The Structural and Dynamic Insights into the Ala97Ser Amyloidogenic Mutation in Transthyretin.

Transthyretin (TTR), a homo-tetrameric protein encoded by the TTR gene, can lead to amyloid diseases when destabilized by mutations. The TTR-Ala97Ser (A97S) mutation is the predominant pathogenic variant found in Han-Taiwanese patients and is associated with late-onset familial amyloid polyneuropathy (FAP), which presents a rapid progression of symptoms affecting peripheral nerves and the heart. In this study, we combined nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to investigate how the A97S mutation impacts the structure and dynamics of TTR.

Improving Executive Function and Dual-Task Cost in Parkinson Disease: A Randomized Controlled Trial.

Background And Purpose: Dual-task walking is challenging for people with Parkinson disease (PD). Gait performance worsens while executing dual tasks, possibly due to a decline in executive function (EF). This study aimed to investigate the effects of dual-task training on EF and dual-task cost (DTC) in people with PD and to explore whether training-induced changes in EF were associated with changes in DTC.

Magnetic resonance radiomics-derived sphericity correlates with seizure in brain arteriovenous malformations.

Objectives: Angioarchitectural analysis of brain arteriovenous malformations (BAVMs) is qualitative and subject to interpretation. This study quantified the morphology of and signal changes in the nidal and perinidal areas by using MR radiomics and compared the performance of MR radiomics and angioarchitectural analysis in detecting epileptic BAVMs.

Materials And Methods: From 2010 to 2020, a total of 111 patients with supratentorial BAVMs were retrospectively included and grouped in accordance with the initial presentation of seizure.

Plasma Matrix Metalloproeteinase-9 Is Associated with Seizure and Angioarchitecture Changes in Brain Arteriovenous Malformations.

Both angiogenesis and inflammation contribute to activation of matrix metalloproeteinase-9 (MMP-9), which dissolves the extracellular matrix, disrupts the blood-brain barrier, and plays an important role in the pathogenesis of brain arteriovenous malformations (BAVMs). The key common cytokine in both angiogenesis and inflammation is interleukin 6 (IL-6). Previous studies have shown elevated systemic MMP-9 and decreased systemic vascular endothelial growth factor (VEGF) in BAVM patients.

The clinical and imaging features of FLNA positive and negative periventricular nodular heterotopia.

Background: Periventricular nodular heterotopia (PVNH) is caused by abnormal neuronal migration, resulting in the neurons accumulate as nodules along the surface of the lateral ventricles. PVNH often cause epilepsy, psychomotor development or cognition problem. Mutations in FLNA (Filamin A) is the most common underlying genetic etiology.

Clinical characteristics and long-term outcome of cerebral cavernous malformations-related epilepsy.

Objective: Cerebral cavernous malformations (CCMs) present variably, and epileptic seizures are the most common symptom. The factors contributing to cavernoma-related epilepsy (CRE) and drug resistance remain inconclusive. The outcomes of CRE after different treatment modalities have not yet been fully addressed.

Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics.

Objective: Pathogenic variants in DCX on the X chromosome lead to lissencephaly and subcortical band heterotopia (SBH), brain malformations caused by neuronal migration defects. Its product doublecortin (DCX) binds to microtubules to modulate microtubule polymerization. How pathogenic DCX variants affect these activities remains not fully investigated.

Gamma Knife radiosurgery for cerebral cavernous malformation.

This is a retrospective study examining the efficacy and safety of Gamma Knife radiosurgery (GKS) in treating patients with cerebral cavernous malformations (CCMs). Between 1993 and 2018, 261 patients with 331 symptomatic CCMs were treated by GKS. The median age was 39.

Cellular secretion and cytotoxicity of transthyretin mutant proteins underlie late-onset amyloidosis and neurodegeneration.

Transthyretin amyloidosis (ATTR) is a progressive life-threatening disease characterized by the deposition of transthyretin (TTR) amyloid fibrils. Several pathogenic variants have been shown to destabilize TTR tetramers, leading to aggregation of misfolded TTR fibrils. However, factors that underlie the differential age of disease onset amongst amyloidogenic TTR variants remain elusive.

Biophysical characterization and modulation of Transthyretin Ala97Ser.

Objective: Ala97Ser (A97S) is the major transthyretin (TTR) mutation in Taiwanese patients of familial amyloid polyneuropathy (FAP), characterized by a late-onset but rapidly deteriorated neuropathy. Tafamidis can restore the stability of some mutant TTR tetramers and slow down the progression of TTR-FAP. However, there is little understanding of the biophysical features of A97S-TTR mutant and the pharmacological modulation effect of tafamidis on it.

Novel SCA19/22-associated KCND3 mutations disrupt human K 4.3 protein biosynthesis and channel gating.

Mutations in the human voltage-gated K channel subunit K 4.3-encoding KCND3 gene have been associated with the autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22). The precise pathophysiology underlying the dominant inheritance pattern of SCA19/22 remains elusive.

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.

Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding.

Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan.

Objective: The clinical and genetic profiles of hereditary transthyretin amyloidosis (ATTR) in Chinese populations remain elusive. We aim to characterize the features of ATTR in a Taiwanese cohort of Han Chinese descent.

Methods: Seventy-nine patients with molecularly confirmed ATTR from 57 Taiwanese families were identified by sequencing the transthyretin gene ().

Contributions of Animal Models to the Mechanisms and Therapies of Transthyretin Amyloidosis.

Transthyretin amyloidosis (ATTR amyloidosis) is a fatal systemic disease caused by amyloid deposits of misfolded transthyretin, leading to familial amyloid polyneuropathy and/or cardiomyopathy, or a rare oculoleptomeningeal amyloidosis. A good model system that mimic the disease phenotype is crucial for the development of drugs and treatments for this devastating degenerative disorder. The present models using fruit flies, worms, rodents, non-human primates and induced pluripotent stem cells have helped researchers understand important disease-related mechanisms and test potential therapeutic options.

PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization.

Objective: Variants in human PRRT2 cause paroxysmal kinesigenic dyskinesia (PKD) and other neurological disorders. Most reported variants resulting in truncating proteins failed to localize to cytoplasmic membrane. The present study identifies novel PRRT2 variants in PKD and epilepsy patients and evaluates the functional consequences of PRRT2 missense variations.

Aberrant Sensory Gating of the Primary Somatosensory Cortex Contributes to the Motor Circuit Dysfunction in Paroxysmal Kinesigenic Dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) is conventionally regarded as a movement disorder (MD) and characterized by episodic hyperkinesia by sudden movements. However, patients of PKD often have sensory aura and respond excellently to antiepileptic agents. mutations, the most common genetic etiology of PKD, could cause epilepsy syndromes as well.

Correction: Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias.

[This corrects the article DOI: 10.1371/journal.pone.

Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias.

Background: The inositol 1,4,5-triphosphate (IP3) receptor type 1 gene (ITPR1) encodes the IP3 receptor type 1 (IP3R1), which modulates intracellular calcium homeostasis and signaling. Mutations in ITPR1 have been implicated in inherited cerebellar ataxias. The aim of this study was to investigate the role of ITPR1 mutations, including both large segmental deletion and single nucleotide mutations, in a Han Chinese cohort with inherited cerebellar ataxias in Taiwan.

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded.

Clinical and biophysical characterization of 19 mutations.

Objective: Charcot-Marie-Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta-1 gene (), is the second most common form of Charcot-Marie-Tooth disease (CMT). encodes the GJ beta-1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated.

PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects.

Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene cause a wide spectrum of neurological diseases, ranging from paroxysmal kinesigenic dyskinesia (PKD) to mental retardation and epilepsy. Previously, seven PKD-related PRRT2 heterozygous mutations were identified in the Taiwanese population: P91QfsX, E199X, S202HfsX, R217PfsX, R217EfsX, R240X and R308C. This study aimed to investigate the disease-causing mechanisms of these PRRT2 mutations.