Zellweger Syndrome Research Articles

La sindrome di Zellweger: un lavoro di squadra

A 1-month female infant with hypotonia, feeding difficulties, facial dysmorphic signs, hepatomegaly and seizures was admitted to the neonatal intensive care unit. Brain magnetic resonance revealed regions of cortical dysplasia, diffuse polymicrogyria (prominent in the frontal and perisylvian cortex), reduction of white matter volume, delayed myelination and germinolytic cysts. The result of the plasma dosage of very long chain fatty acids was very high. Genetic testing revealed a homozygous pathogenetic mutation of the HSD17B4 gene. Thus, clinical features together with biochemical and genetic findings led to the diagnosis of Zellweger spectrum disorder (ZSD). ZSD is included in peroxisome biogenesis disorders. Before the biochemical and molecular bases had been fully determined, ZSD was defined by a continuum of three phenotypes: Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. To identify a continuum of severity of the disease, the terms “severe,” “intermediate” and “milder” ZSD are now preferred. The individuals with ZSD mainly come to clinical attention in the newborn period or in childhood. Occasionally, the subtlety of symptoms delays diagnosis until adulthood. There is not specific therapy, in the severe ZSD prognosis is poor and survival is usually not beyond the first year of life.

Пероксисомні біогенні порушення в спектрі синдрому Цельвегера: діагностика, моніторинг і лікування відповідно до рекомендацій глобальної фундації пероксисомних захворювань

Стаття присвячена сучасним принципам діагностики та лікування пероксисомних біогенних порушень у спектрі синдрому Цельвегера відповідно до рекомендацій глобальної фундації пероксисомних захворювань 2016 р. Автори представили клінічні особливості захворювань даного спектра. Ураження нервової, кісткової, сечовидільної, ендокринної, сенсорної систем і зубної емалі є характерною ознакою захворювання. Окремо виділено власне клінічне спостереження, пов’язане з порушенням окислення жирних кислот із дуже довгими ланцюгами в дитини раннього віку. Розділ діагностики захворювань спектра синдрому Цельвегера заснований на світових стандартах і включає маркери β-окислення дуже довголанцюжкових жирних кислот, а також α-окислення пристанової і фітанової кислот, метаболізму піпеколінової кислоти й інших пероксисомних дисфункцій. Остаточний діагноз пероксисомних біогенних порушень у спектрі синдрому Цельвегера на сучасному етапі встановлюється методом генетичного тестування, за допомогою методів секвенування нового покоління для генів PEX. Тяжкість неврологічних розладів і прогредієнтний перебіг захворювання, а також можливість лікування Х-зчепленої адренолейкодистрофії відкрили перспективи скринінгу для Х-зчепленої адренолейкодистрофії (X-ALD), заснованого на комбінації рідинної хроматографії і тандемної мас-спектрометрії (LC-MS/MS), для виявлення підвищених рівнів VLCFA у новонароджених у плямах крові. Клінічний моніторинг із моменту встановлення діагнозу включає корекцію стартових порушень і виявлення симптомів захворювання, що з’являються пізніше.

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts.

Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, PEX1G843D. Our screen identified the nitrogen oxide donor, S-nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in PEX1G843D mutant fibroblasts and leads to increased survival and longer lifespan in an in vivo humanized Drosophila model carrying the PEX1G843D mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS.

Very long chain acylcarnitines and lysophosphatidylcholines in screening of peroxisomal disease in children by tandem mass spectrometry.

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.

PEX26 gene genotype-phenotype correlation in neonates with Zellweger syndrome.

BackgroundZellweger syndrome (ZS) is commonly manifested as facial deformities, hypotonia, and liver dysfunction. However, ZS caused by PEX26 gene mutation shows a broad and dispersed clinical pattern. In this study, the PEX26 gene in ZS was analyzed to enrich its clinical characteristics. Meanwhile, phenotypic and genotypic characteristics of Zellweger spectrum disorder (ZSD) induced by PEX26 mutation were evaluated.MethodsThe clinical data of newborn with ZS in our hospital were analyzed retrospectively. We performed WES and found that the infant carried the PEX26 gene variant. We searched the biomedical literature databases (PubMed, Web of Science, and EMBASE) to compare clinical features and genotypes.ResultsThe neonate developed facial deformities, hypotonia, feeding difficulties, and seizures. Her homozygous variant was found in the PEX26 gene (NM_017929: exon2: c.34del) inherited from both parents. Electronic databases, including our case, reported 32 pathogenic variants in PEX26. We found that variation c.292C> T accounted for the largest proportion of PEX26 mutations (16/66, 24.24%). The proportion of deleterious mutations in ZS patients was significantly higher than that in NALD and IRD patients.ConclusionsWe identified pathogenic variations in the PEX26 gene and expanded the known mutant spectrum. By comparing patients with PEX26 mutations, the study determined that a significantly higher percentage of deleterious mutations in ZS was associated with severe clinical phenotypic characteristics.

Zebrafish model of human Zellweger syndrome reveals organ-specific accumulation of distinct fatty acid species and widespread gene expression changes

In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and kidneys, but little is known about the exact pathogenic mechanism. By disrupting the zebrafish pex2 gene, we established a disease model for ZS and found that it exhibits pathological features and metabolic changes similar to those observed in human patients. By comprehensive analysis of the fatty acid profile, we found organ-specific accumulation and reduction of distinct fatty acid species, such as an accumulation of ultra-very-long-chain polyunsaturated fatty acids (ultra-VLC-PUFAs) in the brains of pex2 mutant fish. Transcriptome analysis using microarray also revealed mutant-specific gene expression changes that might lead to the symptoms, including reduction of crystallin, troponin, parvalbumin, and fatty acid metabolic genes. Our data indicated that the loss of peroxisomes results in widespread metabolic and gene expression changes beyond the causative peroxisomal function. These results suggest the genetic and metabolic basis of the pathology of this devastating human disease.

Compound heterozygous p. Arg949Trp and p. Gly970Ala mutations deteriorated the function of PEX1p: A study on PEX1 in a patient with Zellweger syndrome.

The peroxisome is responsible for a variety of vital pathways in primary metabolism, including the very long-chain fatty-acid oxidation and plasmalogen lipid biosynthesis. Autosomal recessive disorder of the Zellweger spectrum (ZSD) is a major subset of peroxisome biogenesis disorders (PBDs) that can be caused by mutations in any of the 14 PEX genes. Zellweger syndrome (ZS) is the foremost common and severe phenotype within the heterogeneous ZSD. However, missense mutations encode proteins with residual functions, which are associated with phenotypes that are milder than ZS. Mutations in the PEX1 gene are among the most prevalent. PEX1 and PEX6 proteins, belonging to the AAA family of ATPases, form a hexameric complex, which is associated with peroxisome membranes and essential for peroxisome biology. In this study, a two-month-old Iranian boy with hypotonia, poor feeding, and difficulty in breathing was diagnosed with Zellweger syndrome. The parents of the patient were second cousins and healthy and no similar cases were observed in the parents' family. The PEX1 gene was sequenced in the patient and his parents. The compound heterozygous mutations, p. Arg949Trp and p. Gly970Ala, were identified in the patient, while the parents were heterozygous for these alleles. Sequence analysis of the mutant PEX1 D2 domain revealed that mutation p. Arg949Trpprecisely occurred in a conserved arginine residue (P4 Arg), which hinders the substrate processing of the complex. Several database records have reported mutation p. Arg949Trp(R949W) but its clinical significance is given as uncertain. We report here a novel mutation, p. Gly970Ala, which is not recorded before and may prevent proper interaction of PEX1 and PEX6 proteins. In summary, the clinical findings and peroxisome profile of the patient suggested that compound heterozygosity for these two missense mutations resulted in a nonfunctional PEX1/PEX6 complex causing the severe ZS phenotype.

A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder

BackgroundPeroxisome 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 PEX1, PEX6, PEX10, PEX12, or PEX26 genes. MethodsWe 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. ResultsSymptoms 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 PEX26 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). ConclusionsOur clinical cases from Dagestan describe the phenotype associated with the c.347 T>A,p.(Leu116Gln), variant in the PEX26 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.

Identification of the Peroxisomal Biogenesis Factor 1 Gene Point Mutation in an Iranian Family with Zellweger Syndrome (ZS)

Background & Objective: Peroxisome biogenesis disorders (PBDs) are a group of diseases with peroxisomal dysfunction. Wide range of symptoms are associated with the disease which are due to mutations in the PEX genes. The PEX1 mutation occurs in Zellweger syndrome (ZS), a severe autosomal recessive condition with hypotonia, intellectual disability, and hepatic enlargement. The present study determined the molecular aspects of ZS in a family in South Khorasan Province, Iran. Materials & Methods: Whole-exome sequencing (WES) was performed, clinical history was taken, and the family pedigree was drawn. Subsequently, Sanger sequencing was performed for unique primers. Afterwards, in terms of ZS phenotype, in silico studies were done to examine the changes that occurred in the protein structure. Results: The PEX1 (NC_000007.14) mutation was detected at location Chr7q21.2. This chromosomal location was anticipated as the disorder-causing variant. GGT (Glycine) changes to GAT (Aspartate) in codon 843 were confirmed by Sanger sequencing. Examination results of the mentioned family revealed a missense mutation in the PEX1. Conclusion: In conclusion, our study indicated a mutation in the PEX1 in the affected family. This mutation is a missense variant at codon 843 in ZS patients. It has an autosomal recessive inheritance pattern. This mutation may be widespread among Iranian population with ZS and can be used for a more desirable personalized medicine.

Depletion of HNRNPA1 induces peroxisomal autophagy by regulating PEX1 expression

Peroxisomes play an essential role in cellular homeostasis by regulating lipid metabolism and the conversion of reactive oxygen species (ROS). Several peroxisomal proteins, known as peroxins (PEXs), control peroxisome biogenesis and degradation. Various mutations in the PEX genes are genetic causes for the development of inheritable peroxisomal-biogenesis disorders, such as Zellweger syndrome. Among the peroxins, PEX1 defects are the most common mutations in Zellweger syndrome. PEX1 is an AAA-ATPase that regulates the recycling of PEX5, which is essential for importing peroxisome matrix proteins. However, the post-transcriptional regulation of PEX1 is largely unknown. Here, we showed that heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) controls PEX1 expression. In addition, we found that depletion of HNRNPA1 induces autophagic degradation of peroxisome, which is blocked in ATG5-knockout cells. In addition, depletion of HNRNPA1 increased peroxisomal ROS levels. Inhibition of the generation of peroxisomal ROS by treatment with NAC significantly suppressed pexophagy in HNRNPA1-deficient cells. Taken together, our results suggest that depletion of HNRNPA1 increases peroxisomal ROS and pexophagy by downregulating PEX1 expression.

Saudi patient with peroxisome biogenesis disorder with novel variant: a case report

Background: Peroxisomes are cells' organelles that responsible for the metabolism of branched-chain and very-long-chain fatty acids (VLCFA), polyamines, and amino acids. Peroxisomal biogenesis factor 6 (PEX6) is one of the factors required for the import of the proteins into peroxisomes. Mutation in any one of PEX genes will result in Zellweger syndrome (ZS), one of the peroxisome biogenesis disorder. Case Presentation: A 11-year-old girl referred was with central hypotonia and global developmental delay and feeding problems. She has an open and flat fontanel. Liver function tests and thyroid-stimulating hormone were elevated. Plasma VLCFA C26, VLCFA C24/C22, and VLCFA C26/C22 were elevated. Cerebrospinal fluid flow artifact and posterior displacement of the basilar artery findings raised the possibility of increased intracranial pressure. X-ray showed mild irregularity in the end plates of the lumbar vertebrae, bilateral coxa valga, irregularity in the articular surfaces of the ossified epiphysis of the upper and lower limbs, and generalized osteopenia. The audiological assessment profound hearing loss in both ears. Inborn error of metabolism, next-generation sequencing gene panel analysis, and whole exome sequencing showed that no pathogenic or likely pathogenic variants explaining the phenotypes. The single nucleotide polymorphisms testing showed a deletion in PEX6 gene (homozygous variant of uncertain significance). Conclusion: We report a case of ZS associated with a new PEX6 mutation that has not been previously reported in the literature.

Overwhelming sepsis in a neonate affected by Zellweger syndrome due to a compound heterozygosis in PEX 6 gene: a case report

BackgroundPeroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction of peroxisomes. Different forms of PBDs are described; the most severe one is the Zellweger syndrome (ZS). We report on an unusual presentation of Zellweger syndrome manifesting in a newborn with severe and fulminant sepsis, causing death during the neonatal period.Case presentationA term male Caucasian neonate presented at birth with hypotonia and poor feeding associated with dysmorphic craniofacial features and skeletal abnormalities. Blood tests showed progressive leukopenia; ultrasounds revealed cerebral and renal abnormalities. He died on the fourth day of life because of an irreversible Gram-negative sepsis. Post-mortem tests on blood and urine samples showed biochemical alterations suggestive of ZS confirmed by genetic test.ConclusionsZS is an early and severe forms of PBDs. Peroxisomes are known to be involved in lipid metabolism, but recent studies suggest their fundamental role in modulating immune response and inflammation. In case of clinical suspicion of ZS it is important to focus the attention on the prevention and management of infections that can rapidly progress to death.

A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder.

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.

PEX6: An Imaging Overlap Between Peroxisomal and Lysosomal Storage Diseases

Peroxisomal disorders are a group of expanding genetic diseases divided into two major categories: peroxisome biogenesis defects (Zellweger spectrum disorder), and single enzymatic defects. Disorders of Peroxisome Biogenesis occur when there are biallelic pathogenic variants in any of the 13 PEX genes, which code for the peroxins, proteins required for peroxisome biogenesis. This group of disorders includes two distinct phenotypes: Rhizomelic Chondrodysplasia Punctata Type-1 and Zellweger Spectrum Disorders (ZSD), of which Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate, and infantile Refsum is the mildest. The spectrum’s most frequent defects are observed in the proteins PEX1 and PEX6, and the most common clinical presentation is Zellweger spectrum, which is often associated with craniofacial dysmorphism with neurologic abnormalities. Typically, the neuroimaging pattern shows several malformative features, including a range of cortical gyral abnormalities such as microgyria and pachygyria, and impairment of the myelination. Nevertheless, we report two siblings with peroxisomal disorder, with unexpected leukodystrophy pattern of the brain mimicking lysosomal storage disease, with classical imaging features of Krabbe disease on brain magnetic resonance image. By whole exome sequencing, we identified two pathogenic variants in compound heterozygosity in PEX6: Chr6:42.933.455 C&gt;T (c.2435G&gt;A), and Chr6:42.935.188 C&gt;T (c.1802G&gt;A). Thus, a final diagnosis of peroxisome disorder was confirmed. The index cases highlight the importance of considering peroxisome disorders as a differential diagnosis for patients with imaging features that resemble Krabbe disease.

Serum very long-chain fatty acids (VLCFA) levels as predictive biomarkers of diseases severity and probability of survival in peroxisomal disorders.

Peroxisomal disorders (PD) are a heterogeneous group of rare diseases caused by a defect in peroxisome biogenesis or a disruption of a peroxisomal function at a single enzyme or at transporter level. The main biochemical markers for PD are very long-chain fatty acids (VLCFA). The aim of the study was to investigate the correlation of basic diagnostic parameter, i.e. VLCFA, with disease severity, determined through the survival time. We performed a retrospective study in patients with PD (n = 31; aged 1 week—21 years). Evaluation of VLCFA results from patients were as follows: 15 patients with classical Zellweger syndrome (ZS), 3 patients with mild outcome of ZS, 9 individuals with D-Bifunctional Protein Deficiency (DBP), and no specified results in the case of 4 patients. Patients with classical ZS had higher VLCFA levels, compared to individuals with mild form of ZS and also to patients with DBP; for C26:0/C22:0: 0.65±0.18; 0.11±0.09; 0.30±0.13 (P < 0.001) and for C26:0: 5.20±1.78; 0.76±0.46; 2.61±0.97[mg/mL] (P < 0.001) respectively. The only variable parameter, i.e. the one that determines the survival time of patients, was C26:0 (Chi2 = 19,311, P < 0.0001). Correlation coefficient between survival time and C26:0 level was statistically significant (r = -0.762), and the results showed that high levels of C26:0 were associated with short survival time.ConclusionVLCFA levels correlate with the severity of the clinical course of ZS, DBP and mild ZSD. The best predictive value for estimating the projected disease severity and survival time is a concentration of C26:0.

Insufficiency of ciliary cholesterol in hereditary Zellweger syndrome

Primary cilia are antenna‐like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis. Cellular cholesterol functions as a direct activator of a seven‐transmembrane oncoprotein called Smoothened (Smo) and thereby induces Smo accumulation on the ciliary membrane where it transduces the Shh signal. However, how cholesterol is supplied to the ciliary membrane remains unclear. Here, we report that peroxisomes are essential for the transport of cholesterol into the ciliary membrane. Zellweger syndrome (ZS) is a peroxisome‐deficient hereditary disorder with several ciliopathy‐related features and cells from these patients showed a reduced cholesterol level in the ciliary membrane. Reverse genetics approaches revealed that the GTP exchange factor Rabin8, the Rab GTPase Rab10, and the microtubule minus‐end‐directed kinesin KIFC3 form a peroxisome‐associated complex to control the movement of peroxisomes along microtubules, enabling communication between peroxisomes and ciliary pocket membranes. Our findings suggest that insufficient ciliary cholesterol levels may underlie ciliopathies.

Recent insights into peroxisome biogenesis and associated diseases.

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.

ETHNIC AND AGE-RELATED PECULIARTIES OF LIPID PEROXIDATION AND ANTIOXIDATIVE PROTECTION

The relevance of this research is determined by a number of factors including Chernobyl tragedy, enforced usage of computer technologies and telecommunication, environmental problems, unhealthy diet poor in poor in vegetables and fruits. This promotes the condition for increased free radical production by the body and antioxidant system emaciation. Alzheimer’s and Parkinson’s diseases, lateral amyotrophic sclerosis and cataract, stroke, brain and spine traumatic injuries have been reported as rapidly growing worldwide. Less common diseases with ethio-pathogenetic mechanisms mentioned above include peroxisomal biogenesis disorders (X-linked adrenoleukodystrophy, Zellweger syndrome), Friedreich ataxia, Niemann-Pick diseases, neurodegeneration accompanied with brain iron accumulation, infantile neuroaxonal dystrophy, ferritinopathy, aceruloplasminemia. Intensive production of free oxygen species underlies the emergence of the diseases, therefore studying their ethiology, pathogenesis, clinical courses and the approaches in their early detection, treatment and prevention is one of the priority directions for genetics, biology, theoretical and applied medicine in order to determine important ethnic and age-related differences. This is of quite significance as many diseases known before as age-related now are affecting more and more of young population. Some diseases are traditionally more prevalent in some populations identified as races due to their common ancestry. It also includes altered prevalence and patterns in different ethnic groups. But nowadays the population of many countries is become more and more ethnically mixed. This is critical in diagnosing and managing some diseases as cardiovascular diseases, some autism forms with epilepsy, ischemic-hypoxic encephalopathy in children. The authors highlight lately determined mechanisms of the impairment in pro-oxidative-antioxidative status as well as some modern medicines and approaches for the correction for some pathological conditions.

Rare health conditions 34: Zellweger syndrome, Stickler syndrome, mucormycosis and Zollinger-Ellison syndrome

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than 1 person in every 2000 and many healthcare assistants (HCAs) and nurses will encounter some of these conditions, given the high number of these conditions. This 34th article will briefly explore four of these conditions: Zellweger syndrome, Stickler syndrome, mucormycosis and Zollinger-Ellison syndrome.

Pipecolic Acid Quantification Using Gas Chromatography-coupled Mass Spectrometry.

Pipecolic acid (Pip), a non-proteinacious product of lysine catabolism, is an important regulator of immunity in plants and humans alike. For instance, Pip accumulation is associated with the genetic disorder Zellweger syndrome, chronic liver diseases, and pyridoxine-dependent epilepsy in humans. In plants, Pip accumulates upon pathogen infection and is required for plant defense. The aminotransferase ALD1 catalyzes biosynthesis of Pip precursor piperideine-2-carboxylic acid, which is converted to Pip via ornithine cyclodeaminase. A variety of methods are used to quantify Pip, and some of these involve use of expensive amino acid analysis kits. Here, we describe a simplified procedure for quantitative analysis of Pip from plant tissues. Pipecolic acid was extracted from leaf tissues along with an internal standard norvaline, derivatized with propyl chloroformate and analyzed by gas chromatography-coupled mass spectrometry using selective ion mode. This procedure is simple, economical, and efficient and does not involve isotopic internal standards or multiple-step derivatizations.