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

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 ß-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.

Low donor chimerism may be sufficient to prevent demyelination in adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by white matter degeneration caused by adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene mutations, which lead to an accumulation of very-long-chain fatty acids (VLCFA). Hematopoietic stem cell transplantation (HSCT) is the most effective treatment; however, the ratio of donor-to-recipient cells required to prevent the progression of demyelination is unclear. The proband was diagnosed with the childhood cerebral form of ALD at 5 years of age based on the clinical phenotype, elevated plasma VLCFA levels, and pathogenic ABCD1 mutation c.293C>T (p.Ser98Leu). Soon after the diagnosis, he became bedridden. At 1 year of age, his younger brother was found to carry the same ABCD1 mutation; despite being asymptomatic, at 1 year and 9 months, head magnetic resonance imaging (MRI) showed high-signal-intensity lesions in the cerebral white matter. The patient underwent unrelated cord blood transplantation (UCBT) with a reduced conditioning regimen, which resulted in mixed chimerism. For 7 years after UCBT, the donor chimerism remained low (<10%) in peripheral blood and cerebrospinal fluid. However, even though a second HSCT was not performed, his neurological symptoms and brain MRI findings did not deteriorate. Our case suggests that even a small number of donor cells may prevent demyelination in ALD. This is an important case when considering the timing of a second HSCT.

Role of MRI in X-linked adrenoleukodystrophy-A case report.

X-linked adrenoleukodystrophy is a rare inherited peroxisomal disorder that occurs due to a genetic mutation. This mutation impairs normal transport of very long-chain fatty acids (VLCFAs) into peroxisomes, hence impeding VLCFA breakdown leading to its accumulation in plasma and tissues of the body. Due to its X-linked inheritance, it classically affects young males with most cases diagnosed during childhood. There are characteristic MRI findings in brain which can aid in diagnosis of X-ALD. We hereby present a case of a 10-year-old boy who presented with neurological and behavioral deterioration with MRI findings suggestive of X-ALD. MRI not only aids in diagnosis of X-ALD but can also identify the pattern of brain involvement which serves an important role in prognosis and outcome of the disease.

The Clinical Impact of CLIR Tools toward Rapid Resolution of Post-Newborn Screening Confirmatory Testing for X-Linked Adrenoleukodystrophy in California.

Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To determine retrospectively the likelihood that these were true positive cases, we used a web-based post-analytical tool in Collaborative Laboratory Integrated Reports (CLIR). Confirmatory plasma very long-chain fatty-acids (VLCFA) profiles for ALD screen positive infant boys were run through the CLIR ALD tool. We compared the distribution by ABCD1 variant classification (pathogenic, likely pathogenic, VUS, and no variant) with the CLIR tool score interpretation (non-informative, possibly ALD, likely ALD, and very likely ALD) and the current case diagnosis. The study showed that CLIR tool positive interpretations were consistent with 100% of the pathogenic and likely pathogenic variants on the ABCD1 gene if a more conservative guideline was used. The tool interpretations were also consistent with screened cases that were determined to not have disease (our no-disorder group). The CLIR tool identified 19 diagnosed ALD cases with VUS to be potential false positives, representing a 40% reduction among all diagnosed ALD cases with VUS. The reduction could be extended to 65% if a more aggressive threshold was used. Identifying such preventable false positives could alleviate the follow-up burden for patients, their families, and California Special Care Centers.