Distinctive Deposition Patterns of Sporadic Transthyretin-Derived Amyloidosis in the Atria: A Forensic Autopsy-Based Study.

Left-to-right differences in the histopathologic patterns of transthyretin-derived amyloid (ATTR) deposition in the atria of older adults have not yet been investigated. Hence, this study evaluated heart specimens from 325 serial autopsy subjects. The amount of ATTR deposits in the seven cardiac regions, including both sides of atria and atrial appendages, was evaluated semiquantitatively. Using digital pathology, we quantitatively evaluated the immunohistochemical deposition burden of ATTR in the myocardium. We identified 20 sporadic ATTR cardiac amyloidosis cases (nine males). All patients had ATTR deposition in the left atrial regions of the myocardium. In the semiquantitative analysis, 14 of the 20 cases showed more severe ATTR deposition on the left atrial regions than on the right side, with statistically significant differences in the pathology grading (p < 0.01 for both the atrium and atrial appendage). Quantitative analysis further supported the difference. Moreover, six had ATTR deposition in the epineurium and/or neural fibers of the atria. Cluster analysis revealed that ATTR deposition in the myocardium was significantly more severe in males than in females. The heterogeneous distribution of amyloid deposits between atria revealed in this study may impair the orderly transmission of the cardiac conduction system and induce arrhythmias, which may be further aggravated by additional neuropathy in the advanced phase. This impairment could be more severe among males. These findings emphasize that atrial evaluation is important for individuals with sporadic ATTR cardiac amyloidosis, particularly for early detection.

Clinicopathological Appearance of Epidermal Growth-Factor-Containing Fibulin-like Extracellular Matrix Protein 1 Deposition in the Lower Gastrointestinal Tract: An Autopsy-Based Study.

This study examined the patterns of epidermal growth-factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) deposition in the small intestine and colon to evaluate the association between the histopathological severity of EFEMP1 deposition and constipation and determine the colocalization of amyloid transthyretin (ATTR) and EFEMP1 deposits. In 40 older cases (≥80 years of age), EFEMP1 deposition in the small intestine initiated in the submucosal and subserous vessels, subserous interstitium, and serosa (early stage), progressing to the muscularis propria and peri-Auerbach plexus area (intermediate stage), and finally spreading diffusely to other areas, excluding the mucosa and muscularis mucosa (advanced stage). The colon had a similar pattern of progression. During the middle-to-advanced stages, amyloid formation was observed in some vascular and serous deposits. A subgroup of cases was identified in which EFEMP1 deposition was the only presumed cause of constipation. Additionally, we demonstrated the colocalization of ATTR and EFEMP1 deposition. Apple-green birefringence was detected under polarized light only in approximately one-half of the cases in the small intestine and one-third of the cases in the colon. These findings strongly suggest that EFEMP1 deposits are correlated with pathological conditions of the lower gastrointestinal tract. As the histopathological diagnosis using Congo red-stained specimens is challenging, the combined use of elastic fiber staining and EFEMP1 immunohistochemistry is recommended to identify EFEMP1 deposition.

Tachycardia-Induced Cardiomyopathy in an Infant with Atrial Flutter and Prolonged Recovery of Cardiac Function.

Background: Tachycardia-induced cardiomyopathy (TIC) is caused by prolonged tachycardia, leading to left ventricular dilatation and systolic dysfunction with heart failure. Although TIC is more common in adults, it is rare in early infancy. Methods: Clinical testing was performed as part of medical evaluation and management. Next-generation sequencing (NGS) was conducted for a patient with TIC. A literature review on TIC was also conducted. Results: The case involved a 5-month-old infant referred to the hospital due to symptoms of heart failure lasting at least two months. The infant's heart rate was 200 beats per minute, the left ventricular ejection fraction fell below 14%, and electrocardiograms showed atrial flutter, suggesting TIC. After cardioversion, there was no recurrence of atrial flutter, and cardiac function improved 98 days after tachycardia arrest. The NGS did not identify any pathogenic variants. The literature review identified eight early infantile cases of TIC. However, no previous reports described a case with such a prolonged duration of TIC as ours. Conclusions: This is the first report of a case of prolonged TIC in a child with the documented time to recover normal cardiac function. The improvement of cardiac function depends on the duration of TIC. Early recognition and intervention in TIC are essential to improve outcomes for infantile patients, as timely treatment offers the potential for recovery.

Prevalence and clinicopathological features of primary age-related tauopathy (PART): A large forensic autopsy study.

INTRODUCTION: Primary age-related tauopathy (PART), often regarded as a minimally symptomatic pathology of old age, lacks comprehensive cohorts across various age groups. METHODS: We examined PART prevalence and clinicopathologic features in 1589 forensic autopsy cases (≥40 years old, mean age ± SD 70.2 ± 14.2 years). RESULTS: PART cases meeting criteria for argyrophilic grain diseases (AGD) were AGD+PART (n = 181). The remaining PART cases (n = 719, 45.2%) were classified as comorbid conditions (PART-C, n = 90) or no comorbid conditions (pure PART, n = 629). Compared to controls (n = 208), Alzheimer's disease (n = 133), and AGD+PART, PART prevalence peaked in the individuals in their 60s (65.5%) and declined in the 80s (21.5%). No significant clinical background differences were found (excluding controls). However, PART-C in patients inclusive of age 80 had a higher suicide rate than pure PART (p < 0.05), and AGD+PART showed more dementia (p < 0.01) and suicide (p < 0.05) than pure PART. DISCUSSION: Our results advocate a reevaluation of the PART concept and its diagnostic criteria. HIGHLIGHTS: We investigated 1589 forensic autopsy cases to investigate the features of primary age-related tauopathy (PART). PART peaked in people in their 60s in our study. Many PART cases over 80s had comorbid pathologies in addition to neurofibrillary tangles pathology. Argyrophilic grain disease and Lewy pathology significantly affected dementia and suicide rates in PART. Our results suggest that the diagnostic criteria of PART need to be reconsidered.

Sudden unexpected death after initial infusion of rituximab for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma: an autopsy case.

BACKGROUND: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL. CASE PRESENTATION: An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1ß, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein. CONCLUSION: Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.

Amyloid-Forming Corpora Amylacea and Spheroid-Type Amyloid Deposition: Comprehensive Analysis Using Immunohistochemistry, Proteomics, and a Literature Review.

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography-tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that the CAs in these organs primarily consisted of common proteins (ß2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of the amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked ß2-microglobulin and lysozyme and exhibited evident destruction of the surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

Novel MYH7 Variant in the Neonate of a Mother with Gestational Diabetes Mellitus Showing Left Ventricular Hypertrophy and Noncompaction.

BACKGROUND: Left ventricular hypertrophy (LVH) is a well-recognized cardiac dysfunction in infants of mothers with gestational diabetes mellitus (GDM). Left ventricular noncompaction (LVNC) is a cardiomyopathy that is morphologically characterized by numerous prominent trabeculations and deep intertrabecular recesses on cardiovascular imaging. However, there have been no case reports on neonates of mothers with GDM showing LVH and LVNC. CASE PRESENTATION: A patient, with LVH of a mother with GDM, was delivered at 36 weeks of gestation. Prominent trabeculations in the LV, suggesting LVNC, instead of LVH, were apparent 1 week after birth. A heterozygous deletion variant in the MYH7 gene (NM_000257.4: c.1090T>C, p.Phe364Leu) was discovered through genetic testing using a cardiomyopathy-associated gene panel in the patient and his father and the older brother who had LVNC. The patient is now 5 years old and does not have major cardiac events, although LVNC persisted. This is the first case of LVH secondary to a mother with GDM and LVNC with a novel variant in the MYH7 gene. CONCLUSION: Genetic testing should be conducted to obtain an accurate outcome and medical care in a patient with LVH and subsequently prominent hypertrabeculation in the LV.

Transthyretin-derived amyloid (ATTR) and sarcoidosis: Does ATTR deposition cause a granulomatous inflammatory response in older adults with sarcoidosis?

This study aimed to assess the frequency and association between transthyretin-derived (ATTR) amyloidosis and sarcoidosis in a large autopsy cohort including many cases of sudden cardiac death (SCD). We identified 73 sporadic ATTR amyloidosis cases and 11 sarcoidosis cases, among which we found two cases with concomitant ATTR amyloidosis and sarcoidosis (2.4% of all cases; 2.7% within the sporadic ATTR group). The first case involved a 92-year-old man who experienced SCD. In this patient's heart, we observed ATTR deposition and noncaseating epithelioid granulomas consistent with sarcoidosis. Focally, ATTR deposits and granulomas co-localized, with histiocyte phagocytosis of transthyretin-immunoreactive fragments. However, in most lesions, they were distributed independently. The second case was that of an 86-year-old woman who also experienced SCD. In this patient, we detected ATTR deposition in the heart and lung, while noncaseating epithelioid granulomas were only observed in the lung, liver, kidney, and thyroid. Furthermore, no co-localization of the two lesions was observed. Based on these findings, we concluded that the coexistence of ATTR amyloidosis and sarcoidosis was likely coincidental. Nevertheless, despite the rarity of the combination of these two diseases, it should be recognized as a potential cause of SCD, especially among elderly people.

Neuropathology of patients with preclinical or early clinical Alzheimer's disease with pathogenic PSEN1_p. L392V: Comparison of advanced siblings.

INTRODUCTION: Neuropathological investigation of presymptomatic or early symptomatic presenilin-1 (PSEN1) mutation carriers in familial Alzheimer's disease (AD) is extremely scarce. METHODS: We report the autopsy findings of brothers with familial AD. Case 1 is a 45-year-old man without obvious cognitive impairment, who committed suicide. Case 2 is a 57-year-old older brother of Case 1 with advanced AD symptoms, who died of hypothermia during wondering. RESULTS: In both cases, abundant amyloid plaques positive for amyloid ß (Aß) were found throughout the brain. Progression of neuronal loss and increasing amount and extension of neurofibrillary tangle pathology were evident in Case 2. Genetic investigation revealed a PSEN1_p. L392V mutation in both cases. DISCUSSION: The present study shows a possible neuropathological boundary between symptomatic and preclinical AD with pathogenic PSEN1 mutation. Additional clinicopathological investigation for familial AD-related mutation carriers may be significant to explore the association between familial AD and suicide.

Sudden unexpected death of a young adult due to subarachnoid hemorrhage associated with polyarteritis nodosa: Clinicopathological appearance and literature review.

A 28-year-old male was found dead in his bedroom. There were no anomalies in his birth and medical history, and there was no family history of sudden unexpected death (SUD). Autopsy showed subarachnoid hemorrhage (SAH) with basilar top inflammatory pseudoaneurysm rupture accompanied by fibrinoid necrosis in the aneurysm wall. Active and healed arteritides in small- to medium-sized arteries were identified in the brain, heart, and systemic connective tissue, which was consistent with polyarteritis nodosa (PAN). Furthermore, pneumatosis cystoides intestinalis was observed in the ascending colon. Hepatitis B virus infection and antineutrophil nuclear antibodies were negative. Genetic investigation using whole-exome sequencing showed no mutations among autoinflammatory-related genes, including UBA1, MEFV, and ADA2. SAH due to rupture of a pseudoaneurysm formed by PAN was considered as the cause of death in the present case. Although myocardial ischemia linked to coronary arteritis is a recognized trigger for SUD in PAN, our study showed that rupture of inflammatory pseudoaneurysm in the cerebral artery can also cause SUD in younger subjects with PAN, even if prodromal symptoms are not evident before death.

Comprehensive pathological and genetic investigation of three young adult myotonic dystrophy type 1 patients with sudden unexpected death.

OBJECTIVES: The mechanism and pathological substrate of arrhythmogenic events in dystrophic myopathy type 1 (DM1) have not been fully established, especially for patients without progression of motor and/or cardiac disability. Therefore, we aimed to clarify the pathological appearance and genetic factors, other than CTG repeats in DMPK, associated with sudden cardiac death in patients with DM1. METHODS: A pathological investigation including the cardiac conduction system in the heart and whole-exome sequencing was conducted for three young adults (Patient 1; 25-year-old female, Patient 2; 35-year-old female, Patient 3; 18-year-old male) with DM1 who suffered sudden death. RESULTS: Only Patient 1 showed abnormal electrocardiogram findings before death. The pathological investigation showed severe fibrosis of the atrioventricular conduction system in Patient 1 and severe fatty infiltration in the right ventricle in Patient 2. Several minimal necrotic/inflammatory foci were found in both patients. Patient 3 showed no significant pathological findings. A genetic investigation showed CORIN_p.W813* and MYH2_p. R793* in Patient 1, KCNH2_p. V794D and PLEC_p. A4147T in Patient 2, and SCN5A_p.E428K and SCN3B_ p.V145L in Patient 3 as highly possible pathogenic variants. CONCLUSION AND RELEVANCE: The present study showed varied heart morphology in young adults with DM1 and sudden death. Synergistic effects of various genetic factors other than CTG repeats may increase the risk of sudden cardiac death in DM1 patients, even if signs of cardiac and skeletal muscle involvement are mild. Comprehensive genetic investigations, other than CTG repeat assessment, may be useful to estimate the risk of sudden cardiac death in DM1 patients.

An autopsy case of infective aortic aneurysm with Pasteurella multocida infection: clinicopathological appearance and a review of literatures.

Here, we showed our clinicopathological findings of infected aortic aneurysm (IAA) with Pasteurella multocida, which is a Gram-negative coccobacillus and is part of the normal oral flora of many animals. The patient was a 76-year-old male animal owner with a history of diabetes mellitus, alcoholic liver damage, and laryngeal cancer. He died 16 days after admission without undergoing operation because of poor general condition. Autopsy showed saccular outpouching with loss of the existing aortic wall and marked neutrophilic infiltration in the suprarenal abdominal aorta. Rupture was not evident. A polymerase chain reaction assay using DNA extracted from formalin-fixed paraffin-embedded specimen of the aneurysmal wall detected the Pasteurella multocida gene, therefore we conclude that the present case was IAA of native aorta with Pasteurella multocida infection. A review of the literature showed that IAA of native aorta with Pasteurella multocida infection is opportunistic and that liver disorder, alcohol addiction, diabetes mellitus, and animal bite may increase its risk. On the other hand, aortic endograft infection with Pasteurella multocida frequently occurred without an immunocompromised state. Pasteurella multocida may be a distinct causative microorganism in IAA, and/or sepsis when the participant is an animal owner.

Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report.

Background: Left ventricular noncompaction (LVNC) is a rare inherited cardiomyopathy with a broad phenotypic spectrum. The genotype-phenotype correlations in fetal-onset LVNC have not yet been fully elucidated. In this report, we present the first case of severe fetal-onset LVNC caused by maternal low-frequency somatic mosaicism of the novel myosin heavy chain 7 (MYH7) mutation. Case presentation: A 35-year-old pregnant Japanese woman, gravida 4, para 2, with no significant medical or family history of genetic disorders, presented to our hospital. In her previous pregnancy at 33 years of age, she delivered a male neonate at 30 weeks of gestation with cardiogenic hydrops fetalis. Fetal echocardiography confirmed LVNC prenatally. The neonate died shortly after birth. In the current pregnancy, she again delivered a male neonate with cardiogenic hydrops fetalis caused by LVNC at 32 weeks of gestation. The neonate died shortly after birth. Genetic screening of cardiac disorder-related genes by next-generation sequencing (NGS) was performed which revealed a novel heterozygous missense MYH7 variant, NM_000257.3: c.2729A > T, p.Lys910Ile. After targeted and deep sequencing by NGS, the same MYH7 variant (NM_000257.3: c.2729A > T, p.Lys910Ile) was detected in 6% of the variant allele fraction in the maternal sequence but not in the paternal sequence. The MYH7 variant was not detected by conventional direct sequencing (Sanger sequencing) in either parent. Conclusions: This case demonstrates that maternal low-frequency somatic mosaicism of an MYH7 mutation can cause fetal-onset severe LVNC in the offspring. To differentiate hereditary MYH7 mutations from de novo MYH7 mutations, parental targeted and deep sequencing by NGS should be considered in addition to Sanger sequencing.

Argyrophilic grain disease is common in older adults and may be a risk factor for suicide: a study of Japanese forensic autopsy cases.

BACKGROUND: Neuropathological diagnosis of argyrophilic grain disease (AGD) is currently based primarily on the combination of argyrophilic grain (AG) visualized using Gallyas-Braak silver staining, phosphorylated tau-positive pretangles, coiled bodies, and ballooned neuron detection. Although AGD is common in patients with dementia and/or prominent psychiatric symptoms, whether it is a distinct neurological disease entity or a by-product of the aging process remains unclear. METHODS: In 1449 serial forensic autopsy cases > 40 years old (823 males and 525 females, aged 40-101 years, mean age 70.0 ± 14.1 years), we examined the frequency and comorbid pathology of AGD cases and investigated the clinical appearance by comparing those with non-AGD cases using the propensity score. RESULTS: Of the 1449 cases, we detected 342 AGD cases (23.6%; mean age 79.7 years; 177 males and 165 females). The AGD frequency and stage increased with age (P < 0.001). Among AGD cases, 80 (23.4%) patients had dementia, and 51 (15.2%) had a history of psychiatric hospital visits. The frequency of suicide and history of psychiatric disorders were significantly higher in AGD cases than in AGD-negative cases, matched for age, sex, and comorbidity pathology, with a relative risk of suicide of 1.72 (1.30-2.26). The frequency of suicide was significantly higher in AGD cases than in non-AGD cases in female but not male cases. The relative risk of suicide increased to 2.27 (1.20-4.30) and 6.50 (1.58-26.76) in AGD patients with Lewy and progressive supranuclear palsy pathology, respectively, and decreased to 0.88 (0.38-2.10) in those with advanced AD pathology. In AGD cases, 23.4% had dementia; however, the difference was not significant after controlling for age, sex, and comorbid pathology. CONCLUSION: Our study demonstrated that AGD is a significant and isolated risk factor for psychiatric hospital visits and suicide completion. In older adults, AGs may contribute to the progression of functional impairment of the limbic system, which leads to psychiatric disorders and suicide attempts.

Acute benzyl alcohol intoxication: An autopsy case report.

INTRODUCTION: The main mechanism of death and the pathological appearance of cases of benzyl alcohol intoxication has not been fully investigated. Autopsy reports of cases of benzyl alcohol intoxication have not been published. CASE PRESENTATION: A 24-year-old man was found in the state of cardiopulmonary arrest at a construction site. He had been performing paint stripping. He was immediately transferred to the hospital, but he did not recover. An autopsy showed focal coloring of the skin without any major caustic injury. A histopathological investigation showed vacuolar degeneration in the epidermis and dermo-epidermal junction, and severe erosion of the tracheal and bronchial mucosa. No pathological changes in the kidney were evident. A neuropathological investigation showed central chromatolysis of neuronal cells in pontine nuclei and grumose degeneration in the cerebellar dentate nucleus. The blood content of benzyl alcohol was 780.0 µg/mL. LESSONS: Present case suggest that multiple pathways of exposure may be associated with more rapid progression in acute benzyl alcohol intoxication, and that early and/or severe involvement of the central nervous system rather than renal dysfunction may be associated with an early death.

An autopsy case of sudden unexpected death of a young adult with progressive intraventricular conduction delay.

Herein, we describe an autopsy case of the sudden unexpected death of a 23-year-old man. Retrospective analysis of electrocardiograms revealed progressive widening of the QRS interval. Autopsy showed mild mitral valve prolapse and hypertrabeculation of the left ventricle. Microscopic examination revealed very scarce but considerable minimal myocardial necrotic foci in the left ventricle, and a marked reduction in conduction fibers in the left branch. These findings may be associated with intraventricular conduction delay. Genetic investigation revealed four rare possibly pathogenic variants, including the Emery-Dreifuss muscular dystrophy-associated genetic variant SYNE2_p.A6155 V that is evaluated as pathogenic by most in silico predictive tools. The other possibly pathogenic variants detected were PLEC_p.P973L, TTN_p.I22171T, and p.A12216T. Although these variants are reported to have uncertain significance in the guidelines of the American College of Medical Genetics and Genomics, progressive conduction delay may have been associated with vulnerability of myocytes due to Emery-Dreifuss muscular dystrophy-associated genetic variants in the present case. Younger individuals with progressive conduction delay may require medical work-up and genetic investigation, even if they have no other clinical signs and no or mild structural heart disease.

Pathological Appearance of a Case of Preclinical Multiple System Atrophy: A Comparison With Advanced Cases.

We aimed to investigate the frequency of multiple system atrophy (MSA) in a large number of forensic autopsies and characterize the pathological appearance of preclinical MSA. We investigated a series of 1930 brains from forensic autopsies. In addition to performing immunohistochemistry for phosphorylated α-synuclein, the levels of 3 autonomic nervous system markers (catecholaminergic, serotonergic, and cholinergic) were used to assess the peripheral nerve (heart and superior cervical ganglion) and medulla oblongata. The results were compared to those of healthy control and Parkinson disease (PD) cases. Four cases (0.21%) were identified as having MSA. Cases 1-3 were symptomatic, and Case 4 was incipient; that is, although no neuronal loss was evident, the cerebellar dentate nucleus exhibited marked grumose degeneration. Immunohistochemistry revealed a marked reduction in autonomic nervous system marker levels expressed in the medulla; this reduction was more prominent in the 3 symptomatic MSA cases than in the PD case. The opposite occurred for the peripheral nerve. Case 4 exhibited mild cholinergic nerve reduction. Two cases showed possible significant pathological changes in the heart. Grumose degeneration, few oligodendroglial cytoplasmic inclusions without neuronal loss, and less reduction of autonomic nervous tissue were more prominent in the preclinical case than in symptomatic cases.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with neurenteric cyst. An autopsy case showing unusual fatal outcome.

A 53-year-old man with a history of an untreated brain mass was taken to Toyama Prefectural Central Hospital by emergency transport. Computed tomography revealed an intracranial hypo-attenuated lesion exhibiting mass effect. Several calcified foci were observed around the lesion. His radiographical diagnosis was meningioma with calcification and edema. He suddenly showed tonic seizure after admission; therefore an emergency craniotomy was performed. However, he unfortunately died due to advanced cerebral edema. Microscopic findings of the surgically obtained materials were consistent with neurenteric cyst (NC). Intracranial hard masses were found adjacent to NCs, and the masses were composed of fibrous cartilage-like matrix with extensive linear calcification and the presence of surrounding round-to-oval epithelioid cells. Thus, calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with NC was considered the most appropriate diagnosis of the present case. To the best of our knowledge, this is the first report of such a case. The present case suggests that delay of treatment might cause a poor outcome, at least in CAPNON associated with NC. Careful investigations, including the underlying pathology, may be essential when considering the etiology of CAPNON and its treatment strategies.

Pathological and Comprehensive Genetic Investigation of Autopsy Cases of Idiopathic Bradyarrhythmia.

BACKGROUND: Idiopathic bradyarrhythmia is considered to be due to pathological degeneration of the cardiac conduction system (CCS) during aging. There appears to have been no comprehensive genetic investigations in patients with idiopathic bradyarrhythmia.Methods and Results: Ten autopsy cases with advanced bradyarrhythmia (6 men and 4 women; age: 70-94 years, 81.5±6.9 years; 5 cases each of sinus node dysfunction [SND] and complete atrioventricular block [CAVB]) were genetically investigated by using whole-exome sequencing. Morphometric analysis of the CCS was performed with sex-, age- and comorbidity-matched control cases. As a result, severe loss of nodal cells and distal atrioventricular conduction system were found in SND and CAVB, respectively. However, the conduction tissue loss was not significant in either the atrioventricular node or the proximal bundle of His in CAVB cases. A total of 13 heterozygous potential variants were found in 3 CAVB and 2 SND cases. Of these 13 variants, 4 were missense in the known progressive cardiac conduction disease-related genes: GATA4 and RYR2. In the remaining 9 variants, 5 were loss-of-function mutation with highly possible pathogenicity. CONCLUSIONS: In addition to degenerative changes of selectively vulnerable areas in the heart during advancing age, the vulnerability of the CCS, which may be associated with "rare variants of small effect," may also be a contributing factor to the degeneration of CCS, leading to "idiopathic" bradyarrhythmia.