Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. RESULTS: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

Peak expiratory flow is a reliably household pulmonary function parameter correlates with disease severity and survival of patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease; most ALS patients die within 3 to 5 years after symptom onset, usually as a consequence of respiratory failure. In the present study, we aim to screen the survival-related pulmonary function parameters, and to explore the predictive value of peak expiratory flow (PEF) in disease severity and prognosis in patients with ALS. METHODS: The discovery cohort included 202 ALS patients, and the demographic and clinical characteristics of eligible patients were collected and pulmonary function tests were performed using MS-PFT spirometer. In the validation cohort, 62 newly diagnosed ALS patients performed the pulmonary function test by MS-PFT spirometer and household peak flow meter (KOKA) simultaneously. RESULTS: Among 12 pulmonary function parameters, FVC, FEV1, PEF, MEF75%, and MVV were identified to be independent predictive factors for survival. PEF was highly correlated with FVC (r = 0.797), MVV (r = 0.877), FEV1 (r = 0.847), and MEF75% (r = 0.963). Besides, the values of PEF were positively associated with disease severity (ALSFRS-R score, rs = 0.539, P < 0.0001), and negatively associated with progression rate (ΔALSFRS-R, rs = -0.316, P < 0.0001). Finally, we also confirmed that the values of KOKA-measured PEF were highly correlated with the ones measured using MS-PFT spirometer (r = 0.9644, p < 0.0001). CONCLUSIONS: Our work emphasizes the critical role of PFTs in predicting prognosis of ALS patients. PEF is an easily available pulmonary function index, which is also a promising indicator in predicting disease severity and survival for ALS patients.

Whole exome sequencing reveals a broader variant spectrum of Charcot-Marie-Tooth disease type 2.

Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous inherited neuropathy. Although new causative and disease-associated genes have been identified for CMT2 in recent years, molecular diagnoses are still lacking for a majority of patients. We here studied a cohort of 35 CMT2 patients of Chinese descent, using whole exome sequencing to investigate gene mutations and then explored relationships among genotypes, clinical features, and mitochondrial DNA levels in blood as assessed by droplet digital PCR. We identified pathogenic variants in 57% of CMT2 patients. The most common genetic causes in the cohort were MFN2 mutations. Two patients with typical CMT phenotype and neuromyotonia were detected to harbor compound heterozygous variations in the HINT1 gene. In conclusion, our work supports that the molecular diagnostic rate of CMT2 patients can be increased via whole exome sequencing, and our data suggest that assessment of possible HINT1 mutations should be undertaken for CMT2 patients with neuromyotonia.

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China. METHODS: Seven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients. RESULTS: Two TARDBP mutations in exon 6 (p.M337 V and p.G348C) were identified in 5 unrelated families. Four of these 5 families carried the same p.M337 V mutation (family 1II3, family 2II6, family 3II4, and family 4II4), and the p.G348C mutation was identified in family 5 (II5). Among the 215 sporadic patients, only a single nucleotide polymorphism (p.A366A) was detected in 5 patients, and no responsible mutation was identified. Among the TARDBP-linked familial ALS patients, the average age of onset was 57.0 ± 4.7 years, and a trend towards higher rates of bulbar (50.0%, 6/12) onset and upper limb (41.7%, 5/12) onset than lower rates of limb onset (8.3%, 1/12) was observed. Furthermore, ALS patients with TARDBP mutations showed a benign disease course, and the average survival was 106.5 ± 41.8 months (n = 8). CONCLUSIONS: We found a high frequency of the TARDBP p.M337 V mutation in familial ALS in south-eastern China. The TARDBP-linked ALS patients showed a benign disease course and prolonged survival.

Effects of nutritional indices and inflammatory parameters on patients received immunotherapy for non-small cell lung cancer.

OBJECTIVE: This research explored the relationship between a patient's nutritional state and inflammatory markers and the prognosis of their non-small cell lung cancer (NSCLC) treatment while receiving a combination of chemotherapy and immunotherapy. METHOD: This retrospective and single-center analysis included NSCLC patients who received a combination of chemotherapy and immunotherapy at the Department of Oncology at Shanghai Lung Hospital. Patients were categorized based on malnutrition, sarcopenia, sarcopenic obesity, and advanced-lung-cancer-inflammation-index (ALI) scores after collecting nutritional and inflammatory indices. Kaplan-Meier and the Cox models were utilized to analyze survival. RESULTS: There was a significant correlation between malnutrition, sarcopenia, sarcopenic obesity, and low ALI scores with lower overall survival (OS) and progression-free survival (PFS) (p < 0.05). Low ALI score and malnutrition were independent factors influencing patient survival in terms of both OS and PFS (p < 0.01). CONCLUSION: The nutritional and inflammatory indices of immunotherapy-treated NSCLC patients substantially affect their prognosis. Assessing these variables could aid in optimizing treatment strategies and improving patient outcomes. Additional research is required to comprehend the intricate relationship between nutrition, inflammation, and cancer progression and to develop individualized therapies.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Decreased serum creatinine levels predict short survival in amyotrophic lateral sclerosis.

OBJECTIVE: To explore the associations between serum creatinine and creatine kinase (CK) levels with survival in male and female ALS patients. METHODS: A prospective cohort study was carried out including 346 ALS patients with repeated serum creatinine and CK measurements. Kaplan Meier analysis and multivariable Cox regression were used to perform survival analysis. RESULTS: There were 218 male and 128 female patients, and the males had significantly higher baseline serum creatinine and CK levels than females. After multivariable Cox regression analysis, lower baseline serum creatinine levels were associated with a short survival in both male (≤61 µmol/L, HR: 1.629; 95%CI: 1.168-2.273) and female ALS patients (≤52 µmol/L, HR: 1.677; 95%CI: 1.042-2.699), whereas, the serum CK levels were not correlated with survival. Besides, creatinine levels were positively associated with ALSFRS-R scores, and inversely with the decline rate of ALSFRS-R per month. During follow-up, serum creatinine levels tended to be decreased along with the disease progression, and the higher decline rate of creatinine per month (>1.5) showed significantly shorter survival, compared to the lower group (≤1.5) (30.0 months vs. 65.0 months, Chi square = 28.25, P < 0.0001). INTERPRETATION: Serum creatinine could be a reliable and easily accessible prognostic chemical marker for ALS, and decreased baseline creatinine levels could predict a poor prognosis and a short survival in both male and female ALS patients.

Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth disease.

Biallelic mutations in the sorbitol dehydrogenase (SORD) encoding gene were recently identified as a common genetic cause in autosomal-recessive CMT patients. Here, we investigated the clinical, genetic, and electrophysiological characteristics of three CMT patients with biallelic SORD mutations from a Chinese cohort. Two patients harbored c.757delG (p.A253Qfs*27) homozygous mutations, and one patient carried both c.757delG (p.A253Qfs*27) and c.625C>T (p.R209X) compound heterozygous mutations. Interestingly, the two patients homozygous for the c.757delG mutation exhibited positive responses for pinprick test. In conclusion, we confirmed SORD mutations as causative for CMT and further expanded the mutational and phenotypic spectrum of SORD-related CMT.

Serum Uric Acid Levels Predict Mortality Risk in Male Amyotrophic Lateral Sclerosis Patients.

Objective: To explore the associations between serum uric acid levels with survival in male and female ALS patients. Methods: A longitudinal cohort study was carried out including 313 sporadic and 16 familial ALS patients with repeated serum uric acid measurements. Multivariate Cox regression models were used to evaluate the survival-related factors. Results: There were 207 male and 122 female, and the mean age of onset was 55.7 ± 11.2 years old. The male patients had significantly higher baseline uric acid levels than that in female patients (342.4 ± 91.4 vs. 279.3 ± 71.4 µmol/L; p < 0.0001). The uric acid levels were inversely associated with the decline rate of ALSFRS-R per month (ΔALSFRS-R). After multivariate Cox regression analysis, a survival advantage was found in male, but not female, with higher serum uric acid levels. In males, a shorter diagnostic delay (≤10 m), lower BMI at baseline (≤18.70 kg/m2), faster disease progression (ΔALSFRS-R > 0.63), and lower baseline uric acid levels (≤292 µmol/L, HR: 1.936; 95% CI: 1.334-2.810) were associated with a shorter survival. During follow-up, the serum uric acid levels were not significantly altered over time. Conclusion: There is an inverse correlation between baseline serum uric acid levels and risk of death, prominently in male ALS patients.

Median Nerve-Neurophysiological Index Correlates With the Survival of Patients With Amyotrophic Lateral Sclerosis.

Objective: This study aims to explore the association between median nerve-neurophysiological index (NI) and survival of patients with amyotrophic lateral sclerosis (ALS). Methods: A retrospective case series with a prospective follow-up study was performed in 238 patients with ALS. Their clinical profiles and NI were recorded. Kaplan-Meier curves and Cox regression were adopted to perform survival analysis. Results: The median survival time of all ALS cases was 33.0 months. Multivariate analysis showed that older age of onset, shorter diagnostic delay, higher ΔALSFRS-R, and faster progression {NI ≤ 2.15; hazard ratio [HR] = 1.543 [95% confidence interval (CI), 1.136-2.094]} were associated with short survival. NI was correlated with ALSFRS-R at baseline (r s = 0.3153; p < 0.0001) and ALSFRS-R at different time points of follow-up (r s = 0.5127; p < 0.0001). The higher NI slope of decline (> 0.25) showed shorter survival compared with the lower group (≤ 0.25; 34.0 vs. 52.0 months; p = 0.0003). A predictive model was constructed based on the age of onset, diagnostic delay, median nerve NI, and ΔALSFRS-R. The higher predictive score (> 14) showed significantly shorter survival compared with the lower group (≤ 14; HR = 3.907, 95% CI, 2.857-5.342). Conclusion: Median nerve NI and its slope of decline were predictive of survival of ALS.

Prognostic analysis of amyotrophic lateral sclerosis based on clinical features and plasma surface-enhanced Raman spectroscopy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a wide range of survival times. We aimed to explore prognostic factors related to short survival based on clinical features and plasma metabolic signatures using surface-enhanced Raman spectroscopy (SERS). One hundred and thirty-eight sporadic ALS cases were enrolled serially, including 62 for the short-duration group (≤3 years) and 76 for the long-duration group (>3 years). Multivariate analysis showed that an older age of onset (>60 years; odds ratio [OR] = 3.98, 95% CI: 1.09-14.53), lower body mass index (BMI) (<18.5; OR = 6.80, 95% CI: 1.36-33.92), and lower ALSFRS-R score (<35; OR = 6.03, 95% CI: 1.42-25.63) were associated with higher odds of tracheotomy or death, while a higher uric acid (UA) level showed a protective effect (>356.36 µmol/L; OR = 0.19, 95% CI: 0.05-0.73). SERS analysis showed significant differences between the two groups, and pathway analysis highlighted five main metabolic pathways, including metabolisms of glutathione, pyrimidine, phenylalanine, galactose, and phenylalanine-tyrosine-tryptophan biosynthesis. In conclusion, age of onset, BMI, ALSFRS-R score and UA, together with dysregulation of glucose, amino acid, nucleic acid, and antioxidant metabolism contributed to disease progression, and are therefore potential therapeutic targets for ALS.

A "Triple Trouble" Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a "complex disease plus" patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy. METHODS: Standard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification (MLPA), whole exome sequencing (WES), and targeted methylation sequencing. RESULTS: The patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient's mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES. CONCLUSIONS: The present study described a "tripe trouble" with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.

Four-year follow-up of a Wilson disease pedigree complicated with epilepsy and hypopituitarism: Case report with a literature review.

RATIONALE: Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism with excellent prognosis if treated timely. However, WD is usually prone to neglect and misdiagnosis at an early stage. We reported a rare WD pedigree, and the clinical features, laboratory tests, and gene mutations were analyzed in detail. PATIENT CONCERNS: The patient was a 17-year-old and 136-cm-tall girl who presented with limb weakness, combined with multi-organ disorders including blind eye, epilepsy, and hypopituitarism. DIAGNOSES: Clinical tests showed a low serum ceruloplasmin level, high urinary copper excretion and Kayser-Fleischer (K-F) rings. She carried a compound heterozygous mutations in ATP7B gene (c.2828G>A and c.3884C>T). Her younger brother, as an asymptomatic patient, manifested with elevation of transaminases but without neurological and hepatic symptoms. They were diagnosed as WD finally. INTERVENTIONS: They were treated with sodium dimercaptosulphonate, supplemented with zinc gluconate, vitamin B6, vitamin C, as well as restriction of dietary copper. OUTCOMES: The urinary copper excretion and serum transaminase level decreased gradually. The abnormal signals in brainstem and basal ganglia were also remarkably decreased after 4-year of de-copper treatment. LESSONS: As to the patients with complicated clinical manifestations, the extrapyramidal symptom and basal ganglia signals should be concerned. The serum ceruloplasmin detection and ATP7B gene mutation screening are necessary.