Cerebello-brainstem dominant form of X-linked adrenoleukodystrophy with intrafamilial phenotypic variability

Jae-Hwan Choi; Hyun Sung Kim; Eun Hye Oh; Jae Hyeok Lee; Chong Kun Cheon

doi:10.3389/fneur.2022.999419

Cerebello-brainstem dominant form of X-linked adrenoleukodystrophy with intrafamilial phenotypic variability

Front Neurol. 2022 Nov 9:13:999419. doi: 10.3389/fneur.2022.999419. eCollection 2022.

Authors

Jae-Hwan Choi^{1

2}, Hyun Sung Kim¹, Eun Hye Oh¹, Jae Hyeok Lee^{1

2}, Chong Kun Cheon^{2

3}

Affiliations

¹ Department of Neurology, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, Yangsan, South Korea.
² Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea.
³ Division of Medical Genetics and Metabolism, Department of Pediatrics, Pusan National University School of Medicine, Pusan National University Children's Hospital, Yangsan, South Korea.

Abstract

Objectives: This study aimed to describe the clinical and radiological characteristics of a cerebello-brainstem dominant form of X-linked adrenoleukodystrophy (X-ALD).

Methods: Three affected members from a family with cerebellar ataxia received full neurological, laboratory and radiological examinations. Genetic diagnoses were confirmed using whole-exome sequencing and protein structural modeling.

Results: All affected members presented with slurred speech, ataxia, and spasticity, but showed obvious differences in phenotypic severity and radiological findings. The levels of very long-chain fatty acids (VLCFA) were elevated in each member, while only one had adrenal dysfunction. Genetic analysis identified a hemizygous missense mutation (c.887A>G, p.Tyr296Cys) of the ATP-binding cassette subfamily D member 1 gene (ABCD1) in all affected members, which is likely to destabilize the overall structure of the ABCD1 protein.

Conclusions: We report a cerebello-dominant form of X-ALD caused by a missense variant in ABCD1. This report highlights intrafamilial phenotypic variability in X-ALD.

Keywords: ABCD1; adrenoleukodystrophy; cerebellar ataxia; phenotype; very long-chain fatty acids.