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Orphanet Journal of Rare Diseases Nov 2023Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are...
BACKGROUND
Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs.
METHODS
Three patients with ZSD (2 M, 1 F; age range 8-17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy.
RESULTS
X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20-19.92) and 2.90-fold (range 1.43-4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio.
CONCLUSIONS
In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.
Topics: Humans; Child; Adolescent; Child, Preschool; Young Adult; Adult; Adrenoleukodystrophy; Zellweger Syndrome; Leukocytes, Mononuclear; Peroxisomes; Oxidation-Reduction
PubMed: 37974207
DOI: 10.1186/s13023-023-02940-x -
Parkinsonism & Related Disorders Aug 2019X-linked adrenoleukodystrophy (ALD) and Zellweger spectrum disorder (ZSD) are peroxisomal diseases characterized by accumulation of very long chain fatty acids (VLCFA)...
INTRODUCTION
X-linked adrenoleukodystrophy (ALD) and Zellweger spectrum disorder (ZSD) are peroxisomal diseases characterized by accumulation of very long chain fatty acids (VLCFA) in plasma and tissues. Considering the wide variability of manifestation, patients of ALD and atypical ZSD are easily misdiagnosed as hereditary spastic paraplegia (HSP) on their clinical grounds. Here, we aimed to determine the frequency of peroxisome diseases and compare their phenotypic spectra with HSP.
METHODS
We first applied targeted sequencing in 120 pedigrees with spastic paraplegia, and subsequently confirmed 74 HSP families. We then performed whole exome sequencing for the probands of the 46 remaining pedigrees lacking known HSP-causal genes. Detailed clinical, radiological features, and VLCFA analyses are presented.
RESULTS
Seven ALD pedigrees with ABCD1 mutations and one ZSD family harboring bi-allelic mutations of PEX16 were identified. Clinically, in addition to spastic paraplegia, four ALD probands presented adrenocortical insufficiency, and the ZSD proband and her affected sister both developed thyroid problems. VLCFA analysis showed that ratios of C24/C22 and C26/C22 were specifically increased in ALD probands. Moreover, three ALD probands and the ZSD proband had abnormalities in brain or spinal imaging.
CONCLUSIONS
Our study reports the first ZSD case in China that manifested spastic paraplegia, and emphasized the finding that peroxisomal diseases comprise a significant proportion (8/120) of spastic paraplegia entities. These findings extend our current understanding of the ALD and ZSD diseases.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Adult; China; Female; Humans; Male; Membrane Proteins; Pedigree; Spastic Paraplegia, Hereditary; Young Adult; Zellweger Syndrome
PubMed: 31227335
DOI: 10.1016/j.parkreldis.2019.06.008 -
Frontiers in Pediatrics 2022Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome...
BACKGROUND
Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome assembly. The presence of peroxisome enzyme deficiencies leads to complex developmental sequelae, progressive disabilities, and multiorgan damage, due to intracellular accumulation of very-long-chain fatty acids (VLCFAs).
CASE PRESENTATION
We report the case of an infant affected by ZS in which agammaglobulinemia, detected through neonatal screening of congenital immunodeficiencies, appeared as a peculiar trait standing out among all the other classical characteristics of the syndrome. The exome analysis through next-generation sequencing (NGS), which had previously confirmed the diagnostic suspicion of ZS, was repeated, but no mutations causative of inborn error of immunity (humoral defect) were detected.
CONCLUSION
In this case, no genetic variants accountable for the abovementioned agammaglobulinemia were detected. Given that the scientific literature reports the involvement of peroxisomes in the activation of Nuclear Factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway, which is crucial for B-cell survival, with this work, we hypothesize the existence of a link between ZS and humoral immunodeficiencies. Further studies are required to confirm this hypothesis.
PubMed: 35402347
DOI: 10.3389/fped.2022.852943 -
Advances in Experimental Medicine and... 2020Zellweger syndrome disorders (ZSD) is the principal group of peroxisomal disorders characterized by a defect of peroxisome biogenesis due to mutations in one of the 13...
Zellweger syndrome disorders (ZSD) is the principal group of peroxisomal disorders characterized by a defect of peroxisome biogenesis due to mutations in one of the 13 PEX genes. The clinical spectrum is very large with a continuum from antenatal forms to adult presentation. Whereas biochemical profile in body fluids is classically used for their diagnosis, the revolution of high-throughput sequencing has extended the knowledge about these disorders. The aim of this review is to offer a large panorama on molecular basis, clinical presentation and treatment of ZSD, and to update the diagnosis strategy of these disorders in the era of next-generation sequencing (NGS).
Topics: Adult; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Infant, Newborn, Diseases; Mutation; Peroxisomes; Zellweger Syndrome
PubMed: 33417208
DOI: 10.1007/978-3-030-60204-8_6 -
Molecular Genetics and Metabolism... Jun 2020
PubMed: 32373468
DOI: 10.1016/j.ymgmr.2020.100590 -
Neurological Sciences : Official... Jul 2021At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger...
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.
Topics: Child; Egypt; Founder Effect; Humans; Infant, Newborn; Membrane Proteins; Mutation; Peroxisomal Disorders; Zellweger Syndrome
PubMed: 33123925
DOI: 10.1007/s10072-020-04843-2 -
Orphanet Journal of Rare Diseases Jun 2023
Correction: Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
PubMed: 37322480
DOI: 10.1186/s13023-023-02752-z -
The International Journal of... Nov 2023
Topics: Humans; Takotsubo Cardiomyopathy; Predictive Value of Tests; Heart; Electrocardiography; Acute Coronary Syndrome
PubMed: 37530970
DOI: 10.1007/s10554-023-02921-y -
EMBO Reports Oct 2021Zellweger spectrum disorder (ZSD) is the most severe peroxisomal biogenesis disorder (PBD). Why ZSD patients not only loose functional peroxisomes but also present with...
Zellweger spectrum disorder (ZSD) is the most severe peroxisomal biogenesis disorder (PBD). Why ZSD patients not only loose functional peroxisomes but also present with severe mitochondrial dysfunction was a long-standing mystery. In this issue, Nuebel et al (2021) identified that loss of peroxisomes leads to re-routing of peroxisomal proteins to mitochondria, thereby impairing mitochondrial structure and function. The findings provide the first molecular understanding of the mitochondrial-peroxisomal link in ZSD.
Topics: Humans; Mitochondria; Peroxins; Peroxisomal Disorders; Peroxisomes; Zellweger Syndrome
PubMed: 34414648
DOI: 10.15252/embr.202153790 -
EMBO Reports Oct 2021Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological...
Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
Topics: Humans; Mitochondria; Peroxins; Peroxisomal Disorders; Peroxisomes; Zellweger Syndrome
PubMed: 34351705
DOI: 10.15252/embr.202051991