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Paediatric Drugs Mar 2024Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left...
Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations.
Topics: Animals; Humans; Cryopyrin-Associated Periodic Syndromes; Mevalonate Kinase Deficiency; Hereditary Autoinflammatory Diseases; Interleukin-1; Simian Acquired Immunodeficiency Syndrome; Interleukin 1 Receptor Antagonist Protein
PubMed: 38376736
DOI: 10.1007/s40272-023-00615-5 -
Molecular Syndromology Jun 2024Acyl-CoA binding domain containing 5 (ACBD5) deficiency is a newly defined inborn peroxisomal disorder with only 7 patients reported to date. Herein, we report a patient...
INTRODUCTION
Acyl-CoA binding domain containing 5 (ACBD5) deficiency is a newly defined inborn peroxisomal disorder with only 7 patients reported to date. Herein, we report a patient with ACBD5 deficiency who was diagnosed after a complicated diagnostic process.
CASE PRESENTATION
A 6-year-old male patient was admitted with complaints of neuromotor regression and visual disturbances. He had spastic paraparesis dominated with axial hypotonic posturing and horizontal nystagmus. His very-long-chain fatty acid levels were within normal ranges with a slightly elevated C26:0/C22:0 ratio. Brain magnetic resonance imaging revealed white matter involvement. Clinical exome sequencing displayed a novel homozygous intronic splice site variant (c.936 + 2T>G) in the ACBD5 (NM_145698.5) gene.
CONCLUSION
With this report, a novel variant in ACBD5 deficiency was described. Macular dystrophy was demonstrated with optical coherence tomography imaging for the first time in the literature in ACBD5 deficiency. In order to contribute to the knowledge about the clinical, biochemical, and genetic spectrum of ACBD5 deficiency, new patients need to be defined.
PubMed: 38841324
DOI: 10.1159/000535534 -
Cell Reports Feb 2024Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles,...
Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles, present in virtually every eukaryotic cell and mediating key processes in immunometabolism. To date, the full spectrum of PBDs remains to be identified, and the impact PBDs have on immune function is unexplored. This study presents a characterization of the hepatic immune compartment of a neonatal PBD mouse model at single-cell resolution to establish the importance and function of peroxisomes in developmental hematopoiesis. We report that hematopoietic defects are a feature in a severe PBD murine model. Finally, we identify a role for peroxisomes in the regulation of the major histocompatibility class II expression and antigen presentation to CD4 T cells in dendritic cells. This study adds to our understanding of the mechanisms of PBDs and expands our knowledge of the role of peroxisomes in immunometabolism.
Topics: Animals; Mice; Zellweger Syndrome; Peroxisomes; Antigen Presentation; Peroxisomal Disorders
PubMed: 38329874
DOI: 10.1016/j.celrep.2024.113744 -
European Journal of Medical Genetics Apr 2024The PEX11β gene contains four exons and encodes peroxisomal membrane protein 11β, which is involved in peroxisome proliferation and division. Pathogenic variants in...
The PEX11β gene contains four exons and encodes peroxisomal membrane protein 11β, which is involved in peroxisome proliferation and division. Pathogenic variants in this gene result in a rare genetic disorder with autosomal recessive inheritance called peroxisome biogenesis disorder 14B (MIM: 614920). Here, we report two affected siblings with a novel variant (NM_003846: c.11G > A, p. Trp4Ter) in the PEX11β gene that was identified by whole exome sequencing and confirmed by Sanger sequencing. The proband is a 22-year-old Iranian female who was born to consanguineous parents. The homozygous variant (NM_003846: c.11G > A, p. Trp4Ter) in the PEX11β gene was identified in the proband, who presented with cataracts, strabismus, nystagmus, intellectual disability, developmental delay, speech disorders, dry skin, and behavioral problems. Her younger affected brother, who had the same homozygous variant, suffered from similar but slightly milder symptoms. This paper reports the seventh family in the world with novel pathogenic variants in the PEX11β gene as the cause of peroxisome biogenesis disorder 14B. Additionally, the phenotypes of the previously reported patients are reviewed. Some of the phenotypes, such as bilateral congenital cataracts and intellectual disability, were present in all patients. However, other observed symptoms in previous cases, such as abnormal gait, myopia, abnormal muscle strength, hearing loss, gastrointestinal problems, skeletal disorders, and seizures, were not observed in the patients of this study. Further studies on this disorder could be valuable in determining the precise phenotype characteristics of this disease.
Topics: Female; Male; Humans; Young Adult; Adult; Siblings; Iran; Family; Cataract; Intellectual Disability; Membrane Proteins; Peroxisomal Disorders
PubMed: 38423277
DOI: 10.1016/j.ejmg.2024.104928 -
The Journal of Clinical Endocrinology... Oct 2023Incidence and causes of primary adrenal insufficiency (PAI) have not been comprehensively studied in children.
CONTEXT
Incidence and causes of primary adrenal insufficiency (PAI) have not been comprehensively studied in children.
OBJECTIVE
Our objective was to describe the epidemiology and to assess causes of PAI in Finnish children.
METHODS
A population-based descriptive study of PAI in Finnish patients aged 0-20 years.Diagnoses referring to adrenal insufficiency in children born in 1996-2016 were collected from the Finnish National Care Register for Health Care. Patients with PAI were identified by studying patient records. Incidence rates were calculated in relation to person-years in the Finnish population of same age.
RESULTS
Of the 97 patients with PAI, 36% were female. The incidence of PAI was highest during the first year of life (in females 2.7 and in males 4.0/100 000 person-years). At 1-15 years of age, the incidence of PAI in females was 0.3/100 000 and in males 0.6/100 000 person-years. Cumulative incidence was 10/100 000 persons at age of 15 years and 13/100 000 at 20 years. Congenital adrenal hyperplasia was the cause in 57% of all patients and in 88% of patients diagnosed before age of 1 year. Other causes among the 97 patients included autoimmune disease (29%), adrenoleukodystrophy (6%), and other genetic causes (6%). From the age of 5 years, most of the new cases of PAI were due to autoimmune disease.
CONCLUSION
After the first-year peak, the incidence of PAI is relatively constant through ages 1-15 years, and 1 out of 10 000 children are diagnosed with PAI before the age of 15 years.
Topics: Male; Humans; Child; Female; Adult; Adolescent; Infant; Addison Disease; Adrenal Insufficiency; Adrenal Hyperplasia, Congenital; Causality; Adrenoleukodystrophy
PubMed: 37216903
DOI: 10.1210/clinem/dgad283 -
International Journal of Neonatal... Nov 2023Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the gene, encoding for the adrenoleukodystrophy protein (ALDP), leading to defective peroxisomal...
Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the gene, encoding for the adrenoleukodystrophy protein (ALDP), leading to defective peroxisomal β-oxidation of very long-chain and branched-chain fatty acids (VLCFA). ALD manifests in both sexes with a spectrum of phenotypes, but approximately 35% of affected males develop childhood cerebral adrenoleukodystrophy (CCALD), which is lethal without hematopoietic stem cell transplant performed before symptoms start. Hence, ALD was added to the Recommended Uniform Screening Panel after the successful implementation in New York State (2013-2016). To date, thirty-five states have implemented newborn screening (NBS) for ALD, and a few programs have reported on the successes and challenges experienced. However, the overall impact of NBS on early detection of ALD has yet to be fully determined. Here, we conducted a retrospective analysis of VLCFA testing performed by our reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA) over 10 years. Rate of detection, age at diagnosis, and male-to-female ratio were evaluated in patients with abnormal results before and after NBS implementation. After NBS inclusion, a significant increase in abnormal results was observed (471/6930, 6.8% vs. 384/11,670, 3.3%; < 0.0001). Patients with ALDP deficiency identified via NBS were significantly younger (median age: 30 days vs. 21 years; < 0.0001), and males and females were equally represented. ALD inclusion in NBS programs has increased pre-symptomatic detection of this disease, which is critical in preventing adrenal crisis as well as the severe cerebral form.
PubMed: 37987477
DOI: 10.3390/ijns9040064 -
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 -
American Journal of Medical Genetics.... Aug 2023Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for...
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.
Topics: Humans; Infant, Newborn; Zellweger Syndrome; ATPases Associated with Diverse Cellular Activities; Genetic Association Studies; Neonatal Screening; Lysophosphatidylcholines
PubMed: 37144748
DOI: 10.1002/ajmg.a.63234 -
Frontiers in Neurology 2023SCPx deficiency is a rare disorder of peroxisomal beta-oxidation dysfunction, and it has only been documented in two patients thus far. In the previously reported...
SCPx deficiency is a rare disorder of peroxisomal beta-oxidation dysfunction, and it has only been documented in two patients thus far. In the previously reported patients, both patients were primarily presented with slowly progressive dystonia or ataxia, and they both displayed symmetrical lesions in the thalamus and brainstem on magnetic resonance imaging. This study presents the third patient exhibiting a similar neuroimaging abnormality but a notably different clinical phenotype characterized by episodic psychosis. Through whole-exome sequencing, we identified a homozygous splicing mutation in (c.674 + 1G > C), and further RNA sequencing revealed exon 8 skipping in the mature transcripts of . This study significantly expands our understanding of the genotypic and phenotypic spectrum associated with related metabolic encephalopathy.
PubMed: 37905191
DOI: 10.3389/fneur.2023.1270793 -
RMD Open Feb 2024Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens...
OBJECTIVE
Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS).
METHODS
From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit.
RESULTS
At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout.
CONCLUSION
Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.
Topics: Adult; Humans; Child; Female; Adolescent; Male; Prospective Studies; Quality of Life; Familial Mediterranean Fever; Cryopyrin-Associated Periodic Syndromes; Mevalonate Kinase Deficiency; Registries; Antibodies, Monoclonal, Humanized
PubMed: 38360038
DOI: 10.1136/rmdopen-2023-003890