of Roussy and Levy (1926) are given. The possibility of extensor plantar responses in patients with Charcot-Marie-Tooth and Refsum's disease without structural lesion of the pyramidal tract is pointed out. The existence of the association between Friedreich's ataxia and Charcot-Marie-Tooth disease is criticised. It is emphasised that spinocerebellar degeneration (other than Friedreich's ataxia) presenting with distal limb weakness and wasting and sensory impairment may mimic Charcot-Marie-Tooth disease.
Topics: Adolescent; Adult; Aged; Cerebellar Ataxia; Charcot-Marie-Tooth Disease; Child; Diagnosis, Differential; Female; Friedreich Ataxia; Humans; Male; Middle Aged; Motor Neurons; Muscular Atrophy; Neural Conduction; Refsum Disease; Sensation
PubMed: 6186770
DOI: 10.1136/jnnp.45.12.1085 -
The FEBS Journal Jan 2011Fatty acids (FAs) can be degraded via different mechanisms including α-, β- and ω-oxidation. In humans, a range of different genetic diseases has been identified in... (Review)
Review
Fatty acids (FAs) can be degraded via different mechanisms including α-, β- and ω-oxidation. In humans, a range of different genetic diseases has been identified in which either mitochondrial FA β-oxidation, peroxisomal FA β-oxidation or FA α-oxidation is impaired. Treatment options for most of these disorders are limited. This has prompted us to study FA ω-oxidation as a rescue pathway for these disorders, based on the notion that if the ω-oxidation of specific FAs could be upregulated one could reduce the accumulation of these FAs and the subsequent detrimental effects in the different groups of disorders. In this minireview, we describe our current state of knowledge in this area with special emphasis on Refsum disease and X-linked adrenoleukodystrophy.
Topics: Animals; Cytochrome P-450 Enzyme System; Enzyme Induction; Fatty Acids; Humans; Lipid Metabolism, Inborn Errors; Oxidation-Reduction
PubMed: 21156023
DOI: 10.1111/j.1742-4658.2010.07947.x -
Scandinavian Journal of Public Health Feb 2022Norway and Sweden are similar countries in terms of socioeconomics and health care. Norway implemented extensive COVID-19 measures, such as school closures and...
Norway and Sweden are similar countries in terms of socioeconomics and health care. Norway implemented extensive COVID-19 measures, such as school closures and lockdowns, whereas Sweden did not. To compare mortality in Norway and Sweden, two similar countries with very different mitigation measures against COVID-19. Using real-world data from national registries, we compared all-cause and COVID-19-related mortality rates with 95% confidence intervals (CI) per 100,000 person-weeks and mortality rate ratios (MRR) comparing the five preceding years (2015-2019) with the pandemic year (2020) in Norway and Sweden. In Norway, all-cause mortality was stable from 2015 to 2019 (mortality rate 14.6-15.1 per 100,000 person-weeks; mean mortality rate 14.9) and was lower in 2020 than from 2015 to 2019 (mortality rate 14.4; MRR 0.97; 95% CI 0.96-0.98). In Sweden, all-cause mortality was stable from 2015 to 2018 (mortality rate 17.0-17.8; mean mortality rate 17.1) and similar to that in 2020 (mortality rate 17.6), but lower in 2019 (mortality rate 16.2). Compared with the years 2015-2019, all-cause mortality in the pandemic year was 3% higher due to the lower rate in 2019 (MRR 1.03; 95% CI 1.02-1.04). Excess mortality was confined to people aged ⩾70 years in Sweden compared with previous years. The COVID-19-associated mortality rates per 100,000 person-weeks during the first wave of the pandemic were 0.3 in Norway and 2.9 in Sweden.
Topics: Aged; COVID-19; Communicable Disease Control; Humans; Mortality; Norway; Pandemics; SARS-CoV-2; Sweden
PubMed: 34609261
DOI: 10.1177/14034948211047137 -
Current Topics in Medicinal Chemistry 2013The Cytochrome P450 4 (CYP4) family of enzymes in humans is comprised of thirteen isozymes that typically catalyze the ω-oxidation of endogenous fatty acids and... (Review)
Review
CYP4 enzymes as potential drug targets: focus on enzyme multiplicity, inducers and inhibitors, and therapeutic modulation of 20-hydroxyeicosatetraenoic acid (20-HETE) synthase and fatty acid ω-hydroxylase activities.
The Cytochrome P450 4 (CYP4) family of enzymes in humans is comprised of thirteen isozymes that typically catalyze the ω-oxidation of endogenous fatty acids and eicosanoids. Several CYP4 enzymes can biosynthesize 20- hydroxyeicosatetraenoic acid, or 20-HETE, an important signaling eicosanoid involved in regulation of vascular tone and kidney reabsorption. Additionally, accumulation of certain fatty acids is a hallmark of the rare genetic disorders, Refsum disease and X-ALD. Therefore, modulation of CYP4 enzyme activity, either by inhibition or induction, is a potential strategy for drug discovery. Here we review the substrate specificities, sites of expression, genetic regulation, and inhibition by exogenous chemicals of the human CYP4 enzymes, and discuss the targeting of CYP4 enzymes in the development of new treatments for hypertension, stroke, certain cancers and the fatty acid-linked orphan diseases.
Topics: Animals; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Hydroxyeicosatetraenoic Acids; Molecular Structure; Molecular Targeted Therapy; Structure-Activity Relationship
PubMed: 23688133
DOI: 10.2174/15680266113139990110 -
JIMD Reports 2016Infantile Refsum disease (IRD) is one of the less severe of Zellweger spectrum disorders (ZSDs), a group of peroxisomal biogenesis disorders resulting from a generalized...
Infantile Refsum disease (IRD) is one of the less severe of Zellweger spectrum disorders (ZSDs), a group of peroxisomal biogenesis disorders resulting from a generalized peroxisomal function impairment. Increased plasma levels of very long chain fatty acids (VLCFA) and phytanic acid are biomarkers used in IRD diagnosis. Furthermore, an increased plasma level of phytanic acid is known to be associated with neurologic damage. Treatment of IRD is symptomatic and multidisciplinary.The authors report a 3-year-old child, born from consanguineous parents, who presented with developmental delay, retinitis pigmentosa, sensorineural deafness and craniofacial dysmorphisms. While the relative level of plasma C26:0 was slightly increased, other VLCFA were normal. Thus, a detailed characterization of the phenotype was essential to point to a ZSD. Repeatedly increased levels of plasma VLCFA, along with phytanic acid and pristanic acid, deficient dihydroxyacetone phosphate acyltransferase activity in fibroblasts and identification of the homozygous pathogenic mutation c.2528G>A (p.Gly843Asp) in the PEX1 gene, confirmed this diagnosis. Nutritional advice and follow-up was proposed aiming phytanic acid dietary intake reduction. During dietary treatment, plasma levels of phytanic acid decreased to normal, and the patient's development evaluation showed slow progressive acquisition of new competences.This case report highlights the relevance of considering a ZSD in any child with developmental delay who manifests hearing and visual impairment and of performing a systematic biochemical investigation, when plasma VLCFA are mildly increased. During dietary intervention, a biochemical improvement was observed, and the long-term clinical effect of this approach needs to be evaluated.
PubMed: 26303611
DOI: 10.1007/8904_2015_487 -
International Journal of Molecular... Jan 2022Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is...
Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of mice in better understanding disease mechanism in fatty acid α-oxidation disorders.
Topics: Animals; Brain; Carbon-Carbon Lyases; Cytochrome P450 Family 2; Cytochrome P450 Family 4; Fatty Acids; Female; Gene Knockout Techniques; Kidney; Lipidomics; Liver; Male; Mice; Oxidation-Reduction; Peroxisomes; Phytanic Acid; Phytol; Proteomics
PubMed: 35055171
DOI: 10.3390/ijms23020987