ABCD1 Gene Mutations: Mechanisms and Management of Adrenomyeloneuropathy

Volmrich, Alyssa M; Cuénant, Lauren M; Forghani, Irman; Hsieh, Sharon L; Shapiro, Lauren T.

doi:10.2147/tacg.s359479

Cited by 7 publications

(3 citation statements)

References 112 publications

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“…Although both pathogenic variants reported here were predicted to cause a complete absence of the ABCD1 protein, the variant c.253delC in exon 1 led to the most severe cerebral X-ALD, while c.1275delA in exon 4 caused moderate AMN phenotype. The culprit seems to be multifactorial and besides toxicity of the accumulated VLCFA, modifier genes and environmental/epigenetic factors might contribute [ 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy

Dohr

Tokic

Gastager-Ehgartner

et al. 2023

IJMS

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X-linked adrenoleukodystrophy (X-ALD) is a rare inborn error of the peroxisomal metabolism caused by pathologic variants in the ATP-binding cassette transporter type D, member 1 (ABCD1) gene located on the X-chromosome. ABCD1 protein, also known as adrenoleukodystrophy protein, is responsible for transport of the very long chain fatty acids (VLCFA) from cytoplasm into the peroxisomes. Therefore, altered function or lack of the ABCD1 protein leads to accumulation of VLCFA in various tissues and blood plasma leading to either rapidly progressive leukodystrophy (cerebral ALD), progressive adrenomyeloneuropathy (AMN), or isolated primary adrenal insufficiency (Addison’s disease). We report two distinct single nucleotide deletions in the ABCD1 gene, c.253delC [p.Arg85Glyfs*18] in exon 1, leading to both cerebral ALD and to AMN phenotype in one family, and c.1275delA [p.Phe426Leufs*15] in exon 4, leading to AMN and primary adrenal insufficiency in a second family. For the latter variant, we demonstrate reduced mRNA expression and a complete absence of the ABCD1 protein in PBMC. Distinct mRNA and protein expression in the index patient and heterozygous carriers does not associate with VLCFA concentration in plasma, which is in line with the absence of genotype–phenotype correlation in X-ALD.

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Section: Discussionmentioning

confidence: 99%

Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy

Dohr

Tokic

Gastager-Ehgartner

et al. 2023

IJMS

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“…Approximately 40% of individuals with AMN have some degree of brain involvement in neuroimaging. In approximately 20% of individuals with AMN, brain involvement eventually progresses and leads to cognitive and behavioral decline implying cerebral involvement ( 50 ). Clinical manifestations of cerebral involvement in individuals with AMN are identical to those observed with primary adult cerebral ALD, with the additional symptom of pre-existing myelopathy.…”

Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

“…Clinical manifestations of cerebral involvement in individuals with AMN are identical to those observed with primary adult cerebral ALD, with the additional symptom of pre-existing myelopathy. Current guidelines on surveillance in individuals with pathogenic variants in ABCD1 is to perform MRI of the brain annually, as the development of cerebral changes even in late adulthood is known ( 50 ).…”

Section: Imaging Presentations: Difference From Childhood Leukodystro...mentioning

confidence: 99%

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions

Muthusamy¹,

Sivadasan²,

Dixon³

et al. 2023

Front. Neurol.

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Adult-onset leukodystrophies though individually rare are not uncommon. This group includes several disorders with isolated adult presentations, as well as several childhood leukodystrophies with attenuated phenotypes that present at a later age. Misdiagnoses often occur due to the clinical and radiological overlap with common acquired disorders such as infectious, immune, inflammatory, vascular, metabolic, and toxic etiologies. Increased prevalence of non-specific white matter changes in adult population poses challenges during diagnostic considerations. Clinico-radiological spectrum and molecular landscape of adult-onset leukodystrophies have not been completely elucidated at this time. Diagnostic approach is less well-standardized when compared to the childhood counterpart. Absence of family history and reduced penetrance in certain disorders frequently create a dilemma. Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling. In this review article, we aimed to formulate an approach to adult-onset leukodystrophies that will be useful in routine practice, discuss common adult-onset leukodystrophies with usual and unusual presentations, neuroimaging findings, recent advances in treatment, acquired mimics, and provide an algorithm for comprehensive clinical, radiological, and genetic evaluation that will facilitate early diagnosis and consider active treatment options when available. A high index of suspicion, awareness of the clinico-radiological presentations, and comprehensive genetic evaluation are paramount because treatment options are available for several disorders when diagnosed early in the disease course.

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Terra incognita of glial cell dynamics in the etiology of leukodystrophies: Broadening disease and therapeutic perspectives

Chaudhary,

Rehman,

Agarwal

et al. 2024

Life Sciences

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ABCD1 Gene Mutations: Mechanisms and Management of Adrenomyeloneuropathy

Cited by 7 publications

References 112 publications

Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy

Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions

Terra incognita of glial cell dynamics in the etiology of leukodystrophies: Broadening disease and therapeutic perspectives

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