Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

Palakuzhiyil, Shruti V; Christopher, Rita; Chandra, Sadanandavalli Retnaswami

doi:10.4331/wjbc.v11.i3.99

Cited by 14 publications

(15 citation statements)

References 63 publications

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“…Defects in ABCD1 protein prevent β-oxidation of VLCFAs, leading to its accumulation in tissue and plasma ( 1 ). According to age of onset, affected site and progression rate, multiple phenotypes of X-ALD are recognized, including cerebral ALD, adrenomyeloneuropathy, Addison's and asymptomatic ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

X‑linked adrenoleukodystrophy caused by maternal ABCD1 mutation and paternal X chromosome inactivation

Lai

2022

Exp Ther Med

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X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It is caused by defects in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, resulting in impaired peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs). As an X-linked recessive disease, female X-ALD carriers are typically asymptomatic. In the present study, a 7-year-old girl was diagnosed with cerebral ALD. Brain magnetic resonance imaging revealed asymmetric demyelination of bilateral white matter. Plasma VLCFAs level showed a substantial increase. Whole exome and Sanger sequencing revealed an ABCD1 c.919C>T (p.Q307X) heterozygous pathogenic mutation, which was inherited from the asymptomatic mother. X chromosome inactivation (XCI) analysis revealed that the normal paternal X chromosome was almost completely inactivated. Thus, the maternal ABCD1 mutation and paternal XCI were responsible for causing the disease in the patient. XCI may be one reason female X-ALD carriers can be symptomatic.

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Section: Introductionmentioning

confidence: 99%

X‑linked adrenoleukodystrophy caused by maternal ABCD1 mutation and paternal X chromosome inactivation

Lai

2022

Exp Ther Med

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“…According to the known intra-familial variability, it was supposed that other (epi)genetic factors contribute to the phenotype of patients with ABCD1 mutations [21].…”

Section: Introductionmentioning

confidence: 99%

A Large Family with p.Arg554His Mutation in ABCD1: Clinical Features and Genotype/Phenotype Correlation in Female Carriers

Campopiano

Femiano

Chiaravalloti

et al. 2021

Genes

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X-linked adrenoleukodystrophy (X-ALD, OMIM #300100) is the most common peroxisomal disorder clinically characterized by two main phenotypes: adrenomyeloneuropathy (AMN) and the cerebral demyelinating form of X-ALD (cerebral ALD). The disease is caused by defects in the gene for the adenosine triphosphate (ATP)-binding cassette protein, subfamily D (ABCD1) that encodes the peroxisomal transporter of very-long-chain fatty acids (VLCFAs). The defective function of ABCD1 protein prevents β-oxidation of VLCFAs, which thus accumulate in tissues and plasma, to represent the hallmark of the disease. As in many X-linked diseases, it has been routinely expected that female carriers are asymptomatic. Nonetheless, recent findings indicate that most ABCD1 female carriers become symptomatic, with a motor disability that typically appears between the fourth and fifth decade. In this paper, we report a large family in which affected males died during the first decade, while affected females develop, during the fourth decade, progressive lower limb weakness with spastic or ataxic-spastic gait, tetra-hyperreflexia with sensory alterations. Clinical and genetic evaluations were performed in nine subjects, eight females (five affected and three healthy) and one healthy male. All affected females were carriers of the c.1661G>A (p.Arg554His, rs201568579) mutation. This study strengthens the relevance of clinical symptoms in female carriers of ABCD1 mutations, which leads to a better understanding of the role of the genetic background and the genotype-phenotype correlation. This indicates the relevance to include ABCD1 genes in genetic panels for gait disturbance in women.

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“…AMN is the most common phenotype of X‐ALD. In this subtype, patients generally have spinal cord dysfunction that is further categorized by the presence or absence of cerebral involvement 5 . AMN symptoms include ataxia, gait disturbances and spastic paraparesis.…”

Section: Introductionmentioning

confidence: 99%

“…ALD is caused by mutations in the ATP‐binding cassette sub‐family D member 1 ( abcd1) gene on the X chromosome that encodes the adrenoleukodystrophy protein (ALDP), an adenosine triphosphate (ATP)‐binding‐cassette (ABC) transporter located on the peroxisomal membrane. This protein, expressed in the adrenal glands, brain, kidney, liver, lungs, placenta and testis, is responsible for the transport of VLCFAs from the cytosol into the peroxisome for degradation by β‐oxidation 4,5 . The genetic mutation in ALD renders this transporter defective, leading to the accumulation of cytosolic VLCFAs 6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…It typically starts with cognitive and vasomotor function impairment, before rapidly progressing to neurologic deficits like spastic quadriparesis, vision loss and, eventually, death. 5,11 Although the peak age for onset of symptoms in children is 7 years, cALD can also occur in adults, initially presenting as adrenal symptoms, then progressing to AMN and eventually developing into cALD. 12 Being an X-linked disease, males are more frequently and severely affected than females.…”

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confidence: 99%

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Translational and clinical pharmacology considerations in drug repurposing for X‐linked adrenoleukodystrophy—A rare peroxisomal disorder

Tieu

Sahasrabudhe

Orchard

et al. 2021

Brit J Clinical Pharma

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X‐linked adrenoleukodystrophy (X‐ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology and potential drug–target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early‐stage clinical trials will improve the success of repurposed drugs for X‐ALD as well as other rare diseases.

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Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

Cited by 14 publications

References 63 publications

X‑linked adrenoleukodystrophy caused by maternal ABCD1 mutation and paternal X chromosome inactivation

X‑linked adrenoleukodystrophy caused by maternal ABCD1 mutation and paternal X chromosome inactivation

A Large Family with p.Arg554His Mutation in ABCD1: Clinical Features and Genotype/Phenotype Correlation in Female Carriers

Translational and clinical pharmacology considerations in drug repurposing for X‐linked adrenoleukodystrophy—A rare peroxisomal disorder

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