Transactivation response DNA-binding protein of 43 kDa proteinopathy and lysosomal abnormalities in spastic paraplegia type 11.

Spastic paraplegia type 11 (SPG11) is the most common autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. Spatacsin, a protein encoded by the SPG11 gene, is associated with autophagy. SPG11 patients show spastic paraplegia, intellectual disability, dementia, and parkinsonism. A previous neuropathological analysis of SPG11 cases reported neurodegeneration mimicking amyotrophic lateral sclerosis without transactivation response DNA-binding protein of 43 kDa (TDP-43) deposits and unique sequestosome 1 (SQSTM1)-positive neuronal inclusions. We performed a neuropathological examination of two Japanese patients with complicated spastic paraplegia with thinning of the corpus callosum from different families, and one was genetically diagnosed as having SPG11. Both cases showed diffuse atrophy of the brain and spinal cord. Depigmentation of the substantia nigra was also observed. Immunohistochemistry revealed widespread distribution of areas showing TDP-43 aggregation in the central nervous system. The TDP-43 deposits in the thalamus and substantia nigra especially resembled skein-like inclusions. Unique SQSTM1-positive neuronal inclusions, as previously reported, were widespread in the whole central nervous system as well as the dorsal root ganglia. Double-labeling immunofluorescence of the dorsal root ganglia revealed that the unique, large SQSTM1-positive cytoplasmic inclusions of the ganglion cells were labeled with lysosome-associated membrane protein 1 and lysosome-associated membrane protein 2. This is the first report showing TDP-43 pathology in SPG11. The common neuropathological findings of TDP-43-positive inclusions in both the cases imply a causal connection between the TDP-43 proteinopathy and autophagy dysfunction in SPG11.

Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)-binding protein 1 in Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Immunohistochemical studies using the 1C2 antibody for polyglutamine expansion have detected characteristic intranuclear inclusions (INIs) in affected neurons in HD. Further, in vitro and mouse models of HD have shown that the INIs recruit several proteins relating to RNA splicing and translation. In the present study, we immunohistochemically investigated the association of INIs with various heterogeneous nuclear ribonucleoproteins in the cerebral cortex of four autopsy cases of HD. Fused in sarcoma (FUS) was colocalized with 1C2-positive nuclear inclusions in all examined cases. Localization of poly (rC)-binding protein 1 (PCBP1) in 1C2-positive nuclear inclusions was also observed. Double immunofluorescence revealed complete or partial loss of the normal, diffuse nuclear distribution of FUS or PCBP1 in neurons with 1C2-positive nuclear inclusions. This maldistribution of FUS in cortical neurons suggests a severe disturbance of messenger RNA processing, which may be a common pathogenetic mechanism of FUS-related familial amyotrophic lateral sclerosis.

A Case in which Eosinophilic Meningoencephalitis Occurred during Oral Corticosteroid Tapering and after Switching from Anti-IL-5 to Anti-IgE Treatment.

A 49-year-old man with severe eosinophilic asthma, sinusitis, and esophagitis was admitted with a sudden severe headache. The patient was diagnosed with eosinophilic meningoencephalitis based on frontotemporal abnormalities on brain magnetic resonance imaging and high eosinophil counts in the cerebrospinal fluid. His allergic-disease control levels were poor, requiring regular oral corticosteroid (OCS) use. He was switched from anti-interleukin (IL)-5 to anti-IgE therapy because of worsening urticaria and asthma symptoms during OCS tapering. We suspect this was a case of complex eosinophilic meningoencephalitis caused by the combination of OCS tapering and anti-IL-5 therapy cessation that acquired anti-IgE antibody sensitization based on positive drug-induced lymphocyte stimulation test results.

Altered Functional Connectivity during Mild Transient Respiratory Impairment Induced by a Resistive Load.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without altering transcutaneous oxygen saturation. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptual area (postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores. These findings may provide new insights into the visual networks that contribute to mild respiratory impairments.

Hereditary Neuralgic Amyotrophy with a Lesion Distal to the Brachial Plexus on Magnetic Resonance Imaging.

A 35-year-old woman first experienced left upper limb weakness at 17 years old, after which it repeatedly recurred and then remitted. She was diagnosed with carpal tunnel syndrome with median nerve hyperintensity by magnetic resonance imaging (MRI). Surgical treatment was ineffective. We suspected hereditary neuralgic amyotrophy because of enlargement distal to the brachial plexus on MRI and administered steroid therapy, after which the weakness improved. Genetic testing revealed a point mutation in SEPT9. Because lesions outside the brachial plexus can be seen in hereditary neuralgic amyotrophy, the diagnosis should be based on typical characteristics and the family history.

Association of Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease with Coronavirus Disease 2019 Vaccination and Infection: A Case Report of Cortical Encephalitis and Transverse Myelitis Relapse.

We herein report a case of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) that occurred following coronavirus disease 2019 (COVID-19) vaccination and its subsequent relapse after COVID-19 infection. A 34-year-old woman developed cortical encephalitis in the right temporoparietal lobe one week after receiving the mRNA-1273 vaccine. The cerebrospinal fluid was positive for anti-MOG antibody. Her symptoms gradually improved after three courses of intravenous methylprednisolone therapy. Six months later, she experienced a relapse of transverse myelitis following COVID-19 infection. Despite treatment with plasma exchange, the patient remained paralyzed in both lower limbs. We herein review the relationship between MOGAD and COVID-19 vaccination/infection.

[A case of localized fasciitis with ulcerative colitis].

A 36-year-old man with ulcerative colitis presented with bloody stools at the beginning of October 2020. His condition had been stable without treatment since diagnosis 4 years prior. He was administered 4,000 mg of salazosulfapyridine orally and the bloody stools resolved. Fifteen days after treatment, he was admitted to our hospital with swelling and pain in his right lower leg. Laboratory results revealed an elevated erythrocyte sedimentation rate (43 mm/hr) and mildly elevated C-reactive protein levels (4.08 mg/dl). His D-dimer level was also elevated at 7.6 µg/ml. MRI using fat saturated T2-weighted imaging demonstrated marked hyperintensity in the fascia of the lower leg flexor and blood vessels of interstitial. In gadolinium-enhanced T1-weighted images, the deep veins were found to be dilated and the vein walls and their surrounding areas strongly contrasted, suggestive of localized fasciitis. No abnormalities were found on biopsy of his right gastrocnemius muscle on the 5th day after admission. Two days after the muscle biopsy, the patient began experiencing swelling and pain in his left lower leg. The high intensity lesions in his right leg were reduced on MRI performed the same day, but that of the fascia between the left gastrocnemius and soleus muscles was noted. We administered 60 mg (1.0 mg/kg/day) of prednisolone orally on day 9 and the pain and swelling in both legs promptly resolved. The prednisolone was tapered to 5 mg/day and as of the time of writing, resolution of pain and swelling has been maintained. Gastrocnemius myalgia syndrome, which causes pain and localized fasciitis, is often reported as a complication of Crohn's disease but is rare in conjunction with ulcerative colitis. It is important that clinicians are aware of this syndrome so it can be recognized early and successfully treated.

Anti-glycine receptor antibody-positive progressive encephalomyelitis with rigidity and myoclonus initially presenting with one-sided stiff face: A case report.

Background: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome, a rare cerebrospinal disease that causes brainstem symptoms, myoclonus, muscle rigidity, and hyperekplexia. Case presentation: A 71-year-old man experienced left-sided stiff face, and was subsequently admitted to our hospital because of the appearance of left-dominant lower limb myoclonus. Muscle rigidity followed 3 days later. Magnetic resonance imaging revealed no abnormality. An electrophysiological examination showed a toughness of the antagonistic muscle following evocation of the Achilles tendon reflex, and a tonic phenomenon affecting the left facial muscles during the blink reflex. The patient's serum was positive for anti-glycine receptor (anti-GlyR) antibody, suggesting PERM. The patient was administered steroids, immunoglobulin therapy, and immunosuppressive drugs. He gradually improved after these therapies and became able to walk using a walker. Conclusions: We conclude that this was a rare case of anti-GlyR antibody-positive PERM with unilateral brainstem symptoms, myoclonus, and muscle rigidity.

Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

Combined treatment with prednisolone and tacrolimus for myasthenia gravis with invasive thymoma.

We describe a case of recurrent invasive thymoma associated with myasthenia gravis that responded to combined treatment with prednisolone and tacrolimus. The patient suffered from a myasthenic crisis and received methylprednisolone pulse therapy and partial thymomectomy. Low maintenance doses of prednisolone and tacrolimus shrank the size of the invasive thymoma and maintained the patient without any myasthenic symptoms. We stress the usefulness of combined treatment with tacrolimus and prednisolone for invasive thymoma, especially for unresectable tumors.

Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors.

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-beta protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment enhanced caspase-4 and -9 activities in I143T-mutant PS1-transfected cells, while hydrogen peroxide treatment enhanced caspase-4, -8 and -9 activities in G384A-mutant PS1-transfected cells, indicating diverse apoptosis-promoting effects of PS1 gene mutations. In addition, treatment with a beta-secretase inhibitor or gamma-secretase inhibitor significantly attenuated the effects of the PS1 mutants on caspase-3/7 activation and recovered cell viability. Our present data suggest that these PS1 mutants accelerate the activation of initiator caspases and promote apoptosis, which may be associated, at least in part, with amyloid-beta production.

Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.

Symmetrical brainstem encephalitis caused by herpes simplex virus.

We describe a 53-year-old man with herpes simplex virus (HSV) brainstem encephalitis diagnosed based by positive HSV immunoglobulin M antibodies from cerebrospinal fluid. The MRI findings of this case had three unique features. First, the lesions were symmetrical. Second, the lesions may have been associated with reactivation of HSV infection in the region of the trigeminal nerve. Third, diffusion-weighted and apparent diffusion coefficient (ADC) imaging, conducted for the first time on an HSV brainstem encephalitis case, suggested that the lesions were associated with vasogenic edema.

Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14.

Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAs 1-3, 6-8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient.

MIBG myocardial scintigraphy in progressive supranuclear palsy.

BACKGROUND AND OBJECTIVES: Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is an effective tool for distinguishing Parkinson's disease (PD) from other diseases accompanied by parkinsonism. Unlike other Parkinsonian diseases, in PD, MIBG accumulation in the heart tends to decrease. However, previous studies have reported that a decrease in MIBG accumulation also occurs in progressive supranuclear palsy (PSP). Thus, we analyzed the relationship between the degree of MIBG accumulation decrease, clinical symptoms, and brainstem atrophy in PSP. METHODS: We retrospectively collected data from patients who underwent MIBG myocardial scintigraphy and compared MIBG indices (heart to mediastinum [H/M] ratio, washout rate) between subjects with PSP and other diseases including PD. In addition, we evaluated the relationship between clinical characteristics, MIBG accumulation, and brainstem atrophy in patients with PSP. RESULTS: Patients with PSP had a significantly lower early H/M ratio compared with multiple system atrophy with predominant parkinsonism (MSA-P) patients, and a control group. In PSP patients there was a correlation between the decrease in delay H/M ratio, atrophy of the pons, and clinical severity as evaluated by Hoehn and Yahr score. CONCLUSION: Unlike in PD, PSP patients exhibited a mild decrease in MIBG accumulation in MIBG myocardial scintigraphy, which may be related to brainstem atrophy.

Bilateral cingulate cortices lesions in two autoantibodies directed against MOG (MOG-Ab)-positive patients.

There are no specific radiologic features in MOG-Ab (autoantibodies directed against myelin oligodendrocyte glycoprotein)-associated diseases. We present two MOG-Ab-positive patients with symmetrical lesions in the bilateral cingulate cortex of the frontal and parietal lobes. Those lesions showed hyperperfusion in acute phase and hypoperfusion in chronic phase on brain SPECT. In both patients, steroid therapy was effective in acute phase and for prevention of recurrence. High signal in the bilateral cingulate cortex on MR T2-weighted and FLAIR images might to be one of the unique findings considered MOG-Ab associated diseases.

TDRKH is a candidate gene for an autosomal dominant distal hereditary motor neuropathy.

Distal hereditary motor neuropathies (dHMNs) comprise a group of clinically and genetically heterogeneous inherited lower motor neuron syndromes mainly characterized by a distal-predominant pattern of progressive muscle atrophy, weakness and hyporeflexia, without sensory dysfunction. Although at least 21 causative genes for dHMN have been reported, mutational scanning of these genes often fails to identify the causative variants in dHMN cohorts, suggesting that additional causative genes remain to be identified. We studied a four-generation pedigree of a Japanese family with autosomal dominant dHMN to provide insight into the pathogenetic basis of the disease. Neurological examinations were performed on all six family members enrolled in this study. Whole-exome sequencing (WES) was used to identify the causative gene for dHMN. The clinical features of the patients included muscle weakness with distal extensor dominancy in the lower extremities, accompanied by facial and neck flexor muscle impairment, no sensory involvement, and areflexia. Nerve conduction studies demonstrated axonal changes mainly in the peroneal nerve. WES combined with rigorous filtering revealed three missense variants (NM_001083964: c.851G > A [p.Arg284His] in TDRKH, NM_002858: c.1654G > T [p.Gly552Cys] in ABCD3, NM_001005164: c.898A > T [p.Ile300Phe], in OR52E2). The variant in TDRKH is located in a conserved region of the tudor domain which is also present in the survival of motor neuron (SMN) protein, encoded by the SMN1 gene. Therefore, we concluded the variant in TDRKH is likely to be responsible for dHMN in our pedigree.

Reversible Conduction Failure in Anti-lactosylceramide-antibody-positive Combined Central and Peripheral Demyelination.

We describe a 60-year-old woman with combined central and peripheral demyelination who presented with obstinate constipation, weakness in the lower limbs, and a bilateral sensory disturbance below her chest followed by girdle sensation in the right region of the abdomen, which was responsive to steroid therapy and plasmapheresis. Serum anti-lactosylceramide antibody was positive without anti-neurofascin 155 antibody or anti-galactocerebroside antibody positivity. Two months later, the patient had a first relapse that was responsive to steroid treatment. A nerve conduction study confirmed reversible conduction failure (RCF) in both episodes. Our case is unique in that she had an RCF episode as well as some similarities to encephalomyeloradiculoneuropathy.

Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough.

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of <-3 on both 3p12-q13 and 3p22-p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

Differential contributions of spinal and cortical motoneurons to input-output properties of human small hand muscle.

OBJECTIVE: It is not fully understood how the stimulus/response curves obtained by transcranial magnetic stimulation (TMS) reflect the function of the cortico-motoneuronal (CM) and spinal motoneuronal (SM) systems in healthy subjects. To understand these response functions, we studied patients with amyotrophic lateral sclerosis (ALS) whose upper but not lower motor neurons were affected. METHODS: First, we determined the effects of voluntary muscle contraction and intensity of TMS on the motor evoked potentials (MEPs) of the first dorsal interossei (FDI) muscle in ten healthy control subjects (mean age: 35.1 +/- 6.7 years) and two older female subjects (60 and 64 years old). Second, we investigated whether this relationship was altered in two ALS patients (60-year-old woman and 69-year-old man). The MEPs were recorded at different degrees of voluntary contraction by threshold stimulus intensities (TSIs) or at different levels of TMS with the muscle at rest. RESULTS: In the controls, the MEP amplitudes of the FDI muscle elicited by TSI increased linearly with muscle contraction (right: Y = 0.068X + 0.754; left: Y = 0.0670X + 0.807), whereas the MEP amplitudes elicited by different TMS intensities increased sigmoidally with a flexion point at 1.10-1.15 TSI: right: Amp = 2.21/[1 + exp[(S50-Stim)/K]], S50 = 10.73, K = 4.70; left: Amp = 2.90/[1 + exp[(S(50)-Stim)/K]], S50 = 13.64, K = 5.98. The latter was abnormal only on one side of each ALS patient. DISCUSSION: From these results, we suggest that the sigmoidal TMS intensity-size curves reflect mainly CM activities, while the linear contraction-size curves reflect SM activities.