Ming-Jen Lee

National Taiwan University Hospital · Department of Neurology

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. Neurophysio...

Background Hereditary transthyretin amyloid cardiomyopathy (hATTR‐CM) is a progressive and fatal disease. Recent evidence indicates that bone scintigraphy may serve as a tool to monitor the effectiveness of hATTR‐CM treatment. The objective of this study was to examine how eplontersen therapy influences the semiquantitative uptake of technetium‐99m...

Background Transthyretin cardiomyopathy (ATTR-CM) is a debilitating disease that has received much attention since the emergence of novel treatments. The Transthyretin Cardiomyopathy Clinical Trial showed that tafamidis, a transthyretin tetramer stabilizer, effectively reduced the declines in functional capacity and quality of life. However, Ala97S...

Neurofibromatosis type 1 (NF1) stands as a prevalent neurocutaneous disorder. Approximately a quarter of NF1 patients experience the development of plexiform neurofibromas, potentially progressing into malignant peripheral nerve sheath tumors (MPNST). FT895, an HDAC11 inhibitor, exhibits potent anti-tumor effects on MPNST cells and enhances the cyt...

Background Transthyretin cardiac cardiomyopathy (ATTR-CM) is a rare but life-threatening disease. Tafamidis is an effective treatment for patients with ATTR-CM, however its long-term effects on cardiac remodeling and cardiac amyloid deposition are unknown. This study aimed to used cardiac magnetic resonance (CMR) to investigate the effects of tafam...

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease. A97S (p.Ala117Ser) is the most common transthyretin genetic mutation in Taiwan. Tafamidis is a transthyretin stabilizer, and it has been shown to improve outcomes. However, its effect on A97S ATTR-CM subtypes remains unknown. Objectives: Thi...

Background: One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. Patients and methods: EXPLORE B is a long-term, prospec...

Background The NOTCH3 mutation is a common cause of hereditary cerebral small vessel disease (CSVD) and may be a cause of spontaneous intracerebral haemorrhage (ICH). We aimed to investigate the clinical/imaging features for identifying the NOTCH3 mutations related ICH. Methods The study was based on a cohort of 749 CSVD patients in Taiwan who r...

Paramyotonia congenita (PMC) is a rare skeletal muscle disorder characterized by muscle stiffness upon repetitive exercise and cold exposure. PMC was reported to be caused by dominant mutations in the SCN4A gene encoding the α subunit of the Nav1.4 channel. Recently, we identified two missense mutations of the SCN4A gene, p.V781I and p.A1737T, in t...

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder. Clinically, the hallmarks of NF1 include skin pigmentation and cutaneous neurofibroma. Some NF1 patients develop plexiform neurofibroma (PN) since early childhood. Pathologically, PN contains abundant Schwann cells, blood vessels and connective tissues, which may trans...

The development of new sequencing technologies in the post-genomic era has accelerated the identification of causative mutations of several single gene disorders. Advances in cell and animal models provide insights into the underlining pathogenesis, which facilitates the development and maturation of new treatment strategies. The progress in bioche...

Cannabidiol (CBD), one of the cannabinoids from the cannabis plant, can relieve the myotonia resulting from sodium channelopathy, which manifests as repetitive discharges of muscle membrane. We investigated the binding kinetics of CBD to Nav1.4 channels on the muscle membrane. The binding affinity of CBD to the channel was evaluated using whole-cel...

The altered expression of chloride intracellular channel 4 (CLIC4) was reported to correlate with tumor progression. Previously, we have shown that the reduced cellular invasion induced by photodynamic therapy (PDT) is associated with suppression of CLIC4 expression in PDT-treated cells. Herein, we attempted to decipher the regulatory mechanisms in...

Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. In addition to skin pigmentation and cutaneous neurofibroma, some patients developed the plexiform neurofibroma since birth. Plexiform neurofibroma has abundant Schwann cells, fibroblasts, mast cells, blood vessels, and connective tissues, which increases...

Paramyotonia congenita (PMC) is a rare hereditary skeletal muscle disorder. The major symptom, muscle stiffness, is frequently induced by cold exposure and repetitive exercise. Mutations in human SCN4A gene, which encodes the α-subunit of Nav1.4 channel, are responsible for PMC. Mutation screening of SCN4A gene from two PMC families identified two...

Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the SCN4A gene encoding the alpha-subunit of the voltage-gated sodium channel Nav1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Nav1.4 channel is expressed in skeletal muscles, and its relat...

Neurofibromatosis type 1 (NF1) is an inherited neurological disorder. Approximately 5–13% of NF1 patients may develop a malignant peripheral nerve sheath tumor (MPNST), which is a neurofibrosarcoma transformed from the plexiform neurofibroma or schwannoma. Given the large size and easy metastasis of MPNST, it remains difficult to be cured by either...

Familial amyloid polyneuropathy (FAP) is a rare, hereditary peripheral neuropathy commonly caused by mutations in human transthyretin (TTR) gene. Clinically, FAP caused by TTR mutations (TTR-FAP) involves both large and small nerve fibers. Details of early electrophysiological features in TTR-FAP remain unclear. To address this issue, we evaluated...

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by occlusion of bilateral internal carotid and intracerebral arteries with the compensatory growth of fragile small vessels. MMD patients develop recurrent infarctions in the basal ganglia and subcortical regions. Symptoms include transient ischemic attack or stroke, seizures,...

Background The cardiac manifestations of late-onset hereditary transthyretin amyloidosis with p.A97S variant have not been extensively studied, and the prognostic factors remain unclear. Methods The clinical profile, echocardiography, and ECG of patients diagnosed with ATTR p.A97S polyneuropathy between 2000 and 2016 were retrospectively collected...

Abstract Inherited erythromelalgia (IEM), caused by mutations in Nav1.7 channel is characterized by episodic neuropathic pain triggered especially by warm temperature. However, the mechanism underlying the temperature–dependent episodic attacks of IEM remains elusive. We investigated the electrophysiological effect of temperature changes on Nav1.7...

Background Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. The malignant peripheral nerve sheath tumor (MPNST), transformed from NF1 related plexiform neurofibroma, is a rapidly growing and highly invasive tumor. No effective chemotherapeutic agent is currently available. Calebin-A is a derivative from...

PTEN-induced putative kinase 1 (PINK1) is an integral protein in the mitochondrial membrane and maintains mitochondrial fidelity. Pathogenic mutations in PINK1 have been identified as a cause of early-onset autosomal recessive familial Parkinson’s disease (PD). The ubiquitin proteasome pathway is associated with neurodegenerative diseases. In this...

The inhibitors alone did not affect either (A) HO-1 or (B) Nrf2 basal level expression. SH-SY5Y cells were pre-treated for 30 min with LY294002 (20 μM), PD98059 (20 μM), SB23580 (10 μM) or N-Acetyl-L-cysteine (NAC) (10 mM), then MG132 (1 μM) was added for 6 hours. (TIF)

Control IgG showed there was no non-specific interaction in immunofluorescence images. Scale bar: 100 μM. (TIF)

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynam...

Datasets. (ZIP)

Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema and warmth in the extremities upon heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus...

Background Growth hormone (GH) mainly serves an endocrine function to regulate somatic growth, but also serves an autocrine function in lung growth and pulmonary function. Several recent studies have demonstrated the role of autocrine GH in tumor progression in some organs. However, it is not clear whether excessive secretion of GH in the lungs is...

The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first dem...

Mutation of DJ-1 (PARK7) has been linked to the development of early-onset Parkinson's disease (PD). However, the underlying molecular mechanism is still unclear. This study is aimed to compare the sensitivity of nigrostriatal dopaminergic neurons to lipopolysaccharide (LPS) challenge between DJ-1 knockout (KO) and wild-type (WT) mice, and explore...

Up-regulation of IFN-γ and I-TAC is slightly enhanced in DJ-1 knockout mice 1 day after LPS injection. (TIF)

Microglia activation in WT and DJ-1 KO mice 1 day after LPS injection. (TIF)

No synergistic effect of IFN-γ and I-TAC in midbrain neuron-glia mixed cultures. (TIF)

The statistical results of Fig 7B. (TIF)

Familial amyloid polyneuropathy (FAP) caused by a mutation in transthyretin (TTR) gene is an autosomal dominant inherited disorder. The aim of this study is to explore the pathophysiological mechanism of FAP. We prospectively recruited 12 pauci-symptomatic carriers, 18 patients who harbor a TTR mutation, p.A97S, and two-age matched control groups....

Previously, we have found that cancer cells survived from 5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) have abnormal mitochondrial function and suppressed cellular invasiveness. Here we report that both the mRNA expression level and enzymatic activity of histone deacetylase (HDAC) were elevated in the PDT-derived variants with dysf...

Threshold tracking is a new noninvasive approach for detecting axonal excitability changes in vivo. In this study, the authors compared the excitability indices of motor and sensory axons of median and ulnar nerves to determine whether the two nerves behave in a similar or a noninterchangeable way. They also examined whether age affects these indic...

Supplementary Information Table 1.

Autonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This study aimed to investigate the pathology and clinical significance of sudomotor denervation. Skin biopsies were performed on the distal leg of FAP patients with a follow-up duration...

Moyamoya disease (MMD) is a disorder characterized by stenosis of bilateral internal carotid arteries with compensatory angiogenesis of the perforating blood vessels. Familial transmission in MMD is common. Recently, mutations in human RNF213 and ACTA2 genes were identified to be responsible for MMD. The present study was to determine whether Taiwa...

DJ-1 is an oncoprotein that promotes survival of cancer cells through anti-apoptosis. However, DJ-1 also plays a role in regulating IL-1β expression, and whether inflammatory microenvironment built by dysregulated DJ-1 affects cancer progression is still unclear. This study thus aimed to compare the metastatic abilities of melanoma cells in wild-ty...

Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role...

McLeod syndrome is one subtype of rare neuroacanthocytosis syndromes characterized by misshapen red blood cells and progressive degeneration of the basal ganglia. It is an X-linked recessive disorder with mutation in the XK gene of the Kell blood group system with multisystem involvements. Concerning the movement disorders, its dyskinesias are vari...

A recently published genome-wide association study in Caucasian and Asian populations showed a significant association between the bone marrow stromal cell antigen 1 (BST1) SNP rs11724635 and increased risk for Parkinson's disease (PD). To investigate whether BST1 rs11724635 increases the risk of PD, either by itself or in combination with environm...

An investigation on the molecular mechanism of depression state, less attention was focused on changes at the intracellular messenger level. In this study the effects of reserpine, a monoamine depletor, and imipramine, an antidepressant, on serotonin-2 (5-HT2) receptor binding and its second messenger system of rat cerebral cortex were studied. The...

Primary erythromelalgia (PE) is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the α-subunit of the voltage-gated sodium channel, Na(v)1.7, were found to be responsible for PE. Three missense mutations of SCN9A ge...

Cloning strategies of hSCN9A full-length cDNA. (A) The positions of mutations are labeled in blue (I1376V), red (I848T), and green (V1316A) boxes along with the selected restriction enzyme sites. (B) Full-length hSCN9A was cloned into pTracer-EF/V5-His A vector using NotI cutting sites. (C) Fragments A/B/C containing mutation points were subcloned...

Western Blotting for confirmation of the expression of SCN9A proteins in transfected cells. To evalute the expression of SCN9A proteins, the transfected CHO-K1 cells were harvested for Western blotting. CHO-K1 cells transfected with SCN9A wild type and mutant constructs were lysed with 100 µl of 2X SDS sample buffer (125 mM Tris, 4% SDS, 20% Glycer...

Use-dependent effect of mexiletine. Wild type with both I136V and V1316A mutant Nav1.7 channels were treated with1 mM of mexiletine and present with high frequency stimuli (as decribed in methods). N numbers are annotated in parentheses. (PDF)

The restriction map for cloning of human SCN1B and SCN2B cDNA sequences. The SCN1B was inserted flanking by the enzyme cutting site MluI. Under the same promoter for transcription, the SCN2B cDNA was cloned in the cutting site created by the enzymes, SalI and NotI. (PDF)

Fluorescent microscopy of the transfected CHO-K1 cells. The successfully transfected cells demonstrated the bright green fluoscent protein, which were subjected for electrophysiological studies. (PDF)

Immunofluorescence imaging study demonstrated the membrane expression of the Nav1.7 channels in the transfected cells. Cells were cultured on glass coverslip for 24 h after transfection, followed by fixation with 4% paraformaldehyde. The cells were not subjected to permeabilization procedure in order to observing the membrane expression. Cells were...

Neurofibromatosis type 1 (NF1) is one of the most common inherited neurologicaldisorders. Clinically, NF1 is characterized by café-au-lait spots, skinfold freckling,cutaneous and subcutaneous neurofibroma, plexiform neurofibroma, Lisch nodules, bonydefects and frequently by a positive family history in first degree relatives. The causativegene enco...

Mutation in human PTEN induced protein kinase 1 (PINK1) gene is responsible for the second most common form of recessive Parkinson disease (PD). We have identified a single heterozygous PINK1 mutation, P209A, from a cohort of 68 patients with early onset PD. From age 31, this patient developed an asymmetric bradykinesia with rigidity that was L-dop...

Background and purpose: ARHSP-TCC is characterized by progressive leg spasticity, ataxia, and cognitive dysfunction. Although mutations in the human SPG11 gene were identified as responsible for ARHSP-TCC, the cerebral fiber integrity has not been assessed systemically. The objective of this study was to assess cerebral fiber integrity and its cli...

Background: This study aimed to investigate whether the body mass index (BMI) in combination with genetic variations in APOE and APOA5_'T' alleles modulates the risk of sHTG. Methods: There were 255 moderate HTG (TG ≥2.26 and <5.65 mmol/L) and 176 sHTG (TG ≥5.65 mmol/L) and 304 controls (TG <2.26 mmol/L) were recruited. APOE epsilon alleles were...

Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patie...

Primers sequences and PCR conditions for mutational analyses of PRRT2. (DOC)

Clinical features of the index patients with familial PKD/IC with or without PRRT2 mutations. (DOCX)

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlyi...

Acute intermittent porphyria (AIP) is an inherited disorder of heme biosynthesis, the clinical manifestations of which are incompletely understood. In this report, we describe 12 cases of AIP, focusing on the neurological manifestations. Twelve patients were diagnosed with AIP on the basis of characteristic clinical findings, erythrocyte porphobili...

The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combin...

Progranulin is the precursor of granulins, and its downregulation may lead to neurodegeneration. The single-nucleotide polymorphism rs5848 increases the risk of Alzheimer's disease (AD). We explored the association between alleles of rs5848 and the risk of AD in the Taiwanese population. The frequency of the homozygous TT genotype (16.4 vs. 10.0%)...

J. Neurochem. (2011) 117, 643–653. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Mutation in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene causes an autosomal recessive form of PD. However, the etiology related to PINK1 is still not clear. Here, we examined the effect of PINK1 on h...

Familial Alzheimer's disease (FAD) is genetically heterogeneous, autosomal dominant, with nearly 100% penetrance. In FAD, most common causative genetic mutations are presenilin 1 (PSEN1), presenilin 2 and amyloid-β protein precursor. We demonstrate a family presenting as early-onset AD with a rapid deterioration course and seizure developed after 1...

Cerebral amyloid angiopathy, a vasculopathy characterised by the deposition of amyloid fibrils in the arteries and arterioles in the cerebral cortex and meninges, has been reported to be associated with intracerebral haemorrhage and cognitive impairment in the elderly. Advances in neuroimaging and validation of the clinical diagnostic criteria aid...

Familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR) is often associated with impairment of thermonociceptive functions. This study investigated skin innervation and its clinical significance in genetically defined FAP due to a hot-spot Ala97Ser TTR mutation (Ala97Ser). Skin biopsies were performed on the distal leg of pat...

Linkage analysis for hydrocephalus by whole-genome screening. The B6 genotype frequency, defined as the percentage of individual animals that contained at least one copy of the B6 allele, of mutant and control mice was analyzed by whole-genome screening using 287 SNP markers. (0.56 MB TIF)

Genetic map of p23-ST1 mice at the linked locus. Percentages of the B6 allelic frequency at chromosomes 4, 14, and 19 were analyzed. On chromosome 4, the percentages of the B6 allelic frequency in mutant mice (≥ mean +8 SDs, n = 56; open circles) reached 70%; in contrast, in control mice (≤ mean −2 SDs, n = 8; filled circles), it was only 35% in a...

Fine mapping of the genetic map at the linked locus of chromosome 4. Percentages of B6 allele frequency (A) and B6 homozygosity (B) in the linked locus (rs13477838∼rs13477993) on chromosome 4 in mutant and control mice were analyzed using additional SNP (rs13477964, rs6224690, rs27565906, rs134779969, rs6228499, and rs6334695) and STRP (D4Mit249, D...

Morphological characteristics of Iba1-positive microglia. Iba1-positive microglia were classified according to their morphological features: (A) Ramified microglia (resting); (B) rod-like/amoeboid microglia (activated); (C) elongated/bipolar microglia (chronically activated). Representative images of the schematic illustrations (1), immunohistochem...

p23-ST1 mice which exhibited normal bodyweight (A) and locomotor activity (B). (0.44 MB TIF)

Primers used for gene mapping on chromosome 4 (0.69 MB TIF)

2D-MRI analyses of a wildtype C57BL/6J mouse (A) and a p23-ST1 mouse (B) at 3 months old. The representative p23-ST1 mouse showed enlargement of the lateral ventricles. (0.75 MB TIF)

Standard curve for the measurement of urinary volume on 3-mm Whatman chromatography paper. (0.43 MB TIF)

3D-MRI analysis of wildtype C57BL/6J and C3H/HeJ mice at the age of 3 months (0.26 MB TIF)

Serum biochemical parameters and osmolarity of control and mutant mice. Blood samples were collected from mice at the age of 12 months (n = 3 in each group) to produce serum and analyzed for the levels of total-cholesterol (TCHO); triglyceride (TG), glucose (GLU), magnesium (Mg), calcium (Ca), creatinine (CRE), C-reactive protein (CRP), alanine ami...

A Chi-square test to assess the linkage of the B6 allele at rs3091114 on chromosome 4 to hydrocephalus. The two-by-two table demonstrates that the mutant B6 allele in this region was significantly associated with the disease phenotype with χ2 = 16.141, p<0.001. (0.23 MB TIF)