The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients.

Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole-exome sequencing, mitochondrial DNA sequencing and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were leukoencephalopathies related to NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%). Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%) and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R and HTRA1.

Stereoscopic slant contrast revisited.

The perceived slant of a stereoscopic surface is altered by the presence of a surrounding surface, a phenomenon termed stereo slant contrast. Previous studies have shown that a slanted surround causes a fronto-parallel surface to appear slanted in the opposite direction, an instance of "bidirectional" contrast. A few studies have examined slant contrast using slanted as opposed to fronto-parallel test surfaces, and these also have shown slant contrast. Here, we use a matching method to examine slant contrast over a wide range of combinations of surround and test slants, one aim being to determine whether stereo slant contrast transfers across opposite directions of test and surround slant. We also examine the effect of the test on the perceived slant of the surround. Test slant contrast was found to be bidirectional in virtually all test-surround combinations and transferred across opposite test and surround slants, with little or no decline in magnitude as the test-surround slant difference approached the limit. There was a weak bidirectional effect of the test slant on the perceived slant of the surround. We consider how our results might be explained by four mechanisms: (a) normalization of stereo slant to vertical; (b) divisive normalization of stereo slant channels in a manner analogous to the tilt illusion; (c) interactions between center and surround disparity-gradient detectors; and (d) uncertainty in slant estimation. We conclude that the third of these (interactions between center and surround disparity-gradient detectors) is the most likely cause of stereo slant contrast.

Advancements in Nanosystems for Ocular Drug Delivery: A Focus on Pediatric Retinoblastoma.

The eye's complex anatomical structures present formidable barriers to effective drug delivery across a range of ocular diseases, from anterior to posterior segment pathologies. Emerging as a promising solution to these challenges, nanotechnology-based platforms-including but not limited to liposomes, dendrimers, and micelles-have shown the potential to revolutionize ophthalmic therapeutics. These nanocarriers enhance drug bioavailability, increase residence time in targeted ocular tissues, and offer precise, localized delivery, minimizing systemic side effects. Focusing on pediatric ophthalmology, particularly on retinoblastoma, this review delves into the recent advancements in functionalized nanosystems for drug delivery. Covering the literature from 2017 to 2023, it comprehensively examines these nanocarriers' potential impact on transforming the treatment landscape for retinoblastoma. The review highlights the critical role of these platforms in overcoming the unique pediatric eye barriers, thus enhancing treatment efficacy. It underscores the necessity for ongoing research to realize the full clinical potential of these innovative drug delivery systems in pediatric ophthalmology.

Autonomic dysfunction-dominant phenotype in a Chinese family with biallelic GGC repeat expansions in NOTCH2NLC.

The GGC repeat expansions in the NOTCH2NLC gene are associated with multiple neurodegenerative disorders. Herein, we report the clinical phenotype in a family with biallelic GGC expansions in NOTCH2NLC. Autonomic dysfunction was a prominent clinical manifestation in three genetically confirmed patients without dementia, parkinsonism, and cerebellar ataxia for > 12 years. A 7-T brain magnetic resonance imaging in two patients revealed a change in the small cerebral veins. The biallelic GGC repeat expansions may not modify the disease progression in neuronal intranuclear inclusion disease. Autonomic dysfunction-dominant may expand the clinical phenotype of NOTCH2NLC.

Genotypic and phenotypic characteristics of juvenile/adult onset vanishing white matter: a series of 14 Chinese patients.

BACKGROUND: Vanishing white matter (VWM) is one of the most prevalent leukoencephalopathies and is caused by recessive mutations in gene eIF2B1-5. The onset may vary from an antenatal disorder that is rapidly fatal to an adult-onset disorder with chronic progressive deterioration. METHODS: Based on a comprehensive study of 14 juvenile/adult patients diagnosed in our department as well as a review of 71 previously reported cases of genetically confirmed juvenile/adult-onset VWM since 2001, we attempted to delineate the clinical symptoms, disease evolution, episodic aggravation, associated symptoms, MRI findings and genotypic characteristics of adult VWM. RESULTS: The onset age of neuropsychiatric symptoms was 23.4 ± 10.6 years, and the mean follow-up time was 8.1 ± 4.8 years. Major clinical symptoms included headache, epilepsy, cognitive decline, cerebellar ataxia, and urinary disturbances. Episodic aggravation was found in 42.9% of the patients in our series. Molecular studies revealed fourteen novel missense mutations. Diffuse abnormal signals characterized by T1-weighted hypointensity and T2-weighted hyperintensity were observed in the supratentorial white matter. CONCLUSIONS: The symmetrical leukoencephalopathy must be considered in patients of any age with premature ovarian failure or optic neuropathy. The VWM disease spectrum consists of characteristic imaging findings in combination with extremely wide variability in VWM patients.

Genotypic and Phenotypic Characteristics of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy from China.

BACKGROUND AND PURPOSE: Studies have shown characteristics of genotypes and phenotypes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to describe the clinical and genetic characteristics of and correlations between the genotypes and phenotypes observed in CADASIL in China on the basis of exon classification. METHODS: Consecutive Chinese patients with CADASIL were evaluated. The detailed clinical and genetic features of CADASIL patients were collected. Genotypic and phenotypic characteristics were compared among 3 CADASIL groups: group 1 included patients with NOTCH3 mutations in exons 3-4, group 2 included those with NOTCH3 mutations in exon 11, and group 3 included those with NOTCH3 mutations in other exons. RESULTS: A total of 46 patients with CADASIL were evaluated. A comparison of 3 groups with mutations in different NOTCH3 exons revealed that individuals with exon 11 mutations were diagnosed at the oldest age, had the lowest modified Rankin Scale (mRS) scores, and were most likely to have basal ganglia (BG) enlarged perivascular spaces (EPVS) > 20 and atrophy. There were no significant clinical or neuroimaging differences between patients with mutations in exons 3-4 and those with mutations in other exons. CONCLUSIONS: Clinical and neuroimaging features are different among Chinese patients with mutations in exons 3-4, exon 11, or other exons. Exon 11 showed characterized phenotype (the oldest age at diagnosis, the lowest mRS scores, and were most likely to have BG EPVS > 20 and atrophy), there were no significant differences between exons 3-4 and other exons.

Dystonia, spastic tetraplegia, and ataxia due to a novel mutation in the dynamin domain of OPA1.

Movement disorders manifest in various hereditary neurodegenerative diseases. We reported a young man who presented with progressive upper limb dystonia, spastic tetraplegia, and ataxia. Whole-exome sequencing (WES) revealed a novel variant, c.2357A > G, in the dynamin domain of OPA1. No mtDNA deletion was detected in muscle by long-range PCR. Atrophy and decreased glucose metabolism of the basal ganglia were discovered. Decreased mtDNA copy number, fragmented mitochondria, slightly impaired oxidative phosphorylation, and increased autophagy were detected in mutant fibroblasts. Evident oxidative phosphorylation impairment and mtDNA deletions were not involved in the pathogenicity of this mutation unlike mutations in the GTPase domain of OPA1.

Low HALP (Hemoglobin, Albumin, Lymphocyte, and Platelet) Score Increases the Risk of Post-Stroke Cognitive Impairment: A Multicenter Cohort Study.

Objective: The HALP (hemoglobin, albumin, lymphocyte, and platelet) score is a novel indicator that measures systemic inflammation and nutritional status that has not been correlated with the risk of post-stroke cognitive impairment in patients with acute ischemic stroke or transient ischemic attack (TIA). Methods: Study participants were recruited from 40 stroke centers in China. The HALP score was derived using a weighted sum of hemoglobin, albumin, lymphocytes and platelets, and study participants were categorized into 4 groups of equal sizes based on quartiles cutoffs of the HALP score. The Montreal Cognitive Assessment (MoCA)-Beijing Cognitive Assessment Scale (MoCA-Beijing) was performed at 2 weeks and 12 months following stroke onset. Post-stroke cognitive impairment was considered in patients with MoCA-Beijing≤22. Multiple logistic regression methods were employed to evaluate the relationship between the HALP score and the subsequent risk of developing post-stroke cognitive impairment. Results: The study population comprised 1022 patients (mean age 61.6±11.0 years, 73% men). The proportion of individuals with MoCA-Beijing≤22 at 2 weeks was 49.2% and 32.4% at one year. Patients in the lowest quartile of HALP score (<36.56) were observed to harbor the highest risk of post-stroke cognitive impairment at 12 months post-stroke/TIA compared to those in the highest quartile (odds ratio=1.59, 95% CI=1.07-2.37, p=0.022), and lower domain scores for executive function, naming, and attention. There were no statistically significant differences between patients in the different quartiles of HALP score and HALP score at 2 weeks post-stroke/TIA. Conclusion: The HALP score is a simple score that could stratify the risk of post-stroke cognitive impairment in stroke/TIA patients to facilitate early diagnosis and interventions.

Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease.

Background and Objectives: Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China. Methods: The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features were recorded. Brain MRI, skin pathologies, and the number of GGC repeat expansions in the 5' untranslated region of the NOTCH2NLC gene were evaluated in all patients. Results: In total, 223 patients (64.6% female) were recruited; the mean (SD) onset age was 56.7 (10.3) years. The most common manifestations were cognitive impairment (78.5%) and autonomic dysfunction (70.9%), followed by episodic symptoms (51.1%), movement disorders (50.7%), and muscle weakness (25.6%). Imaging markers included hyperintensity signals along the corticomedullary junction on diffusion-weighted imaging (96.6%), white matter lesions (98.1%), paravermis (55.0%), and focal cortical lesions (10.1%). The median size of the expanded GGC repeats in these patients was 115 (range, 70-525), with 2 patients carrying >300 GGC repeats. A larger number of GGC repeats was associated with younger age at onset (r = -0.329, p < 0.0001). According to the proposed clinical classification based on the most prominent manifestations, the patients were designated into 5 distinct types: cognitive impairment-dominant type (34.1%, n = 76), episodic neurogenic event-dominant type (32.3%, n = 72), movement disorder-dominant type (17.5%, n = 39), autonomic dysfunction-dominant type (8.5%, n = 19), and neuromuscular disease-dominant type (7.6%, n = 17). Notably, 32.3% of the episodic neurogenic event-dominant type of NIID has characteristic focal cortical lesions on brain MRI presenting localized cortical edema or atrophy. The mean onset age of the neuromuscular disease-dominant type was 47.2 (17.6) years, younger than the other types (p < 0.001). There was no significant difference in the sizes of GGC repeats among the patients in the 5 types (p = 0.547, Kruskal-Wallis test). Discussion: This observational study of NIID establishes an overall picture of the disease regarding clinical, imaging, and genetic characteristics. The proposed clinical classification of NIID based on the most prominent manifestation divides patients into 5 types.

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia.

Background and Purpose: A variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs. Methods: A total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses. Results: The mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28. Conclusion: Causative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs.

Clinical and pathological study of SORD-related distal motor neuropathy caused by novel compound heterozygous mutations in a Chinese patient.

Sorbitol dehydrogenase (SORD) has been identified as the causative gene of autosomal recessive distal hereditary motor neuropathies (dHMN). Here, we describe a 25-year-old woman who presented with progressive weakness of both lower limbs for the previous 10 years. Electrophysiological results suggested only a reduction in the compound muscle action potential (CMAP) amplitude of both the tibial and left deep peroneal nerves and neurogenic changes in needle EMG. A heterozygous c.757delG variant with a splicing c.786 + 1 G>A variant in the SORD gene was identified. A sural nerve biopsy revealed slight axon separation from the myelin sheath and thin myelin sheaths in very few nerve fibres and thickening of the microvasculature basement membrane. Our study expands the pathological and mutation spectrum of the SORD-related neuropathy.

Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL.

OBJECTIVE: There is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1-related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1-related CSVD, and we compared the features of heterozygous HTRA1-related CSVD and CADASIL. METHODS: We carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1-related CSVD and CADASIL were compared. RESULTS: We identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1-related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001). INTERPRETATION: This study shows that most HTRA1-related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra-neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1-related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.

Two Novel Myelin Protein Zero Mutations in a Group of Chinese Patients.

Mutations in the myelin protein zero gene are responsible for the autosomal dominant Charcot-Marie-Tooth disease (CMT). We summarized the genetic and clinical features of six unrelated Chinese families and the genetic spectrum of Chinese patients with myelin protein zero (MPZ) mutations. Our study reports data from a group of Chinese patients consisting of five males and one female with the age of disease onset ranging from 16 to 55 years. The initial symptom in all the patients was the weakness of the lower limbs. Electrophysiological presentations suggested chronic progressive sensorimotor demyelinating polyneuropathy. Overall six mutations were identified in the cohort, including four known mutations [c.103G>T (p.D35Y), c.233C>T (p.S78L), c.293G>A (p.R98H), and c.449-1G>T], and two novel mutations [c.67+4A>G with a mild CMT1B phenotype, and (c.79delG) p.A27fs with a rapidly progressive CMT1B phenotype]. According to the literature review, there are 35 Chinese families with 28 different MPZ mutations. The MPZ mutational spectrum in Chinese patients is very heterogeneous and differs from that of Japanese and Korean individuals, although they do share several common hot spot mutations.

Revaluation of clopidogrel: let the data speak for themselves.

Clopidogrel was believed to be superior to aspirin by the well-known CAPRIE trial. However, no other large clinical trials demonstrated the same results, but all focused on the combination use of clopidogrel with aspirin, and combination therapy in CREDO was called the "Emperor's New Clothes". However, no one overturned the results of these clinical trials by quantitatively analyzing them. We reviewed ten large-scale clinical trials about clopidogrel. On the basis of results of CAPRIE, CREDO and CHARISMA trials, we re-estimated their minimal sample sizes and their powers by three well-established statistical methodologies. From the results of CAPRIE, we inferred that the minimal sample size should be 85 086 or 84 968 but its power was only 30.70%. A huge gap existed. The same was also true of CREDO and CHARISMA trials. Moreover, in CAPRIE trial, 0 was included in the 95% confidence interval and 1 was included in the 95% confidence interval for the relative risk. There were some paradoxical data in CAPRIE trial. We are led to conclude that the results in CAPRIE, CREDO, and from the subgroup analysis in CHARISMA trials were questionable. These results failed to demonstrate that clopidogrel was superior to aspirin or that clopidogrel used in combination with aspirin was better than aspirin alone. The cost-effectiveness analyses by some previous studies were not reliable.

Intracranial Large Artery Abnormalities and Association With Cerebral Small Vessel Disease in CADASIL.

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic arteriopathy, the classic feature of which is small vessel lesions. Studies on intracranial large arteries in CADASIL are not common. We aim to evaluate intracranial large arteries, describing the characteristics of large arteries in CADASIL and their association with cerebral small vessel associated lesions. Methods: Consecutive CADASIL patients from a single-center prospective cohort were analyzed. Brain magnetic resonance imaging and magnetic resonance angiography were performed to assess the intracranial large arteries and cerebral small vessels associated lesions' neuroimaging. Results: The study included 37 CADASIL patients. Of the patients, 28 of them (75.7%) had intracranial large artery abnormalities. Eighteen (48.6%) had congenital variations such as fenestration, vertebral artery (VA) hypoplasia and agenesis, or common trunk and fetus posterior cerebral artery. Seventeen (45.9%) had acquired anomalies such as arterial stenosis, prolongation, or tortuosity (seven of them had both congenital and acquired anomalies). CADASIL patients with anterior circulation middle cerebral artery (MCA) or internal cerebral artery (ICA) severe stenosis were more likely to have ipsilateral asymmetric white matter hyper-density (WMH) distribution. Patients with posterior circulation VA hypoplasia had a higher prevalence of posterior subcortical zone dominant WMH distribution. Conclusion: CADASIL patients can demonstrate various intracranial large artery abnormalities which might influence the development of microangiopathy. Assessment of great vessels seems essential in CADASIL.

QT Interval Dispersion as a Predictor of Clinical Outcome in Acute Ischemic Stroke.

Background and Purpose: QT dispersion (QTd) abnormalities are widely documented in stroke patients. This study aims to investigate the association between QTd and clinical outcomes in IS patients. Methods: IS patients registered in the Blood Pressure and Clinical Outcome in transient ischemic attack (TIA) or IS (BOSS) registry between 2012 and 2014 within 24 h of onset were analyzed. In this prospective observational study, we identified 1,522 IS cases with adequate electrocardiographic evaluations to assess QTd after the index stroke. Patients were classified into four groups based on the quartile of QTd, with the lowest group as the reference. The primary stroke outcome was defined as a modified Rankin Scale score ≥3 at 1-year. Multiple logistic regressions were utilized to investigate the association between QTd and outcome events. Results: The mean QTd across all cases was 57 ms (40-83). Functional dependency or death was documented in 214 (14.98%) cases at 1 year. After adjusting for confounders, the prevalence of death and major disability (mRS ≥ 3) showed significant differences according to the quartile of QTd, with the risk of death and major disability (mRS ≥ 3) at 1 year being significantly higher for patients in Q4 than for those in Q1 (adjusted OR = 1.626, 95% CI:1.033-2.560). However, there were no significant correlation between QTd and the event outcomes at 1 year. Conclusions: QTd was associated with poor functional outcomes at 1 year. QTd is a useful surrogate marker for adverse functional prognosis, which might help to stratify risk in patients with acute IS.

Three novel mutations in a group of Chinese patients with X-linked Charcot-Marie-Tooth disease.

The X-linked form of Charcot-Marie-Tooth disease type1 (CMTX1) is the second most common hereditary motor and sensory neuropathy caused by mutations in the gap junction beta 1 (GJB1) gene. Here, we report the clinical and genetic features of six unrelated Chinese patients with CMTX1, which were identified by genetic analysis. Among the 6 identified mutations, 3 were previously unknown (c.31A > T, c.42 C > G and c.423 del C). The six patients showed typical signs of CMT with a median age of onset of 16.5 years (range: 13-30). Sensorineural hearing loss was confirmed in the patient with the c.423 del C mutation. White matter lesions on brain magnetic resonance imaging (MRI) were observed in two patients. The three newly identified GJB1 mutations expand the clinical and mutational spectrum of CMTX1.

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies.

The white matter disease spectrum is associated with many genetic diseases, including AARS2, CADASIL, ALD, and others. In this study, to determine the novel alanyl-tRNA synthetase 2 mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. We identified 5 rare variants (c.452T>C chr6:44279256 p.M151T, c.1871G>A chr6:44272054 p.W624X, c.802A>G chr6:44278128 p.M268V, c.1703-1704del chr6:-44272430-44272431 p.Q568fs, and c.179C>A chr6-44280882 p.P60H) with varying expression in 4 independent Chinese families with leukodystrophy. These single nucleotide variants (SNVs), or deletion mutations, each induced a frameshift, causing a missense mutation in alanyl-tRNA synthetase 2. These findings suggested that all mutations might contribute to the development of leukodystrophy in the examined family members. Combined with previous findings, our data confirmed that the novel mutations are located in leukodystrophy-related risk genes. We also summarized all the alanyl-tRNA synthetase 2 mutations related to the onset of leukodystrophies in adults.

Clinical, electrophysiological, genetic, and imaging features of six Chinese Han patients with hereditary neuropathy with liability to pressure palsies (HNPP).

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. This study summarizes the clinical, electrophysiological, genetic, and imaging features of six unrelated Chinese Han patients with HNPP. Age of onset was within the second decade in five patients, and 46 years of age in one patient. Weakness or numbness in a unilateral lower extremity was the most common symptom in 5 patients, and bilateral sensorineural hearing loss was also detected in one patient. Electrophysiological presentations suggested demyelinating sensory-motor polyneuropathy in the group. Magnetic resonance imaging (MRI) of the cervical and lumbar spine revealed varying degrees of degeneration in five patients, and mild kyphosis of cervical vertebral bodies in 2 teen-aged patients. In addition, cranial MRI of one patient showed scattered demyelination in the frontal lobes. Targeted next-generation-sequencing (NGS) revealed a PMP22 deletion in five patients and a heterozygous c.199G>A mutation in exon 4 of PMP22 in one patient. The I92V variant of lipopolysaccharide-induced tumor necrosis factor (LITAF) gene was found in one patient. There was no relationship between the Ile92Val variant of LITAF and age of onset in this group, albeit the sample size was very small.

A novel homozygous NDRG1 mutation in a Chinese patient with Charcot-Marie-Tooth disease 4D.

Charcot-Marie-Tooth disease 4D (CMT4D) is characterized by severe peripheral neuropathy and deafness. It is caused by mutations in the N-myc downstream-regulated gene 1 (NDRG1). We report a Chinese man with a homozygous mutation c.675C > T of NDRG1 that resulted in Q185X, representing the third known CMT4D patient of non-European ancestry. The patient presented with a 15-year-long history of progressive limb weakness accompanied by hearing loss and dysarthria. There was abnormal differentiation and increased interpeak latencies in brainstem auditory evoked potentials. Compound muscle action potentials (CMAP) of the peripheral nerves were not elicited in distal segments, while prolonged distal latencies and decreased CMAP were present in proximal nerves. A mild enlargement of the lateral ventricles showed in brain magnetic resonance imaging studies. Q185X of NDRG1 is a novel mutation with CMT4D, which are demonstrated in Asian population. Q185X of the NDRG1 expands the clinical and mutational spectrum of CMT4D.