Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC).

[LORENZO'S OIL AND ADRENOLEUKODYSTROPHY EXAMINING AN ARTIFICIAL INTELLIGENCE TOOL INTENDED FOR CONDUCTING LITERATURE SEARCHES AND ANALYSES].

Adrenoleukodystrophy is a genetic metabolic disorder characterized by a heterogeneous phenotype. Its severe form, known as cerebral adrenoleukodystrophy, involves unpredictable cerebral damage and progressive central nervous system deterioration. This rare condition became famous because of a Hollywood movie in which the Italian parents of a child with the condition supposedly discovered a medication for treating the condition.

Peroxisomal dysfunction interferes with odontogenesis and leads to developmentally delayed teeth and defects in distinct dental cells in Pex11b-deficient mice.

Human peroxisomal biogenesis disorders of the Zellweger syndrome spectrum affect skeletal development and induce tooth malformations. Whereas several peroxisomal knockout mouse studies elucidated the pathogenesis of skeletal defects, little information is available on how dental pathologies arise in peroxisomal biogenesis disorder patients. To understand the impact of severe peroxisomal dysfunction on early odontogenesis, here we performed morphometric studies on developing molars of new-born Pex11b knockout mice.

Distinguishing gene variant severity for mild, severe, and atypical peroxisome biogenesis disorders in .

Peroxisomal biogenesis disorders (PBD) are autosomal recessive disorders caused by loss-of-function mutations of one of the genes responsible for peroxisomal formation. Impaired peroxisome assembly causes severe multisystemic failure with patient phenotypes ranging from epilepsy, liver disease, feeding issues, biochemical abnormalities, and neurodegeneration. Variants in the same gene can produce wide differences in severity, ranging from individuals with death in the first year of life to adults with milder complications.

Normal very long-chain fatty acids level in a patient with peroxisome biogenesis disorders: a case report.

Background: Zellweger spectrum disorders (ZSDs) are a group of peroxisome biogenesis disorders (PBDs) with different variants in the PEX genes. The main biochemical marker for screening peroxisomal disorders is very long-chain fatty acids (VLCFAs). The study reveals a rare case of PBD in the Zellweger spectrum in which she had normal plasma VLCFA levels.

Mevalonate kinase deficiency: an updated clinical overview and revision of the SHARE recommendations.

Mevalonate kinase deficiency (MKD), a rare auto-inflammatory disorder, arises from mutations in the gene, disrupting isoprenoid biosynthesis, and affecting cellular processes. This comprehensive review provides an updated perspective on MKD, including its aetiology, pathogenesis, diagnostic modalities, and therapeutic strategies. Based on recent research and clinical advances, our objective is to bridge the knowledge gaps in the 2015 SHARE guidelines.

Tandem mass spectrometry of serum cholestanoic (C) acids - Typical concentration ranges and application to the study of peroxisomal biogenesis disorders.

Background: Primary bile acid synthesis is impaired in peroxisomal disorders, leading to the accumulation of long-chain bile acids, specifically dihydroxycholestanoic and trihydroxycholestanoic acids. Quantification of the diastereoisomers of these C bile acids is essential for the differential diagnosis of these disorders.

Methods: High-performance liquid chromatography electrospray ionization-tandem mass spectrometry with stable-isotope dilution was used to quantify all eight diastereoisomers of cholestanoic acids in serum.

Redox system and ROS-related disorders in peroxisomes.

Peroxisomes are essential organelles that help mitigate the oxidative damage caused by reactive oxygen species (ROS) through their antioxidant systems. They perform functions such as α-oxidation, β-oxidation, and the synthesis of cholesterol and ether phospholipids. During the breakdown of specific metabolites, peroxisomes generate ROS as byproducts, which can either be neutralized or contribute to oxidative stress.

Variable clinical phenotypes of alpha-methylacyl-CoA racemase deficiency: Report of four cases and review of the literature.

Alpha-methylacyl-CoA-racemase (AMACR) deficiency (MIM#604489) is a peroxisomal disorder resulting in the accumulation of pristanic acid, dihydroxycholestanoic acid (DHCA), and trihydroxycholestanoic acid (THCA), with variable clinical features and age of onset from infancy to late adulthood. The purpose of this report is to define clinical variations and follow-up data in AMACR deficiency emphasizing treatment with a review of cases reported in the literature. Here, four patients, from two families, diagnosed with AMACR deficiency and showing phenotypic heterogeneity are presented.

From gene to therapy: a review of deciphering the role of ABCD1 in combating X-Linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic disorder caused by ABCD1 mutations, resulting in the buildup of very-long-chain fatty acids, leading to significant neurological decline and adrenal insufficiency. Despite advancements in understanding the mechanisms of X-ALD, its pathophysiology remains incompletely understood, complicating the development of effective treatments. This review provides a comprehensive overview of X-ALD, with a focus on the genetic and biochemical roles of ABCD1 and the impacts of its mutations.

Experiences of mothers of long-term surviving patients with cerebral adrenoleukodystrophy: a qualitative study.

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder. Its cerebral form presents as a learning and behavioral disorder that, if untreated, leads to rapid neurological regression, disability, and death within 10 years of diagnosis. Therefore, the disease significantly impacts patients' quality of life, making quality of life assessment crucial for effective medical treatment and care.

Regulation of Mitochondrial and Peroxisomal Metabolism in Female Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role.

Role of ACSBG1 in Brain Lipid Metabolism and X-Linked Adrenoleukodystrophy Pathogenesis: Insights from a Knockout Mouse Model.

"Bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during mouse brain development, facilitating the activation of long-chain fatty acids (LCFA) and their incorporation into lipid species that are crucial for brain function. ACSBG1 converts LCFA into acyl-CoA derivatives, supporting vital metabolic processes. Fruit fly mutants lacking ACSBG1 exhibited neurodegeneration and had elevated levels of very long-chain fatty acids (VLCFA), characteristics of human X-linked adrenoleukodystrophy (XALD).

Nutritional Counseling and Mediterranean Diet in Adrenoleukodystrophy: A Real-Life Experience.

: Adrenoleukodystrophy (X-ALD) is a metabolic disorder caused by dysfunctional peroxisomal beta-oxidation of very-long-chain fatty acids (VLCFAs). A VLCFA-restricted Mediterranean diet has been proposed for patients and carriers to reduce daily VLCFA intake. : We retrospectively evaluated plasma VLCFAs in a cohort of 36 patients and 20 carriers at baseline and after 1 year of restricted diet.

Role and Function of Peroxisomes in Neuroinflammation.

Peroxisomes are organelles involved in many cellular metabolic functions, including the degradation of very-long-chain fatty acids (VLCFAs; C ≥ 22), the initiation of ether-phospholipid synthesis, and the metabolism of reactive oxygen species. All of these processes are essential for the maintenance of cellular lipid and redox homeostasis, and their perturbation can trigger inflammatory response in immune cells, including in the central nervous system (CNS) resident microglia and astrocytes. Consistently, peroxisomal disorders, a group of congenital diseases caused by a block in peroxisomal biogenesis or the impairment of one of the peroxisomal enzymes, are associated with neuroinflammation.

Characterizing visual processing deficits in cerebral adrenoleukodystrophy.

Background And Objectives: Cerebral adrenoleukodystrophy (CALD) can cause visual impairment, but early symptoms are often missed or misdiagnosed. The framework of cerebral visual impairment (CVI) distinguishes deficits in sensory detection ("lower order") from those of perception and interpretation ("higher order"). This study describes visual deficits in patients with CALD and higher order visual function assessed with a virtual reality (VR) interface combined with eye tracking.

The p97-UBXD8 complex maintains peroxisome abundance by suppressing pexophagy.

Peroxisomes are vital organelles involved in key metabolic functions in eukaryotic cells. Their significance is highlighted by peroxisome biogenesis disorders; severe childhood diseases marked by disrupted lipid metabolism. One mechanism regulating peroxisome abundance is through selective ubiquitylation of peroxisomal membrane proteins that triggers peroxisome degradation via selective autophagy (pexophagy).

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy.

Background: Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy.

Methods: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI).

Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy.

Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics.