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Frontiers in Cell and Developmental... 2022Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and... (Review)
Review
Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and organelles but also fuel substrates for energy production. However, our current knowledge of lipid processing in the retina are very limited. Peroxisomes play a critical role in lipid homeostasis and genetic disorders with peroxisomal dysfunction have different types of ocular complications. In this review, we focus on the role of peroxisomes in lipid metabolism, including degradation and detoxification of very-long-chain fatty acids, branched-chain fatty acids, dicarboxylic acids, reactive oxygen/nitrogen species, glyoxylate, and amino acids, as well as biosynthesis of docosahexaenoic acid, plasmalogen and bile acids. We also discuss the potential contributions of peroxisomal pathways to eye health and summarize the reported cases of ocular symptoms in patients with peroxisomal disorders, corresponding to each disrupted peroxisomal pathway. We also review the cross-talk between peroxisomes and other organelles such as lysosomes, endoplasmic reticulum and mitochondria.
PubMed: 36187472
DOI: 10.3389/fcell.2022.982564 -
Current Opinion in Endocrinology,... Feb 2020Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular... (Review)
Review
PURPOSE OF REVIEW
Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular dysfunction. The present review is intended to describe the current knowledge of the pathophysiology of ALD and provide an update regarding newborn screening, diagnosis, monitoring, and treatment.
RECENT FINDINGS
New York State initiated newborn screening for ALD on December 30, 2013. Successful ALD newborn screening has led to its addition on other state newborn screens and recommendations for universal screening. Initial incidence reports, based on newborn screening, suggest ALD may be more common than previously described. The Pediatric Endocrine Society has published guidance for monitoring newborn males with ALD and case reports suggest biochemical adrenal insufficiency can be present during early infancy. Allogeneic hematopoietic stem cell transplant and gene therapy have been effective at halting the progression of cerebral ALD.
SUMMARY
Early diagnosis and monitoring for progression of ALD can prevent adrenal crisis and treat the cerebral form of the disease. Initial guidelines for surveillance are likely to evolve as newborn screening not only aids in early detection and therapeutic interventions for ALD, but also expands our knowledge of the natural history of ALD.
Topics: Adrenal Insufficiency; Adrenoleukodystrophy; Child; Diagnosis, Differential; Disease Progression; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Male; Neonatal Screening; Peroxisomal Disorders
PubMed: 31789721
DOI: 10.1097/MED.0000000000000515 -
Rheumatology (Oxford, England) Aug 2023Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in contrast to autoimmune diseases because of the lack of... (Review)
Review
Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in contrast to autoimmune diseases because of the lack of involvement of the adaptive immune system and circulating autoantibodies. The four monogenic AIDs first described are called the 'historical' AIDs and include FMF (associated with MEFV mutations), cryopyrinopathies (associated with NLRP3 mutations), TNF receptor-associated periodic syndrome (associated with TNFRSF1A mutations) and mevalonate kinase deficiency (MKD; associated with MVK mutations). In the last 10 years, >50 new monogenic AIDs have been discovered due to genetic advances. The most important discovery for adult patients is VEXAS syndrome associated with somatic UBA1 mutations leading to an AID affecting mostly elderly men. Diagnosis of monogenic AIDs is based on personal and family history and detailed analysis of symptoms associated with febrile attacks in the context of elevated peripheral inflammatory markers. This review proposes a practical approach for the diagnosis of the main monogenic AIDs among adult patients.
Topics: Male; Humans; Adult; Aged; Hereditary Autoinflammatory Diseases; Fever; Cryopyrin-Associated Periodic Syndromes; Mevalonate Kinase Deficiency; Familial Mediterranean Fever; Pyrin
PubMed: 36575989
DOI: 10.1093/rheumatology/keac712 -
American Journal of Medical Genetics.... Sep 2020The spectrum of peroxisomal disorders is wide and comprises individuals that die in the first year of life, as well as people with sensorineural hearing loss, retinal...
The spectrum of peroxisomal disorders is wide and comprises individuals that die in the first year of life, as well as people with sensorineural hearing loss, retinal dystrophy and amelogenesis imperfecta. In this article, we describe three patients; two diagnosed with Heimler syndrome and a third one with a mild-intermediate phenotype. We arrived at these diagnoses by conducting complete ophthalmic (National Eye Institute), auditory (National Institute of Deafness and Other Communication Disorders), and dental (National Institute of Dental and Craniofacial Research) evaluations, as well as laboratory and genetic testing. Retinal degeneration with macular cystic changes, amelogenesis imperfecta, and sensorineural hearing loss were features shared by the three patients. Patients A and C had pathogenic variants in PEX1 and Patient B, in PEX6. Besides analyzing these cases, we review the literature regarding mild peroxisomal disorders, their pathophysiology, genetics, differential diagnosis, diagnostic methods, and management. We suggest that peroxisomal disorders are considered in every child with sensorineural hearing loss and retinal degeneration. These patients should have a dental evaluation to rule out amelogenesis imperfecta as well as audiologic examination and laboratory testing including peroxisomal biomarkers and genetic testing. Appropriate diagnosis can lead to better genetic counseling and management of the associated comorbidities.
Topics: ATPases Associated with Diverse Cellular Activities; Adolescent; Adult; Amelogenesis Imperfecta; Child; Female; Genetic Counseling; Hearing Loss, Sensorineural; Humans; Male; Membrane Proteins; Nails, Malformed; Pedigree; Peroxisomal Disorders; Phenotype; Retinal Degeneration; Young Adult
PubMed: 32866347
DOI: 10.1002/ajmg.c.31823 -
Cells Dec 2021X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the gene and the accumulation of very long-chain fatty... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories ('biobanking') as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Biomarkers; Genetic Diseases, X-Linked; Humans
PubMed: 34943935
DOI: 10.3390/cells10123427 -
La Revue Du Praticien Oct 2023MEVALONATE KINASE DEFICIENCY. Mevalonate kinase deficiency is a rare, autosomal recessive, auto- inflammatory disease, linked to mutations in the gene MVK, resulting in...
MEVALONATE KINASE DEFICIENCY. Mevalonate kinase deficiency is a rare, autosomal recessive, auto- inflammatory disease, linked to mutations in the gene MVK, resulting in the activation of pyrin inflammasome and hypersecretion of interleukin-1β (IL-1β). The clinical spectrum realizes a continuum which extends from the mild phenotype of the partial MVK deficiency (hyperimmunoglobulinemia D) resulting in periodic fever syndrome to a letal form of mevalonate aciduria (MA, complete MVK deficiency). Symptoms occur before the age of one, often with a trigger. The partial MVK deficiency (HIDS) is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, aphthous stomatitis, digestive, articular and cutaneous symptoms. There is in more in mevalonate aciduria a psychomotor retardation, a failure to thrive, a cerebellar ataxia and a dysmorphic syndrome. The diagnosis is based on the mevalonic aciduria during febrile attack and the search for mutations in MVK. The most severe patients can be treated by anti-IL-1.
Topics: Humans; Mevalonate Kinase Deficiency; Mevalonic Acid; Fever; Mutation; Phenotype
PubMed: 38354005
DOI: No ID Found -
Advances in Experimental Medicine and... 2020Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the... (Review)
Review
Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the diverse functions of this organelle in brain physiology and neurodegeneration, with a particular focus on oxidative stress. We first briefly summarize what is known about the various nexuses among peroxisomes, the central nervous system, oxidative stress, and neurodegenerative disease. Next, we provide a comprehensive overview of the complex interplay among peroxisomes, oxidative stress, and neurodegeneration in patients suffering from primary peroxisomal disorders. Particular examples that are discussed include the prototypic Zellweger spectrum disorders and X-linked adrenoleukodystrophy, the most prevalent peroxisomal disorder. Thereafter, we elaborate on secondary peroxisome dysfunction in more common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Finally, we highlight some issues and challenges that need to be addressed to progress towards therapies and prevention strategies preserving, normalizing, or improving peroxisome activity in patients suffering from neurodegenerative conditions.
Topics: Adrenoleukodystrophy; Alzheimer Disease; Humans; Multiple Sclerosis; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Peroxisomes; Zellweger Syndrome
PubMed: 33417204
DOI: 10.1007/978-3-030-60204-8_2 -
Molecular Diagnosis & Therapy Nov 2021Elivaldogene autotemcel (SKYSONA™, eli-cel; Lenti-D™ gene therapy) is a gene therapy that has been developed by bluebird bio for the treatment of cerebral... (Review)
Review
Elivaldogene autotemcel (SKYSONA™, eli-cel; Lenti-D™ gene therapy) is a gene therapy that has been developed by bluebird bio for the treatment of cerebral adrenoleukodystrophy (CALD), a rare, X-linked genetic disease that mainly affects the nervous system and adrenal glands. In July 2021, elivaldogene autotemcel received its first approval (in the EU) for the treatment of for the treatment of early CALD in patients < 18 years of age, with an ABCD1 genetic mutation, and for whom a human leukocyte antigen (HLA)-matched sibling haematopoietic stem cell (HSC) donor is not available. This article summarizes the milestones in the development of elivaldogene autotemcel leading to this first approval.
Topics: Adrenoleukodystrophy; Genetic Therapy; Humans
PubMed: 34424497
DOI: 10.1007/s40291-021-00555-1 -
Sleep Medicine Mar 2022X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain...
OBJECTIVE/BACKGROUND
X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD.
PATIENTS/METHODS
We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments.
RESULTS AND CONCLUSIONS
Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22-54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life.
Topics: Adrenoleukodystrophy; Adult; Female; Humans; Male; Middle Aged; Neurodegenerative Diseases; Pilot Projects; Prevalence; Quality of Life; Restless Legs Syndrome; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; Young Adult
PubMed: 35245789
DOI: 10.1016/j.sleep.2022.02.008 -
Annals of Indian Academy of Neurology 2022
PubMed: 35693670
DOI: 10.4103/aian.AIAN_486_21