[Providing Opportunities for Close Examination of Lynch Syndrome after Microsatellite Instability Testing in a Hospital Setting].

Microsatellite instability(MSI)testing is performed in cancer patients to determine the indication for chemotherapy with immune checkpoint inhibitors. We report on our scheme to ensure that Lynch syndrome patients are offered the opportunity for genetic counseling and genetic testing. Two hundred and eight cancer patients(107 males and 101 females, 20- 87 years, mean 63.3 years)underwent MSI testing at our hospital between February 2019 and November 2021. From February 2019 to December 2020, the MSI testing was performed with a consent document that included a commentary on Lynch syndrome, and the results were explained only by the attending cancer doctors. Eleven(8.6%)of the 136 cases had MSI-high, but none of them led to a visit to the genetic medicine department. The Genome Center in our hospital, which was operational from April 2020, undertook information sharing by multiple professions and established a system to provide appropriate support to cancer doctors. Consecutively, 72 MSI tests were performed between January and November 2021, and 2 patients(2.8%)with MSI-high(1 with endometrial cancer and 1 with colorectal cancer)were referred to the Department of Clinical Genetics for genetic counseling. Through genetic testing, both were diagnosed with Lynch syndrome, and information on future surveillance and health care for blood relatives was provided.

[Antibody production capacity after COVID-19 vaccination in immune-mediated neuromuscular diseases under immunotherapy].

The post-vaccination antibody response in patients with immune-mediated neuromuscular diseases under immuno-suppressive therapy has not been sufficiently verified. The Japanese Society of Neurology has stated that coronavirus disease 2019 (COVID-19) vaccination should be given priority in patients with immunotherapy-associated neuromuscular diseases; however, data on antibody production to a novel mRNA vaccine are scarce in these patients. In this study, we aimed to measure residual antibody titers after the second dose and produced antibodies after the third dose of SARS-CoV-2 mRNA vaccine in 25 patients with neuromuscular diseases under immuno-suppressive therapy (disease group). We compared the disease group antibody titers with those of 829 healthy employees in our hospital (control group). The disease group included 17 patients with myasthenia gravis, 4 with multiple sclerosis, 3 with inflammatory muscle disease, and 1 with chronic inflammatory demyelinating polyneuropathies. Seven cases of the disease group showed negative antibody levels (<15.0 s/co) before the third vaccination, and antibody titers in the positive cases ranged from 16.9 to 4,589.0 s/co. Three of the seven antibody-negative cases turned positive after the third vaccination, and all but one of the antibody-positive cases showed a booster effect, with antibody titers after the third dose ranging from 245.1 to 85,374.0 s/co (1.0 to 885.0 times higher than those before vaccination). Although the immune response in the disease group was modest compared to the control group, in which antibody titers after the third vaccination ranged from 67.8 to 150,000 s/co (0.9 to 5,402.1 times higher than those before vaccination), the result indicated that a constant immune response was achieved under immuno-suppressive therapy. Even in the control group, three participants tested negative for residual antibody before the third inoculation, and four of the antibody-positive participants (27.7-24,054.0 s/co) lacked a booster effect after the third vaccination.

Guillain-Barré Syndrome Associated with COVID-19 in a Japanese Male.

April 2021 saw a widespread outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Osaka, Japan. We encountered the case of a 52-year-old man who had Guillain-Barré syndrome associated with coronavirus disease 2019 (COVID-19). After the relief of the respiratory symptoms owing to COVID-19, the patient experienced muscle weakness, which spread from his fingers to his extremities, and was unable to walk. Further examinations revealed mild protein elevation in the cerebrospinal fluid. In addition, nerve conduction studies showed demyelinating polyneuropathy, leading to the diagnosis of Guillain-Barré syndrome. After the administration of intravenous immunoglobulin and intravenous methylprednisolone, his symptoms drastically improved, and he was able to walk unaided 21 days after the onset of symptoms. On day 40, the patient was discharged with minimal muscle fatigue. Because Guillain-Barré syndrome associated with COVID-19 is expected to have a good prognosis, early diagnosis and treatment are important. Therefore, Guillain-Barré syndrome should be considered as a possible factor for muscle weakness during and after COVID-19 treatment.

Cellular analysis of SOD1 protein-aggregation propensity and toxicity: a case of ALS with slow progression harboring homozygous SOD1-D92G mutation.

Mutations within Superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS), accounting for approximately 20% of familial cases. The pathological feature is a loss of motor neurons with enhanced formation of intracellular misfolded SOD1. Homozygous SOD1-D90A in familial ALS has been reported to show slow disease progression. Here, we reported a rare case of a slowly progressive ALS patient harboring a novel SOD1 homozygous mutation D92G (homD92G). The neuronal cell line overexpressing SOD1-D92G showed a lower ratio of the insoluble/soluble fraction of SOD1 with fine aggregates of the misfolded SOD1 and lower cellular toxicity than those overexpressing SOD1-G93A, a mutation that generally causes rapid disease progression. Next, we analyzed spinal motor neurons derived from induced pluripotent stem cells (iPSC) of a healthy control subject and ALS patients carrying SOD1-homD92G or heterozygous SOD1-L144FVX mutation. Lower levels of misfolded SOD1 and cell loss were observed in the motor neurons differentiated from patient-derived iPSCs carrying SOD1-homD92G than in those carrying SOD1-L144FVX. Taken together, SOD1-homD92G has a lower propensity to aggregate and induce cellular toxicity than SOD1-G93A or SOD1-L144FVX, and these cellular phenotypes could be associated with the clinical course of slowly progressive ALS.

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

[A survivor of Hodgkin lymphoma manifesting dropped head syndrome as a late-onset complication of radiotherapy: a case report].

We report the case of a 50-year-old female survivor of Hodgkin lymphoma (HL), who developed dropped head syndrome (DHS). The patient was diagnosed with HL at 20 years of age, and underwent chemo-radiotherapy, which led to complete remission. Undergoing supplemental therapy for post-radiation hypothyroidism, she had twin babies. She noticed white stains on her neck at the age of 30, and the decolored area gradually expanded. Sixteen years after the radiotherapy (RT), her posterior neck muscle strength began to decline. She had to make considerable efforts to keep her neck straight, and came to experience a severe pain in the neck and shoulders. The patient visited our department due to DHS at the age of 50. She had leukoderma, muscle weakness, and muscle atrophy in the neck and para-spinal region, which were consistent with the area of RT. The strength was preserved in the other parts of the muscle, including the proximal upper limbs. Sensory nerve disorder was not detected. The serum creatine kinase level was slightly elevated. Cervical spine or cervical cord disease that can cause DHS was not detected by MRI examination. The MRI and CT images revealed marked atrophy in the posterior neck and para-spinal muscles. The electromyogram revealed myopathic changes, and the cause of her DHS was diagnosed as radiation-induced myopathy. DHS is a well-known late-onset radiation injury, and Japanese cases have been reported in elderly persons with laryngeal or lung cancer. However, there have been no Japanese case reports of radiation-induced DHS due to RT against HL in younger persons. The patient had visited several clinics and hospitals before she came to our hospital, but RT-induced DHS had been overlooked. Greater recognition and consideration is required for DHS as one of the various issues arising after long passage of HL survivors.

A case of possible paraneoplastic neurological syndrome presenting as multiple cranial nerve palsies associated with gallbladder cancer.

We report the case of a patient who had developed multiple cranial nerve palsies in the course of possible paraneoplastic neurological syndrome (PNS) associated with gallbladder cancer. Twelve days prior to visiting our hospital, a 69-year-old man began experiencing neurological symptoms, beginning with diplopia and progressing to ptosis of the left palpebra and subsequent complete closure of the eye within 8 days. Results of the initial medical examination indicated paresis of left oculomotor (III) and abducens (VI) nerves. MRI of the brain revealed no focal lesion that could have resulted in compression of the affected nerves, while further examination ruled out diabetes mellitus, infection, vasculitis, and other systemic autoimmune diseases as potential causes. Gadolinium-enhanced MRI revealed high intensity located in the oculomotor nerves, and steroid pulse therapy was performed based on the assumption of inflammatory diseases. Although slight improvement was observed with respect to the left extraocular paresis, subsequent emergence of bilateral facial nerve (VII) palsy, right abducens nerve palsy, and right oculomotor nerve palsy occurred in succession. PET/CT performed under suspicion of PNS, confirmed the presence of gallbladder cancer. Surgical extirpation of the cancer occurred 3 months following the appearance of left oculomotor paralysis, after which the patient underwent postoperative chemotherapy. All cranial nerve palsies resolved within 2 months after the operation, and both cancer and PNS have shown no recurrence for over 5 years. Pathological examination of the resected tumor revealed well-differentiated tubular adenocarcinoma showing some signs of epithelial-mesenchymal transition, typically an indicator of a poor prognosis. Nevertheless, lymph node metastasis did not progress beyond N2, and the cancer was completely removed by lymph node dissection. Therefore, the presence of multiple cranial palsies in this patient led to early detection of the asymptomatic gallbladder cancer and immediate administration of life-saving treatment.

Episodic ataxia type 2 manifests as epileptiform electroencephalographic activity with no epileptic attacks in two family members.

Here, we report two cases of episodic ataxia type 2 (EA2) in a 63-year-old woman and her 36-year-old daughter. The mother experienced recurrent attacks of cerebellar dysfunction lasting 4 to 5 hours since the age of 41 years. On several occasions, she was admitted to the emergency room, where she was diagnosed with epilepsy or stroke. Based on these diagnoses, she was treated with antiepileptic or anticoagulant drugs, but both treatments were eventually discontinued. The frequency of the attacks increased after the patient reached the age of 62. Interictal neurological examination demonstrated signs of slight cerebellar ataxia, i.e. saccadic eye movements, gaze-directed nystagmus, and mild truncal ataxia. Brain magnetic resonance imaging (MRI) showed cerebellar vermis atrophy. Electroencephalography (EEG) revealed various spike and wave patterns: solitary spikes, spike-and-slow wave complexes, and slow wave bursts. Photoparoxysmal response (PPR) type 3 was also observed. Treatment with acetazolamide abolished the patient's attacks almost completely. The daughter started experiencing 5- to 10-minute ataxic episodes at the age of 16 years. Based on her epileptiform EEG activities with PPR (type 2), antiepileptic drugs (valproate and zonisamide) were prescribed. Despite pharmacological treatment, the attacks recurred; however, their frequency gradually decreased with time, until they almost entirely disappeared when the patient was 33. Unfortunately, migraine-like headaches arose instead. Subtle truncal ataxia was observed during interictal periods. Sanger sequencing of the exons of the CACNA1A gene revealed a novel single base deletion (c.3575delA) in both patients. Despite the difference in age of onset and clinical course, both patients showed clearly epileptiform EEG activities without experiencing the concurrent epileptic episodes. Thus, EA2 is a disease that may be misdiagnosed as epilepsy or stroke in the field of emergency medicine.

[Cases of three patients undergoing chemotherapy for gastric cancer who developed Trousseau's syndrome].

Trousseau's syndrome involves unexplained thrombotic events along with malignancy. We report the cases of 3 patients undergoing chemotherapy for gastric cancer in whom Trousseau's syndrome occurred. Case 1 involved a 43-year-old woman undergoing S-1/cisplatin( CDDP) combination therapy as first-line chemotherapy for type 4 remnant gastric cancer( cT4bN2M1P1/stage IV) who experienced left hemiplegia. Cerebral hemorrhage of the right parietal lobe was diagnosed by computed tomography( CT), and thrombosis from the upper sagittal sinus to the right sinus sigmoideus was diagnosed by magnetic resonance venography( MRV). Case 2 involved a 59-year-old man undergoing S-1/irinotecan (CPT-11) combination therapy as second-line chemotherapy for type 3 gastric cancer( cT3N1M0H1/stage IV) who experienced ataxic, stuttering, and left membrum inferius paralysis. Multiple cerebral infarction of the right parietal lobe was diagnosed by magnetic resonance imaging (MRI). Case 3 involved a 67-year-old woman undergoing S-1/CDDP combination therapy as preoperative chemotherapy for type 3 gastric cancer( cT4aN1M0/stage IIIA) who experienced right cerebellum incontinentia, nystagmus, and right facioplegia. Multiple cerebral infarction of the right cerebellum and pedunculus cerebellaris medius was diagnosed by MRI. An anticoagulant was administered orally for stroke, and chemotherapy for gastric cancer was resumed after activities of daily living( ADL) improved in all 3 patients. Recurrent stroke was not diagnosed in any of the 3 patients. Patients with malignancy often exhibit hypercoagulability associated with cancer. Accordingly, periodic blood tests for coagulation should be performed and dehydration should be prevented to prevent strokes in cancer patients.

Misfolded SOD1 forms high-density molecular complexes with synaptic molecules in mutant SOD1-linked familial amyotrophic lateral sclerosis cases.

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we report identification of various synaptic molecules forming molecular complexes with misfolded SOD1 in mutant SOD1-associated FALS patient tissues as well as in cellular FALS models. In the FALS cellular model system, we found that membrane depolarization that mimics synaptic hyperactivation/excitotoxicity could cause misfolding of mutant SOD, as well as acceleration of misfolded SOD1-synaptic protein complex formation. These results suggest that inhibition of synaptic release mechanism by association of misfolded SOD1 with synaptic molecules plays a role in the dysfunction of FALS.

Depression in patients with subacute myelo-optico-neuropathy (SMON).

OBJECTIVE: We investigated the psychiatric disorders in subacute myelo-optico-neuropathy (SMON) patients by structured interview. The prevalence of major depressive disorder in SMON patients was estimated by structured interview and using Beck's depression inventory (BDI) questionnaires. MATERIALS AND METHODS: Psychiatric conditions were evaluated in 26 SMON patients (9 males, 17 females, mean age 70.7 years) living in Kyoto prefecture through a structured interview given by psychiatrists. BDI questionnaires and clinical symptoms of SMON were investigated in 106 patients, ranging from 51 to 91 years in age (mean, 73.5) with SMON patients living in Kinki area. BDI questionnaires were obtained from 92 age-matched aged healthy people, ranging from 57 to 91 years in age (mean, 75.8), living in Kyoto city. RESULTS: Among the psychiatric disorders in SMON patients, the prevalence of major depressive disorder and suicidal ideation significantly increased during the period of clioquinol intake and four patients (15.4%) out of 26 SMON patients still suffer from major depressive disorder. The prevalence of major depressive disorder in SMON patients was estimated at 15.1% (16/106) and this percentage was about seven times as frequent as in the age-matched aged healthy people (2.2%; 2/92). In female SMON patients, the degree of the depressive states was significantly correlated with the severe degree of dysesthesia of the lower extremities, and it was inversely correlated with the duration of SMON disease and the total scores of the Barthel index. CONCLUSION: This is the first report that shows the prevalence of major depressive disorder in SMON patients at present, which was seven times more frequent than age-matched aged healthy persons.

Microsomal enzyme induction and clinical aggravation of porphyria: the evaluation of human urinary 6beta-hydroxycortisol/cortisol ratio as the index of hepatic CYP3A4 activity.

The clinical aspect of porphyria has been investigated, and it is well known that porphyrinogens such as estrogens and alcohol or other inducers of P450 isoenzymes exacerbate the porphyric state. However, there can be a delay in diagnosing porphyria and a difficulty in selecting safe medicine for it even today. A 21-year-old woman developed epilepsy, disturbance of mental state, and spastic tetraparesis during the convalescent period after acute viral encephalitis. She was diagnosed with porphyria after the fifth hospitalization. In the course of modifying her anticonvulsant regimen, the authors examined the 6beta-hydroxycortisol/cortisol ratio (6beta-OHF/F) in her urine, which can be the index of hepatic CYP3A4 activity, with electrospray ionization/mass spectrometry/mass spectrometry (ESI/MS/MS). Generalized and partial complex seizures, other neurological signs and symptoms, and laboratory data were improved after modification of her anticonvulsant regimen. This is the first report of evaluating the urinary 6beta-hydroxycortisol/cortisol ratio in a case of porphyria.

[Disturbance of jaw-opening due to extension of syringobulbia to the pons--a case report].

We report a patient with syringobulbia extending to the pons, who could not open his mouth widely. He had been involved in the traffic accident at 16 years of age. Since them he had suffered numbness in the left neck and arm. At age 30, he became unable to open the mouth widely with pain in the left jaw joint. He also noted dysphagia and tinnitus. Neurologically, there were vocal cord paresis, dysesthesia of the face, ageusia and cerebellar ataxia all on the left side. Brain MRI revealed syringobulbia which extended to the pons. Spinal MRI revealed syringomyelia through the entire spinal cord. The syrinx of the spinal cord seemed to connect with the brainstem lesion. EMG of the masticatory muscles revealed paradoxical activity in the left masticatory muscles. We concluded that disturbance of jaw-opening in this case was caused by syringobulbia, the lesion of which could involve masticatory central pattern generator in the brainstem.