Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Late-Onset Leukodystrophy Mimicking Hereditary Spastic Paraplegia without Diffuse Leukodystrophy on Neuroimaging Tongxia Zhang1,2 Purpose: Leukodystrophies are frequently regarded as childhood disorders, but they can Chuanzhu Yan1,3 occur at any age, and the clinical and imaging patterns of the adult-onset form are usually Yiming Liu1 different from the better-known childhood variants. Several reports have shown that various Lili Cao1 late-onset leukodystrophies, such as X-linked adrenoleukodystrophy and Krabbe disease, Kunqian Ji1 may present as spastic paraplegia with the absence of the characteristic white matter lesions on neuroimaging; this can be easily misdiagnosed as hereditary spastic paraplegia. The Duoling Li1 objective of this study was to investigate the frequency of late-onset leukodystrophies in Lingyi Chi2,4,5 1 patients with spastic paraplegia. Yuying Zhao Patients and Methods: We performed genetic analysis using a custom-designed gene 1Research Institute of Neuromuscular and panel for leukodystrophies in 112 hereditary spastic paraplegia-like patients. Neurodegenerative Diseases and Results: We identified pathogenic mutations in 13 out of 112 patients, including five patients Department of Neurology, Qilu Hospital, Shandong University, Jinan, People’s Republic with adrenomyeloneuropathy, three with Krabbe disease, three with Alexander disease, and of China; 2School of Basic Medical Sciences, two with cerebrotendinous xanthomatosis. In terms of clinical manifestations, in addition to Cheeloo College of Medicine, Shandong spastic paraplegia, three adrenomyeloneuropathy probands also had adrenocortical insuffi­ University, Jinan, People’s Republic of China; 3Mitochondrial Medicine Laboratory, Qilu ciency, two Alexander disease probands developed urinary retention, one CTX proband Hospital (Qingdao), Shandong University, developed cataracts and chronic diarrhea and the other presented with chronic diarrhea and Qingdao, People’s Republic of China; 4Brain Science Research Institute, Qilu Hospital, mild tendon xanthomatosis. None of the patients had evidence of diffuse leukodystrophy on Shandong University, Jinan, People’s Republic neuroimaging. 5 of China; Department of Neurosurgery, Conclusion: Patients with late-onset spastic paraplegia should be screened for underlying Qilu Hospital, Shandong University, Jinan, People’s Republic of China leukodystrophies, irrespective of the presence of additional complicating symptoms and neuroimaging abnormalities. Keywords: targeted next-generation sequencing, pathogenic mutations, genetic causes, leukodystrophy frequency, magnetic resonance imaging Correspondence: Lingyi Chi Department of Neurosurgery, Qilu Hospital, Shandong University, No. 107 Wenhua West Road, Jinan City, Shandong Introduction Province, 250012, People’s Republic of Leukodystrophies are frequently regarded as disorders of childhood, but they can affect China Tel +86-18560085730 humans of any age, and the clinical and imaging patterns of the adult-onset form are Email [email protected] usually different from the better-known childhood variants.1 In routine clinical practice, Yuying Zhao white matter lesions on magnetic resonance imaging (MRI) are frequently regarded as Department of Neurology, Qilu Hospital, Shandong University, No. 107 Wenhua a hallmark of leukodystrophies; however, these lesions can be very mild or even absent West Road, Jinan City, Shandong in some late-onset patients. Several reports have shown that various late-onset leuko­ Province, 250012, People’s Republic of China dystrophies, such as X-linked adrenoleukodystrophy (ALD) and Krabbe disease (KD), Tel +86-18560085530 may present as spastic paraplegia (SP) without leukodystrophy on neuroimaging and be Fax +86-531-82169217 2–5 Email [email protected] easily misdiagnosed as hereditary spastic paraplegia (HSP) on clinical grounds. Neuropsychiatric Disease and Treatment 2021:17 1451–1458 1451 © 2021 Zhang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Zhang et al Dovepress Currently, no effective treatment is available for HSP, sequencing (NGS) was performed. The sets of variants but recent breakthroughs in the treatment of leukodystro­ were classified into “pathogenic”, “likely pathogenic”, phy, such as enzyme replacement therapy and hematopoie­ “variants of uncertain significance” (VUS), “likely tic stem cell transplantation,6–8 have provided more benign”, or “benign” according to guidelines from the opportunities for improving the clinical outcome of American College of Medical Genetics and Genomics patients with leukodystrophy. Therefore, the early differ­ (ACMG). The “pathogenic” variants consistent with the entiation of leukodystrophy from HSP is of great impor­ clinical phenotypes were determined to be responsible for tance in improving patients’ prognosis and in providing pathogenic mutations. Subsequently, three different web early treatment opportunities for other pedigree members. tools were used to predict the functional effects of the To investigate the frequency of late-onset leukodystro­ “likely pathogenic” and “VUS” variants: polyphen2 phies in patients with SP and to compare their phenotypic (http://genetics.bwh.harvard.edu/pph2/), Mutation Taster spectra with HSP in the Chinese population, in this study, (http://www.Mutationtaster.org/), and SIFT (http://sift. 112 patients with late-onset spasticity lacking common jcvi.org/www/SIFT_enst_submit.html). The “likely HSP-causal genes and diffuse leukodystrophy on neuroi­ benign” and “benign” variants were excluded because of maging were screened for underlying genetic causes asso­ their low pathogenic risk. Finally, candidate variants were ciated with leukodystrophies. confirmed by Sanger sequencing. Segregation tests were performed if the DNA of the proband’s immediate family Patients and Methods member was available, and the final pathogenic mutations were determined in combination with the clinical Patient Recruitment information. Our cohort included 112 patients with progressive lower limb spasticity admitted to Qilu Hospital of Shandong University for diagnosis or management between January 2016 and Biochemical Examination and Clinical June 2020. Written informed consent was obtained from all Investigation study participants for genetic analysis, and the study was If the results were indicative of inborn metabolic disor­ carried out with institutional ethical approval. ders, we conducted additional biochemical examinations, The inclusion criteria were as follows: (1) age of onset including enzymatic activity and very long-chain fatty of spastic gait ≥ 14 years; (2) evidence of a detailed acids (VLCFA), to confirm the diagnosis. Clinical data, examination, including blood tests, blood amino acid and including neurological and psychiatric assessments, neu­ fatty carnitine screening, urine organic acid screening, roimaging results, and neuro-electrophysiological features cerebrospinal fluid, and neuroimaging, to exclude other were collected to predict genotypic and phenotypic potential etiologies including metabolic derangements characteristics. (including vitamin B12 and folic acid deficiency, hepatic myelopathy, methylmalonic acidemia, urea cycle disor­ Results ders, and phenylketonuria), infection, inflammation, vas­ We identified pathogenic mutations in 13 of the 112 cular abnormalities, and spinal cord compression; (3) brain patients, including five patients with adrenomyeloneuro­ MRI showed no evidence of diffuse white matter lesions; pathy (AMN), three with KD, three with Alexander dis­ (4) no causative genes were found during the gene screen­ ease (AxD), and two with cerebrotendinous xanthomatosis ing for SPG4 and SPG 11, which are the most common (CTX). Each proband’s variants and the predictions are types of HSP. A flow chart describing the selection proce­ listed in Table 1. Four probands with a positive family dure of the cohort is shown in Supplementary Figure 1. history were found through family investigation. Targeted Next-Generation Sequencing Clinical Characteristics of the 13 Patients Firstly, a custom-designed probe library containing 130 Among the 13 patients, 11 were male and 2 were female. known pathogenic genes reported to be associated with The age at onset of spasticity varied between 16 and 70 years hereditary leukoencephalopathies was synthesized old, with an average age of 39 years. Spastic paraplegia was (Supplementary Table 1). Genomic DNA was extracted the main finding in all patients, but in clinical and laboratory from peripheral blood lymphocytes and next-generation examinations, we found three AMN probands presenting 1452 https://doi.org/10.2147/NDT.S296424 Neur opsychiatric Disease and Treatment 2021:17 DovePress Dovepress Zhang et al Table 1 Genomic Features of the 13 Patients Patient Mutation Genomic Amino Acid HGMD