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Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2021To investigate the value of very long chain acylcarnitine (VLCAC) and lysophosphatidylcholine (LPC) in screening of peroxisomal disease in children. Eighteen children...
To investigate the value of very long chain acylcarnitine (VLCAC) and lysophosphatidylcholine (LPC) in screening of peroxisomal disease in children. Eighteen children with peroxisomal disease, including 14 cases of X-linked adrenoleukodystrophy (X-ALD group) and 4 cases of Zellweger syndrome (ZS group) diagnosed based on clinical symptoms, MRI and genetic tests were enrolled in the study; and 200 healthy children were selected as control group. Samples of dried blood spots were collected from all subjects, VLCAC and LPC in dried blood spots were extracted by solvent containing internal isotopic standards hexacosanoylcarnitine (H-C26) and C26:0 lysophosphatidylcholine (H-C26:0-LPC). The eicosanoylcarnitine (C20), docosanoylcarnitine (C22), tetracosanoylcarnitine (C24), hexacosanoylcarnitine (C26), C20:0 lysophosphatidylcholine (C20:0-LPC), C22:0 lysophosphatidylcholine (C22:0-LPC), C24:0 lysophosphatidylcholine (C24:0-LPC) and C26:0 lysophosphatidylcholine (C26:0-LPC) were detected by tandem mass spectrometry (MS/MS). The above 8 indicators and the ratios were compared among the groups using Kruskal-Wallis test and Mann-Whitney test; the contribution of each index to the disease were analyzed by partial least square method. Except C24:0-LPC/C20:0-LPC, there were significant differences in all indicators and ratios among all groups (<0.05 or <0.01). There were differences in most indicators and ratios between X-ALD group and the control group, as well as between ZS group and the control group, but there was no difference between the X-ALD group and the ZS group. PLS-DA analysis showed that the peroxisome disease group (including X-ALD group and ZS group) and the control group were able to be completely separated, and C26 had the highest variable importance for the projection (VIP) value. MS/MS detection of VLCAC and LPC can be used as a screening method for peroxisomal disease, and C26 may be a sensitive indicator for diagnosis.
Topics: Carnitine; Child; Dried Blood Spot Testing; Humans; Lysophosphatidylcholines; Tandem Mass Spectrometry
PubMed: 34704420
DOI: 10.3724/zdxbyxb-2021-0254 -
Molecular Genetics and Metabolism... Dec 2020Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures,...
INTRODUCTION
Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features, and other complications. The gene encodes DBP which is essential for oxidation of peroxisomal substrates. We describe 4 patients - 2 unrelated female girls and 2 monozygotic twin sisters - with DBP deficiency and phenotypic diversity.
PATIENT REPORTS
Patient 1 presented neonatally with hypotonia and seizures, and later on developed global developmental delay and regression, sensorineural hearing loss, nystagmus and cortical blindness. The brain MRI demonstrated bilateral peri-sylvian polymicrogyria. Whole exome sequencing revealed 2 mutations in the gene (c.752G>A, p.(Arg251Gln); c.868 + 1delG).Patient 2 presented with hypotonia, motor delay, and sensorineural hearing loss in infancy, considerable developmental regression during her fourth year, nystagmus, and peripheral neuropathy. Brain MRI demonstrated cerebellar atrophy and abnormal basal ganglia and white matter signal, which appeared after the age of two years. Whole exome sequencing revealed 2 mutations in the gene (c.14 T>G, p.(Leu5Arg); c.752G>A, p.(Arg251Gln)).Patients 3 and 4, two female monozygotic twins, presented with hypotonia, developmental delay, and macrocephaly from birth, and later on also sensorineural hearing loss, infantile spasms and hypsarrhythmia, and adrenal insufficiency. Brain MRI demonstrated delayed myelination, and an assay of peroxisomal beta oxidation suggested DBP deficiency. Sequencing of the gene revealed the same 2 mutations as in patient 1.
DISCUSSION
We describe 4 patients with variable and diverse clinical picture of DBP deficiency and particularly emphasize the clinical, biochemical, and neuroimaging characteristics. Interestingly, the clinical phenotype varied even between patients with the exact two mutations in the gene. In addition, in two of the three patients in whom levels of VLCFA including phytanic acid were measured, the levels were within normal limits. This is expanding further the clinical spectrum of this disorder, which should be considered in the differential diagnosis of every patient with hypotonia and developmental delay especially if accompanied by polymicrogyria, seizures, sensorineural hearing loss, or adrenal insufficiency regardless of their VLCFA profile.
PubMed: 32904102
DOI: 10.1016/j.ymgmr.2020.100631 -
PloS One 2023Peroxisomes are membrane-enclosed organelles with important roles in fatty acid breakdown, bile acid synthesis and biosynthesis of sterols and ether lipids. Defects in...
Peroxisomes are membrane-enclosed organelles with important roles in fatty acid breakdown, bile acid synthesis and biosynthesis of sterols and ether lipids. Defects in peroxisomes result in severe genetic diseases, such as Zellweger syndrome and neonatal adrenoleukodystrophy. However, many aspects of peroxisomal biogenesis are not well understood. Here we investigated delivery of tail-anchored (TA) proteins to peroxisomes in mammalian cells. Using glycosylation assays we showed that peroxisomal TA proteins do not enter the endoplasmic reticulum (ER) in both wild type (WT) and peroxisome-lacking cells. We observed that in cells lacking the essential peroxisome biogenesis factor, PEX19, peroxisomal TA proteins localize mainly to mitochondria. Finally, to investigate peroxisomal TA protein targeting in cells with fully functional peroxisomes we used a proximity biotinylation approach. We showed that while ER-targeted TA construct was exclusively inserted into the ER, peroxisome-targeted TA construct was inserted to both peroxisomes and mitochondria. Thus, in contrast to previous studies, our data suggest that some peroxisomal TA proteins do not insert to the ER prior to their delivery to peroxisomes, instead, mitochondria can be involved.
Topics: Animals; Peroxisomes; Membrane Proteins; Endoplasmic Reticulum; Intracellular Membranes; Mitochondria; Mammals
PubMed: 38039321
DOI: 10.1371/journal.pone.0295047 -
Cureus Sep 2023Zellweger spectrum disorder (ZSD) is a group of autosomal recessive peroxisomal disorders caused by gene mutations that commonly present with symptoms of severe...
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive peroxisomal disorders caused by gene mutations that commonly present with symptoms of severe hypotonia, epileptic seizures, failure to thrive, hepatomegaly, craniofacial dysmorphisms, and sensorineural hearing loss. This article highlights three patients born with ZSD in Central California. All three patients were born to Mixteco mothers. Patients were genetically analyzed, which revealed mutations that correspond to ZSD. They presented with hypotonia at birth, abnormal hepatic panels, and increased fatty acid levels, findings consistent with Zellweger syndrome (ZS). However, only two of three patients displayed sensorineural hearing loss. Two of the patients failed to survive more than one year of age, which reflects the average life expectancy of an infant presenting with ZS. Observed and recorded cases of ZS in the Mixteco population have been postulated to be related to consanguinity and/or a founder effect. Studies have shown that autosomal recessive diseases are more prevalent in consanguineous populations. Consanguinity has been denied by patient 1 and is unknown for patients 2 and 3. Founder mutations have been implicated in areas with high rates of autosomal recessive diseases. All three of our Mixteco patients share a distinct lineage as well as a mutation at , leading us to believe that they suffered from an inherited founder mutation. The Mixteco population is not studied well enough to come to a definitive conclusion; however, the recognition of the relationship between ZS and Mixteco background is important, as it allows parents to plan accordingly and increases awareness in the community.
PubMed: 37842507
DOI: 10.7759/cureus.45162 -
Journal of Applied Genetics Feb 2020Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of...
Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene-c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.
Topics: ATPases Associated with Diverse Cellular Activities; Adolescent; Biomarkers; Brain; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Infant; Magnetic Resonance Imaging; Male; Membrane Proteins; Phenotype; Severity of Illness Index; Symptom Assessment; Young Adult; Zellweger Syndrome
PubMed: 31628608
DOI: 10.1007/s13353-019-00523-w -
Oxford Medical Case Reports Jun 2024Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment...
Pigmentary retinal dystrophy (PRD) is a group of inherited disorders involving the progressive degeneration of rod and cone photoreceptors and the retinal pigment epithelium (RPE), which can progress to pigmentary retinopathy (PR). We present a case of PRD in a female pediatric patient who has pathogenic variants in the PRPH2 and PEX1 genes. The patient has associated macular edema and secondary visual impairment. Treatment has included serial dexamethasone intravitreal implant injections and topical dorzolamide. The PEX1 gene mutation is associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum (PBD-ZSS) and resulting retinal dystrophies. The PRPH2 mutation may play a role in macular edema and PRD, as it is implicated in macular degeneration, choroid defects, and photoreceptor dysfunction. In this case, we review multiple gene mutations playing potential etiologic roles for PRD and discuss care management.
PubMed: 38860019
DOI: 10.1093/omcr/omae067 -
Frontiers in Cell and Developmental... 2020Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both...
Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both transcriptional and post-transcriptional feedback regulation, for which sterol regulatory element-binding proteins (SREBPs) are essential; such homeostasis is dysregulated in peroxisome-deficient knockout mice. Here, we compared the regulation of cholesterol biosynthesis in Chinese hamster ovary (CHO-K1) cells and in three isogenic peroxisome-deficient CHO cell lines harboring gene mutations. Peroxisome deficiency activated expression of cholesterogenic genes, however, cholesterol levels were unchanged. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein levels were increased in mutant cells, whereas HMGCR activity was significantly decreased, resulting in reduced cholesterol synthesis. U18666A, an inhibitor of lysosomal cholesterol export, induced cholesterol biosynthetic enzymes; yet, cholesterol synthesis was still reduced. Interestingly, peroxisome deficiency promoted ER-to-Golgi SREBP cleavage-activating protein (SCAP) trafficking even when cells were cholesterol-loaded. Restoration of functional peroxisomes normalized regulation of cholesterol synthesis and SCAP trafficking. These results highlight the importance of functional peroxisomes for maintaining cholesterol homeostasis and efficient cholesterol synthesis.
PubMed: 33240873
DOI: 10.3389/fcell.2020.560266 -
International Journal of Molecular... Oct 2022Peroxisomal biogenesis disorders (PBDs) are a heterogeneous group of genetic diseases. Multiple peroxisomal pathways are impaired, and very long chain fatty acids...
Peroxisomal biogenesis disorders (PBDs) are a heterogeneous group of genetic diseases. Multiple peroxisomal pathways are impaired, and very long chain fatty acids (VLCFA) are the first line biomarkers for the diagnosis. The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease. The vast majority of PBDs belong to Zellweger Spectrum Disordes (ZSDs) and represents a continuum of overlapping clinical symptoms, with Zellweger syndrome being the most severe and Heimler syndrome the less severe disease. Mild clinical conditions frequently present normal or slight biochemical alterations, making the diagnosis of these patients challenging. In the present study we used a combined WES and RNA-seq strategy to diagnose a patient presenting with retinal dystrophy as the main clinical symptom. Results showed the patient was compound heterozygous for mutations in . VLCFA were normal, but retrospective analysis of lysosphosphatidylcholines (LPC) containing C22:0-C26:0 species was altered. This simple test could avoid the diagnostic odyssey of patients with mild phenotype, such as the individual described here, who was diagnosed very late in adult life. We provide functional data in cell line models that may explain the mild phenotype of the patient by demonstrating the hypomorphic nature of a deep intronic variant altering mRNA processing.
Topics: Humans; ATPases Associated with Diverse Cellular Activities; RNA-Seq; Retrospective Studies; Membrane Proteins; Zellweger Syndrome; Hearing Loss, Sensorineural; Deafness; Biomarkers; RNA, Messenger; Fatty Acids
PubMed: 36293220
DOI: 10.3390/ijms232012367 -
Molecular Genetics and Metabolism... Jun 2021Peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders that affect multiple organ systems. Approximately 80% of PBD patients...
BACKGROUND
Peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders that affect multiple organ systems. Approximately 80% of PBD patients are classifiedin the Zellweger syndrome spectrum, which is generally caused by mutations in the , or genes.
METHODS
We present the clinical characteristics of three male members with cholestatic hepatopathy and developmental delay. Next-Generation Sequencing (NGS) was used to analyze 52 genes responsible for hereditary diseases with cholestasis. The variant was confirmed by Sanger sequencing. Dried blood spot (DBS) samples of 537 newborns from Dagestan were tested for the presence of that mutation. The frequency of the mutant allele in the population of Dagestan wasestimated using the Hardy-Weinberg equilibrium.
RESULTS
Symptoms of disease manifested from the first months of life as severe hepatic dysfunction and developmental delay. Physical examination showed jaundice, hepatosplenomegaly, coagulopathy, and normal or slightly elevated level of gamma-glutamyltransferase (GGT), similar to progressive familial intrahepatic cholestasis. The level of C26 and ratio of C26/C22 in plasma were increased. A nucleotide variant in the gene was identified: NM_017929.6:c.347 T>A, p.(Leu116Gln) in a homozygous state. Parents and healthy siblings were heterozygous for the mutant allele. This variant was not described in the Database of Single Nucleotide Polymorphism (dbSNP), it is not registered in the Human Gene Mutation Database (HGMD) v. 2020.1. The frequency of the mutant allele in the population of Dagestan is estimated to be less than 0.000931 (99% CI, 0.000929-0.000934).
CONCLUSIONS
Our clinical cases from Dagestan describe the phenotype associated with the c.347 T>A,p.(Leu116Gln), variant in the gene. We show that the onset of the clinical picture in patients with Zellweger syndrome spectrum could start with severe hepatic dysfunction and cholestasis. We suggest that biochemical screening of PBD in infants with cholestasis is necessary.
PubMed: 33912394
DOI: 10.1016/j.ymgmr.2021.100754 -
Molecular Genetics and Metabolism... Sep 2020Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin...
Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in : the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes genes.
PubMed: 32596134
DOI: 10.1016/j.ymgmr.2020.100615