A Compound Heterozygous Pathogenic Variant in B4GALNT1 Is Associated With Axonal Charcot-Marie-Tooth Disease

Background@#and PurposePathogenic variants in B4GALNT1 have been reported to cause hereditary spastic paraplegia 26. This study has revealed that a novel compound heterozygous pathogenic variant in B4GALNT1 is associated with axonal Charcot-Marie-Tooth disease (CMT). @*Methods@#Whole-exome sequencing (WES) was used to identify the causative factors and characterize the clinical features of a Korean family with sensorimotor polyneuropathy. Functional assessment of the mutant genes was performed using a motor neuron cell line. @*Results@#The WES revealed a compound heterozygous pathogenic variant (c.128dupC and c.451G>A) in B4GALNT1 as the causative of the present patient, a 53-year-old male who presented with axonal sensorimotor polyneuropathy and cognitive impairment without spasticity. The electrodiagnostic study showed axonal sensorimotor polyneuropathy. B4GALNT1 was critical to the proliferation of motor neuron cells. The compensation assay revealed that the pathogenic variants might affect the enzymatic activity of B4GALNT1. @*Conclusions@#This study is the first to identify a case of autosomal recessive axonal CMT associated with a compound heterozygous pathogenic variant in B4GALNT1. This finding expands the clinical and genetic spectra of peripheral neuropathy.

A Compound Heterozygous Pathogenic Variant in B4GALNT1 Is Associated With Axonal Charcot-Marie-Tooth Disease

Background@#and PurposePathogenic variants in B4GALNT1 have been reported to cause hereditary spastic paraplegia 26. This study has revealed that a novel compound heterozygous pathogenic variant in B4GALNT1 is associated with axonal Charcot-Marie-Tooth disease (CMT). @*Methods@#Whole-exome sequencing (WES) was used to identify the causative factors and characterize the clinical features of a Korean family with sensorimotor polyneuropathy. Functional assessment of the mutant genes was performed using a motor neuron cell line. @*Results@#The WES revealed a compound heterozygous pathogenic variant (c.128dupC and c.451G>A) in B4GALNT1 as the causative of the present patient, a 53-year-old male who presented with axonal sensorimotor polyneuropathy and cognitive impairment without spasticity. The electrodiagnostic study showed axonal sensorimotor polyneuropathy. B4GALNT1 was critical to the proliferation of motor neuron cells. The compensation assay revealed that the pathogenic variants might affect the enzymatic activity of B4GALNT1. @*Conclusions@#This study is the first to identify a case of autosomal recessive axonal CMT associated with a compound heterozygous pathogenic variant in B4GALNT1. This finding expands the clinical and genetic spectra of peripheral neuropathy.

Incidence and Risk Factors for Dementia in Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Korea

BACKGROUND: Diabetes mellitus is associated with an increased risk of dementia. We aimed to comprehensively analyze the incidence and risk factors for dementia and young-onset dementia (YOD) in diabetic patients in Korea using the National Health Insurance Service data.METHODS: Between January 1, 2009 and December 31, 2012, a total of 1,917,702 participants with diabetes were included and followed until the date of dementia diagnosis or until December 31, 2015. We evaluated the incidence and risk factors for all dementia, Alzheimer's disease (AD), and vascular dementia (VaD) by Cox proportional hazards analyses. We also compared the impact of risk factors on the occurrence of YOD and late-onset dementia (LOD).RESULTS: During an average of 5.1 years of follow-up, the incidence of all types of dementia, AD, or VaD was 9.5, 6.8, and 1.3/1,000 person-years, respectively, in participants with diabetes. YOD comprised 4.8% of all dementia occurrence, and the ratio of AD/VaD was 2.1 for YOD compared with 5.5 for LOD. Current smokers and subjects with lower income, plasma glucose levels, body mass index (BMI), and subjects with hypertension, dyslipidemia, vascular complications, depression, and insulin treatment developed dementia more frequently. Vascular risk factors such as smoking, hypertension, and previous cardiovascular diseases were more strongly associated with the development of VaD than AD. Low BMI and a history of stroke or depression had a stronger influence on the development of YOD than LOD.CONCLUSION: The optimal management of modifiable risk factors may be important for preventing dementia in subjects with diabetes mellitus.

Tau Positron Emission Tomography Imaging in Degenerative Parkinsonisms

In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer's disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum. In progressive supranuclear palsy, the globus pallidus and midbrain have shown increased binding most prominently. Tau PET patterns in patients with corticobasal syndrome are characterized by asymmetrical uptake in the motor cortex and underlying white matter, as well as in the basal ganglia. Even in the patients with multiple system atrophy, which is basically a synucleinopathy, ¹⁸F-flortaucipir, a widely used tau PET tracer, also binds to the atrophic posterior putamen, possibly due to off-target binding. These distinct patterns of tau-selective radiotracer binding in the various degenerative parkinsonisms suggest its utility as a potential imaging biomarker for the differential diagnosis of parkinsonisms.

Increased Uptake of AV-1451 in a Subacute Infarction Lesion

¹⁸F-AV-1451 is a tau PET ligand that has high affinity for paired helical filament tau. However, various off-target bindings unrelated to tau have also been reported. Herein, we report a case of 83-year-old woman, who showed abnormal uptake of AV-1451 that was shown to be subacute infarction. Clinicians should recognize that increased uptake of AV-1451 may be related to stroke.

Anti-LGI1 Antibody Limbic Encephalitis Presented with Amnestic Mild Cognitive Impairment

No abstract available.

Anti-LGI1 Antibody Limbic Encephalitis Presented with Amnestic Mild Cognitive Impairment

No abstract available.

A Computed Tomography-Based Spatial Normalization for the Analysis of 18F Fluorodeoxyglucose Positron Emission Tomography of the Brain

OBJECTIVE: We developed a new computed tomography (CT)-based spatial normalization method and CT template to demonstrate its usefulness in spatial normalization of positron emission tomography (PET) images with [18F] fluorodeoxyglucose (FDG) PET studies in healthy controls. MATERIALS AND METHODS: Seventy healthy controls underwent brain CT scan (120 KeV, 180 mAs, and 3 mm of thickness) and [18F] FDG PET scans using a PET/CT scanner. T1-weighted magnetic resonance (MR) images were acquired for all subjects. By averaging skull-stripped and spatially-normalized MR and CT images, we created skull-stripped MR and CT templates for spatial normalization. The skull-stripped MR and CT images were spatially normalized to each structural template. PET images were spatially normalized by applying spatial transformation parameters to normalize skull-stripped MR and CT images. A conventional perfusion PET template was used for PET-based spatial normalization. Regional standardized uptake values (SUV) measured by overlaying the template volume of interest (VOI) were compared to those measured with FreeSurfer-generated VOI (FSVOI). RESULTS: All three spatial normalization methods underestimated regional SUV values by 0.3-20% compared to those measured with FSVOI. The CT-based method showed slightly greater underestimation bias. Regional SUV values derived from all three spatial normalization methods were correlated significantly (p < 0.0001) with those measured with FSVOI. CONCLUSION: CT-based spatial normalization may be an alternative method for structure-based spatial normalization of [18F] FDG PET when MR imaging is unavailable. Therefore, it is useful for PET/CT studies with various radiotracers whose uptake is expected to be limited to specific brain regions or highly variable within study population.

A Case of GNE Myopathy Presenting a Rapid Deterioration during Pregnancy

BACKGROUND: GNE myopathy is characterized by early-adult-onset distal myopathy sparing quadriceps caused by mutations in the GNE gene encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, an enzyme in the sialic-acid synthesis pathway. CASE REPORT: A 27-year-old Korean woman presented a rapid deterioration in strength of the distal lower limbs during her first pregnancy. She was diagnosed with GNE myopathy and carrying the compound heterozygous mutations of the GNE gene (D208N/M29T). CONCLUSIONS: This is a representative case implying that an increased requirement of sialic acid during pregnancy might trigger a clinical worsening of GNE myopathy.

Three Cases of Manifesting Female Carriers in Patients with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy usually affects males. However, females are also affected in rare instances. Approximately 8% of female Duchenne muscular dystrophy (DMD) carriers are manifesting carriers and have muscle weakness to some extent. We investigated the clinical features of 3 female patients with dystrophinopathy diagnosed by clinical, pathological, and genetic studies at our neuromuscular disease clinic. The onset age of manifesting symptoms varied (8-28 years). Muscle weakness grade varied as follows: patient 1 showed asymmetrical bilateral proximal upper and lower extremities weakness, patient 2 showed asymmetrical bilateral upper extremities weakness similar to scapulohumoral muscular dystrophy, and patient 3 had only bilateral asymmetric proximal lower extremities weakness. Two patients had familial histories of DMD (their sons were diagnosed with DMD), but the 1 remaining patient had no familial history of DMD. The serum creatine kinase level was elevated in all patients, but it was not correlated with muscular weakness. An electromyography study showed findings of myopathy in all patients. One patient was diagnosed with a DMD carrier by a muscle biopsy with an immunohistochemical stain (dystrophin). The remaining 2 patients with familial history of DMD were diagnosed by multiplex ligation-dependent probe amplification (MLPA). There were inconsistent clinical features in the female carriers. An immunohistochemical analysis of dystrophin could be useful for female carrier patients. Also, multiplex ligation-dependent probe amplification is essential for the diagnosis of a manifesting female carrier DMD in female myopathic patients because conventional multiplex PCR could not detect the duplication and is less accurate compared to MLPA.

Three Cases of Manifesting Female Carriers in Patients with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy usually affects males. However, females are also affected in rare instances. Approximately 8% of female Duchenne muscular dystrophy (DMD) carriers are manifesting carriers and have muscle weakness to some extent. We investigated the clinical features of 3 female patients with dystrophinopathy diagnosed by clinical, pathological, and genetic studies at our neuromuscular disease clinic. The onset age of manifesting symptoms varied (8-28 years). Muscle weakness grade varied as follows: patient 1 showed asymmetrical bilateral proximal upper and lower extremities weakness, patient 2 showed asymmetrical bilateral upper extremities weakness similar to scapulohumoral muscular dystrophy, and patient 3 had only bilateral asymmetric proximal lower extremities weakness. Two patients had familial histories of DMD (their sons were diagnosed with DMD), but the 1 remaining patient had no familial history of DMD. The serum creatine kinase level was elevated in all patients, but it was not correlated with muscular weakness. An electromyography study showed findings of myopathy in all patients. One patient was diagnosed with a DMD carrier by a muscle biopsy with an immunohistochemical stain (dystrophin). The remaining 2 patients with familial history of DMD were diagnosed by multiplex ligation-dependent probe amplification (MLPA). There were inconsistent clinical features in the female carriers. An immunohistochemical analysis of dystrophin could be useful for female carrier patients. Also, multiplex ligation-dependent probe amplification is essential for the diagnosis of a manifesting female carrier DMD in female myopathic patients because conventional multiplex PCR could not detect the duplication and is less accurate compared to MLPA.

Clinical Usefulness of Molecular Diagnosis in Dystrophin Gene Mutations Using the Multiplex Ligation-dependent Probe Amplification (MLPA) Method

BACKGROUND: Duchenne/Becker muscular dystrophy (DMD/BMD), which is the most common X-linked muscular dystrophy, is caused by mutations in the dystrophin gene. These mutations comprise deletions in approximately 55~65% of patients, duplications in 5~10%, and point mutations or small insertion/deletions in the remainder. Unfortunately, current diagnostic assays for dystrophin do not accurately detect duplication mutations or female carriers. In this study we employed multiplex ligation-dependent probe amplification (MLPA) analysis to detect deletions or duplications of the dystrophin gene in patients with DMD/BMD, and in potential female carriers. METHODS: A total of 41 subjects was recruited for this study, comprising 35 male DMD/BMD patients, 1 female patient with Turner syndrome, and 5 females with a family history of DMD/BMD. The MLPA method was employed to determine the copy number of each of the 79 exons of the dystrophin gene in the 41 subjects. RESULTS: MLPA analysis for dystrophin was informative in 71.4% (25/35) of patients with DMD/BMD patients, identifying deletions in 60.0% (21/35) and duplications in 11.4% (4/35). MLPA analysis showed the presence of a deletion of the DMD gene in one female patient with Turner syndrome. Of the five female patients with a family history of DMD/BMD, this assay revealed exon deletion in one and duplications in one. CONCLUSIONS: The reported findings reveal that the MLPA method is a powerful tool for detecting duplications and female carriers, as well as DMD gene deletions. MLPA should be considered the method of choice for an initial genetic analysis of DMD/BMD patients.

Claude's Syndrome Associated with Neurocysticercosis

Claude's syndrome is a distinctive brainstem syndrome characterized by ipsilateral third cranial nerve palsy with contralateral hemiataxia and is due to an intrinsic or extrinsic lesion in the midbrain. We report a case of Claude's syndrome caused by neurocysticercosis infection. A 68 year-old Asian man was admitted to our hospital because of ataxia, left ptosis, and diplopia. Brain magnetic resonance imaging (MRI) showed a cystic lesion in the midbrain, which was surrounded by ring enhancement and peripheral edema. Neurocysticercosis infection was diagnosed by the cerebral spinal fluid study. The patient was treated with albendazole and steroids. A follow-up brain MRI three months later demonstrated the disappearance of a surrounding brain edema and rim enhancement. The most common cause of Claude's syndrome is cerebrovascular disease and malignancy. However, there is no report caused by neurocysticercosis infection. Therefore, if we encounter Claude's syndrome, we should consider neurocysticercosis infection as one of the etiologic factors.

Clinical Features of the Patients with Seizures after Doxylamine Succinate Overdose / 대한간질학회지

PURPOSE: Doxylamine succinate is an over-the-counter drug commonly used in the treatment of insomnia. It is in the ethanolamine class of antihistamine and is frequently involved in intentional overdoses. Seizures are uncommon, but there are potentially serious complications, making early recognition and treatment essential. METHODS: We reviewed retrospectively the medical records of patients admitted for seizures after a doxylamine succinate overdose from Jan. 1, 1992 to Dec. 31, 2008. We evaluated them with respect to age, sex, amount ingested, clinical symptomatology, time from ingestion to seizure, complication, and prognosis. RESULTS: Among the 146 doxylamine overdose patients, 11 patients developed seizures. Females accounted for 9 (81.8%) patients and the number aged between 20 and 40 years was also 9 cases (81.8%). The average time from ingestion to emergency room visit was 170 minutes (60-360). The average time from ingestion to development of seizures was 188 minutes (60-480). The amount of doxylamine succinate ingested was 750-4,750 mg (mean = 2,425 mg). The frequent anticholinergic symptoms were tachycardia (63.6%), vomiting (45.5%), mydriasis (36.4%), and hypertension (36.4%). Rhabdomyolysis and drug induced hepatitis were observed in 7 cases (63.6%) and 6 cases (54.5%), respectively. Primary treatment included administration of benzodiazepine and conservative care. After more than a 6 month follow-up, no patients developed further seizure. CONCLUSIONS: The incidence of seizure after doxylamine succinate overdose is uncommon and prognosis is good. However, other serious symptoms are commonly combined, and we have to be aware that seizures are a potential complication and should be actively investigated and vigorously treated.

Duchenne Muscular Dystrophy Complicated With Dilated Cardiomyopathy and Cerebral Infarction

Duchenne muscular dystrophy, Cerebral infarction, Dilated cardiomyopathy