Clinical and genetic characteristics of myotonia congenita in Chinese population.

Myotonia congenita (MC) is a rare hereditary muscle disease caused by variants in the CLCN1 gene. Currently, the correlation of phenotype-genotype is still uncertain between dominant-type Thomsen (TMC) and recessive-type Becker (BMC). The clinical data and auxiliary examinations of MC patients in our clinic were retrospectively collected. Electromyography was performed in 11 patients and available family members. Whole exome sequencing was conducted in all patients. The clinical and laboratory data of Chinese MC patients reported from June 2004 to December 2022 were reviewed. A total of 11 MC patients were included in the study, with a mean onset age of 12.64 ± 2.73 years. The main symptom was muscle stiffness of limbs. Warm-up phenomenon and percussion myotonia were found in all patients. Electromyogram revealed significant myotonic charges in all patients and two asymptomatic carriers, while muscle MRI and biopsy showed normal or nonspecific changes. Fourteen genetic variants including 6 novel variants were found in CLCN1. Ninety-eight Chinese patients were re-analyzed and re-summarized in this study. There were no significant differences in the demographic data, clinical characteristics, and laboratory findings between 52 TMC and 46 BMC patients. Among the 145 variants in CLCN1, some variants, including the most common variant c.892 G>A, could cause TMC in some families and BMC in others. This study expanded the clinical and genetic spectrum of Chinese patients with MC. It was difficult to distinguish between TMC and BMC only based on the clinical, laboratory, and genetic characteristics.

Rituximab-induced gut microbiota changes in Chinese neuromyelitis optica spectrum disorders.

BACKGROUND: Recent evidence shows that immunosuppressive agents can affect the gut microbiota in autoimmune diseases. However, the relationship between the gut microbiome and B-cell depletion immunotherapy in neuromyelitis optica spectrum disorder (NMOSD) remains poorly understood. OBJECTIVES: To evaluate the distinct intestinal microbial patterns and serum cytokine levels after short-term rituximab treatment (three months) in patients with NMOSD. METHODS: Firstly, we conducted a cross-sectional study involving 46 treatment-naïve NMOSD patients and 48 matched healthy controls. We collected fecal specimens, which were then analyzed using next-generation sequencing, and quantified serum cytokines. Subsequently, fecal and serum samples were re-collected and re-evaluated in 31 of the 46 treatment-naïve NMOSD patients after RTX treatment. RESULTS: Comparing the gut microbiome of treatment-naïve NMOSD patients to that of healthy controls revealed low α-diversity and distinct microbial compositions in the former. The microbial composition in NMOSD patients underwent changes following three months of RTX treatment. Specifically, the levels of IL-17F and IL-6 decreased, while those of IL-10 and TNFα increased after RTX treatment. LEfSe analysis identified 27 KEGG categories with significantly differential abundances between NMOSD patients and RTX treatment group. CONCLUSIONS: Our study provides a comprehensive understanding of the gut microbiota landscape in the context of B-cell depletion immunotherapy. We observed dysbiosis in the gut microbiome of NMOSD patients, which was partially alleviated by three months of RTX treatment. This suggests that B-cell depletion may play a crucial role in driving changes in the gastrointestinal environment.

Encephalitis-like episodes with cortical edema and enhancement in patients with neuronal intranuclear inclusion disease.

OBJECTIVES: Neuronal intranuclear inclusion disease (NIID) exhibited significant clinical heterogeneities. However, the clinical features, radiographic changes, and prognosis of patients with encephalitis-like NIID have yet to be systematically elucidated. METHODS: Clinical data including medical history, physical examination, and laboratory examinations were collected and analyzed. Skin and sural nerve biopsies were conducted on the patient. Repeat-primed PCR (RP-PCR) and fluorescence amplicon length PCR (AL-PCR) were used to detect the expansion of CGG repeat. We also reviewed the clinical and genetic data of NIID patients with cortical enhancement. RESULTS: A 54-year-old woman presented with encephalitis-like NIID, characterized by severe headache and agitative psychiatric symptoms. The brain MRI showed cortical swelling in the temporo-occipital lobes and significant enhancement of the cortical surface and dura, but without hyperintensities along the corticomedullary junction on diffusion-weighted image (DWI). A biopsy of the sural nerve revealed a demyelinating pathological change. The intranuclear inclusions were detected in nerve and skin tissues using the p62 antibody and electron microscopy. RP-PCR and AL-PCR unveiled the pathogenic expansion of CGG repeats in the NOTCH2NLC gene. A review of the literature indicated that nine out of the 16 patients with cortical lesions and linear enhancement exhibited encephalitis-like NIID. CONCLUSION: This study indicated that patients with encephalitis-like NIID typically exhibited headache and excitatory psychiatric symptoms, often accompanied by cortical edema and enhancement of posterior lobes, and responded well to glucocorticoid treatment. Furthermore, some patients may not exhibit hyperintensities along the corticomedullary junction on DWI, potentially leading to misdiagnosis.

Homozygous variant in COQ7 causes autosomal recessive hereditary spastic paraplegia.

Biallelic mutations in the coenzyme Q7 (COQ7) encoding gene were recently identified as a genetic cause of distal hereditary motor neuropathy. Here, we explored the clinical, electrophysiological, pathological, and genetic characteristics of a Chinese patient with spastic paraplegia associated with recessive variants in COQ7. This patient carried a novel c.322C>A (p.Pro108Thr) homozygous variant. Sural biopsy revealed mild mixed axonal and demyelinating degeneration. Immunoblotting showed a significant decrease in the COQ7 protein level in the patient's fibroblasts. This study confirmed that COQ7 variant as a genetic cause of HSP, and further extended spastic paraplegia to the phenotypic spectrum of COQ7-related disorders.

TG/HDL-c ratio as a predictor of progressive infarction in patients with anterior circulation single subcortical infarction.

BACKGROUND: The contributors predicting progressive infarction (PI) in patients with anterior circulation single subcortical infarction (ACSSI) and pontine single infarction (PSI) may be unidentical. The role of triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio on PI is unclear. The purpose of our study is to evaluate the correlation between TG/HDL-c ratio and PI in patients with ACSSI or PSI. METHODS: Between January 2020 and October 2022, we retrospectively enrolled 738 patients including 638 ACSSI patients and 100 PSI patients to analyze. Demographic characteristics, clinical information, and laboratory data were collected within 24 h of admission. RESULTS: PI occurred in 143 (19.4%) patients. In univariate analysis, patients with PI had higher initial National Institutes of Health Stroke Scale (NIHSS) scores, higher discharge NIHSS scores, higher levels of fasting glucose, total cholesterol, TG, low-density lipoprotein cholesterol, and TG/HDL-c ratio, but lower levels of creatinine compared to patients with non-PI (p < .05). Furthermore, the results of the subgroup analyses revealed the independent association between TG/HDL-c ratio and PI in ACSSI patients (OR 1.079, 95% CI 1.009-1.153, p = .026) rather than in PSI patients. Additionally, a receiver operating characteristic curve indicated that the optimal predictive cutoff value of the TG/HDL-c ratio was 3.985, and a TG/HDL-c ratio ≥3.985 was more likely to experience PI in ACSSI patients. CONCLUSION: In conclusion, the TG/HDL-c ratio was independently associated with PI in patients with ACSSI.

A novel score to predict progression in anterior circulation single subcortical infarction patients.

OBJECTIVE: Progressive infarction (PI) has a negative effect on functional prognosis. Our study aimed to develop and validate a risk score for predicting PI in patients with anterior circulation single subcortical infarction (ACSSI). METHODS: Between January 2020 and October 2022, we retrospectively enrolled 638 eligible patients with ACSSI. Two-thirds of the eligible patients were randomly allocated to the training cohort (n = 425). Another resampling sample was formed through the bootstrap method and was used as the validation group (n = 425). Multivariate logistic regression analysis was used to identify the independent factors associated with PI. Each factor was then point assigned based on ß-coefficient and a risk scoring system was developed. This scoring system was internally validated through 1000-bootstrap resamplings. The C-statistic and Hosmer-Lemeshow test were used to assess model discrimination and calibration. RESULTS: PI occurred in 121 patients, accounting for 19.0% of the total patients. A 7-point NTS score system based on the initial NIHSS score, triglyceride-glucose index, and the number of infarct slices on axial diffusion-weighted imaging was developed. The NTS score showed good discrimination and calibration in the training cohort (C-statistic = 0.686; p value of Hosmer-Lemeshow test = 0.797) and validation cohort (C-statistic = 0.681; p value of Hosmer-Lemeshow test = 0.451). The three risk levels for predicting PI in the training and validation cohorts based on NTS score were as follows: low (0-2, 9.6% vs. 9.3%), intermediate (3-5, 28.2% vs. 26.7%), and high risk (6-7, 60.2% vs. 57.4%). INTERPRETATION: The NTS score is a valid and convenient risk score for predicting PI in ACSSI patients.

Clinical characteristics of autoimmune encephalitis with co-existence of multiple anti-neuronal antibodies.

BACKGROUND: An increasing number of cases of autoimmune encephalitis (AE) with co-existing multiple anti-neuronal antibodies have been reported in recent years. However, the clinical significance of the concurrent presence of multiple anti-neuronal antibodies in patients with AE remains unclear. METHODS: We retrospectively enrolled AE patients with multiple anti-neuronal antibodies treated at our center between August 2019 and February 2022. We also reviewed cases reported in multiple literature databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed on selection process. And then the clinical and laboratory data of these cases were collected for review and summary. RESULTS: A total of 83 AE cases with multiple antibodies (9 cases from our center and 74 cases from the literatures reviewed) were identified. In our center, nine patients presented with encephalitis symptoms, clinically characterized as disturbed consciousness, seizures, cognitive impairment, and psychiatric disorders. Of the 83 cases, 73 cases had co-existence of 2 types of antibodies, 8 cases had 3 types, and 2 cases had 4 types. Thirty-nine cases (39/83, 46.9%) were confirmed or suspected of also having a tumor, of which the most common was lung cancer (28/83, 33.7%). Partial or complete recovery was achieved in 57 cases (57/83, 68.6%), while 26 cases (26/83, 31.3%) died during treatment or follow-up. CONCLUSIONS: AE with co-existing multiple anti-neuronal antibodies is a specific subgroup, that is increasingly recognized in clinical practice. The co-existence of multiple anti-neuronal antibodies has a major impact on clinical features, disease progression, and prognosis.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization.

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurologic disorders characterized by progressive lower-extremity spasticity. Despite the identification of several HSP-related genes, many patients lack a genetic diagnosis. OBJECTIVES: The aims were to confirm the pathogenic role of biallelic COQ4 mutations in HSP and elucidate the clinical, genetic, and functional molecular features of COQ4-associated HSP. METHODS: Whole exome sequences of 310 index patients with HSP of unknown cause from three distinct populations were analyzed to identify potential HSP causal genes. Clinical data obtained from patients harboring candidate causal mutations were examined. Functional characterization of COQ4 variants was performed using bioinformatic tools, single-cell RNA sequencing, biochemical assays in cell lines, primary fibroblasts, induced pluripotent stem cell-derived pyramidal neurons, and zebrafish. RESULTS: Compound heterozygous variants in COQ4, which cosegregated with HSP in pedigrees, were identified in 7 patients from six unrelated families. Patients from four of the six families presented with pure HSP, whereas probands of the other two families exhibited complicated HSP with epilepsy or with cerebellar ataxia. In patient-derived fibroblasts and COQ4 knockout complementation lines, stable expression of these missense variants exerted loss-of-function effects, including mitochondrial reactive oxygen species accumulation, decreased mitochondrial membrane potential, and lower ubiquinone biosynthesis. Whereas differentiated pyramidal neurons expressed high COQ4 levels, coq4 knockdown zebrafish displayed severe motor dysfunction, reflecting motor neuron dysregulation. CONCLUSIONS: Our study confirms that loss-of-function, compound heterozygous, pathogenic COQ4 variants are causal for autosomal recessive pure and complicated HSP. Moreover, reduced COQ4 levels attributable to variants correspond with decreased ubiquinone biosynthesis, impaired mitochondrial function, and higher phenotypic disease severity. © 2023 International Parkinson and Movement Disorder Society.

Pathologic changes in neuronal intranuclear inclusion disease are linked to aberrant FUS interaction under hyperosmotic stress.

CGG repeat expansion in NOTCH2NLC is the genetic cause of neuronal intranuclear inclusion disease (NIID). Previous studies indicated that the CGG repeats can be translated into polyglycine protein (N2CpolyG) which was toxic to neurons by forming intranuclear inclusions (IIs). However, little is known about the factors governing polyG IIs formation as well as its molecular pathogenesis. Considering that neurogenetic disorders usually involve interactions between genetic and environmental stresses, we investigated the effect of stress on the formation of IIs. Our results revealed that under hyperosmotic stress, N2CpolyG translocated from the cytoplasm to the nucleus and formed IIs in SH-SY5Y cells, recapitulating the pathological hallmark of NIID patients. Furthermore, N2CpolyG interacted/ co-localized with an RNA-binding protein FUS in the IIs of cellular model and NIID patient tissues, thereby disrupting stress granule formation in cytoplasm under hyperosmotic stress. Consequently, dysregulated expression of microRNAs was found both in NIID patients and cellular model, which could be restored by FUS overexpression in cultured cells. Overall, our findings indicate a mechanism of stress-induced pathological changes as well as neuronal damage, and a potential strategy for the treatment of NIID.

The intestinal microbiota exerts a sex-specific influence on neuroinflammation in a Parkinson's disease mouse model.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by chronic and progressive symptoms; it is more prevalent in men than in women. The sex-specific influence of the intestinal microbiota has been associated with some neurodegenerative diseases, but the relationship with PD is currently unclear. In this study, we treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a PD mouse model, and we utilised an antibiotic cocktail (Abx) to deplete the intestinal microbiota to evaluate the influence of the intestinal microbiota on male and female PD mice. MPTP treatment obviously caused bradykinesia and low mobility in female and male mice. Meanwhile, Abx treatment exerted a greater effect on male mice than female mice. Western blotting and immunofluorescence revealed that male mice treated with MPTP had higher expression of α-synuclein and proteins related to neuroinflammation and intestinal inflammation based on activation of glial cells and the TLR4-MyD88 signalling pathway. The sex-specific differences could be due to the different composition of the intestinal microbiota. Specifically, female mice had significantly higher abundance of Allobaculum, Turicibacter and Ruminococcus than male mice. Moreover, the abundance of the probiotic genus Bifidobacterium showed opposite trends in male and female mice. Our results indicate that the intestinal microbiota has an important effect on PD mice, especially male mice, by influencing neuroinflammation through the microbiota-gut-brain axis. In the future, there should be a focus on providing more reliable evidence for the pathogenesis and precise treatment of PD.

Weaning difficulty after severe pneumonia in adult-onset mitochondrial myopathy with A3243G mutation in the mitochondrial tRNA gene: A case report.

Background: Mitochondrial myopathy is a group of diseases caused by abnormal mitochondrial structure or function. The mitochondrial myopathy impacts muscles of the whole body and exhibits variable symptoms. Respiratory muscle deficits deteriorate pulmonary function in patients with severe pneumonia. Case presentation: We report the case of a male patient with severe pneumonia-induced respiratory failure. He was abnormally dependent invasive ventilator-assisted ventilation after his condition had improved. Then we found abnormal ventilator waveform and a decline in muscle strength of him. Mitochondrial myopathy was ultimately confirmed by muscle pathological biopsy and body fluid genetic testing. Vitamin B complex, coenzyme Q10, Neprinol AFD, l-arginine, and MITO-TONIC were used to improve mitochondrial function and muscle metabolism. After treatment, discomfort associated with chest tightness, fatigue, cough, and sputum disappeared, and the patient was discharged. Conclusion: This case presented an uncommon cause of difficult weaning and extubation-acute onset of mitochondrial myopathy. Muscle biopsy and genetic testing of body fluid are essential for diagnosing mitochondrial myopathy. The A3243G mutation in the MT-TL1 gene of mitochondrial DNA contributes to pathogenesis of this case.

Knockout of Rnf213 Ameliorates Cerebral Ischemic-reperfusion Injury by Inhibiting Neuronal Apoptosis Through the Akt/GSK-3ß/ß-catenin/Bcl-2 Pathway.

Previous studies by us and others have shown that RING finger protein 213 (RNF213) is associated with cerebrovascular disease and systemic vasculopathy. Indeed, Rnf213 mRNA expression is increased in cerebral ischemia reperfusion injury (CIRI). The purpose of the present study was to investigate the role of Rnf213 in CIRI. Using the middle cerebral artery occlusion (MCAO) model, we confirmed that the expression of RNF213 protein was significantly upregulated in neurons in the ischemic penumbra. Rnf213 knockout mice were successfully generated using CRISPR/Cas9 technology. According to TTC staining and Bederson neurological scale, removal of Rnf213 decreased brain infarct volume and improved neurological deficit score, although the restoration of cerebral blood flow after MCAO was similar in WT and Rnf213-/- mice. In addition, the levels of p-Akt, p-GSK-3ß, ß-catenin and Bcl-2 were significantly increased 24 h after MCAO in the ischemic penumbra of the Rnf213-/- mice compared to WT mice, indicating that Rnf213 removal may ameliorate neuronal apoptosis by regulating the Akt/GSK-3ß/ß-catenin/Bcl-2 signaling pathway. Taken together, our study reveals that Rnf213 regulates neuronal apoptosis in CIRI, therefore impacting on brain infarct volume in brain ischemia.

Ischemic patterns and their angiographic risk factors in adult patients with moyamoya disease.

OBJECTIVE: The present study aims to determine whether angiographic differences increase the risk of ischemic pattern among adult patients with moyamoya disease (MMD). METHODS: From January 2020 to December 2021, we retrospectively enrolled 123 ischemic or asymptomatic adult patients diagnosed as MMD. Angiographic changes including Suzuki stage, moyamoya vessels, anterior choroidal artery (AChoA) dilatation, lenticulostriate artery (LSA) dilatation, posterior communicating artery (PcomA) dilatation, and posterior cerebral artery (PCA) involvement were evaluated for all patients. RESULTS: Among the 123 participants, 35 ischemic patients and 88 asymptomatic patients were analyzed. There was no significant difference of Suzuki stage, AChoA dilatation, LSA dilatation, and PcomA dilatation between ischemic group and asymptomatic group. The grading of moyamoya vessels differed significantly but was not a factor associated with ischemic pattern after adjusting multiple related confounders. However, the frequency of PCA steno-occlusive changes in ischemic patients was statistically higher than that in asymptomatic patients (54.3% vs 34.1%, p = 0.039). Furthermore, PCA involvement was a risk factor associated with ischemic form and remained statistically significant after the multivariate adjustment (p = 0.033, 95% CI 1.092-8.310). INTERPRETATION: PCA involvement is closely related to the presentation of ischemic stroke but other angiographic features had no association with ischemic pattern in adult MMD.

Dyslipidemia is associated with progressive infarction in anterior circulation single subcortical infarction patients.

BACKGROUND: The predictors of progressive infarction (PI) in patients with anterior circulation single subcortical infarction (ACSSI) and pontine single infarction (PSI) may be different. Our study aims to evaluate the association between various lipid markers and PI in patients with ACSSI or PSI. METHODS: A total of 629 patients (546 patients diagnosed as ACSSI and 83 patients diagnosed as PSI) were retrospectively enrolled between January 2020 and October 2022. Seven lipid markers including total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB) and lipoprotein(a) were collected within 24 h after admission. RESULTS: There were 119 patients with PI, accounting for 18.9% of the total. Univariate analysis showed that the levels of TC, TG, LDL-c, and ApoB in total patients with PI were higher than those in patients without PI (P < 0.05), while there were no significant differences in HDL-c, ApoA-I, and lipoprotein(a) (P > 0.05). In branch atheromatous disease patients, TC, TG, and ApoA-I were independently associated with PI after adjusting some confounding factors. Additionally, multivariate logistic regression analysis of the infarct location subgroup demonstrated TG and LDL-c were related to PI in patients with ACSSI (P < 0.05) but not in patients with PSI. Furthermore, receiver operating characteristic curves were established to compare the predictive abilities of TC, TG, LDL-c, and ApoB, and demonstrated TG was a better indicator to predict PI in ACSSI patients compared to other lipid markers. CONCLUSION: TG and LDL-c are associated with progressive infarction in patients with ACSSI, and TG was a superior predictor for PI compared to other lipid markers.

Background and roles: myosin in autoimmune diseases.

The myosin superfamily is a group of molecular motors. Autoimmune diseases are characterized by dysregulation or deficiency of the immune tolerance mechanism, resulting in an immune response to the human body itself. The link between myosin and autoimmune diseases is much more complex than scientists had hoped. Myosin itself immunization can induce experimental autoimmune diseases of animals, and myosins were abnormally expressed in a number of autoimmune diseases. Additionally, myosin takes part in the pathological process of multiple sclerosis, Alzheimer's disease, Parkinson's disease, autoimmune myocarditis, myositis, hemopathy, inclusion body diseases, etc. However, research on myosin and its involvement in the occurrence and development of diseases is still in its infancy, and the underlying pathological mechanisms are not well understood. We can reasonably predict that myosin might play a role in new treatments of autoimmune diseases.

Skin biopsy and neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with variable clinical phenotypes. There is a considerable delay in the definite diagnosis, which primarily depends on postmortem brain pathological examination. Although CGG repeat expansion in the 5'-untranslated region of NOTCH2NLC has been identified as a disease-associated variant, the pathological diagnosis is still required in certain NIID cases. Intranuclear inclusions found in the skin tissue of patients with NIID dramatically increased its early detection rate. Skin biopsy, as a minimally invasive method, has become widely accepted as a routine examination to confirm the pathogenicity of the repeat expansion in patients with suspected NIID. In addition, the shared developmental origin of the skin and nerve system provided a new insight into the pathological changes observed in patients with NIID. In this review, we systematically discuss the role of skin biopsy for NIID diagnosis, the procedure of skin biopsy, and the pathophysiological mechanism of intranuclear inclusion in the skin.

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia.

BACKGROUND: More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion. OBJECTIVE: The objective of this study was to confirm a novel SCA subtype caused by CAG expansion. METHODS: We performed long-read whole-genome sequencing combined with linkage analysis in a five-generation Chinese family, and the finding was validated in another pedigree. The three-dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro-2a cells. RESULTS: We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5-6 in controls), whereas the number of 3' pure CAG repeats was up to 32 to 87 (4-16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro-2a transfected with 54 or 100 CAG repeats. CONCLUSIONS: This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ-mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.