Genetic spectrum and clinical features of adult leukoencephalopathies in a Chinese cohort

Abstract Objective Leukoencephalopathies are a group of heterogeneous disorders characterized by the degeneration of white matter, resulting in a variety of progressive neurological symptoms. To date, over 60 genes linked to genetic leukoencephalopathies have been discovered through whole‐exome sequencing (WES) and long‐read sequencing. Nonetheless, the genetic diversity and clinical variability of these disorders among various racial groups remain largely unknown. Therefore, this study aims to analyze the genetic spectrum and clinical features of Chinese adult leukoencephalopathies and compare the genetic profiles in different populations. Methods A total of 129 patients suspected of possible genetic leukoencephalopathy were enrolled and underwent WES and dynamic mutation analysis. Bioinformatics tools were used to predict the pathogenicity of these mutations. Skin biopsies were conducted for further diagnosis. Genetic data sources from different populations were collected from published articles. Results Genetic diagnosis was established in 48.1% of patients, with WES identifying 57 pathogenic or likely pathogenic variants in 39.5% of cases. NOTCH3 and NOTCH2NLC were the most common mutated genes, accounting for 12.4% and 8.5% of cases, respectively. Dynamic mutation analysis revealed NOTCH2NLC GGC repeat expansions in 8.5% of patients. Different mutations resulted in varying clinical symptoms and imaging findings. Comparisons of genetic profiles between different populations showed distinct mutational spectrums in adult leukoencephalopathies. Interpretation This study highlights the importance of genetic testing for accurate diagnosis and improved clinical management of these disorders. It also sheds light on the genetic heterogeneity of adult leukoencephalopathies across different races, emphasizing the need for further research on this topic.


Introduction
Leukodystrophies and genetic leukoencephalopathies are considered a rare group of degenerative white matter disorders leading to a progressive syndrome including various combinations of cognitive and neuropsychiatric changes, movement disorders, spasticity and seizures, accompanied by widespread cranial white matter change on MRI T2/fluid-attenuated inversion recovery (FLAIR) sequences. 1,2 Given variable and overlapping presentations and similar imaging changes, it is not easy to delineate the subtypes of adult leukoencephalopathies only from clinical viewpoints and metabolic or biochemical testing. Meanwhile, patients with genetic leukoencephalopathies often endure a long miserable time before accepting a definitive diagnosis or may not receive a diagnosis at all. 3 Leukodystrophies and genetic leukoencephalopathies can present in children or adults, advances have been made in the diagnostic approach in children, but little is made about genetic methods in adults. 4 Therefore, genetic investigations are essential to make a definitive diagnosis of such disorders.
Along with the use of whole-exome sequencing (WES) and analysis of phenotype-genotype correlation, more than 60 genes have been found to be associated with adult leukoencephalopathies representative of great genetic heterogeneity. 5 However, given that the causative mutations were only ascertained in 13.3%-26% of affected patients with different ethnic origins using WES or focused exome sequencing, it remained difficult and elusive for genetic diagnosis of adult leukoencephalopathies. 5,6 Recently, noncoding GGC repeat expansions in NOTCH2NLC, FMR1, NUTM2B-AS1 have been identified as the causative dynamic mutations based on the long read sequencing technology for three types of adult leukoencephalopathies: neuronal intranuclear inclusion disease (NIID), fragile X tremor/ataxia syndrome (FXTAS) and oculopharyngeal myopathy with leukoencephalopathy (OPML), respectively. 7 Notably, NOTCH2NLC GGC repeat expansions causing neuronal intranuclear inclusion disease has been regarded as the most common reason for adult-onset nonvascular leukoencephalopathies in Japanese populations, while this disorder is not common in European populations with adult-onset leukoencephalopathy. 8,9 Therefore, it is necessary to further conduct genetic researches on adult leukoencephalopathies by combining WES and dynamic mutation analysis, especially in different populations.
In this study, we conducted WES and dynamic mutation analysis on a cohort of Chinese patients diagnosed with adult leukoencephalopathies. Subsequently, we performed genotype-phenotype correlation analysis to enhance the clinical recognition of these disorders. Furthermore, we compared the genetic profiles of this cohort with those of other populations, in order to elucidate the ethnic variation in the manifestation of adult leukoencephalopathies.

Patients
Patients were widely recruited from the Department of Neurology in the First Affiliated Hospital of Zhengzhou University between June 2019 and May 2022. The primary inclusion criteria comprised of (1) the observation of prominent white matter hyperintensity (WMH) on T2/ FLAIR MRI, (2) the manifestation of a progressive neurological syndrome, and (3) a minimum age of 16 years. Subjects were excluded if laboratory tests indicated the presence of acquired white matter disease caused by factors such as vascular, inflammatory, infective, neoplastic, toxic, or drug-induced factors. A total of 129 patients, suspected of having possible genetic leukoencephalopathy, were ultimately enrolled in the study. All patients underwent comprehensive clinical evaluation, including standardized medical history and neurological examinations conducted by two senior neurologists. The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University, and all subjects provided informed consent.
The effect of variants on gene function was evaluated based on missense variant predicted tools, including SIFT (http://sift.jcvi.org/), Polyphen-2 (http://genetics.bwh.harvard. edu/pph2/), and CADD (http://cadd.gs.washington.edu/snv). All variants were classified as pathogenic, likely pathogenic, benign, likely benign, or uncertain significance according to the American College of Medical Genetics and Genomics (ACMG) guidelines. 10 Only pathogenic and likely pathogenic variants were considered as the disease causative variants and the pathogenicity of the remaining variants needs further investigation. Possible disease causative variants were confirmed by Sanger sequencing on ABI 3730 XL Genetic Analyzer. Co-segregation analysis was performed on all available family members. The novelty of causative variants was determined according to ClinVar (http://www.ncbi.nlm.nih.gov/ clinvar) and HGMD (http://www.hgmd.org) databases.

Dynamic mutation analysis
Repeat-primed PCR (RP-PCR) and fluorescence amplicon length PCR (AL-PCR) were used to detect the presence of dynamic mutation and determine the exact trinucleotide repeat number in NOTCH2NLC, FMR1, and NUTM2B-AS1, as described previously. 11 Capillary electrophoresis of the PCR products was used to perform on A 35009 L Genetic Analyzer (Applied Biosystems) to analyze the fragment length, and the allele size was determined using Gen-eScan 1,000 ROX Size Standard (Applied Biosystems). Briefly, a saw-tooth tail pattern in RP-PCR electropherograms suggested the presence of trinucleotide repeat expansions, and the length of the highest signal peak in AL-PCR electropherograms was used for fragment length. According to previous reports, NOTCH2NLC GGC repeat expansion has three forms: normal (<40 repeats), intermediate (41-60 repeats), and pathogenic (>60 repeats); and FMR1 GGC repeat has four forms: normal (6-44 repeats), intermediate (45-54 repeats), premutation (55-200 repeats), and full mutation (>200 repeats). 12,13 Abnormal NUTM2B-AS1 CGG repeat expansion will be considered if the number of repeats is much higher than that of healthy controls according to our previous report. 14

Skin biopsy and immunohistochemistry
Three-millimeter diameter skin punch biopsies were performed at the lateral distal leg and neck under 20 mg/ml lidocaine local anesthesia according to the previously reported protocol. 15 The tissues were embedded in paraffin and sectioned at 4-lm thickness using the Leica clinical microtome (HistoCore BIOCUT, Germany). The sections were stained with hematoxylin and eosin, anti-ubiquitin antibody (ab7780, Abcam, 1:400), or anti-p62 antibody (ab56416, Abcam, 1:800). Photomicrographs were captured with a fluorescence microscope (Nikon, Eclipse Ni).

Genetic data from different populations
The genetic data for patients with adult leukoencephalopathies from various populations were obtained through a comprehensive search of published literature. The search was conducted on PubMed, using search terms such as "adult leukoencephalopathy" or "genetic leukoencephalopathy," in combination with "whole-exome sequencing" or "focus-exome sequencing" or "NOTCH2NLC" or "FMR1" or "NUTM2B-AS1." A total of six articles, published between 2015 and 2022, containing detailed genetic data of Asians and Caucasians, were identified and reviewed. Additionally, reference lists of these articles were examined to locate further relevant literature for consultation.
To assess the unresolved genetic causes in our cohort, we subsequently investigated trinucleotide repeat expansions of 3 additional genes (NOTCH2NLC, FMR1, and NUTM2B-AS1) in the 129 patients. Surprisingly, we found NOTCH2NLC GGC expansions in 11 patients, which was the second most common causative gene in our cohort (11/129, 8.5%). The number of repeats of NOTCH2NLC GGC is 66 to 170, which can be used as a diagnostic basis for NIID. However, no patients harbored expanded trinucleotide repeats of FMR1 or NUTM2B-AS1.
Brain MRI scans of the NIID patients revealed symmetrical and confluent white matter hyperintensities (WMHs) on T2/FLAIR, which were primarily distributed in the frontoparietal lobes (100.0%) and deep and periventricular areas, including the U-fibers (90.9%; Fig. 2E). WMHs were also present in the corpus callosum (54.5%), brainstem (27.3%), temporal lobe (27.3%), and occipital lobe (18.2%). WMH in the cerebellar middle peduncle and vermis was observed in only one patient ( Fig. 2F and G). Hyperintense signals were detected in nine patients (81.8%) on DWI, mainly in the frontoparietal lobes, along with the corticomedullary junction (Fig. 2H).  (Fig. 3A). In addition, WMH in the external capsule was a specific manifestation and was observed in 11 (68.8%) patients (Fig. 3B). Multiple lacunar infarcts (Fig. 3C) and cerebral microbleeds occurred in 9 (56.2%) and 3 (18.8%) patients, respectively. Diffusion tensor imaging (DTI) was available in one case and showed diffuse tract damage (Fig. 3D). Furthermore, three patients with mutations in HTRA1 were identified, two of whom carried single heterozygous mutations causing CADASIL2, and one patient carried compound heterozygous mutations causing CARASIL. The average age at onset was 49.0 AE 4.0 (range 45-53) years. Two CADASIL2 patients presented with symptoms such as ischemic stroke, cognitive decline, and psychiatric symptoms. The CARASIL patient presented with spastic gait, low back pain, cognitive decline, and parkinsonism. The image manifestations of CADASIL2 and CARASIL were similar to those of CADASIL, with prominent WMHs in the frontoparietal lobes and periventricular area, and multiple lacunar infarcts. WMH in the external capsule was observed in one CADASIL2 patient and one CARASIL patient (Fig. 3E), and typical temporal pole involvement was only found in the CARASIL patient (Fig. 3F). Additionally, a lumbar MRI revealed herniated disks with degenerative changes in one CADASIL2 patient.
Moreover, three patients with mutations in COL4A1 were identified, with an average age at onset of 39.3 AE 3.1 years. Two patients presented with ischemic stroke, followed later by ataxia and limited eye movement. One patient started with parkinsonism and then developed ataxia and cognitive decline. MRI in these cases demonstrated prominent WMHs in the frontoparietal and periventricular area without the involvement of temporal poles, but the involvement of the external capsule was found in one case (Fig. 3G). Multiple lacunar infarcts were observed in all cases. Susceptibility weighted imaging (SWI) was available in two cases and revealed pontine and occipital microbleeds in one patient and diffuse microbleeds affecting lobar, thalamic, basal ganglia, and cerebellar regions in the other patient (Fig. 3H).

Inherited metabolic disorders with leukodystrophies
The present study identified a cohort of patients who were diagnosed with leukodystrophies associated with inherited metabolic disorders resulting from mutations in genes related to inborn errors of metabolism. Specifically, four male patients were diagnosed with ALD due to carrying a hemizygote mutation in ABCD1, with an average age at onset of 39.0 AE 6.6 (range 31-47) years. The clinical symptoms included peripheral neuropathy (3, 75.0%), spastic gait (3, 75.0%), cognitive decline (2, 50.0%), autonomic dysfunction (2, 50.0%), dysarthria (1, 25.0%) and tremor (1, 25.0%). Brain MRI revealed that WMHs were concentrated in the frontoparietal lobes and paraventricular area, corpus callosum, and brainstem, with diffusionweighted imaging (DWI) abnormality and calcifications found in some cases. Additionally, subcortical U-fibers and external capsule were affected in one case (Fig. 4A), and contrast enhancement showed slight enhancement of the lesion.
Furthermore, three patients carrying homozygous compound heterozygous CYP27A1 mutations causing CTX exhibited clinical symptoms such as ataxia, cataract, muscle atrophy, peripheral neuropathy, epilepsy, and pescavu. Brain MRI showed WMHs in the periventricular area, brainstem, and cerebellum (Fig. 4B), with DWI abnormality found in one case.
Two patients with compound heterozygous PAH mutations causing PKU exhibited clinical symptoms of headache, cognitive decline, ataxia, and personality change, with WMHs found in the periventricular area, lobar area, and corpus callosum (Fig. 4C). After 1 year of treatment with a low phenylalanine diet, their clinical symptoms improved and the WMHs were significantly reduced.
Moreover, the study identified three patients with compound heterozygous CBS mutations causing homocystinurias, compound heterozygous DPYD mutations causing DPD deficiency, and homozygous GALC mutations causing Krabbe Disease, respectively. These patients exhibited clinical symptoms such as lower limb numbness and weakness, cognitive decline, blurred vision, and generalized epileptic seizure. Brain MRI revealed WMHs in different regions, with restricted diffusion found in some cases (Fig. 4D).
In addition, two patients with GFAP mutations causing AxD were identified. One patient presented with limb weakness at the age of 34, and over the next 4 years, she developed progressive bradykinesia and ataxia. Similar symptoms were observed in her sister, who carried the same mutation. MRI showed extensive WMHs in the frontoparietal lobes and periventricular area, as well as atrophy and signal intensity changes in the medulla. The other patient was a 67-year-old farmer with progressive parkinsonism and autonomic dysfunction for 3 years. MRI demonstrated symmetric WMHs in the frontoparietal lobes and paraventricular area (Fig. 4G), while the brainstem was not obviously involved.
Moreover, compound heterozygous mutations in AARS2 and DARS2 were detected in two male patients with slowly progressive ataxia and peripheral neuropathy. MRI findings in the former patient revealed extensive WMHs in the bilateral frontoparietal lobes, periventricular area, and corpus callosum (Fig. 4H). The latter patient showed diffuse WMHs in the bilateral centrum semiovale, paraventricular area, cerebellum, and brainstem ( Fig. 4I and J).

Inherited CNS hypomyelinating leukodystrophies
Two patients were diagnosed with 4H syndrome, a condition characterized by CNS hypomyelination, due to compound heterozygous mutations in the POLR3A and POLR3B genes, respectively. The first patient, a 49-yearold woman, presented with a 20-year history of ataxia and limb weakness. MRI revealed T2-weighted hyperintensity of the left parietal lobe and bilateral cerebral peduncles. The second patient, a 32-year-old woman, experienced a cognitive decline for 25 years and had an epileptic seizure at the age of 24, followed by intermittent dizziness. MRI demonstrated diffuse, symmetric T2 hyperintensity in the cerebral white matter bilaterally and slight brain atrophy (Fig. 4K). Additional examinations revealed hypodontia and myopia, but normal gonadal function in the second patient.

Other diseases with white matter involvement
In this study, we identified several patients with other genetic disorders presenting with prominent white matter involvement that were not leukodystrophies. Two patients were identified with homozygous or compound heterozygous ATP7B mutations, consistent with the diagnosis of Wilson disease. One of these patients presented with dysarthria and dysphagia at 19 years of age and developed parkinsonism over the following 13 years. MRI revealed the presence of scattered symmetrical WMHs in various regions of the brain. The other patient presented with mild postural tremor and progressive dysarthria over a 20-year period and was diagnosed with symmetrical WMHs in the frontoparietal lobe, external capsule, midbrain, and pons based on brain MRI at 39 years of age (Fig. 4L).
In addition, two patients were diagnosed with PFBC due to JAM2 and PDGFB mutations, respectively. The patient with a homozygous JAM2 mutation developed ataxia at age 31, while the patient with a heterozygous PDGFB mutation developed dizziness and fever at 18 years old. Brain MRI showed symmetrical WMHs in the frontoparietal and temporal lobes, as well as in the periventricular areas. SWI and CT imaging showed symmetric calcifications in the subcortical region, cerebellum, thalami, basal ganglia, and cerebral peduncle.

Comparison of genetic profiles in different populations
Comparison of genetic profiles among distinct populations was conducted to elucidate the ethnic disparities in adult leukoencephalopathies. Data on other populations were obtained from previous studies. 5,6,8,9,32,33 In some cases, due to the unavailability of WES/focused exome sequencing or dynamic mutation analysis in certain studies, results were compared separately.

Comparison of dynamic mutation data
Screening for expansions of the GGC repeat region in NOTCH2NLC was conducted in cohorts of Chinese mainland, Taiwan region, Japanese, and British individuals ( Fig. 5E-I). Among our cohort of 78 patients with adult leukoencephalopathy who were negative for WES, 11 (14.1%) were found to carry an expanded NOTCH2NLC allele, with a median repeat size of 104. In a study by Wu et al.,39 (26.5%) out of 147 WESnegative patients were found to harbor an expanded NOTCH2NLC allele, with a median GGC repeat size of 120. 33 These findings suggest that abnormal expansions of the NOTCH2NLC GGC repeat region may contribute to up to 22.2% of unresolved leukoencephalopathies in Chinese mainland populations (Fig. 5E). In a cohort of Taiwan region patients with genetically unsolved nonvascular leukoencephalopathies, 32 (19.8%) out of 161 were found to have an expanded NOTCH2NLC allele, with a median GGC repeat size of 116 (Fig. 5F). 32 In a Japanese cohort of patients with adult leukoencephalopathy, 12 (12.9%) out of 93 carried an abnormal NOTCH2NLC GGC expansion, with a median repeat size of 115 (Fig. 5G). 8 Taken together, NOTCH2NLC GGC expansions account for approximately 19.6% of WESunresolved leukoencephalopathy cases in the Asian population (Fig. 5H). In contrast, in a British cohort of 52 patients with adult-onset leukoencephalopathy without a known genetic diagnosis, none were found to have an expanded NOTCH2NLC allele (Fig. 5I). 9 These results suggest that while NOTCH2NLC is an important genetic

Discussion
This study conducted a comprehensive genetic investigation to identify the genetic spectrum for adult leukoencephalopathies in a Chinese cohort, and established a relationship between genotypes and clinical phenotypes. The results showed that WES combined with dynamic mutation analysis increased the diagnostic rate to 48.1% in the leukoencephalopathy cohort, with NOTCH3 and NOTCH2NLC being the most commonly mutated genes. The different mutant genotypes were found to have great differences in phenotypes. The comparison of genetic profiles demonstrated a different mutational spectrum for adult leukoencephalopathies in Asians than in Caucasians.
Although WES technology has significantly improved the diagnosis of leukoencephalopathies, it has its limitations, such as difficulty in detecting copy number variations and non-coding area variations. 34 Recent long-read sequencing technology has solved these problems, as evidenced by the discovery of noncoding CGG repeat expansions of NOTCH2NLC, FMR1, and NUTM2B-AS1 in three leukoencephalopathies patients based on long-read sequencing technology. 7,11,35,36 This suggests an important role of dynamic mutation in genetic leukoencephalopathies.
In this study, we investigated dynamic mutations in Chinese patients with adult leukoencephalopathies and discovered that 8.5% of patients had NOTCH2NLC GGC repeat expansions, but none had FMR1 and NUTM2B-AS1 repeat expansions. Cognitive decline, autonomic dysfunction, limb weakness, headache, and parkinsonism were observed as common manifestations of NIID. Additionally, we observed a stroke-like episode in one patient, which initially led to a misdiagnosis. Previous studies have identified episodic encephalopathy as a specific manifestation with a strong diagnostic value for NIID. These episodes include sudden disturbance of consciousness, stroke-like episodes, encephalitis-like episodes, or psychiatric symptoms, observed in 5.0%-66.7% of NIID patients. 37 Besides, high-intensity signal along the corticomedullary junction that affects subcortical U-fibers on DWI is considered a reliable indicator of NIID. 37 However, this feature was absent in 18.2% of our NIID patients, indicating insufficient sensitivity. This similar radiological change was also observed in FXTAS and OPML patients, suggesting inadequate specificity of this feature. 7 Therefore, overemphasizing such high-intensity DWI signals may result in misdiagnosis or underdiagnosis. Further genetic investigations are warranted for patients exhibiting such features.
The vasculopathy-related genes were found to be common causes of adult leukoencephalopathies in different ethnic populations, but the mutational hotspot and clinical features had great genetic heterogeneities. Cysteinerelated mutations in NOTCH3 were confirmed to be the cause of CADASIL, but recent studies have also identified the pathogenicity of cysteine-sparing NOTCH3 mutations, such as the p.R75P mutation in Korea and Japan. 38,39 Some novel cysteine-sparing mutations in NOTCH3, such as p.R90H and p.V237M, were also found in our study. In addition, most of our CADASIL patients presented with ischemic stroke or recurrent TIA and a few suffered from migraine, which was different from Caucasians due to the higher proportion of migraine in Caucasians. 40 Inherited metabolic disorders are common causes of child leukoencephalopathies, 41 but they were found not to be rare in our adult leukoencephalopathies cohort. Several metabolic disorders were identified that affected very long chain fatty acid profile (ALD), serum cholestanol/urinary bile alcohols (CTX), specific enzyme activities (PKU and Krabbe disease) and plasma amino acid profile (homocystinuria). [42][43][44][45][46] The study failed to detect the ARSA mutation that causes metachromatic leukodystrophy, the most frequent diagnosis among childhood leukoencephalopathies, which may be attributed to different genetic profiles. 41 Inherited metabolic disorders with leukoencephalopathies have an earlier age at onset, a milder phenotype with a slower progression, and common features such as spastic gait, ataxia, cognitive decline, and peripheral neuropathy. Besides, white matter involvement on MRI is usually symmetrical and widely distributed.
This is the first study to compare the genetic profiles of adult leukoencephalopathies in different populations. Our study suggested that the genetic spectrum of adult leukoencephalopathy patients was different between Asians and Caucasians but similar within Asians. NOTCH3 mutations were classical causes of both Asians and Caucasians. However, NOTCH2NLC mutations were the hotspot of Asians instead of Caucasians. The proportion of NOTCH2NLC mutations, as well as the number of GGC repeats, is similar in different regions of Asia. We speculate that the Asian population has a founder effect on the NOTCH2NLC mutation. The fact that NOTCH2NLC GGC expansions appear to be more common in Asian populations compared to Caucasian populations is an important finding, and has implications for clinical practice. Clinicians should consider screening for these expansions in patients with adult leukoencephalopathy of Asian descent who have undergone negative WES testing. It is important to note, however, that NOTCH2NLC expansions do not account for all cases of adult leukoencephalopathy in Asian populations. Therefore, further research is needed to identify other genetic causes of this condition in these populations. Additionally, it remains unclear why NOTCH2NLC expansions appear to be more prevalent in certain ethnic groups, and future studies should explore this question further.
The study had some limitations. First, in clinical practice, suspected cases of genetic leukoencephalopathies are typically evaluated using a diagnostic algorithm that includes the exclusion of classical leukodystrophies via hematological, biochemical, and metabolic testing. 1 However, since classical leukodystrophies are also considered genetic leukoencephalopathies, we included these patients in our study and performed genetic testing to obtain a complete genetic profile. Second, it is important to note that different inclusion criteria were used in previously published studies when comparing the genetic profiles of different populations. For example, classical leukodystrophies were excluded in the Caucasian cohort, which makes it inappropriate to directly compare the proportion of different diseases in these studies. 5 To reduce the bias caused by different diagnostic criteria, we excluded the genes responsible for classical leukodystrophies. Despite our efforts, the preliminary conclusion regarding the genetic profiles of adult leukoencephalopathies in Asian and Caucasian populations should be considered with caution, and further well-designed case-control studies will be needed to verify the genetic heterogeneity among different populations.
In contemporary clinical practice, gene diagnoses have become increasingly important due to the critical role they play in the management and treatment of various genetic disorders. This study highlights the significance of genetic testing in diagnosing leukoencephalopathies, which is imperative for conducting systematic research on the management and treatment of these disorders. For instance, hematopoietic stem-cell transplantation (HSCT) has recently been established as an effective therapeutic strategy for HDLS, ALD, and other leukoencephalopathies. [47][48][49][50] Additionally, substrate reduction therapy has shown promise in reducing the accumulation of storage material in Krabbe disease. 51 In summary, this study presents a comprehensive genetic approach to diagnose approximately 50% of Chinese patients with adult leukoencephalopathies. The identification of common pathogenic genes such as NOTCH3, NOTCH2NLC, CSF1R, and ABCD1 serves to improve clinical recognition and inform genotype-phenotype correlation analysis. Furthermore, the comparison of genetic profiles highlights a different genetic spectrum for adult leukoencephalopathies in Asian and Caucasian populations, emphasizing the need for population-specific research on the management and treatment of these disorders.

Supporting Information
Additional supporting information may be found online in the Supporting Information section at the end of the article.