Topographical metal burden correlates with brain atrophy and clinical severity in Wilson's disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) is a post-processing technique that creates brain susceptibility maps reflecting metal burden through tissue magnetic susceptibility. We assessed topographic differences in magnetic susceptibility between participants with and without Wilson's disease (WD), correlating these findings with clinical severity, brain volume, and biofluid copper and iron indices. METHODS: A total of 43 patients with WD and 20 unaffected controls, were recruited. QSM images were derived from a 3T MRI scanner. Clinical severity was defined using the minimal Unified Wilson's Disease Rating Scale (M-UWDRS) and Montreal Cognitive Assessment scoring. Differences in magnetic susceptibilities between groups were evaluated using general linear regression models, adjusting for age and sex. Correlations between the susceptibilities and clinical scores were analyzed using Spearman's method. RESULTS: In age- and sex-adjusted analyses, magnetic susceptibility values were increased in WD patients compared with controls, including caudate nucleus, putamen, globus pallidus, and substantia nigra (all p < 0.01). Putaminal susceptibility was greater with an initial neuropsychiatric presentation (n = 25) than with initial hepatic dysfunction (n = 18; p = 0.04). Susceptibility changes correlated negatively with regional brain volume in almost all topographic regions. Serum ferritin, but not serum copper or ceruloplasmin, correlated positively with magnetic susceptibility level in the caudate nucleus (p = 0.04), putamen (p = 0.04) and the hippocampus (p = 0.03). The dominance of magnetic susceptibility in cortical over subcortical regions correlated with M-UWDRS scores (p < 0.01). CONCLUSION: The magnetic susceptibility changes could serve as a surrogate marker for patients with WD.

Unique clinical and electrophysiological features in the peripheral nerve system in patients with sialidosis - a case series study.

BACKGROUND: To investigate the peripheral nervous system involvement in S sialidosis with typical features of myoclonus, seizure, and giant waves in somatosensory evoked potentials suggesting hyperexcitability in the central nervous system. METHODS: The clinical presentation of patients with genetically confirmed sialidosis was recorded. Neurophysiological studies, including nerve conduction studies (NCSs), F-wave studies, and needle electromyography (EMG), were performed on these patients. RESULTS: Six patients (M/F: 2:4) were recruited. In addition to the classical presentation, intermittent painful paresthesia was noted in four patients, and three of whom reported it as the earliest symptom. In the NCSs, one patient had reduced compound muscle action potential amplitudes in the right ulnar nerve, while another patient had prolonged distal motor latency in the bilateral tibial and peroneal nerves. Prolonged F-wave latency (83.3%), repeater F-waves (50%), and neurogenic polyphasic waves in EMG (in 2 out of 3 examined patients) were also noted. Interestingly, a very late response was noted in the F-wave study of all patients, probably indicating lesions involving the proximal peripheral nerve or spinal cord. CONCLUSION: In addition to the central nervous system, the peripheral nervous system is also involved in sialidosis, with corresponding clinical symptoms. Further study on these phenomena is indicated.

Substantia nigra nigrosome-1 imaging correlates with the severity of motor symptoms in Parkinson's disease.

BACKGROUND: Nigrosome-1 imaging has been used for assisting the diagnosis of Parkinson's disease (PD). We aimed to examine the diagnostic performance of loss of nigrosome-1 in PD and the correlation between the size of the nigrosome-1 and motor severity of PD. METHODS: We included 237 patients with PD and 165 controls. The motor severity of PD was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III score and Hoehn-Yahr staging. The 3 or 1.5 Tesla susceptibility-weighted imaging combined with a deep-learning algorithm was applied for detecting the loss and the size of nigrosome-1. Clinical correlations and diagnostic performance of size of nigrosome-1 were also investigated. RESULTS: The mean nigrosome-1 size was significantly smaller in PD patients than in controls (0.06 ± 0.07 cm2 vs. 0.20 ± 0.05 cm2, P < 0.001). The area under the receiver operating characteristic curve (AUC) of the established model showed 0.94 accuracy (95% confidence interval [CI]: 0.87, 1.01, P < 0.01) in differentiating between the PD and control groups. Moreover, the partial loss of nigrosome-1 detected with SWI had an AUC of 0.96 in discriminating early-stage PD from controls (95% CI: 0.88, 1.02, P < 0.001). After adjusting for age, sex, disease duration, and levodopa equivalent daily dose, the estimated size of nigrosome-1 was negatively associated with the UPDRS part III motor score (ρ = -0.433, P < 0.001), but not with Mini-Mental State Examination scores (ρ = 0.006, P = 0.894). CONCLUSIONS: The extent of loss and the size of nigrosome-1 may potentially assist in the diagnosis of PD. Nigrosome-1 size reflects the motor severity of PD.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

DYNC1H1 variant associated with epilepsy: Expanding the phenotypic spectrum.

DYNC1H1 variants are associated with peripheral neuronal dysfunction and brain morphology abnormalities resulting in neurodevelopmental delay. However, few studies have focused on the association between DYNC1H1 variants and epilepsy. Herein, we report a case of drug-resistant focal epilepsy associated with a pathogenic variant of DYNC1H1. We further summarized the clinical, genetic, and neuroimaging characteristics of patients with DYNC1H1 variant-associated epilepsy from the relevant literature. This report expands the phenotypic spectrum of DYNC1H1-related disorder to include early-onset epilepsy, which is frequently associated with neurodevelopmental delay and intellectual disability, malformations of cortical development, and neuromuscular, ophthalmic, and orthopedic involvement.

Ultrasound imaging and treatment in a rare case with bilateral supinator syndrome.

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A case of senile-onset progressive hemiballism and cognitive decline with diffuse brain iron accumulations.

The etiologies for adults presenting with hemiballism are usually acquired lesions in the contralateral side of subthalamic nucleus. We present a 71-year-old woman with progressive onset of left hemiballism, orolingual dyskinesia and cognitive decline for 3 years. A rare genetic etiology was the final diagnosis for this index patient. In this movement disorder round, we describe our approach to this clinical presentation, and discuss the phenomenon and radiological features of this rare genetic disorder.

Determinants for Control of Status Epilepticus in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND: Treatment guideline for status epilepticus (SE) specifically in patients with anti-N-methyl- D-aspartate receptor (anti-NMDAR) encephalitis is insufficient. This study aimed to clarify the determinants for the control of SE in adult patients with anti-NMDAR encephalitis. METHODS: Medical records of all patients with anti-NMDAR encephalitis hospitalized between Jan. 2010 and Sep. 2019 were analyzed for the time sequence of seizures and treatments, and antiepileptic drug (AED) regimens related to SE. The outcomes were control of SE and seizures, and the discharge score of modified Rankin Scale (mRS). RESULTS: All eight patients had seizures and seven (87.5%) suffered from SE which lasted for 3.6 ± 3.9 days. Five patients (71.4%) had SE earlier than using IT, whose SE was controlled by AEDs alone (n = 4) or combined with teratomas resection (n = 1). Another two patients suffered from SE after receiving IT, and one of them had SE only for 1 hour. Moreover, all SE patients received increased types and dosages of AEDs at SE end. A shorter duration of refractory SE was associated with its later occurrence after seizure onset (p = 0.005) and longer duration of AEDs use before SE (p = 0.026). All cases achieved seizure freedom after receiving AEDs and IT. CONCLUSIONS: In these patients with anti-NMDAR encephalitis, all the SE which occurred before initiating IT was successfully controlled by AEDs alone or combined with teratoma resection, and later onset of refractory SE was associated with a shorter SE duration.

Lactate peak in muscle disclosed by magnetic resonance spectroscopy in a patient with CPEO-plus syndrome.

A 25-year-old man complained of progressive diplopia and limb weakness for 3 years. Mitochondrial myopathy was suspected according to clinical presentation, elevated serum lactate concentration, and muscle histopathology. However, next-generation mtDNA sequencing (mtDNA NGS) of the blood only revealed a likely benign variant in the MT-CO1 gene (m.6510G > A). An mtDNA NGS study on the muscle sample revealed a large mtDNA deletion (m.5788-m.16071). The patient was diagnosed as having CPEO-plus syndrome related to the large mtDNA deletion. Notably, magnetic resonance spectroscopy revealed a doublet peak at 1-2 ppm in his edematous right vastus lateralis, which indicated lactate accumulation. Thus, muscle imaging and appropriate genetic tests facilitated the diagnosis of mitochondrial myopathy.

Novel Phenotype of 6p25 Deletion Syndrome Presenting Juvenile Parkinsonism and Brain Calcification.

BACKGROUND: Chromosome 6p25 deletion syndrome is a rare neurocristopathy with variable clinical features. The objective of the current study was to describe a novel phenotype for autosomal-dominant chromosome 6p25 deletion syndrome. The presentation included bilateral basal ganglia and subcortical calcifications and juvenile parkinsonism, resembling primary familial brain calcification. METHODS: Phenotypic characterization, exome sequencing, and oligonucleotide array were carried out in the index family. RESULTS: The index patient and her mother had a history of developmental delay, mild facial dysmorphism, Axenfield eye anomalies, slight intellectual disability, and subsequently developed levodopa-responsive parkinsonism in early adulthood. Brain-computed tomography showed bilateral basal ganglia and subcortical calcifications. Magnetic resonance imaging revealed diffuse white matter lesions. A 99mTc TRODAT single-photon emission computed tomography scan revealed bilateral dopaminergic denervation. Whole-exome sequencing and oligonucleotide array-based comparative genomic hybridization revealed a 2.27-Mb chromosome 6pter-p24 deletion, which cosegregated within the family. CONCLUSIONS: Our findings extended the current phenotypic spectrum of chromosome 6p25 deletion syndrome. © 2020 International Parkinson and Movement Disorder Society.

Frontal variant of Alzheimer's disease with asymmetric presentation mimicking frontotemporal dementia: Case report and literature review.

INTRODUCTION: Frontal variant of Alzheimer's disease (fvAD) is a rare nonamnestic syndrome of Alzheimer's disease (AD). Differentiating it from behavior variant of frontotemporal dementia (bvFTD), which has implications for treatment responses and prognosis, remains a clinical challenge. METHODS: Molecular neuroimaging and biofluid markers were performed for the index patient for accurate premortem diagnosis of fvAD. The clinical, neuroimaging, and biofluid characteristics of the patient were compared to those reported in previous studies of fvAD from 1999 to 2019. RESULTS: A 66-year-old man presented with progressive executive dysfunction, personality and behavioral changes, and memory decline since age 59. He had no family history of neurodegenerative disorders. A stimulus-sensitive myoclonus was noted over his left upper extremity. Neuropsychological assessment revealed moderate dementia with a Mini-Mental State Exam score of 10/30 and compromised executive and memory performance. Brain imaging showed asymmetrical atrophy and hypometabolism over the right frontal and temporal areas, mimicking bvFTD. However, we observed increased tau depositions based on 18 F-labeled T807 Tau PET in these areas and diffusely increased amyloid deposition based on 11 C-labeled Pittsburgh compound B positron emission tomography (PET). Plasma biomarker measures indicated an AD profile with increased Aß1-42 (18.66 pg/ml; cutoff: 16.42 pg/ml), Aß1-42/Aß1-40 ratio (0.45; cutoff: 0.30), total tau (29.78 pg/ml; cutoff: 23.89 pg/ml), and phosphorylated tau (4.11 pg/ml; cutoff: 3.08 pg/ml). These results supported a diagnosis of fvAD. CONCLUSIONS: Our results with asymmetrical presentations extend current knowledge about this rare AD variant. Application of biofluid and molecular imaging markers could assist in early, accurate diagnosis.

Clinical and electrophysiological characteristics of a type 1 sialidosis patient with a novel deletion mutation in NEU1 gene.

BACKGROUND/PURPOSE: Type 1 sialidosis is a rare autosomal recessive lysosomal storage disease caused by Neuraminidase 1 (NEU1) gene mutations. We report a type 1 sialidosis patient with a novel deletion mutation in NEU1 and compared the phenotypes within different ethnicities. METHODS: Targeted next generation sequencing and segregation analysis were performed to identify the causative gene mutation of the index patient. The clinical and electrophysiological characteristics of the patient were compared to those reported in previous studies of type 1 sialidosis from 1996 to 2019. RESULTS: A 16-year-old boy presented with progressive onset of seizure, myoclonus, and ataxia since 5 years of age. Targeted next generation sequencing revealed the pathogenic missense variant c.544A>G (p.Ser182Gly) and the novel c.314_352del (p.A106_G118del) deletion in NEU1 in a compound heterozygote state. The leukocyte neuraminidase activity was significantly decreased (0.0323 nmol/mg protein/hour, normal reference: 0.326 ± 0.095 nmol/mg protein/hour). A total of 46 patients were identified in 18 reports from the literature. The most common symptoms were myoclonus (100%), followed by ataxia (88.3%) and seizure (72.5%). Notably, impaired cognition (50.0% vs. 21.7%, P = 0.04) and cherry-red spots (61.1% vs. 40.7%, P = 0.02) were less frequently reported in Asian patients than in Caucasian patients. Abnormal somatosensory evoked potentials with giant cortical waves and prolonged visual evoked potential latency were found consistently in Asian and Caucasian patients, and could be a surrogate marker of early diagnosis. CONCLUSION: Our findings suggest a distinct phenotype of infrequent cherry-red spots and abnormal evoked potentials in Asian patients with type 1 sialidosis.