-
Frontiers in Neurology 2024[This corrects the article DOI: 10.3389/fneur.2022.1072256.].
[This corrects the article DOI: 10.3389/fneur.2022.1072256.].
PubMed: 38510379
DOI: 10.3389/fneur.2024.1376447 -
Orphanet Journal of Rare Diseases Mar 2024Adrenoleukodystrophy (ALD) is a multifaceted, X-linked, neurodegenerative disorder that comprises several clinical phenotypes. ALD affects patients through a variety of...
BACKGROUND
Adrenoleukodystrophy (ALD) is a multifaceted, X-linked, neurodegenerative disorder that comprises several clinical phenotypes. ALD affects patients through a variety of physical, emotional, social, and other disease-specific factors that collectively contribute to disease burden. To facilitate clinical care and research, it is important to identify which symptoms are most common and relevant to individuals with any subtype of ALD.
METHODS
We conducted semi-structured qualitative interviews and an international cross-sectional study to determine the most prevalent and important symptoms of ALD. Our study included adult participants with a diagnosis of ALD who were recruited from national and international patient registries. Responses were categorized by age, sex, disease phenotype, functional status, and other demographic and clinical features.
RESULTS
Seventeen individuals with ALD participated in qualitative interviews, providing 1709 direct quotes regarding their symptomatic burden. One hundred and nine individuals participated in the cross-sectional survey study, which inquired about 182 unique symptoms representing 24 distinct symptomatic themes. The symptomatic themes with the highest prevalence in the overall ALD sample cohort were problems with balance (90.9%), limitations with mobility or walking (87.3%), fatigue (86.4%), and leg weakness (86.4%). The symptomatic themes with the highest impact scores (on a 0-4 scale with 4 being the most severe) were trouble getting around (2.35), leg weakness (2.25), and problems with balance (2.21). A higher prevalence of symptomatic themes was associated with functional disability, employment disruption, and speech impairment.
CONCLUSIONS
There are many patient-relevant symptoms and themes that contribute to disease burden in individuals with ALD. These symptoms, identified by those having ALD, present key targets for further research and therapeutic development.
Topics: Adult; Humans; Cross-Sectional Studies; Adrenoleukodystrophy; Phenotype; Surveys and Questionnaires; Patient Reported Outcome Measures
PubMed: 38504253
DOI: 10.1186/s13023-024-03129-6 -
Annals of Indian Academy of Neurology 2024
PubMed: 38495248
DOI: 10.4103/aian.aian_983_23 -
International Journal of Molecular... Feb 2024Since its discovery in 2012, the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) system has supposed a... (Review)
Review
Since its discovery in 2012, the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) system has supposed a promising panorama for developing novel and highly precise genome editing-based gene therapy (GT) alternatives, leading to overcoming the challenges associated with classical GT. Classical GT aims to deliver transgenes to the cells via their random integration in the genome or episomal persistence into the nucleus through lentivirus (LV) or adeno-associated virus (AAV), respectively. Although high transgene expression efficiency is achieved by using either LV or AAV, their nature can result in severe side effects in humans. For instance, an LV (NCT03852498)- and AAV9 (NCT05514249)-based GT clinical trials for treating X-linked adrenoleukodystrophy and Duchenne Muscular Dystrophy showed the development of myelodysplastic syndrome and patient's death, respectively. In contrast with classical GT, the CRISPR/Cas9-based genome editing requires the homologous direct repair (HDR) machinery of the cells for inserting the transgene in specific regions of the genome. This sophisticated and well-regulated process is limited in the cell cycle of mammalian cells, and in turn, the nonhomologous end-joining (NHEJ) predominates. Consequently, seeking approaches to increase HDR efficiency over NHEJ is crucial. This manuscript comprehensively reviews the current alternatives for improving the HDR for CRISPR/Cas9-based GTs.
Topics: Animals; Humans; CRISPR-Cas Systems; Recombinational DNA Repair; DNA End-Joining Repair; Gene Editing; Genetic Therapy; Mammals
PubMed: 38473704
DOI: 10.3390/ijms25052456 -
Medical Sciences (Basel, Switzerland) Jan 2024Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and... (Review)
Review
Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and thus, imaging techniques like MRI can be used for a more definitive diagnosis. These diseases are characterized as cerebral lesions with characteristic demyelinating patterns which can be used as differentiating tools. In this review, we talk about these MRI study findings for each leukodystrophy, associated genetics, blood work that can help in differentiation, emerging diagnostics, and a follow-up imaging strategy. The leukodystrophies discussed in this paper include X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe's disease, Pelizaeus-Merzbacher disease, Alexander's disease, Canavan disease, and Aicardi-Goutières Syndrome.
Topics: Humans; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Adrenoleukodystrophy; Neurodegenerative Diseases; Pelizaeus-Merzbacher Disease
PubMed: 38390857
DOI: 10.3390/medsci12010007 -
Cureus Jan 2024Adrenoleukodystrophy, a rare genetic disease associated with the X chromosome (X-ALD - X-linked adrenoleukodystrophy), predominantly affects males and stems from...
Adrenoleukodystrophy, a rare genetic disease associated with the X chromosome (X-ALD - X-linked adrenoleukodystrophy), predominantly affects males and stems from mutations in the gene, responsible for transporting very long chain fatty acids (VLCFA) into peroxisomes. It leads to adrenal insufficiency (AI) and axonal demyelination. In males, the phenotype varies from isolated adrenocortical insufficiency and progressive myelopathy to cerebral adrenoleukodystrophy (CALD). The aim of this case series is to characterize patients with different clinical presentations of X-ALD with follow-up at a tertiary Portuguese hospital. All four patients were males, and the median age at the diagnosis was 5 years. Three patients were diagnosed through family screening, with the oldest already displaying hyperpigmentation. Two distinct forms were identified: adolescent CALD (25%) and isolated primary adrenal insufficiency (75%). Analytical studies revealed elevated plasma VLCFA levels in all cases, and genetic analysis demonstrated two different mutations in the gene. This disorder requires early diagnosis for improved prognosis. Screening male children with primary AIfor X-ALD using a VLCFA panel should be considered, particularly after ruling out the most common causes or when learning difficulties are evident. Genetic confirmation of the diagnosis is essential, enabling genetic counseling, family planning, and preimplantation genetic diagnosis.
PubMed: 38370996
DOI: 10.7759/cureus.52496 -
Journal of Lipid Research Mar 2024The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's...
The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's time-consuming nature and limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS) has successfully been implemented in certain newborn screening programs to diagnose X-linked adrenoleukodystrophy (ALD). However, the diagnostic potential of very long-chain LPCs concentrations in plasma remains poorly understood. This study sought to evaluate the diagnostic performance of C26:0-LPC and other very long-chain LPCs, comparing them to VLCFA analysis in plasma. The study, which included 330 individuals affected by a peroxisomal β-oxidation deficiency and 407 control individuals, revealed that C26:0- and C24:0-LPC concentrations demonstrated the highest diagnostic accuracy (98.8% and 98.4%, respectively), outperforming VLCFA when C26:0/C22:0 and C24:0/C22:0 ratios were combined (98.1%). Combining C24:0- and C26:0-LPC gave the highest sensitivity (99.7%), with ALD females exhibiting notably higher sensitivity compared with the VLCFA ratio combination (98.7% vs. 93.5%, respectively). In contrast, C22:0-LPC exhibited suboptimal performance, primarily due to its low sensitivity (75%), but we identified a potential use to help distinguish between ALD and Zellweger spectrum disorders. In summary, MS/MS analysis of plasma C24:0- and C26:0-LPC concentrations represents a rapid and straightforward approach to diagnose PDs, demonstrating superior diagnostic accuracy, particularly in ALD females, compared with conventional VLCFA biomarkers. We strongly recommend integrating very-long chain LPC plasma analysis in the diagnostic evaluation of individuals suspected of having a PD.
Topics: Infant, Newborn; Female; Humans; Lysophosphatidylcholines; Tandem Mass Spectrometry; Adrenoleukodystrophy; Neonatal Screening; Biomarkers; Fatty Acids, Nonesterified; Fatty Acids
PubMed: 38320654
DOI: 10.1016/j.jlr.2024.100516 -
Biotech (Basel (Switzerland)) Jan 2024Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular... (Review)
Review
Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, β-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost-benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.
PubMed: 38247731
DOI: 10.3390/biotech13010001 -
Journal of Medical Case Reports Jan 2024This article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN)...
Novel ABCD1 variant causes phenotype of adrenomyeloneuropathy with cerebral involvement in Ukrainian siblings: first adult hematopoietic stem cell transplantation for ALD in Ukraine: a case report.
BACKGROUND
This article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN) associated with a novel splice site mutation in the ABCD1 gene. AMN represents a form of X-linked adrenoleukodystrophy (X-ALD) characterized by demyelination of the spinal cord and peripheral nerves. The case also presents the first adult haematopoietic stem cell transplant (HSCT) for adrenomyeloneuropathy in Ukraine. The rarity of this mutation and its cerebral involvement and the treatment make this case noteworthy and underscore the significance of reporting it to contribute to the existing medical knowledge.
CASE PRESENTATION
The patients of 24 and 31 years initially exhibited progressive gait disturbance, lower extremity pain, and urinary incontinence, with the older sibling experiencing more advanced symptoms of speech, hearing, and vision disturbances. A comprehensive genetic analysis identified an unreported splice site mutation in exon 3 of the ABCD1 gene, leading to the manifestation of AMN. The inheritance pattern was consistent with X-linked recessive transmission. The article also outlines the clinical features, magnetic resonance imaging (MRI), and nerve conduction study (NCS) findings. Moreover, it discusses the genetic profile of the affected individuals and female carriers within the family. The younger sibling underwent HSCT, which was complicated by mediastinal lymph node and lung tuberculosis, adding to the complexity of managing adult ALD patients.
CONCLUSIONS
This report emphasizes the importance of genetic testing in diagnosing and comprehending the underlying mechanisms of rare genetic disorders, such as AMN with cerebral involvement. The identification of a novel splice site mutation expands our understanding of the genetic landscape of this condition. Additionally, the challenges and complications encountered during the hematopoietic stem cell transplant procedure underscore the need for cautious consideration and personalized approaches in adult ALD patients.
Topics: Adult; Humans; Male; Adrenoleukodystrophy; ATP Binding Cassette Transporter, Subfamily D, Member 1; Ethnicity; Hematopoietic Stem Cell Transplantation; Phenotype; Siblings; Ukraine
PubMed: 38245786
DOI: 10.1186/s13256-023-04321-1 -
Medicine Jan 2024Adrenomyeloneuropathy (AMN) is a variant type of X-linked adrenoleukodystrophy, and it is a genetic metabolic disease with strong clinical heterogeneity so that it is... (Review)
Review
RATIONALE
Adrenomyeloneuropathy (AMN) is a variant type of X-linked adrenoleukodystrophy, and it is a genetic metabolic disease with strong clinical heterogeneity so that it is easily misdiagnosed and underdiagnosed. Moreover, most patients with AMN have an insidious clinical onset and slow progression. Familiarity with the pathogenesis, clinical features, diagnosis, and treatment of AMN can help identify the disease at an early stage.
PATIENT CONCERNS
We present a case of 35-year-old male, who was admitted to our hospital due to "immobility of the lower limbs for 2 years and worsening for half a year," accompanied by skin darkening and hyperpigmentation of lips, oral mucosa, and areola since puberty.
DIAGNOSIS
The level of very long-chain fatty acids was high and genetic testing depicted that exon 1 of the ABCD1 gene had a missense mutation of C.761c>T, which was diagnosed as AMN.
INTERVENTIONS
Baclofen was administered to improve muscle tension combined with glucocorticoid replacement therapy.
OUTCOMES
The condition was relieved after half a year.
LESSONS
The clinical manifestations of AMN are diverse. When patients with adrenocortical dysfunction complicated with progressive spastic paraplegia of lower limbs are involved, AMN should be highly suspected, and the determination of very long-chain fatty acids and genetic testing should be performed as soon as possible to confirm the diagnosis because early treatment can help prevent or delay the progression of the disease.
Topics: Male; Humans; Adult; Adrenoleukodystrophy; ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenal Insufficiency; Paraplegia; Lower Extremity; Fatty Acids
PubMed: 38215098
DOI: 10.1097/MD.0000000000036946