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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 -
Nutrients May 2023Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa,...
Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Many patients with ARD require diet modification, psychosocial support, and various specialist visits to manage their symptoms. In this study, we explored the quality of life in individuals with ARD by analyzing retrospective survey data collected by the Coordination of Rare Diseases at Sanford (CoRDS) Registry and Global Defeat Adult Refsum Everywhere (DARE) Foundation. Statistical tests used were frequencies, mean, and median. There were 32 respondents, ranging between 11 and 32 responses for each question. The mean age at diagnosis was 35.5 ± 14.5 years (range 6-64) with 36.4% male and 63.6% female respondents. The average age for retinitis pigmentosa diagnosis was 22.8 ± 15.7 years (range 2-61). Dieticians were the most frequently seen (41.7%) for management of low-phytanic-acid diets. Most participants exercise at least once per week (92.5%). Depression symptoms were reported in 86.2% of the participants. Early diagnosis of ARD is important for managing symptoms and preventing progression of visual impairment due to phytanic acid buildup. Interdisciplinary approach should be used for patients to address physical and psychosocial impairments of ARD.
Topics: Adult; Humans; Male; Female; Child, Preschool; Child; Adolescent; Young Adult; Middle Aged; Refsum Disease; Phytanic Acid; Retrospective Studies; Quality of Life; Retinitis Pigmentosa; Life Style
PubMed: 37299514
DOI: 10.3390/nu15112551 -
Indian Dermatology Online Journal 2023Zellweger syndrome (ZS) is a rare autosomal recessive, peroxisomal biogenesis disorder (PBD) that occurs due to a mutation in any of the thirteen peroxin ) genes. It is...
Zellweger syndrome (ZS) is a rare autosomal recessive, peroxisomal biogenesis disorder (PBD) that occurs due to a mutation in any of the thirteen peroxin ) genes. It is reported to manifest with varying degrees of severity, ranging from non-specific gastrointestinal abnormalities, nail and enamel defects to multisystem involvement (cerebro-hepato-renal syndrome, eye, ear, and neurological abnormalities). Uncombable hair syndrome (UHS) is a rare hair shaft disorder characterized by dry, frizzy, unmanageable hair. Diagnosis of UHS can be confirmed by scanning electron microscopy (SEM), which reveals a triangular cross-section of the hair. We report a case of UHS with a hitherto unreported association of ZS (due to a homozygous mutation of 12).
PubMed: 37266105
DOI: 10.4103/idoj.idoj_467_22 -
Annals of Clinical and Translational... Jul 2023Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF)...
OBJECTIVE
Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF) neurofilament light chain (cNfL) is a sensitive biomarker for detecting CALD and assessing response to hematopoietic stem cell transplantation (HSCT).
METHODS
We conducted a cross-sectional study of 41 male ALD patients. The cNfL levels in patients with the cerebral form of ALD (CALD) or the cerebello-brainstem form of ALD were compared with those in patients with adrenomyeloneuropathy (AMN). The correlation between cNfL levels and MRI-based Loes severity scores was investigated. A longitudinal analysis was performed on patients who underwent multiple CSF examinations.
RESULTS
The cNfL levels in 22 patients with CALD were significantly higher than those in 14 patients with AMN (median, 5545 vs. 1490 pg/mL; p < 0.001). The cutoff cNfL level of 1930 pg/mL showed good sensitivity (95.5%) and specificity (85.7%) for distinguishing CALD from AMN. The cNfL levels were positively correlated with Loes scores (p < 0.001). The cNfL levels in three AMN patients who later converted to CALD increased above the cutoff level during the conversion period, while the cNfL levels in four patients who remained in AMN were consistently below the cutoff. In 10 ALD patients who underwent HSCT, their cNfL levels decreased 3-24 months after HSCT. Two patients whose cNfL increased after HSCT showed deterioration in cognitive functions.
INTERPRETATION
The cNfL level is useful for evaluating the disease activities of ALD and the response to HSCT.
Topics: Humans; Male; Adrenoleukodystrophy; Cross-Sectional Studies; Intermediate Filaments; Biomarkers; Hematopoietic Stem Cell Transplantation
PubMed: 37259474
DOI: 10.1002/acn3.51818 -
Molecular Genetics and Metabolism Jul 2023Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for...
Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.
Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for a panel of genes implicated in peroxisomal diseases are critical tools for the early and accurate detection of these disorders. It is therefore essential to evaluate the clinical validity of the genes included in sequencing panels for peroxisomal disorders. The Peroxisomal Gene Curation Expert Panel (GCEP) assessed genes frequently included on clinical peroxisomal testing panels using the Clinical Genome Resource (ClinGen) gene-disease validity curation framework and classified gene-disease relationships as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. Subsequent to gene curation, the GCEP made recommendations to update the disease nomenclature and ontology in the Monarch Disease Ontology (Mondo) database. Thirty-six genes were assessed for the strength of evidence supporting their role in peroxisomal disease, leading to 36 gene-disease relationships, after two genes were removed for their lack of a role in peroxisomal disease and two genes were curated for two different disease entities each. Of these, 23 were classified as Definitive (64%), one as Strong (3%), eight as Moderate (23%), two as Limited (5%), and two as No known disease relationship (5%). No contradictory evidence was found to classify any relationships as Disputed or Refuted. The gene-disease relationship curations are publicly available on the ClinGen website (https://clinicalgenome.org/affiliation/40049/). The changes to peroxisomal disease nomenclature are displayed on the Mondo website (http://purl.obolibrary.org/obo/MONDO_0019053). The Peroxisomal GCEP-curated gene-disease relationships will inform clinical and laboratory diagnostics and enhance molecular testing and reporting. As new data will emerge, the gene-disease classifications asserted by the Peroxisomal GCEP will be re-evaluated periodically.
Topics: Infant, Newborn; Humans; Neonatal Screening; Molecular Diagnostic Techniques; Databases, Factual; Genetic Testing
PubMed: 37236006
DOI: 10.1016/j.ymgme.2023.107604 -
The Journal of Clinical Endocrinology... Oct 2023Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn...
CONTEXT
Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported.
OBJECTIVE
To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD.
DESIGN
We conducted a retrospective medical chart review of pediatric patients with ALD.
SETTING
All patients were seen in a leukodystrophy clinic in an academic medical center.
PATIENTS
We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys).
MAIN OUTCOME MEASURES
We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD.
RESULTS
Thirty-one (27%) patients were diagnosed with ALD by NBS, and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9, 12.12] months vs 6.05 [3.74, 8.35] years) (P < .001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period.
CONCLUSIONS
Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.
Topics: Male; Infant, Newborn; Humans; Child; Female; Adrenoleukodystrophy; Retrospective Studies; Neonatal Screening; Adrenal Insufficiency; Early Diagnosis
PubMed: 37220095
DOI: 10.1210/clinem/dgad286 -
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 -
Orphanet Journal of Rare Diseases May 2023The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused...
Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.
BACKGROUND
The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused by deficiencies in peroxisome function and are segmented into enzyme-and-transporter defects (defects in single peroxisomal proteins) and peroxisome biogenesis disorders (defects in the peroxin proteins, critical for normal peroxisome assembly and biogenesis). In this study, we employed multivariate supervised and non-supervised statistical methods and utilized mass spectrometry data of neurological patients, peroxisomal disorder patients (X-linked adrenoleukodystrophy and Zellweger syndrome), and healthy controls to analyze the role of common metabolites in peroxisomal disorders, to develop and refine a classification models of X-linked adrenoleukodystrophy and Zellweger syndrome, and to explore analytes with utility in rapid screening and diagnostics.
RESULTS
T-SNE, PCA, and (sparse) PLS-DA, operated on mass spectrometry data of patients and healthy controls were utilized in this study. The performance of exploratory PLS-DA models was assessed to determine a suitable number of latent components and variables to retain for sparse PLS-DA models. Reduced-features (sparse) PLS-DA models achieved excellent classification performance of X-linked adrenoleukodystrophy and Zellweger syndrome patients.
CONCLUSIONS
Our study demonstrated metabolic differences between healthy controls, neurological patients, and peroxisomal disorder (X-linked adrenoleukodystrophy and Zellweger syndrome) patients, refined classification models and showed the potential utility of hexacosanoylcarnitine (C26:0-carnitine) as a screening analyte for Chinese patients in the context of a multivariate discriminant model predictive of peroxisomal disorders.
Topics: Child; Humans; Adrenoleukodystrophy; East Asian People; Multivariate Analysis; Peroxisomal Disorders; Zellweger Syndrome; China
PubMed: 37189159
DOI: 10.1186/s13023-023-02673-x -
Annals of Indian Academy of Neurology 2023Inborn errors of metabolism (IEM) are a rare cause of epilepsy in pediatric age group. Prompt diagnosis is essential, as some of these disorders are treatable.
INTRODUCTION
Inborn errors of metabolism (IEM) are a rare cause of epilepsy in pediatric age group. Prompt diagnosis is essential, as some of these disorders are treatable.
AIM
To determine the prevalence, clinical, and etiological profile of metabolic epilepsy in children.
METHODS
A prospective observational study of children with new onset seizures diagnosed as inherited metabolic disorder in a tertiary care hospital, South India.
RESULTS
Among 10,778 children with new onset seizures, 63 (0.58%) had metabolic epilepsy. The male female ratio was 1.3:1. Onset of the seizures were in neonatal period in 12 (19%), infancy in 35 (55.6%), and between one and 5 years of age in 16 (25.4%) children. Generalised seizures were seen in 46 (73%), followed by multiple seizure types (31.7%). The associated clinical features included developmental delay in 37 (58.7%), hyperactivity in 7 (11%), microcephaly in 13 (20.6%), optic atrophy in 12 (19%), sparse hair and/or seborrheic dermatitis in 10 (15.9%), movement disorder in 7 (11%), and focal deficit in 27 (42.9%) patients. Magnetic resonance imaging brain was abnormal in 44 (69.8%) and diagnostic in 28 (44.4%) patients. Causative metabolic errors included vitamin responsive errors in 20 (31.7%), disorders of complex molecules in 13 (20.6%), amino acidopathies in 12 (19%), organic acidemias in 10 (16%), disorders of energy metabolism in 6 (9.5%), and peroxisomal disorders in 2 (3.2%) patients. With specific treatment, seizure freedom could be achieved in 45 (71%) children. Five children lost to follow-up and two died. Among the remaining 56 patients, 11 (19.6%) had a good neurological outcome.
CONCLUSION
Vitamin responsive epilepsies were the most frequent cause of metabolic epilepsy. Early diagnosis and prompt treatment is necessary as only one-fifth had a good neurological outcome.
PubMed: 37179663
DOI: 10.4103/aian.aian_842_22 -
Acta Neuropathologica Communications May 2023Peroxisomes are eukaryotic organelles that rapidly change in number depending on the metabolic requirement of distinct cell types and tissues. In the brain, these...
Peroxisomes are eukaryotic organelles that rapidly change in number depending on the metabolic requirement of distinct cell types and tissues. In the brain, these organelles are essential for neuronal migration and myelination during development and their dysfunction is associated with age-related neurodegenerative diseases. Except for one study analysing ABCD3-positive peroxisomes in neurons of the frontal neocortex of Alzheimer disease (AD) patients, no data on other brain regions or peroxisomal proteins are available. In the present morphometric study, we quantified peroxisomes labelled with PEX14, a metabolism-independent peroxisome marker, in 13 different brain areas of 8 patients each either with low, intermediate or high AD neuropathological changes compared to 10 control patients. Classification of patient samples was based on the official ABC score. During AD-stage progression, the peroxisome density decreased in the area entorhinalis, parietal/occipital neocortex and cerebellum, it increased and in later AD-stage patients decreased in the subiculum and hippocampal CA3 region, frontal neocortex and pontine gray and it remained unchanged in the gyrus dentatus, temporal neocortex, striatum and inferior olive. Moreover, we investigated the density of catalase-positive peroxisomes in a subset of patients (> 80 years), focussing on regions with significant alterations of PEX14-positive peroxisomes. In hippocampal neurons, only one third of all peroxisomes contained detectable levels of catalase exhibiting constant density at all AD stages. Whereas the density of all peroxisomes in neocortical neurons was only half of the one of the hippocampus, two thirds of them were catalase-positive exhibiting increased levels at higher ABC scores. In conclusion, we observed spatiotemporal differences in the response of peroxisomes to different stages of AD-associated pathologies.
Topics: Humans; Alzheimer Disease; Peroxisomes; Catalase; Pilot Projects; Neocortex
PubMed: 37170361
DOI: 10.1186/s40478-023-01567-0