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Current Neurology and Neuroscience... Oct 2014X-linked adrenoleukodystrophy (X-ALD) is a puzzling inborn error of metabolism with a strikingly heterogeneous clinical spectrum. All patients have mutations in the... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD) is a puzzling inborn error of metabolism with a strikingly heterogeneous clinical spectrum. All patients have mutations in the ABCD1 gene and accumulate very long chain fatty acids in all tissues. Virtually all male X-ALD patients develop adrenocortical insufficiency in childhood and progressive myelopathy and peripheral neuropathy in adulthood. A subset of male patients, however, develops a fatal cerebral demyelinating disease, cerebral adrenoleukodystrophy. Female patients also develop progressive myelopathy and peripheral neuropathy, but generally at a later age than males. They only very rarely develop adrenocortical insufficiency or cerebral adrenoleukodystrophy. This review proposes to simplify the classification of the clinical spectrum of X-ALD and reviews the largely unresolved pathophysiological mechanisms and the current treatment options.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Addison Disease; Adrenoleukodystrophy; Disease Progression; Humans; Mutation; Peripheral Nervous System Diseases; Spinal Cord Diseases
PubMed: 25115486
DOI: 10.1007/s11910-014-0486-0 -
Endocrine Reviews Aug 2020Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical... (Review)
Review
Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 - 17, 2020).
Topics: Adrenal Insufficiency; Adrenoleukodystrophy; Genetic Testing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Male; Neonatal Screening
PubMed: 32364223
DOI: 10.1210/endrev/bnaa013 -
Expert Opinion on Biological Therapy Sep 2022Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the gene. By... (Review)
Review
INTRODUCTION
Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the gene. By adulthood, approximately 40% of the patients develop cerebral ALD, a severe, neuroinflammatory condition that is generally progressive and fatal without intervention.
AREAS COVERED
Historically, only allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to halt progression of cerebral ALD, with superior outcomes obtained when HSCT is performed early in the disease process. More recently, a lentiviral-based gene therapy approach has been investigated as therapy for cerebral ALD as an alternative to allogeneic transplantation. A focused literature review was performed using the terms 'hematopoietic stem cell transplantation,' 'gene therapy' and 'adrenoleukodystrophy' to include relevant literature, especially comparing the experience with gene therapy and HSCT outcomes. We review the history and experience with HSCT in cerebral ALD and its limitations, as well as the information currently available in association with the gene therapy trials for cerebral ALD.
EXPERT OPINION
The data regarding this lentiviral-based gene therapy approach and its relative risks and benefits is still being evaluated. This information is explored in the context of the experience with allogeneic HSCT for cerebral ALD.
Topics: Adrenoleukodystrophy; Adult; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation, Homologous
PubMed: 36107226
DOI: 10.1080/14712598.2022.2124857 -
Frontiers in Endocrinology 2023X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
Topics: Adult; Humans; Male; Female; Child; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Addison Disease; Fatty Acids; Adrenal Cortex; Glucocorticoids
PubMed: 38034003
DOI: 10.3389/fendo.2023.1309053 -
Current Opinion in Endocrinology,... Feb 2023The present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD). (Review)
Review
PURPOSE OF REVIEW
The present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD).
RECENT FINDINGS
Although ALD screening has been on the list of Recommended Uniform Screening Panel since 2016, only 30 states in the United States are currently testing their newborns for this disease. Hematopoietic stem cell transplant (HSCT) remains the only successful treatment option available for early cerebral ALD but does not reverse neurological changes or affect the course of adrenal insufficiency. There remains a significant knowledge gap in our understanding and treatment of this disease. Novel therapies such as gene therapy and gene editing have shown promising results in animal models and are exciting potential treatment options for the future.Recently, the American Academy of Neurologists released their consensus guidelines on the diagnosis, surveillance, and management of ALD.
SUMMARY
Early diagnosis and HSCT are key to improving the morbidity and mortality associated with ALD. The implementation of universal newborn screening for ALD and rigorous investigations of novel diagnostic and therapeutic agents is the need of the hour.
Topics: Humans; Infant, Newborn; Adrenoleukodystrophy; Adrenal Insufficiency; Neonatal Screening; Genetic Therapy; Early Diagnosis
PubMed: 36373727
DOI: 10.1097/MED.0000000000000782 -
Endocrine Development 2011X-linked adrenoleukodystrophy (ALD) is caused by mutations in the ABCD1 gene that encodes a protein of the peroxisomal membrane named ALDP. Mutations in ALDP result in... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is caused by mutations in the ABCD1 gene that encodes a protein of the peroxisomal membrane named ALDP. Mutations in ALDP result in elevated levels of very long chain fatty acids (VLCFA) and reduced VLCFA oxidation in peroxisomes. Three main phenotypes are seen in affected males. The childhood cerebral form manifests usually between ages 4 and 8 years. It initially resembles attention deficit disorder or hyperactivity. Progressive central demyelination with impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within 2 years. The second phenotype, adrenomyeloneuropathy, manifests most commonly in the late twenties as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. The third phenotype, 'Addison disease only', presents with primary adrenocortical insufficiency between age 2 years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality. Approximately 50% of females who are carriers develop neurologic manifestations that resemble adrenomyeloneuropathy but have a later onset (age ≥35 years) and a milder disease. In this review, we will give an overview of the present understanding of ALD, and the implications of new diagnostics and treatment.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Adult; Child; Child, Preschool; Diagnostic Techniques, Endocrine; Female; Humans; Male
PubMed: 21164268
DOI: 10.1159/000321236 -
Endocrinology and Metabolism Clinics of... Jun 1991X-linked adrenoleukodystrophy (ALD) is a disorder of very long chain fatty acid (VLCFA) metabolism that can be diagnosed by demonstrating increased levels of VLCFA in... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is a disorder of very long chain fatty acid (VLCFA) metabolism that can be diagnosed by demonstrating increased levels of VLCFA in plasma and, prenatally, by similar assays in cultured amniocytes or chorionic vilus samples. ALD causes Addison disease frequently in men and occasionally in women. Prompt diagnosis is important for genetic counseling and for the institution of therapies aimed to prevent or ameliorate the progressive neurologic disability that often is associated with this illness.
Topics: Adrenoleukodystrophy; Endocrine Glands; Fatty Acids; Female; Humans; Male; Phenotype; X Chromosome
PubMed: 1879401
DOI: No ID Found -
The Canadian Journal of Neurological... Nov 1982
Comparative Study Review
Topics: Adolescent; Adrenoleukodystrophy; Adult; Child; Child, Preschool; Diffuse Cerebral Sclerosis of Schilder; Electroencephalography; Fatty Acids; Female; Genetic Carrier Screening; Humans; Infant; Infant, Newborn; Male; Myelin Sheath; Phenotype; Tomography, X-Ray Computed; X Chromosome
PubMed: 6758925
DOI: 10.1017/s0317167100044383 -
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 -
Neurology Nov 2022Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive...
Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.
Topics: Infant, Newborn; Humans; Male; Adrenoleukodystrophy; Consensus; Hematopoietic Stem Cell Transplantation; Adrenal Insufficiency; Neonatal Screening
PubMed: 36175155
DOI: 10.1212/WNL.0000000000201374