Refsum Disease Research Articles

Impaired Kidney Function with Renal Tubular Vacuolization and Paracrystals in Adult Refsum Disease: A Case Report

Impaired Kidney Function with Renal Tubular Vacuolization and Paracrystals in Adult Refsum Disease: A Case Report

Dilated cardiomyopathy revealing Refsum disease: a case report

BackgroundRefsum disease is a rare autosomal recessive hereditary disorder of lipid metabolism that results in the accumulation of phytanic acid. This syndrome is characterized with a range of classic symptoms including ataxia, peripheral neuropathy, amyotrophy, retinopathy, ichthyosis, and hearing loss. Later in life, individuals with Refsum disease may present cardiac manifestations, such as arrhythmias or conduction defects (first-degree atrioventricular block and bundle branch block) and hypertrophic or dilated cardiomyopathy, leading to heart failure and sudden death. To the best of our knowledge, this is the first case revealed by cardiac manifestations described in literature.Case presentation: We report the case of 38-year-old white Moroccan male who was admitted in our department for an acute decompensated heart failure episode. Transthoracic echocardiography found a dilated cardiomyopathy with a reduced ejection fraction at 15%. Further evaluation showed different features of Refsum disease. High plasma level of phytanic acid confirmed the diagnosis. Cardiac manifestations are frequent in the late course of the adult Refsum disease and include, cardiomyopathy, electrical abnormalities, and sudden cardiac death. Moreover, arrhythmias remain one of the main causes of death in these patients.ConclusionRefsum’s disease is an autosomal recessive disorder. It presents as retinitis pigmentosa with anosmia, deafness ataxia, and cardiac defects. Current interventions for individuals with Refsum disease consist of dietary phytanic acid restriction and lipid apheresis to control symptoms and enhance quality of life.

Forty-year odyssey to Refsum disease diagnosis: impact of diagnostic delay on effective treatment

Forty-year odyssey to Refsum disease diagnosis: impact of diagnostic delay on effective treatment

Leukodytrophy in Children: 12 Cases

Introduction: Leukodystrophies are a rare geneLc disease characterized by damage of the myelin sheath. They represent a large number of diseases that are heterogeneous by their clinical and physiopathological aspects. Material and Methods: We report 12 cases of leukodystrophies collected at the Neuropediatric Unit of Abderrahim Harouchi Mother and Child Hospital CHU Ibn Rochd, Casablanca, Morocco. Results: The average age of diagnosis was 2 years and 9 months, with a predominance of females (sex raLo:0.33). Consanguinity was found in 5 cases. The onset symptomatology was dominated by psychomotor regression, found in 8 paLents, and seizures in 4 paLents. Motor signs were in the foreground: pyramidal syndrome in 5 cases, hypotonia in 4 cases, tetraparesis in 1 case, dysarthria in 1 case. The lumbar puncture, carried out in 4 paLents, revealed hyperproteinorachy in 3 cases, glycorachy and cytological study were normal. We noLced a decreased level of Aryllsulfatase A in 6 cases. Imaging was performed in all paLents and showed diffuse white ma]er demyelinaLon. MRI allowed us to classify our cases and showed 7 cases of metachromaLc leukodystrophy, 1 case of cavitary leukodystrophy, 1 case of Refsum disease, 1 case of Canavan disease, 1 case of Cockaynes syndrome and 1 case of adrenoleukodystrophy. The electroneuromyogram showed a decrease in nerve conducLon velociLes in 2 cases. Molecular study was performed in one paLent finding a hyccin mutaLon. Conclusion: The diagnosis of leukodystrophies is o_en difficult because of their clinical heterogeneity. The partnership of clinicians with geneLcists may be the key point to improve diagnosis and therapeuLc management.

Biallelic Deletion of PEX26 Exon 4 in a Boy with Phenotypic Features of both Zellweger Syndrome and Infantile Refsum Disease

Introduction: Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy. Methods: The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype. Results: Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient’s clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein’s ability to facilitate essential cellular processes related to peroxisome biogenesis and function. Conclusion: The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations.

PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease.

To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD. We recruited patients from Moorfields Eye Hospital (London, UK) and Buenos Aires, Argentina, who were diagnosed with retinitis pigmentosa and found to have biallelic variants in PHYH, with at least one being c.678+5G>T. Total RNA was purified from PaxGene RNA-stabilized whole-blood samples, followed by reverse transcription to cDNA, PCR amplification of the canonical PHYH transcript, Oxford Nanopore Technologies library preparation, and single-molecule amplicon sequencing. Four patients provided a blood sample. One patient had isolated retinitis pigmentosa and three had mild extraocular findings. Blood phytanic acid levels were normal in two patients, mildly elevated in one, and markedly high in the fourth. Retinal evaluation showed an intact ellipsoid zone as well as preserved autofluorescence in the macular region in three of the four patients. In all patients, we observed in-frame skipping of exons 5 and 6 in 31.1% to 88.4% of the amplicons and a smaller proportion (0% to 11.3% of amplicons) skipping exon 6 only. We demonstrate a significant effect of PHYH:c.678+5G>T on splicing of the canonical transcript. The in-frame nature of this may be in keeping with a mild presentation and higher prevalence in the general population. These data support the classification of the variant as pathogenic, and patients harboring a biallelic genotype should undergo phytanic acid testing.

Bioinformatics Analysis Identifies Potential Hub Genes, Therapeutic Agents and Crucial Pathways in the Pathogenesis of Refsum Disease

Refsum Disease is a infrequent, inherited, autosomal recessive condition. The purpose of this study was to investigate prospective therapeutic drugs to cure Refsum disease and to determine the critical genes/pathways through bioinformatics analysis. Using the text mining method, Refsum disease-related genes were discovered and MCODE plugin, GO & KEGG analyses was used to examine modules. A PPI network was created by STRING and visualized in Cytoscape. Drug-gene interactions were investigated using the drug-gene interaction database. Using the text mining of gene (TMG) method, 64 distinct genes in Homo sapiens linked to Refsum illness. There were 71 edges and 48 nodes in a PPI network. 13 hub node genes were discovered using a cluster analysis of filtering nodes. The genes were then significantly elevated in protein trans-membrane transport, protein import to the peroxisome matrix and fatty acid beta-oxidation, according to the enrichment analysis. We discovered that two already-approved medications could target two of the 13 chosen genes. The findings revealed the hub genes for Refsum illness to be SLC27A2, AGXT, GNPAT, CRAT, HSD17B4, AMACR, CAT, SCP2, PEX13, PEX10, PEX1, PEX7, and PEX2. Additionally, Ibuprofen and alcohol were named as prospective therapeutic agents for the management and therapy of Refsum’s illness. Only bioinformatics tools were used in this study further in-vitro and in-vivo studies are required because phenotypic differences will vary from person to person depending on the expressivity of the gene.

Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12

BackgroundMutations in ABHD12 (OMIM: 613,599) are associated with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) syndrome (OMIM: 612674), which is a rare autosomal recessive neurodegenerative disease. PHARC syndrome is easily misdiagnosed as other neurologic disorders, such as retinitis pigmentosa, Charcot-Marie-Tooth disease, and Refsum disease, due to phenotype variability and slow progression. This paper presents a novel mutation in ABHD12 in two affected siblings with PHARC syndrome phenotypes. In addition, we summarize genotype-phenotype information of the previously reported patients with ABHD12 mutation.MethodsFollowing a thorough medical evaluation, whole-exome sequencing was done on the proband to look for potential genetic causes. This was followed by confirmation of identified variant in the proband and segregation analysis in the family by Sanger sequencing. The variants were interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsA novel pathogenic homozygous frameshift variant, NM_001042472.3:c.601dup, p.(Val201GlyfsTer4), was identified in exon 6 of ABHD12 (ACMG criteria: PVS1 and PM2, PM1, PM4, PP3, and PP4). Through Sanger sequencing, we showed that this variant is co-segregated with the disease in the family. Further medical evaluations confirmed the compatibility of the patients’ phenotype with PHARC syndrome.ConclusionsOur findings expand the spectrum of mutations in the ABHD12 and emphasize the significance of multidisciplinary diagnostic collaboration among clinicians and geneticists to solve the differential diagnosis of related disorders. Moreover, a summary based on mutations found so far in the ABHD12 gene did not suggest a clear genotype-phenotype correlation for PHARC syndrome.

George Alan Garton. 4 June 1922—13 May 2010

Alan Garton and his group at The Rowett Research Institute in Aberdeen made very significant and unique contributions to the understanding of differences in digestion, absorption and metabolism of dietary lipids (fats) and their importance to health in mammalian species, particularly farm animals, but also various aspects of lipid metabolism and health in humans. The group were the first to use commercially available gas chromatography and first, this side of the Atlantic, to employ thin-layer chromatography for lipid analyses. A special adaptation of radio-gas chromatography, developed in-house, also led to the definitive evidence that radio-labelled methylmalonyl-CoA, derived from propionic acid, particularly from grain-fed sheep, can be utilized for fatty acid synthesis. Alan always highlighted the relevance of the group's lipid research to human health and wellbeing, as seen by the role of branched-chain fatty acids in Refsum's disease and the later development of studies of the role of saturated and essential omega-3, -6 and -9 fatty acids, including conjugated linoleic acids and trans fatty acids, in human health and disease by the group.

Phytanic Acid Intake and Lifestyle Modifications on Quality of Life in Individuals with Adult Refsum Disease: A Retrospective Survey Analysis.

Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Many patients with ARD require diet modification, psychosocial support, and various specialist visits to manage their symptoms. In this study, we explored the quality of life in individuals with ARD by analyzing retrospective survey data collected by the Coordination of Rare Diseases at Sanford (CoRDS) Registry and Global Defeat Adult Refsum Everywhere (DARE) Foundation. Statistical tests used were frequencies, mean, and median. There were 32 respondents, ranging between 11 and 32 responses for each question. The mean age at diagnosis was 35.5 ± 14.5 years (range 6-64) with 36.4% male and 63.6% female respondents. The average age for retinitis pigmentosa diagnosis was 22.8 ± 15.7 years (range 2-61). Dieticians were the most frequently seen (41.7%) for management of low-phytanic-acid diets. Most participants exercise at least once per week (92.5%). Depression symptoms were reported in 86.2% of the participants. Early diagnosis of ARD is important for managing symptoms and preventing progression of visual impairment due to phytanic acid buildup. Interdisciplinary approach should be used for patients to address physical and psychosocial impairments of ARD.

Evidence of increases of phytol and chlorophyllide by enzymatic dephytylation of chlorophylls in smoothie made from spinach leaves.

Phytol is a diterpene alcohol found abundantly in nature as the phytyl side chain of chlorophylls. Free form of phytol and its metabolites have been attracting attention because they have a potential to improve the lipid and glucose metabolism. On the other hand, phytol is unfavorable for those who suffering from Refsum's disease. However, there is little information on the phytol contents in leafy vegetables rich in chlorophylls. This study indicated that raw spinach leaves contain phytol of 0.4-1.5mg/100g fresh weight. Furthermore, crude enzyme extracted from the leaves showed the enzyme activities involved in dephytylation of chlorophyll derivatives and they were high at mild alkaline pH and around 45°C, and lowered at 55°C or above. Under the optimum pH and temperature for such enzymes determined in the model reaction using the crude enzyme, phytol content in the smoothie made from raw spinach leaves increased with an increase of chlorophyllide, another reaction product. Comparison between the increased amounts of phytol and chlorophyllide showed that the enzymatic dephytylation of chlorophylls was critically responsible for the increase of phytol in the smoothie. PRACTICAL APPLICATION: Phytol, which is released by the enzymes related to chlorophyll metabolism in plants, has been investigated because of its potential abilities to improve the lipid metabolism and blood glucose level. In contrast to such health benefits, they are known to be toxic for patients suffering from Refsum's disease. This research for the first time reports the phytol content in raw spinach leaves and that phytol can be increased in the smoothie made from spinach leaves by the action of endogenous enzymes on chlorophyll derivatives under a certain condition. These results help control phytol content in the smoothies.

The Value of a Combined Ophthalmogenetic Approach in Differentiating a Presumed Case of Isolated Retinitis Pigmentosa from Refsum Disease

Refsum disease, also known as heredopathia atactica polyneuritiformis (OMIM 266 500), is a rare genetic disorder that is inherited in an autosomal recessive manner.

PEX6 Mutation in a Child with Infantile Refsum Disease—A Case Report and Literature Review

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 PEX6 (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.

Disruption of mitochondrial bioenergetics and calcium homeostasis by phytanic acid in the heart: Potential relevance for the cardiomyopathy in Refsum disease

Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10–30 μM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50–100 μM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca2+, which were prevented by cyclosporin A alone or combined with ADP, suggesting the involvement of the mitochondrial permeability transition (MPT) pore opening. Mitochondrial NAD(P)H content and Ca2+ retention capacity were also decreased by Phyt in the presence of Ca2+. Finally, Phyt significantly reduced cellular viability (MTT reduction) in cultured cardiomyocytes. The present data indicate that Phyt, at concentrations found in the plasma of patients with Refsum disease, disrupts by multiple mechanisms mitochondrial bioenergetics and Ca2+ homeostasis, which could presumably be involved in the cardiomyopathy of this disease.

A CASE REPORT OF ZELLWEGER SYNDROME WITH GLOBAL DEVEOPMENTAL DELAY

Peroxisome biogenesis disorder are related to spectrum of genetic diseases that range from severe Zellweger syndrome to milder infantile Refsum disease. Zellweger syndrome is characterized by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. We report a case of Zellweger syndrome, confirmed by clinical, biochemical and molecular findings, diagnosed in context of dysmorphism, and seizures

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates

ObjectiveBile acid intermediates, 3α,7α,12α-trihydroxycholestanoic acid (THCA) and 3α,7α-dihydroxycholestanoic acid (DHCA), are metabolized in peroxisomes. Some peroxisomal disorders (PDs), such as Zellweger spectrum disorder (ZSD), show an accumulation of bile acid intermediates. In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities. In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness. Here, we established a method for the quantitative determination of bile acid intermediates (THCA/DHCA) for differentiating PDs and assessing bile acid treatment. MethodsSerum samples, obtained from patients with several forms of ZSD as well as peroxisomal β-oxidation enzyme deficiencies, were deproteinized and analyzed using liquid chromatography-mass spectrometry. ResultsLevels of the bile acid intermediates increased significantly in patients with Zellweger syndrome (ZS) and slightly in patients with neonatal adrenoleukodystrophy and infantile Refsum disease (IRD), reflecting the severity of these diseases. One patient with ZS treated with primary bile acids for 6 months showed slightly decreased serum DHCA levels but significantly increased serum THCA levels. One patient with IRD who underwent living-donor liver transplantation showed a rapid decrease in serum THCA and DHCA levels, which remained undetected for 6 years. In all controls, THCA and DHCA levels were below the detection limit. ConclusionThe analytical method developed in this study is useful for diagnosing various PD and validating bile acid treatment. Additionally, it can help predict the prognosis of patients with PD and support treatment strategies.

Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology.

Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization of CVI disease cohorts has been fragmented and lacks integration. By revisiting the genome-wide and phenome-wide association studies (GWAS and PheWAS), we clustered a handful of renowned CVIs into five ontology groups, namely ciliopathies (Joubert syndrome, Bardet–Biedl syndrome, Alstrom syndrome), demyelination diseases (multiple sclerosis, Alexander disease, Pelizaeus–Merzbacher disease), transcriptional deregulation diseases (Mowat–Wilson disease, Pitt–Hopkins disease, Rett syndrome, Cockayne syndrome, X-linked alpha-thalassaemia mental retardation), compromised peroxisome disorders (Zellweger spectrum disorder, Refsum disease), and channelopathies (neuromyelitis optica spectrum disorder), and reviewed several mutation hotspots currently found to be associated with the CVIs. Moreover, we discussed the common manifestations in the brain and the eye, and collated animal study findings to discuss plausible gene editing strategies for future CVI correction.

The physiological functions of human peroxisomes.

Peroxisomes are subcellular organelles that play a central role in human physiology by catalyzing a range of unique metabolic functions. The importance of peroxisomes for human health is exemplified by the existence of a group of usually severe diseases caused by an impairment in one or more peroxisomal functions. Among others these include the Zellweger spectrum disorders, X-linked adrenoleukodystrophy, and Refsum disease. To fulfill their role in metabolism, peroxisomes require continued interaction with other subcellular organelles including lipid droplets, lysosomes, the endoplasmic reticulum, and mitochondria. In recent years it has become clear that the metabolic alliance between peroxisomes and other organelles requires the active participation of tethering proteins to bring the organelles physically closer together, thereby achieving efficient transfer of metabolites. This review intends to describe the current state of knowledge about the metabolic role of peroxisomes in humans, with particular emphasis on the metabolic partnership between peroxisomes and other organelles and the consequences of genetic defects in these processes. We also describe the biogenesis of peroxisomes and the consequences of the multiple genetic defects therein. In addition, we discuss the functional role of peroxisomes in different organs and tissues and include relevant information derived from model systems, notably peroxisomal mouse models. Finally, we pay particular attention to a hitherto underrated role of peroxisomes in viral infections.

Hereditary dystrophies of the posterior segment of the retina

Hereditary dystrophies of the posterior segment are the common name for a group of syndromic diseases in which the retina is affected. Until recently, the information available on these diseases has been limited and a wide range of clinical findings were reported. However, recent advances in genetics research suggest a better outlook. Here we review the recent advances in the following: Pseudoxanthoma Elasticum, Refsum Disease, Bietti Cryistalline Dystrophy, Alport’s Syndrome