Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

Ying-Hao Chen,Jin-An Huang,Bing-Wen Soong,Yi-Chung Lee,Yi-Chu Liao,Yu-Shuen Tsai,Pei-Chien Tsai,Yuh-Cherng Guo,Cheng-Tsung Hsiao,Zhi-Ying Wu

doi:10.1371/journal.pone.0177296

Abstract

Adrenoleukodystrophy (ALD) is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD) in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1) were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118), sporadic ataxia with autonomic dysfunctions (n = 296), and sporadic ataxia without autonomic dysfunctions (n = 102). Brain MRIs were scrutinized for white matter hyperintensity (WMH) in the parieto-occipital lobes, frontal lobes, corticospinal tracts, pons, middle cerebellar peduncles and cerebellar hemispheres. Two ABCD1 mutations (p.S108L and p.P623fs) previously linked to cerebral ALD and adrenomyeloneuropathy but not AVALD were identified. ALD accounts for 0.85% (1/118) of the patients with molecularly unassigned hereditary ataxia and 0.34% (1/296) of the patients with sporadic ataxia with autonomic dysfunctions. WMH in the corticospinal tracts and WMH in the cerebellar hemispheres were strongly associated with AVALD rather than other ataxias. To conclude, ALD accounts for approximately 0.39% (2/516) of adult-onset cerebellar ataxias. This study expands the mutational spectrum of AVALD and underscores the importance of considering ALD as a potential etiology of cerebellar ataxia.

Highlights

Cerebellar ataxia comprises a heterogeneous group of diseases including hereditary ataxia, sporadic degenerative ataxia and acquired ataxia with exogenous etiologies, i.e. intoxication with alcohol or toxins and paraneoplastic syndrome [1, 2]
Patient A-II-1, who carried the p.S108L mutation, was previously diagnosed as hereditary cerebellar ataxia, while patient B-II-2 harboring the p.P623fs mutation was categorized into the group of sporadic ataxia with autonomic dysfunctions (Fig 2)
ALD accounted for 0.85% (1/118) of molecularly unassigned hereditary ataxia and 0.34% (1/296) of sporadic ataxia with autonomic dysfunctions or 0.25% (1/398) of all patients with sporadic ataxia

Summary

Introduction

Cerebellar ataxia comprises a heterogeneous group of diseases including hereditary ataxia, sporadic degenerative ataxia and acquired ataxia with exogenous etiologies, i.e. intoxication with alcohol or toxins and paraneoplastic syndrome [1, 2]. Making diagnosis in patients with a chronic progressive ataxia is clinically challenging since different ataxia diseases may have overlapping phenotypes and heterogeneous presentations [3]. Hereditary diseases may manifest as adult-onset sporadic ataxia. 2–22% of sporadic cases carry a genetic mutation, most frequently Friedreich’s ataxia or spinocerebellar ataxia (SCA) type 6 [6, 7]. X-linked adrenoleukodystrophy (ALD) is often overlooked in the differential diagnosis of adult-onset ataxia. The clinical manifestations of ALD include a rapidly progressive childhood-, adolescence-, or adult-onset cerebral ALD, adrenomyeloneuropathy (AMN) presenting as a progressive paraplegia, and Addison’s disease without neurological deficits [9, 10]. Only a few AVALD cases have been reported [12] and the role of AVALD in patients with cerebellar ataxia remains unclear

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