Ruxu Zhang

Biallelic VRK1 variants are linked to a range of neurogenic disorders, including Charcot-Marie-Tooth and related disease (CMTR), motor neuron diseases, and spinal muscular atrophy (SMA). This study aimed to characterize the genetic and clinical features of VRK1-related peripheral neuropathy in a Chinese cohort with axonal CMTR. Eight families were identified from a cohort of 351 families with axonal CMTR, including axonal CMT and distal hereditary motor neuropathies (dHMN). Clinical and genetic data were retrospectively analyzed. Haplotype analysis investigated the founder effect of the high-frequency variant, and RNA sequencing was conducted for the splice variant. A systematic literature review (PubMed/CNKI, 2009–2025) was performed to compile global cases. VRK1 was the third most common gene in our axonal recessive CMTR cohort. Ten VRK1 variants were identified, including 8 novel variants: c.7C>T, c.83T>G, c.215T>G, c.539C>T, c.879_882del, c.974T>A, c.1073_1076del, and c.1159+2T>A. The nonsense variant c.1124G>A (p.W375*) was present in 4 of 8 families with haplotype analysis supporting a founder effect. RNA sequencing confirmed c.1159+2T>A caused exon 12 skipping and frameshift (p.K357Vfs*39). The clinical phenotypes included dHMN in 7 cases and axonal recessive CMT in one case. Two patients with dHMN exhibited upper motor neuron signs. All patients presented with progressive distal lower limb weakness, without neurodevelopmental impairment. In total, 53 cases from 37 families reported to date (including the present cohort) revealed substantial clinical heterogeneity, with dHMN (28.8%) and SMA (26.9%) being most common. Early-onset cases exhibited rapid progression, whereas later-onset cases had slower courses. This study identifies 8 novel VRK1 variants and confirms the founder effect of p.W375*, expanding the genotypic and phenotypic spectrum of VRK1-related peripheral neuropathy. The clinical presentation in this cohort was predominantly motor-dominant, ranging from dHMN to axonal CMT, with notable phenotypic heterogeneity influenced by the specific protein domain involved. These findings refine the understanding of VRK1-related peripheral neuropathy and provide valuable insights for accurate diagnosis and management.

Transthyretin (TTR) amyloidosis is a protein misfolding disease characterized by amyloid fibril deposition in vital organs, leading to cardiomyopathy (ATTR-CM). Early diagnosis of ATTR-CM remains challenging due to lack of sensitive, rapid screening methods. Here, we report cryo-EM structures of TTR amyloid fibrils extracted from minimally invasive abdominal fat-pad biopsies of three living Ala97Ser ATTR-CM patients. The adipose-derived fibril structures closely mirror those from diseased post-mortem cardiac tissues, validating the use of fat-pad biopsies to investigate the atomic structure of TTR fibrils in living patients. Furthermore, we determined cryo-EM structures of TTR fibrils in complex with two amyloid-binding dyes, Congo Red (CR) and Thioflavin S (ThS), which are widely used in the clinical diagnosis of ATTR-CM. Both CR and ThS predominantly bind to a specific surface arginine site on the TTR fibril via electrostatic interactions. These findings provide structural insights into how small-molecule dyes bind TTR fibrils, offering a molecular foundation for the rational design of TTR-specific tracers to enable early and accurate diagnosis of TTR amyloidosis.

Objective: Our study aimed to report the clinical features and epidemiological characteristics of hereditary transthyretin amyloidosis-polyneuropathy(ATTRv-PN) with TTR Ala97Ser(p.Ala117Ser) mutation from South Mainland China. Methods: We identified 21 patients from 20 families diagnosed with Ala97Ser ATTRv-PN based on strict clinical and electrophysiological criteria from three centers. Clinical and laboratory data were retrospectively retrieved for analysis. Results: A gender imbalance was noted with a male-to-female ratio of 18:3. All patients showed late onset, with the age of onset at 56.5 ± 7.2 years. The predominant initial symptom, reported by 15 patients (71.4%), was numbness. Paraesthesia was present in all patients. Eighteen patients (85.7%) had autonomic dysfunction. Cardiac, renal, and ocular dysfunctions were noted in 17 (80.9%), 4(19.0%), and 4(19.0%) patients, respectively. Nerve conduction studies have shown axonal-type sensorimotor polyneuropathy. The decline in sensory nerve action potentials was more noticeable than in compound muscle action potentials. The nerve damage present in the lower limbs was more severe than that in the upper limbs. Nerve biopsy revealed positive Congo red staining in 11/15 patients (73.3%). Conclusion: ATTRv-PN appears relatively rare in South Mainland China, with our study providing the largest cohort of Ala97Ser mutation cases to date. We found a significant founder effect by combining the clinical and demographic characteristics. That helps us understand the gene’s transmission pathway and lays the foundation for carrier screening and tertiary prevention and control. We also propose a new scoring model and demonstrate that this model allows the profiling of different genotypes of ATTRv-PN, facilitating early clinical detection and diagnosis.

Background and Objectives: Hereditary sensory neuropathies (HSNs) are a group of genetically and clinically heterogeneous diseases. Our study aims to summarize the genetic and clinical features of HSNs in 10 Chinese families.Methods: Clinical data from 10 families with HSNs were collected retrospectively. Genetic screening was performed by whole exome sequencing (WES). Repeated‐primed PCR and capillary electrophoresis were performed for WES‐negative patients to analyze repeat expansions in RFC1.Results: Among the 10 probands with HSNs, eight cases were sporadic, and two had a positive family history. Six probands had early‐onset (onset age < 20 years). Seven probands presented with pure‐HSNs type, and three exhibited HSNs‐complex type with ataxia. Variants in the NTRK1, SPTLC1, COX20, PUM1, and RFC1 genes were detected in six probands. A novel variant, c.444C>A (p.N148K), in NTRK1 was identified in an autosomal recessive inheritance family with HSAN‐IV, and a novel variant, c.182dup (p.H61Qfs*31), in PUM1 was identified in a proband with adult‐onset paresthesia and mild cerebellar ataxia. Additionally, biallelic expansion of the pathogenic variant structure (AAGGG)exp repeat amplification in the RFC1 gene was identified in a proband with sensory neuropathy, ataxia, and right vestibular hypofunction.Conclusions: The novel variants in NTRK1 and PUM1 expanded the genotypic spectrum of HSNs. This study highlights the associations between sensory neuropathies and other symptoms, particularly cerebellar ataxia. Given the ultra‐rarity of HSNs, future multicenter studies with larger cohorts may facilitate the identification of novel variants, improve genetic diagnostic rates, and enhance disease recognition.

Background and Aims: This study aimed to report nine Charcot-Marie-Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR-CMT2S patients reported worldwide. Methods: General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR-CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases. Results: In our CMT2 cohort, we detected 17 AR-CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early-onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR-CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty-nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean +/- SD: 3.43 +/- 3.88 years) and the majority was infantile-onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc. Interpretation: AR-CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR-CMT2S. Furthermore, 17 AR-CMT2S families could provide more resources for natural history study, drug research and development.

Background and Aims: Mutations in ganglioside‐induced differentiation‐associated protein 1 (GDAP1) cause axonal or demyelinating Charcot–Marie–Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1‐related CMT in a Chinese cohort.Methods: Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected.Results: We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra‐familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis.Conclusions: In this study, we conducted an analysis of clinical features of the GDAP1‐related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.