Posterior cerebral artery involvement in unilateral moyamoya disease is exclusively ipsilateral and influenced by RNF213 mutation gene dose: The SUPRA Japan study: PCA involvement in unilateral moyamoya.

OBJECTIVES: The characteristics and clinical implications of posterior cerebral artery (PCA) involvement in unilateral moyamoya disease (U-MMD), such as laterality, frequency of the RNF213 p.R4810K mutation, and clinical outcomes, have not been well studied. POPULATION AND METHODS: We analyzed a cohort of 93 patients with U-MMD who participated in the SUPRA Japan study. Clinical characteristics and radiological examinations were collected from medical records. The presence of the p.R4810K mutation was determined using a TaqMan assay. The clinical outcome was assessed using the modified Rankin Scale (mRS). Univariate and multivariate logistic regression analyses were performed to assess the associations. RESULTS: Among the patients with U-MMD, PCA involvement was observed in 60.0 % (3/5) of patients with homozygous mutation, 11.3 % (7/62) of those with heterozygous mutation, and 3.8 % (1/26) of those with wild type, showing a significant linear trend (p < 0.001 for trend). PCA involvement was observed exclusively on the same side as the affected anterior circulation. Dyslipidemia and cerebral infarction at initial onset were independently associated with mRS ≥1. Hypertension was associated with mRS ≥1 and it was also linked to infarction at initial onset, suggesting a potential confounding effect. Although PCA involvement showed a trend for higher mRS, it was not statistically significant. CONCLUSIONS: Our findings indicate a gene dose effect of the p.R4810K mutation on PCA involvement, with the homozygous state showing the most significant effect. Both genetic and modifiable factors such as dyslipidemia may influence the progression of U-MMD.

[Presurgical Simulation for Brain Arteriovenous Malformation].

Surgical extirpation of brain arteriovenous malformations(AVMs)requires precise pre-surgical simulation. Utilizing image software, widely used with picture archiving and communication systems(PACS), surgeons can generate simulation images that precisely illustrate the proper feeders, passing arteries, and drainers. The crucial steps for creating informative simulation images include: (1)the free rotation of reconstructed 3D digital subtraction angiography(DSA)images; (2)removal of irrelevant arteries(the most important procedure); and(3)construction of stereo imagery of the "core images." This article presents a detailed description of these procedures.

Quantitative regional cerebral blood flow measurement using near-infrared spectroscopy and indocyanine green in patients undergoing superficial temporal to middle cerebral artery bypass for moyamoya disease: a novel method using a frequency filter.

Measuring regional cerebral blood flow (rCBF) after revascularization for moyamoya disease, as a type of ischemic cerebrovascular disease, is crucial. This study aims to validate our novel technology that combines near-infrared spectroscopy (NIRS) with a frequency filter to extract the arterial component. We measured rCBF before and after revascularization for moyamoya disease and at the end of the surgery using NIRO-200NX (Hamamatsu Photonics, Japan) and indocyanine green (ICG). rCBF was calculated using Fick's principle, change in arterial ICG concentrations, and maximum arterial ICG concentration. rCBF measured with NIRS (rCBF_N) was compared with pre- and postoperative rCBF measured with SPECT (rCBF_S). Thirty-four procedures were analyzed. rCBF_N increased from baseline to end of the surgery (mean difference (MD), 2.99 ml/min/100 g; 95% confidence interval (CI), 0.40-5.57 ml/min/100 g on the diseased side; MD, 4.94 ml/min/100 g; 95% CI, 2.35-7.52 ml/min/100 g on the non-diseased side). Similar trends were observed for rCBF_S (MD, 3.98 ml/min/100 g; 95% CI, 2.30-5.67 ml/min/100 g on the diseased side; MD, 2.77 ml/min/100 g; 95% CI, 1.09-4.45 ml/min/100 g on the non-diseased side). Intraclass correlations 3 (ICC3s) between rCBF_N and rCBF_S were weak on the diseased side (ICC3, 0.25; 95% CI, -0.03-0.5; p = 0.07) and the non-diseased side (ICC3, 0.24; 95% CI, -0.05-0.5; p = 0.08). rCBF measurements based on this novel method were weakly correlated with rCBF measurements with SPECT.

"Transcallosal" periventricular anastomosis in moyamoya disease: the fourth periventricular anastomosis and a potential predictor of hemorrhage.

OBJECTIVES: Choroidal anastomosis is a risk factor for hemorrhage in moyamoya disease. One variant of choroidal anastomosis, "transcallosal anastomosis," originates from the medial posterior choroidal artery, and penetrates the corpus callosum to reconstruct the pericallosal artery. We aimed to investigate the prevalence and the bleeding rate of transcallosal anastomosis using sliding thin-slab maximum intensity projection reformatted from magnetic resonance angiography (MRA). MATERIALS AND METHODS: This study included 222 patients. We defined transcallosal anastomosis grades (0-2) and the stenosis of the anterior (ACA, 0-2), middle (MCA, 1-3), and posterior cerebral artery (PCA, 0-2) by MRA scores, independently by two coauthors. RESULTS: Grade-2 transcallosal anastomosis was detected in 21 patients (9.5 %). There were no correlations of the incidence of transcallosal anastomosis with previous bypass surgery (P = 0.23). Multivariate analysis revealed a significantly higher incidence in hemorrhagic onset and younger age (odds ratio [OR] 3.77, and 0.97). Transcallosal anastomosis had statistically significant correlation with ACA and PCA scores (P = 0.01 and 0.03), but not with MCA scores (P = 0.1). In multivariate analysis, ACA scores 1 and 2 were significantly higher (OR, 15.44 and 11.17), and PCA score 1 was also higher (OR, 3.07), but PCA score 2 was not. Interrater agreement for judgment of transcallosal anastomosis grade was strong (κ = 0.89). Two patients with Grade-2 transcallosal anastomosis had late hemorrhage in the corpus callosum (bleeding rate: 2.5 % per year). CONCLUSIONS: Transcallosal anastomosis may be associated with both advanced ACA and moderate PCA stenosis, and cause hemorrhage at the corpus callosum.

Characterization of Healthcare-Associated and Community-Associated Clostridioides difficile Infections among Adults, Canada, 2015-2019.

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015-2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015-2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p<0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.

A multicenter prospective registry of Borden type I dural arteriovenous fistula: results of a 3-year follow-up study.

PURPOSE: Although intracranial dural arteriovenous fistula (DAVF) without retrograde leptomeningeal venous drainage (Borden type I) is reported to have a benign nature, no study has prospectively determined its clinical course. Here, we report a 3-year prospective observational study of Borden type I DAVF. METHODS: From April 2013 to March 2016, consecutive patients with DAVF were screened at 13 study institutions. We collected data on baseline characteristics, clinical symptoms, angiography, and neuroimaging. Patients with Borden type I DAVF received conservative care while palliative intervention was considered when the neurological symptoms were intolerable, and were followed at 6, 12, 24, and 36 months after inclusion. RESULTS: During the study period, 110 patients with intracranial DAVF were screened and 28 patients with Borden type I DAVF were prospectively followed. None of the patients had conversion to higher type of Borden classification or intracranial hemorrhage during follow-up. Five patients showed spontaneous improvement or disappearance of neurological symptoms (5/28, 17.9%), and 5 patients showed a spontaneous decrease or disappearance of shunt flow on imaging during follow-up (5/28, 17.9%). Stenosis or occlusion of the draining sinuses on initial angiography was significantly associated with shunt flow reduction during follow-up (80.0% vs 21.7%, p = 0.02). CONCLUSION: In this 3-year prospective study, patients with Borden type I DAVF showed benign clinical course; none of these patients experienced conversion to higher type of Borden classification or intracranial hemorrhage. The restrictive changes of the draining sinuses at initial diagnosis might be an imaging biomarker for future shunt flow reduction.

[Complications of Superficial Temporal Artery-Middle Cerebral Artery Anastomosis and Their Prevention: Technical Note].

Complications of the superficial temporal artery-middle cerebral artery(STA-MCA)bypass procedure include skin necrosis, MCA vessel wall injury, and thrombotic occlusion of the anastomotic site. First, deprivation of the STA per se induces ischemia of the skin flap. Skin incisions must be designed carefully to avoid isolating some areas from the blood supply. Secondly, the MCA walls can be extremely thin in moyamoya disease; therefore, the fragile vascular walls must be manipulated gently. The MCA walls should not be grasped directly by forceps. Thirdly, intraluminal thrombi can develop after the completion of the anastomosis. Heparin should be administered intravenously as soon as possible when intraluminal thrombi are detected, followed by aspirin loading via a nasogastric tube. Platelet(white)thrombi are fragile and easily disrupted with mechanical vibration. It is essential to treat them before they develop into a large, firm fibrin thrombus that completely occludes the anastomotic site, which would require suture cutting and surgical thrombus removal.

Pregnancy-associated hemorrhagic stroke: A nationwide survey in Japan.

AIM: The number of maternal deaths due to pregnancy-associated hemorrhagic stroke has not decreased despite a gradual decrease of maternal death in Japan. This study aimed to clarify the risk factors of hypertensive disorders of pregnancy-associated hemorrhagic stroke. METHODS: This retrospective study analyzed pregnancy-associated hemorrhagic stroke patients with hypertensive disorders of pregnancy between 2013 and 2017 among 407 Japanese maternal and perinatal centers. Patients were divided into good or poor outcome groups and their maternal backgrounds and neonatal prognoses were compared. RESULTS: We analyzed 61 cases, including 41 survival and 20 death cases, obtained from a secondary survey. Among the 61 hemorrhagic stroke cases, 62% were related to hypertensive disorders. Hypertensive disorders of pregnancy were observed in 75% of death cases. Use of MgSO4 or antihypertensive medication did not differ between the poor and good outcomes groups. In cases with antepartum onset of hypertensive disorders of pregnancy, outcomes were poor in 12 and good in 6 cases. Nine patients with poor outcomes and one with a good outcome had hypertension at the outpatient department without systemic evaluation (p = 0.043). Six poor outcomes patients and one good outcome spent more than 1 day from diagnosis at an outpatient clinic. Neurosurgery was performed in 11 poor outcome patients. CONCLUSION: Pregnant women who present with a hypertensive disorder at an outpatient clinic probably need to undergo blood tests and careful observation. Delayed systemic evaluation and intensive care for only a few days may result in the development of hemorrhage.

Clinical and laboratory interpretation of mitochondrial mRNA variants.

Interpretation of mitochondrial protein-encoding (mt-mRNA) variants has been challenging due to mitochondrial characteristics that have not been addressed by American College of Medical Genetics and Genomics guidelines. We developed criteria for the interpretation of mt-mRNA variants via literature review of reported variants, tested and refined these criteria by using our new cases, followed by interpreting 421 novel variants in our clinical database using these verified criteria. A total of 32 of 56 previously reported pathogenic (P) variants had convincing evidence for pathogenicity. These variants are either null variants, well-known disease-causing variants, or have robust functional data or strong phenotypic correlation with heteroplasmy levels. Based on our criteria, 65.7% (730/1,111) of variants of unknown significance (VUS) were reclassified as benign (B) or likely benign (LB), and one variant was scored as likely pathogenic (LP). Furthermore, using our criteria we classified 2, 12, and 23 as P, LP, and LB, respectively, among 421 novel variants. The remaining stayed as VUS (91.2%). Appropriate interpretation of mt-mRNA variants is the basis for clinical diagnosis and genetic counseling. Mutation type, heteroplasmy levels in different tissues of the probands and matrilineal relatives, in silico predictions, population data, as well as functional studies are key points for pathogenicity assessments.

Correction: Interpretation of mitochondrial tRNA variants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Interpretation of mitochondrial tRNA variants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interpretation of mitochondrial tRNA variants.

PURPOSE: To develop criteria to interpret mitochondrial transfer RNA (mt-tRNA) variants based on unique characteristics of mitochondrial genetics and conserved structural/functional properties of tRNA. METHODS: We developed rules on a set of established pathogenic/benign variants by examining heteroplasmy correlations with phenotype, tissue distribution, family members, and among unrelated families from published literature. We validated these deduced rules using our new cases and applied them to classify novel variants. RESULTS: Evaluation of previously reported pathogenic variants found that 80.6% had sufficient evidence to support phenotypic correlation with heteroplasmy levels among and within families. The remaining variants were downgraded due to the lack of similar evidence. Application of the verified criteria resulted in rescoring 80.8% of reported variants of uncertain significance (VUS) to benign and likely benign. Among 97 novel variants, none met pathogenic criteria. A large proportion of novel variants (84.5%) remained as VUS, while only 10.3% were likely pathogenic. Detection of these novel variants in additional individuals would facilitate their classification. CONCLUSION: Proper interpretation of mt-tRNA variants is crucial for accurate clinical diagnosis and genetic counseling. Correlations with tissue distribution, heteroplasmy levels, predicted perturbations to tRNA structure, and phenotypes provide important evidence for determining the clinical significance of mt-tRNA variants.

Intracranial arterial stenosis associated with Hashimoto's disease: angiographic features and clinical outcomes.

BACKGROUND: Hashimoto's disease has reportedly been associated with stroke; however, cerebrovascular morphology and clinical course remain poorly documented. The present study aimed to determine the angiographic features and clinical outcomes of intracranial arterial stenosis (IAS) associated with Hashimoto's disease in a retrospective cohort. METHODS: Overall, 107 adult patients with IAS were screened for anti-thyroid antibodies; of these, 26 patients tested positive. The 42 affected hemispheres were classified into subgroups according to the steno-occlusion site and the development of abnormal collateral (moyamoya) vessels. These subgroups were dichotomized into moyamoya vessels positive (MM type) and negative (non-MM type). The initial presentation, IAS progression, and vascular events during the follow-up period were compared. RESULTS: The following sites of stenosis were identified: the bifurcation of the internal carotid artery in 11 (26.2%), M1 or A1 in 29 (69.0%), and more distal (M2-M4/A2-A4) in 2 (4.8%) hemispheres. Further, 17 hemispheres were categorized into the MM type and 25 were classified into the non-MM type. During the follow-up period (mean 2.5 years), IAS progression was identified in 8 (32%) hemispheres of the non-MM type and 0 (0%) hemispheres of the MM type (p = 0.041). Ischemic attacks occurred in 5 (20.0%) hemispheres of the non-MM type (4.6%/year) and 0 hemispheres of the MM type (p = 0.08). Further, 4 (23.5%) hemispheres of the MM type experienced intracerebral hemorrhage, whereas none of the non-MM type hemorrhaged (p = 0.012). CONCLUSIONS: Hashimoto's disease-associated IAS exhibits various angiographic morphologies, resulting in different clinical presentations. Screening for anti-thyroid antibodies and careful management based on vascular morphology appears important in adults with IAS.

Impact of a risk-stratified thromboprophylaxis protocol on the incidence of postoperative venous thromboembolism and bleeding.

Efforts to reduce postoperative venous thromboembolism are challenging due to heterogeneity in thromboprophylaxis practice. As a result, a 'one-size-fits-all' approach that accounts for surgery-specific risk, but fails to account for patient-level variation, is often adopted by healthcare networks. Updated clinical practice guidelines have advocated an individualised risk-stratified approach that balances the risk:benefit ratio associated with thromboprophylaxis; however, there are limited data confirming effectiveness of these recommendations on the incidence of postoperative venous thromboembolism and bleeding. We developed the surgical-thrombo-embolism-prevention protocol, a novel risk-stratified algorithm that classified patients into low-, intermediate-, and high-risk profiles according to surgical procedure and patient baseline medical risk. Expert-endorsed risk-specific thromboprophylaxis strategies were then applied. A staged quality improvement program was developed to implement the protocol. We postulated that compliance with the protocol would reduce postoperative venous thromboembolism rates without increasing the incidence of postoperative bleeding. Between June 2013 and March 2018, we evaluated the efficacy, safety and sustainability of this risk-stratified approach in 24,953 surgical admissions at a dedicated cancer centre. By final implementation, program compliance was 91%. Postoperative venous thromboembolism rates reduced from 3.1 per 1000 surgical admissions to 0.6 per 1000 surgical admissions (relative risk reduction 79%; p < 0.005). Postoperative bleeding rates also declined from 10.0 per 1000 surgical admissions to 6.3 per 1000 surgical admissions (relative risk reduction 37%; p = 0.02). Sustained improvement was evident more than 3 years after implementation. Implementation of the surgical-thrombo-embolism-prevention protocol significantly reduced the incidence of postoperative venous thromboembolism supporting its validation at other institutions.

Difference in periventricular anastomosis in child and adult moyamoya disease: a vascular morphology study.

BACKGROUNDS: Periventricular anastomosis (PA), which is a novel term for extended collateral vessels in moyamoya disease (MMD), is reportedly associated with a high risk of intracranial hemorrhage in adult patients. The present study aimed to clarify the similarities and the differences in the development of PA between three MMD groups, classified by age at the time of diagnosis and clinical phenotype. METHODS: This study included 232 hemispheres of 132 patients with MMD who underwent surgical revascularization. The subjects were classified into child ischemic (CI) group, adult ischemic (AI) group, and adult hemorrhagic (AH) group. We evaluated the lenticulostriate (LSA), thalamic (THA), choroidal (ChA), anterior choroidal (AChA), and posterior choroidal (PChA) anastomosis as well as the posterior cerebral artery (PCA) involvement. The PA scores and the sums of each grade of LSA, THA, and ChA anastomosis were also calculated in all of the cases. RESULTS: In a multiple comparison test, the PA scores (P < 0.01), LSA (P < 0.01), and ChA anastomosis (P = 0.013) were more prominent in the CI than in the AI group. The PA scores (P < 0.01) and LSA (P = 0.011), ChA (P < 0.01), AChA (P < 0.01), and PChA anastomosis (P = 0.016) were more prominent in the AH group than in the AI group. The CI and AH groups showed similar characteristics except for PCA involvement. After multivariate adjustments using the AI group as a reference group, the PA scores and the positive rates of LSA and ChA anastomosis remained significantly higher in the CI and AH groups. CONCLUSION: The patterns of PA development in the CI and AH groups were similar in that they were more prominent than in the AI group. These findings may contribute to a better understanding of the progression of ischemic and hemorrhagic MMD.

Prevalence of RNF213 p.R4810K Variant in Early-Onset Stroke With Intracranial Arterial Stenosis.

Background and Purpose- The ring finger protein 213 gene ( RNF213) is a susceptibility gene for moyamoya disease and large-artery ischemic stroke in East Asia. We examined the prevalence and correlates of the RNF213 p.R4810K variant in patients with early-onset ischemic stroke in a Japanese single-center cohort. Methods- We analyzed 70 early-onset stroke patients with intracranial arterial stenosis who developed a noncardioembolic stroke or transient ischemic attack from 20 to 60 years of age. Patients with moyamoya disease were excluded. Results- The RNF213 p.R4810K variant was found in 17 patients (24%), and more often in women than men (38% versus 16%, odds ratio 3.3; 95% CI, 1.1-10.2, P=0.04). The variant was identified in 35% of patients with stenosis in the M1 segment of the middle cerebral artery or the A1 segment of the anterior cerebral artery (odds ratio, 25.0; 95% CI, 1.4-438; P<0.01) but in only one patient (9%) with intracranial posterior circulation stenosis. Conventional atherosclerotic risk factors did not differ between variant carriers and noncarriers. Conclusions- The RNF213 p.R4810K variant is common in early-onset ischemic stroke with anterior circulation stenosis in Japan. Further investigation of the RNF213 gene will provide new insights into pathogenetic mechanisms of early-onset stroke.

Detrimental Effect of Chronic Hypertension on Leptomeningeal Collateral Flow in Acute Ischemic Stroke.

Background and Purpose- We aimed to evaluate the effect of chronic hypertension on acute leptomeningeal collateral flow in patients with large-vessel ischemic stroke using digital subtraction angiography, which is the gold standard for the assessment of collateral circulation. Methods- Of the consecutive ischemic stroke patients from October 2011 to December 2017 seen in our institution, patients with acute occlusion of the M1 segment of the middle cerebral artery confirmed on initial digital subtraction angiography were enrolled. Chronic hypertension was defined as its documentation before the index stroke or as the administration of antihypertensive medications before onset. Angiographic leptomeningeal collateral flow was evaluated according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology Collateral Flow Grading System and dichotomized the findings into excellent (grade 3-4) or poor (grade 0-2) collateral status for analysis. Results- Of the 3759 consecutive ischemic stroke patients, 100 patients were analyzed. Thirty-nine patients (39%) had poor collateral status. Patients with poor collateral status were older, more frequently male, and had chronic hypertension more frequently, shorter time from onset to angiography, and higher admission systolic blood pressure than those with excellent collateral status. Multivariable logistic analysis with prespecified covariates showed a significantly positive association between chronic hypertension and poor collateral status (odds ratio, 2.80; 95% CI, 1.08-7.70; P=0.034). This association was independent of admission systolic blood pressure. The proportion of patients with poor collateral status increased in a stepwise manner in patients without chronic hypertension, hypertensive patients with premorbid antihypertensive medications, and hypertensive patients without antihypertensive medications ( P for trend <0.001). Conclusions- Our data suggest that chronic hypertension has a detrimental effect on acute leptomeningeal collateral flow in patients with cerebral large-vessel occlusion. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02251665.

Restoration of periventricular vasculature after direct bypass for moyamoya disease: intra-individual comparison.

BACKGROUND: While periventricular anastomosis, a unique abnormal vasculature in moyamoya disease, has been studied in relation to intracranial hemorrhage, no study has addressed its change after bypass surgery. The authors sought to test whether direct bypass surgery could restore normal periventricular vasculature. METHODS: Patients who had undergone direct bypass surgery for moyamoya disease at a single institution were eligible for the study. Baseline, postoperative, and follow-up magnetic resonance angiography (MRA) scans were scheduled before surgery, after the first surgery, and 3 to 6 months after contralateral second surgery, respectively. Sliding-thin-slab maximum-intensity-projection coronal MRA images of periventricular anastomoses were scored according to the three subtypes (lenticulostriate, thalamic, and choroidal anastomosis). Baseline and postoperative MRA images were compared to obtain a matched comparison of score changes in the surgical and nonsurgical hemispheres within individuals (intra-individual comparison). RESULTS: Of 110 patients, 42 were identified for intra-individual comparisons. The periventricular anastomosis score decreased significantly in the surgical hemispheres (median, 2 versus 1; p < 0.001), whereas the score remained unchanged in the nonsurgical hemispheres (median, 2 versus 2; p = 0.57); the score change varied significantly between the surgical and nonsurgical hemispheres (p < 0.001). Of the 104 periventricular-anastomosis-positive hemispheres undergoing surgery, 47 (45.2%) were assessed as negative in the follow-up MRA. Among the subtypes, choroidal anastomosis was most likely to be assessed as negative (79.7% of positive hemispheres). CONCLUSIONS: Periventricular vasculature can be restored after direct bypass. The likelihood of correction of choroidal anastomosis is a subject requiring further studies.

Development of Hemorrhage-prone Anastomoses in Asymptomatic Moyamoya Disease-A Comparative Study with Japan Adult Moyamoya Trial.

OBJECTIVE: Present study was aimed to precisely evaluate the angio-architectures in patients with asymptomatic moyamoya disease (MMD) by comparing with those with hemorrhagic stroke. METHODS: This study used the data set of cerebral angiography in Asymptomatic Moyamoya Registry (AMORE) Study and Japan Adult Moyamoya (JAM) Trial at enrollment. The development of 3 subtypes of collateral vessels, including lenticulostriate, thalamic, and choroidal anastomosis, was evaluated on cerebral angiography. Suzuki's angiographical stage and posterior cerebral artery (PCA) involvement were also assessed. These findings were compared between asymptomatic (AMORE) and hemorrhagic (JAM) groups. RESULTS: This study included 55 hemispheres of 35 patients in asymptomatic group and 75 hemispheres of 75 patients in hemorrhagic group. In asymptomatic group, thalamic anastomosis was less developed than in hemorrhagic group (P = .011), but there were no significant differences in the development of lenticulostriate and choroidal anastomosis between the 2 groups (P = .077 and P = .26, respectively). Suzuki's stage was more progressed and the prevalence of PCA involvement was significantly higher in hemorrhagic group than in asymptomatic group (P = .0033 and P = .016, respectively). CONCLUSIONS: This study reveals no significant differences in the development of choroidal anastomoses between asymptomatic and hemorrhagic-onset MMD. On the other hand, disease stage and PCA involvement were less advanced in asymptomatic MMD than in hemorrhagic-onset MMD. These findings strongly suggest a certain subgroup of asymptomatic patients with MMD is at potential risk for hemorrhagic stroke.

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.