Revisiting the relevance of Hirano bodies in neurodegenerative diseases.

AIMS: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. METHODS: This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. RESULTS: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. CONCLUSIONS: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

Enterocolic granulomatous phlebitis associated with epidermal growth factor-containing fibulin-like extracellular matrix protein 1 deposition and focal amyloid properties: A case report.

A woman in her 60s with rheumatoid arthritis was admitted with fever and abdominal pain. Laparoscopic examination with the differential diagnosis of peritoneal neoplasm and infection revealed granulomatous phlebitis in the resected greater omentum. Amorphous eosinophilic deposits observed in the resected tissue exhibited focal, weak positivity for Congo red but were strongly positive for thioflavin S, confirming their focal amyloid properties. Marked degeneration of elastic fibers was also evident. Electron microscopy revealed deposits around the affected elastic fibers. Immunohistochemistry revealed the deposition of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) along with T-cell-predominant lymphocytic inflammation. The definitive diagnosis was granulomatous enterocolic lymphocytic phlebitis (ELP) associated with EFEMP1 deposition exhibiting focal amyloid properties (EFEMP1/AEFEMP1), supported by proteomics analysis. This type of vasculitis is similar to amyloid-ß-related angiitis of the central nervous system. Thus, we speculate that granulomatous ELP also results from an immune response that recognizes EFEMP1/AEFEMP1 deposits as foreign material and attempts to remove them. Confirmation of EFEMP1/AEFEMP1 deposition with Congo red staining is challenging, particularly in the presence of inflammation, and warrants comprehensive evaluation.

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.

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.

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.

Lack of difference between amyloid-beta burden at gyral crests and sulcal depths in diverse neurodegenerative diseases.

AIMS: The aim of this study is to clarify whether there is a difference in amyloid-beta burden between gyral crests (GCs) and sulcal depths (SDs) in different neurodegenerative proteinopathies. METHODS: We analysed the burden and distribution of amyloid-beta deposition in post-mortem brain samples from 138 autopsies, including Alzheimer's disease (n = 30), Down's syndrome (n = 11), Lewy body disease (LBD; n = 53), multiple system atrophy (n = 8) and progressive supranuclear palsy (n = 36). We applied quantitative amyloid-beta burden analysis to compare amyloid-beta deposition in both GCs and SDs. We also evaluated the prevalence of amyloid-beta plaques in both regions in samples exhibiting high or low amounts of amyloid-beta pathology. RESULTS: Amyloid-beta burden was evaluated in 67 and 84 samples of the frontal and temporal cortices, respectively. We did not find significant differences in the amyloid-beta burden between GCs and SDs in these regions in any examined disease. In addition, amyloid-beta plaques were almost evenly distributed in both regions in cases with low amounts of amyloid-beta pathology. Females in the LBD group showed significantly higher amyloid-beta burden than males (temporal cortex, p < 0.01). Furthermore, only one LBD case showed SD-predominant deposition associated with the coarse-grained plaques. CONCLUSIONS: We have shown that amyloid-beta is almost evenly distributed in both GCs and SDs in the frontal and temporal lobes from the early stage, in diverse neurodegenerative diseases. Sex may contribute to differences in the amyloid-beta burden. The coarse-grained plaque may show SD-predominant neuritic tau deposition that must be carefully distinguished from chronic traumatic encephalopathy-related SD tau pathology.

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.

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.

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.

Histopathology of acute colchicine intoxication: novel findings and their association with clinical manifestations.

A 32-year-old woman attempted suicide by ingesting Gloriosa bulbs and died approximately 2 days later. Toxicological examination revealed a potentially fatal blood concentration of colchicine (0.096 mg/L). In addition to the increased mitotic figures in the gastrointestinal mucosa, a unique finding for acute colchicine intoxication, pathological examination showed microvesicular lipid droplets in the liver, kidney, heart, and conduction system. Furthermore, central chromatolysis of neurons was observed in the pontine nucleus, medial accessory olivary nucleus, nucleus of the solitary tract, and nucleus ambiguus. Grumose degeneration of the cerebellar dentate nucleus was also evident. These pathological findings may help identify colchicine intoxication, even in the absence of evidence suggesting ingestion during autopsy. Moreover, pathological changes in the heart and central nervous system may be associated with the development of serious complications of acute colchicine intoxication.

An autopsy case of pure nigropathy with TUBA4A nonsense mutation.

We showed the results of pathological and genetic investigation for an autopsy case who was evaluated as longstanding Parkinson's disease (PD) in alive. Neuropathological investigation showed "pure nigropathy" without Lewy and tau pathology, and genetic analyses using next-generation sequencing detected novel TUBA4A nonsence mutation. Subsequent physiological study added to strength the hypothesis that the variant is pathogenic one. Present case showed TUBA4A is not only responsible gene for amyotrophic lateral sclerosis/frontotemporal dementia but also PD associated pure nigropathy. Also we found minimal but significant tau pathology high possibly associated with long-term deep brain stimulation in subthalamic nucleus.

Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice.

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.

Effects of sporadic transthyretin amyloidosis frequently on the gallbladder and the correlation between amyloid deposition in the gallbladder and heart: A forensic autopsy-based histopathological evaluation.

The aim of the study is to evaluate the clinicopathological features of cholecystic ATTR deposition in patients with cardiac involvement, investigate the correlation of amyloid deposition severity in the gallbladder and the heart, and compare its prevalence in the gallbladder and other organs. Fifty patients with sporadic ATTR amyloidosis were identified. Of these, we evaluated 15 patients who underwent gallbladder sampling accurately. Among 10 patients (67%) with cholecystic deposition, six exhibited detectable deposition in the hematoxylin and eosin-stained specimens, and all of them displayed obstructive vascular deposition (VD). The severity of gall bladder VD was statistically correlated with that of cardiac VD and atrial interstitial deposition (ID). Additionally, all patients exhibiting cholecystic ID displayed severe ventricular and atrial IDs. In visceral organs excluding the heart, amyloid deposition was commonly observed in the lungs (93%), followed by the gastrointestinal tract (47%-80%), liver (60%) and periosteal tissues (53%). The involvement of the gallbladder was prevalent and comparable to that of the gastrointestinal tract. Moreover, the severity of cholecystic deposition was correlated with that of cardiac deposition. Therefore, pathologists should be aware that sporadic ATTR amyloidosis is a common condition and should not be overlooked.

Sex-dependent expression of prostatic markers and hormone receptors in cystic tumor of the atrioventricular node: A histopathological study of three cases.

We pathologically investigated three autopsy cases of cystic tumor of the atrioventricular node (CTAVN) with sudden death. Case 1 was a 36-year-old woman without any clinical history. Case 2 was a 76-year-old man with an implanted pacemaker for complete atrioventricular block. Case 3 was a 45-year-old man with a history of first-degree AV block and sinus bradycardia. Microscopically, all three cases showed the bilayered structure of tumor glands and corpora amylacea in the glandular lumens. Immunohistochemically, the inner cells of the tumor glands were positive for cytokeratin CAM5.2, CEA, EMA, olfactomedin-4 and alpha-methylacyl-coenzyme A racemase; the outer cells were positive for p63 and cytokeratin high molecular weight. In Case 1, androgen receptor and estrogen receptor were negative; progesterone receptor was focally positive in both the inner and outer cells. In Case 2, androgen receptor showed intermediate positivity in the inner cells; estrogen receptor and progesterone receptor were positive in the outer cells. Positive expression of both prostate-specific antigen and prostate-specific acid phosphate were found in the inner cells of both male cases. Because CTAVN cells exhibit different degrees of the prostatic phenotype depending on the patient's sex, we believe that CTAVN may originate from urogenital sinus tissue in some cases.

MAP1B-LC1 prevents autophagosome formation by linking syntaxin 17 to microtubules.

In fed cells, syntaxin 17 (Stx17) is associated with microtubules at the endoplasmic reticulum-mitochondria interface and promotes mitochondrial fission by determining the localization and function of the mitochondrial fission factor Drp1. Upon starvation, Stx17 dissociates from microtubules and Drp1, and binds to Atg14L, a subunit of the phosphatidylinositol 3-kinase complex, to facilitate phosphatidylinositol 3-phosphate production and thereby autophagosome formation, but the mechanism underlying this phenomenon remains unknown. Here we identify MAP1B-LC1 (microtubule-associated protein 1B-light chain 1) as a critical regulator of Stx17 function. Depletion of MAP1B-LC1 causes Stx17-dependent autophagosome accumulation even under nutrient-rich conditions, whereas its overexpression blocks starvation-induced autophagosome formation. MAP1B-LC1 links microtubules and Stx17 in fed cells, and starvation causes the dephosphorylation of MAP1B-LC1 at Thr217, allowing Stx17 to dissociate from MAP1B-LC1 and bind to Atg14L. Our results reveal the mechanism by which Stx17 changes its binding partners in response to nutrient status.

Autopsy of a multiple lobar hemorrhage case with amyloid-ß-related angiitis.

A 92-year-old man died of multiple lobar hemorrhage with amyloid-ß protein (Aß)-related angiitis (ABRA) with an unusual pathological appearance. Although he had shown relatively rapid progressive dementia, starting 1 year before death, there was no detailed clinical investigation, and no immunosuppressive or anticoagulant therapy, because of his advanced age. The autopsy showed two lobar hemorrhagic lesions in the right parietal lobe and temporal lobes. Microscopically, almost all the brain's blood vessels showed cerebral amyloid angiopathy with many foci of transmural vasculitis. Infiltrating cells were predominantly CD8-positive T-lymphocytes, but we observed no granulomatous inflammation with appearance of multinucleated giant cells. We found fibrinoid necrosis in some blood vessels and disruption of these blood vessels in the arachnoid space-cerebral cortex junction in the hemorrhagic lesion at the temporal lobe. We also observed an unusual, neutrophil-predominant, abscess-like vasculitis in the subarachnoid space; almost all such unusual vasculitides were located at a short distance from the two lobar hemorrhagic lesions. Serum anti-neutrophil cytoplasmic myeloperoxidase and proteinase-3 antibodies were negative, and the genotype of the apolipoprotein E (ApoE) gene (ApoE) was ε2/ε3. Although we did not observe some of ABRA's typical histopathological findings, transmural and vascular destructive inflammation with Aß deposition was consistent with ABRA. Vulnerability of blood vessels to fibrinoid necrosis might be associated with disruption of the relevant blood vessels, leading to lobar hemorrhage. ABRA exhibits various clinical and histopathological findings, depending on the patient's age, immune function status, treatment, and ApoE genotype. This is the first case and the oldest (92 years old) autopsy of ABRA associated with ApoE-ε2/ε3 genotype.

[Retrospective Study of Image Quality in Pediatric Cardiac Cine MRI].

In pediatric cardiac cine magnetic resonance imaging (MRI), it must overcome several challenges including the patient's size and higher heart rate. The aim of this study was to retrospectively evaluate imaging optimization. Cardiac cine MRI data from 24 patients was analyzed (age range: 3 months-10 years, average age: 5 years, male/female: 11/13, R-R interval: 450±4 to 819±7 ms). About 11 cases out of 24 have good image quality. For small variations in the R-R interval and higher temporal resolution improved image quality with significant difference (P<0.05, Mann-Whitney U-test). In this study, values of temporal resolution <30 ms yielded good image quality for heart rates over 100 bpm. On the other hands, the factors dependent on the patient like heart rate and ejection fraction have no significant difference. The segmentation of data acquisition is more significant than recording small fields of view or thin slices for infantile and pediatric cardiac cine MRI. Similar to adult cases, variations in heart rate affect the image quality; however, we demonstrated that using segmentation of data acquisition results in improved image quality.

Sudden unexpected death with rare compound heterozygous variants in PRICKLE1.

Progressive myoclonus epilepsy-ataxia syndrome (EPM5) is an autosomal recessive form of progressive myoclonus epilepsy that has been associated with a homozygous missense mutation in PRICKLE1. We report a 23-year-old male who died shortly after refractory convulsion and respiratory failure. Autopsy showed unilateral hippocampal malformation without significant neuronal loss or gliosis. Genetic analysis that targeted both epilepsy and cardiac disease using next-generation sequencing revealed two variants of PRICKLE1. Additional investigation showed that the patient's father (p.Asp760del) and mother (p.Asp201Asn) each had a mutation in this gene. The present case shows that EPM5 can also be caused by compound heterozygous mutations.

Minimal inflammatory foci of unknown etiology may be a tentative sign of early stage inherited cardiomyopathy.

Although relatively uncommon, pathologists may encounter minimal inflammatory foci in the absence of typical structural heart disease; however, the clinicopathological significance of minimal inflammatory foci, including correlation with sudden unexpected death, is unexplored. From 1072 serial autopsy subjects, cases with unexplained minimal inflammatory foci, the extent of which was under 1% of the whole examined ventricle, were extracted to exclude cases with borderline/focal myocarditis resulting from local, systemic infection, or autoimmune mechanisms. Immunohistochemistry and genetic analysis targeting viral genomes and heart disease-related genes using next generation sequencing were performed. We detected 10 cases with unexplained minimal inflammatory foci (five males, five females, aged 15-68 years). The cause and/or manner of death were sudden unexpected death (6 cases, 60%), sudden unexpected death with epilepsy (1 case, 10%), drowning in a hot bath (1 case, 10%), and suicide (2 cases, 20%). In none of these cases was pathogen-derived DNA or RNA detected. In 8 of the 10 cases (80%), 17 possible pathogenic genetic variants causative for arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy; DSP was the most frequently involved gene (three cases with two different variants), followed by LAMA4 and MYBPC3 (two cases, two variants for each gene), LDB3 (two cases, one variant), and the remaining 10 variants occurred in seven cases (DSC2, RYR2, SOS1, SCN5A, SGCD, LPL, PKP2, MYH11, GATA6, and DSG2). All mutations were missense mutations. DSP_Lys1581Glu and DSC2_p.Thr275Met were classified according to American College of Medical Genetics and Genomics consensus statement guidelines as pathogenic or likely pathogenic for arrhythmogenic cardiomyopathy in three patients (30%). The remaining 15 variants were classified as potentially pathogenic variants. Unexplained minimal inflammatory foci may be an early sign of inherited cardiomyopathy, and such cases might already have arrhythmogenic potential that can lead to sudden unexpected death. Detection of minimal inflammatory foci by careful pathological examination may indicate the value of conducting comprehensive genetic analysis, even if significant structural abnormalities are not evident.