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Italian Journal of Pediatrics Jul 2024Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose...
BACKGROUND
Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD.
METHODS
We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics.
RESULTS
Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum.
CONCLUSIONS
Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.
Topics: Humans; Adrenoleukodystrophy; Male; Retrospective Studies; ATP Binding Cassette Transporter, Subfamily D, Member 1; Child; Diagnostic Errors; Magnetic Resonance Imaging; Addison Disease
PubMed: 38956688
DOI: 10.1186/s13052-024-01669-y -
International Journal of Hematology Jul 2024Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and...
Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m fludarabine and 180 mg/m Mel or 42 g/m treosulfan were used as conditioning.
PubMed: 38951435
DOI: 10.1007/s12185-024-03810-3 -
BioRxiv : the Preprint Server For... Jun 2024The "bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during the development of the mouse brain, facilitating the activation of long-chain...
The "bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during the development of the mouse brain, facilitating the activation of long-chain fatty acids (LCFAs) and their integration into essential lipid species crucial for brain function. Through its enzymatic activity, ACSBG1 converts LCFAs into acyl-CoA derivatives, supporting vital processes like membrane formation, myelination, and energy production. Its regulatory role significantly influences neuronal growth, synaptic plasticity, and overall brain development, highlighting its importance in maintaining lipid homeostasis and proper brain function. Originally discovered in the fruit fly brain, ACSBG1 attracted attention for its potential implication in X-linked adrenoleukodystrophy (XALD) pathogenesis. Studies using Drosophila melanogaster lacking the ACSBG1 homolog, bubblegum, revealed adult neurodegeneration with elevated levels of very long-chain fatty acids (VLCFA). To explore ACSBG1's role in fatty acid (FA) metabolism and its relevance to XALD, we created an ACSBG1 knockout (Acsbg1 ) mouse model and examined its impact on lipid metabolism during mouse brain development. Phenotypically, Acsbg1 mice resembled wild type (w.t.) mice. Despite its primary expression in tissues affected by XALD, brain, adrenal gland and testis, ACSBG1 depletion did not significantly reduce total ACS enzyme activity in these tissues when using LCFA or VLCFA as substrates. However, analysis unveiled intriguing developmental and compositional changes in FA levels associated with ACSBG1 deficiency. In the adult mouse brain, ACSBG1 expression peaked in the cerebellum, with lower levels observed in other brain regions. Developmentally, ACSBG1 expression in the cerebellum was initially low during the first week of life but increased dramatically thereafter. Cerebellar FA levels were assessed in both w.t. and Acsbg1 mouse brains throughout development, revealing notable differences. While saturated VLCFA levels were typically high in XALD tissues and in fruit flies lacking ACSBG1, cerebella from Acsbg1 mice displayed lower saturated VLCFA levels, especially after about 8 days of age. Additionally, monounsaturated ω9 FA levels exhibited a similar trend as saturated VLCFA, ω3 polyunsaturated FA levels werewhile elevated in Acsbg1 mice. Further analysis of specific FA levels provided additional insights into potential roles for ACSBG1. Notably, the decreased VLCFA levels in Acsbg1 mice primarily stemmed from changes in C24:0 and C26:0, while reduced ω9 FA levels were mainly observed in C18:1 and C24:1. ACSBG1 depletion had minimal effects on saturated long-chain FA or ω6 polyunsaturated FA levels but led to significant increases in specific ω3 FA, such as C20:5 and C22:5. Moreover, the impact of ACSBG1 deficiency on the developmental expression of several cerebellar FA metabolism enzymes, including those required for synthesis of ω3 polyunsaturated FA, was assessed; these FA can potentially be converted into bioactive signaling molecules like eicosanoids and docosanoids. In conclusion, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.
PubMed: 38948805
DOI: 10.1101/2024.06.19.599741 -
Degenerative Neurological and... 2024X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder caused by a pathogenic variant of the ABCD1 gene, leading to impaired peroxisomal function and the...
BACKGROUND
X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder caused by a pathogenic variant of the ABCD1 gene, leading to impaired peroxisomal function and the accumulation of very long-chain fatty acids (VLCFAs). ALD presents a wide range of neurological and adrenal symptoms, ranging from childhood cerebral adrenoleukodystrophy to adrenomyeloneuropathy and adrenal insufficiency. Newborn screening (NBS) for ALD is available in some regions but remains lacking in others, such as India.
CASE PRESENTATION
We present a case of a 10-year-old boy with ALD who presented with seizures, progressive weakness, visual impairment, and adrenal insufficiency. Despite symptomatic management and dietary adjustments, the disease progressed rapidly, leading to respiratory failure and eventual demise. The diagnosis was confirmed through molecular analysis and elevated VLCFA levels. Neuroimaging revealed characteristic white matter changes consistent with ALD.
CONCLUSION
ALD is a devastating disease with no cure, emphasizing the importance of early detection through newborn screening and genetic testing. Management strategies include adrenal hormone therapy, gene therapy, and allogenic stem cell transplantation, as well as investigational treatments such as VLCFA normalization. Our case advocates the need for worldwide NBS and pediatric neurologic follow-up to enable early intervention and improve patient outcomes. Additionally, the association between ALD, recurrent febrile seizures, and unexplained developmental delay warrants further investigation to better understand disease progression and potential therapeutic targets.
PubMed: 38912366
DOI: 10.2147/DNND.S442985 -
Nature Reviews. Neuroscience Jun 2024Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved... (Review)
Review
Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.
PubMed: 38898231
DOI: 10.1038/s41583-024-00829-7 -
Journal of Neuroimmunology Jun 2024The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We...
The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.
PubMed: 38897089
DOI: 10.1016/j.jneuroim.2024.578395 -
BioRxiv : the Preprint Server For... Jun 2024X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy...
X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Similar mutations in ABCD1 may result in a spectrum of phenotypes in males with slow progressing adrenomyeloneuropathy (AMN) and fatal cerebral adrenoleukodystrophy (cALD) dominating the majority of cases. Mouse model of X-ALD does not capture the phenotype differences and an appropriate model to investigate mechanism of disease onset and progress remains a critical need. Induced pluripotent stem cell (iPSC)-derived and cell models derived from them have provided useful tools for investigating cell-type specific disease mechanisms. Here, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two each of apparently healthy control, AMN and cALD patients with non-integrating mRNA-based reprogramming. iPSC lines expanded normally and expressed pluripotency markers Oct4, SOX2, Nanog, SSEA and TRA-1-60. Expression of markers SOX17, brachyury, Desmin, Oxt2 and beta tubulin III demonstrated the ability of the iPSCs to differentiate into all three germ layers. iPSC-derived lines from CTL, AMN and cALD male patients were differentiated into astrocytes. Differentiated AMN and cALD astrocytes lacked ABCD1 expression and accumulated VLCFA, a hallmark of X-ALD. These patient astrocytes provide disease-relevant tools to investigate mechanism of differential neuroinflammatory response and metabolic reprogramming in X-ALD. Further these patient-derived human astrocyte cell models will be valuable for testing new therapeutics.
PubMed: 38854155
DOI: 10.1101/2024.05.31.596696 -
Brain : a Journal of Neurology Jun 2024Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is...
Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is hematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor, or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible to HSCT (n= 8) or awaiting HSCT (n= 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient rapidly died from Covid19. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT.
PubMed: 38832897
DOI: 10.1093/brain/awae169 -
Molecular Therapy : the Journal of the... May 2024X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the...
X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very-long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent β-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivo base editing or prime editing can be harnessed to ameliorate ALD. We developed a humanized mouse model of ALD by inserting a human cDNA containing the pathogenic variant into the mouse Abcd1 locus. The humanized ALD model showed increased levels of VLCFAs. To correct the mutation, we tested both base editing and prime editing and found that base editing using ABE8e(V106W) could correct the mutation in patient-derived fibroblasts at an efficiency of 7.4%. Adeno-associated virus (AAV)-mediated systemic delivery of NG-ABE8e(V106W) enabled robust correction of the pathogenic variant in the mouse brain (correction efficiency: ∼5.5%), spinal cord (∼5.1%), and adrenal gland (∼2%), leading to a significant reduction in the plasma levels of C26:0/C22:0. This established humanized mouse model and the successful correction of the pathogenic variant using a base editor serve as a significant step toward treating human ALD disease.
PubMed: 38796705
DOI: 10.1016/j.ymthe.2024.05.027