Cardiomyopathy in an Adolescent with McLeod Syndrome: Searching Beyond the Routine Assessment.

Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome

Dilative cardiomyopathy displaying double trouble etiology: Myocarditis and Mcleod syndrome?

Introduction: McLeod syndrome (MLS) is a rare X-linked recessive disorder affecting multiple systems. Herein, we present the clinical symptoms, laboratory diagnostic results, and genetic characteristics of a patient with MLS caused by a novel c.459_460insC variation in the XK gene. Case Presentation: A 58-year-old male Chinese patient presented with neurological symptoms, seeking belated medical attention at the hospital. Numerous laboratory tests indicated a high likelihood of MLS, featuring chronic granulomatosis and neuroacanthocytosis. The patient’s blood samples were sent to the Blood Center of Zhejiang Province, China, for further analysis. Sequencing analysis revealed a novel hemizygous c.459_460insC variation in exon 2 of the XK gene. Therefore, we identified a patient with MLS possessing a novel genetic variation (GenBank Accession No. OQ473658). Conclusion: Our findings elucidate a novel c.459_460insC variation associated with MLS, resulting in a frameshift and premature stop codon (p.Leu154Profs*45). The clinical manifestations, laboratory examination, and XK gene analysis in this case will aid in diagnosing MLS in future patients.

McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.

WITHDRAWN: Novel Xp21.1 deletion associated with unusual features in a large McLeod syndrome kindred

McLeod syndrome, encoded by the gene XK, is a rare and progressive disease that shares important similarities with Huntington disease but has widely varied neurologic, neuromuscular, and cardiologic manifestations. Patients with McLeod syndrome have a distinct hematologic presentation with specific transfusion requirements. Because of its X-linked location, loss of the XK gene or pathogenic variants in this gene are principally associated with the McLeod blood group phenotype in male patients. The clinical manifestation of McLeod syndrome results from allelic variants of the XK gene or as part of a contiguous gene deletion syndrome involving XK and adjacent genes, including those for chronic granulomatous disease, Duchenne muscular dystrophy, and retinitis pigmentosa. McLeod syndrome typically manifests as neurologic and cardiologic symptoms that evolve in individuals beginning at approximately 40 years of age. Diagnosis of McLeod syndrome encompasses a number of specialties, including neurology and transfusion medicine. However, information regarding the molecular basis of the syndrome is incomplete, and clinical information is difficult to find. The International Society of Blood Transfusion has recently compiled and curated a listing of XK alleles associated with the McLeod phenotype. Of note, McLeod syndrome caused by structural variants as well as those cases diagnosed as part of a contiguous gene deletion syndrome were previously classified under a singular allele designation. This review discusses the clinical manifestations and molecular basis of McLeod syndrome and provides a comprehensive listing of alleles with involvement in the syndrome published to date. This review highlights the clinical diversity of McLeod syndrome and discusses the development of molecular tools to elucidate genetic causes of disease. A more precise and systematic genetic classification is the first step toward correlating and understanding the diverse phenotypic manifestations of McLeod syndrome and may guide clinical treatment of patients and support for affected and carrier family members. This review provides a knowledge base for neurologists, hematologists, and clinical geneticists on this rare and debilitating disease.

Background Dilated cardiomyopathy (DCM) is defined as the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or significant coronary heart disease. The diagnostic work-up for patients with DCM includes cardiac imaging and cardiac magnetic resonance (CMR) is the gold-standard method for detailed morphological caracterization. Although there is a limited diagnostic role for radionuclide imaging in DCM, myocardial perfusion single-photon emission computed tomography (SPECT) is commonly performed to exclude ischemic etiology. Purpose The aim of this study was to compare the findings of myocardial perfusion SPECT (MPS) and CMR in non-ischemic DCM. Methods We included 35 patients that had been diagnosed with DCM and underwent MPS and CMR for etiological diagnosis in our institution between January 2020 and December 2023. We evaluated left ventricular motility, thickening and perfusion defects in MPS, the presence of late gadolinium enhancement (LGE) in CMR and the values of left ventricular ejection fraction (LVEF), end-systolic and end-diastolic volumes in both exams. Results 24 patients were male (69%), with a median age of 65,9 ± 11,8 years. Ischemic etiology for DCM was excluded based on CMR in 25 patients, 6 patients were diagnosed with alcoholic DCM, 3 patients with familial DCM and 1 with chemotherapy-induced cardiotoxicity. In 23 patients (66%), MPS showed diffuse motility and thickening abnormalities. In MPS, 34 patients (97%) had perfusion defects and 17 (50%) had reversible defects. 14 patients (41%) had only one perfusion defect while 20 (59%) patients had 2 or more. The septal wall was the most affected (24 patients - 69%). In 24 patients (69%), CMR showed LGE suggestive of fibrosis and in 88% of these patients the fibrosis was seen in the septal wall. A moderate correlation (0,508) was found between LVEF in MPS and CMR. 8 patients (33%) presented LGE in CMR and had non-reversible perfusion defects in the same myocardial wall in MPS while 12 patients (50%) presented with reversible perfusion defects in the same LGE location. Of the 12 patients that presented with LGE in CMR and reversible defects in MPS, 7 (58%) had total or parcial but significant reversibility and 5 (42%) had partial but non-significant reversibility. Conclusions The presence of perfusion defects is common in non-ischemic DCM. In most patients the perfusion defects (MPS) and fibrosis (CMR) were seen in the septal wall. Reversible defects may be explained by microvascular dysfunction known to play a role in DCM pathogenesis. These findings should be taken into account in the interpretation of MPS results in the etiological diagnosis of DCM.

Risk stratification in dilated cardiomyopathy (DCM) is imprecise, relying largely on echocardiographic left ventricular ejection fraction (LVEF) and severity of heart failure symptoms. Adverse cardiovascular events are increased by the presence of myocardial scarring. Late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging is the gold standard for identifying myocardial scars. We examined the association between LGE on CMR imaging and adverse clinical outcomes during long-term follow-up of Asian patients with DCM. Consecutive patients with DCM undergoing CMR imaging at a single Asian academic medical centre between 2005 and 2015 were recruited. Clinical outcomes were tracked using comprehensive electronic medical records and mortality was determined by cross-linkages with national registries. Presence and distribution of LGE on CMR imaging were determined by investigators blinded to patient outcomes. Primary endpoint was a composite of heart failure hospitalisations, appropriate implantable cardioverter-defibrillator shocks and cardiovascular mortality. Of 86 patients, 64.0% had LGE (80.2% male; mean LVEF 30.1% ± 12.7%). Mid-wall fibrosis (71.7%) was the most common pattern of LGE distribution. Over a mean follow-up period of 4.9 ± 3.2 years, 19 (34.5%) patients with LGE reached the composite endpoint compared to 4 (12.9%) patients without LGE (p = 0.01). Presence of LGE, but not echocardiographic LVEF, independently predicted the primary endpoint (hazard ratio 4.15 [95% confidence interval 1.28-13.50]; p = 0.02). LGE presence independently predicted adverse clinical events in Asian patients with DCM. Routine use of CMR imaging to characterise the myocardial substrate is recommended for enhanced risk stratification and should strongly influence clinical management.

Background Desmoplakin-related cardiomyopathy (DSP-CM) can present with either dilated or nondilated left ventricular (LV) phenotypes and is characterized by a high arrhythmic burden, placing patients at significant risk of sudden cardiac death. Although previous studies have highlighted the diagnostic value of ring-like late gadolinium enhancement (LGE) patterns on cardiac magnetic resonance (CMR) in DSP-CM, CMR is not always readily available. Aim of the study: This study aimed to evaluate whether echocardiographic and electrocardiographic (ECG) parameters could help identify DSP-CM in clinical settings where CMR may be less accessible. Methods We prospectively enrolled all consecutive patients diagnosed with DSP-CM harboring pathogenic or likely pathogenic DSP variants evaluated at our center. A control group consisted of age-matched patients with dilated cardiomyopathy (DCM) of other various etiologies. All participants underwent detailed ECG and echocardiographic evaluations. ECG tracings were analyzed using the EP Calipers application to assess QRS duration, QRS fragmentation (pattern classified as RSR’, RnS, Rn, RSn, RSR’S’ – Figure 1) and dispersion calculated as the difference between maximal and minimal QRS duration in the standard 12-lead ECG, and conduction defects. Results A total of 18 patients with DSP-CM and 50 with DCM (15 TTN, 4 LMNA, 2 DMD, and 27 negative genetic tests via next-generation sequencing) were included and matched for age (39.4±12.1 in DSP-CM vs. 39.1±14.2 in DCM; p=NS). Notably, DSP-CM was more common among women (66% vs. 38%; p=0.03). Compared to DCM, DSP-CM patients exhibited lower LV end-diastolic volumes, higher LVEF, and a nondilated right ventricle with similar systolic function (see Table 1). However, ECG changes were more pronounced in DSP-CM: wider QRS intervals, higher QRS dispersion, more frequent left axis deviation, and a higher incidence of low QRS voltage. Using receiver operating characteristic (ROC) analysis, we derived predictive cutoffs for each significant parameter (QRS duration >103.5 ms, QRS dispersion >9.5 ms, LVEF >37.5%, LV end-diastolic volume <67 mL, presence of RnS or Rn pattern, left anterior fascicular block, and low voltage). Each parameter was assigned 1 point to build a predictive score. This score demonstrated an area under the curve (AUC) of 0.894, and a cutoff of ≥3 points predicted the presence of a DSP variant with 88.9% sensitivity and 74% specificity. Conclusions Patients with DSP-CM typically present with smaller, less dysfunctional LV relative to other forms of DCM; however, their ECG abnormalities are more pronounced. In clinical scenarios where CMR may be limited, this combination of echocardiographic and ECG findings can serve as a valuable tool to prompt further genetic investigation for DSP gene variants.Figure 1.QRS fragmentation patterns Table 1

Purpose: The present study was aimed to assess the prevalence, location, and patterns of late gadolinium enhancement (LGE) in idiopathic dilated cardiomyopathy (DCM) on cardiac magnetic resonance (CMR) imaging and to correlate the left ventricular (LV) functions obtained by cine CMR with the values obtained by echocardiography. Methods: This was a prospective single-center study covering a 2-year study period. The authors studied the prevalence, location, and patterns of LGE in idiopathic DCM on CMR and correlated the ventricular functions obtained by CMR with those obtained by echocardiography. Results: LGE was seen in 18/40 (45%) and was absent in 22/40 (55%) of patients. With regard to location, septal enhancement was the most common, seen in 8 (20%) followed by free-wall enhancement in 4 (10%) and a concomitant septal and free-wall enhancement in 6 (15%). In terms of pattern, midwall enhancement was observed in 10 (25%), subepicardial in 2 (5%), subendocardial in 4 (10%), and focal and transmural enhancement in 1 each. The maximum correlation for calculation of LV ejection fraction (EF) was obtained between CMR and two-dimensional echocardiography (P = 0.442). Conclusion: CMR is an accurate tool to determine the phenotype of DCM by identifying the presence, location, and pattern of LGE which has a prognostic value and is used to guide management. CMR is the most accurate assessment tool for the calculation of EF and other volumetric variables in DCM.

78-Year-Old Woman With Intermittent Chest Pain and Palpitations

This study investigated the discriminability of quantitative radiomics features extracted from cardiac magnetic resonance (CMR) images for hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and healthy (NOR) patients. The data of two hundred and eighty-three patients with HCM (n = 48) or DCM (n = 52) and NOR (n = 123) were extracted from two publicly available datasets. Ten feature selection methods were first performed on twenty-one different sets of radiomics features extracted from the left ventricle, right ventricle, and myocardium segmented from CMR images in the end-diastolic frame, end-systolic frame, and a combination of both; then, nine classical machine learning methods were trained with the selected radiomics features to distinguish HCM, DCM, and NOR. Ninety classification models were constructed based on combinations of the ten feature selection methods and nine classifiers. The classification models were evaluated, and the optimal model was selected. The diagnostic performance of the selected model was also compared to that of state-of-the-art methods. The random forest minimum redundancy maximum relevance model with features based on LeastAxisLength, Maximum2DDiameterSlice, Median, MinorAxisLength, Sphericity, VoxelVolume, Kurtosis, Flatness, and Skewness was the highest performing model, achieving 91.2% classification accuracy. The cross-validated areas under the curve on the test dataset were 0.938, 0.966, and 0.936 for NOR, DCM, and HCM, respectively. Furthermore, compared with those of the state-of-the-art methods, the sensitivity and accuracy of this model were greatly improved. A predictive model was proposed based on CMR radiomics features for classifying HCM, DCM, and NOR patients. The model had good discriminability. • The first-order features and the features extracted from the LOG-filtered images have potential in distinguishing HCM patients from DCM patients. • The features extracted from the RV play little role in distinguishing DCM from HCM. • The VoxelVolume of the myocardium in the ED frame is important in the recognition of DCM.

Objective: To compare the differences in cardiac magnetic resonance (CMR) characteristics between dilated cardiomyopathy (DCM) patients accompanied by left ventricular hypertrabeculation and those with isolated DCM, and to investigate the impact of left ventricular hypertrabeculation on the prognosis of DCM patients. Methods: This single-center retrospective cohort study enrolled DCM patients who were admitted to Peking Union Medical College Hospital from November 2016 to March 2025. Basic clinical data and CMR parameters of the patients were collected. According to the results of echocardiography, the patients were divided into the isolated DCM group and the DCM with left ventricular hypertrabeculation group. Patients were followed up through outpatient visits or telephone calls. The composite endpoint consisting of cardiovascular death, heart failure hospitalization, and malignant arrhythmia events (ventricular fibrillation, sustained ventricular tachycardia) was used as the outcome event. Univariate and multivariate Cox proportional hazards regression models were used to analyze the risk factors affecting the prognosis of DCM patients. Survival analysis was performed using Kaplan-Meier curves, and the log-rank test was used to compare the differences in the incidence of outcome events between groups. Subgroup analysis was conducted according to the range of left ventricular late gadolinium enhancement (LGE) (≥7.5% and <7.5%). Results: A total of 114 DCM patients were enrolled, including 65 in the isolated DCM group and 49 in the DCM with left ventricular hypertrabeculation group. In the isolated DCM group, the patients had an age of (44±16) years, with 44 males (68%); in the DCM with left ventricular hypertrabeculation group, the patients had an age of (40±17) years, with 32 males (65%). Regarding echocardiographic parameters, there were no statistically significant differences in left ventricular ejection fraction ((34±8)% vs. (32±11)%) and left ventricular end-diastolic diameter ((65±8) mm vs. (66±8) mm) between the isolated DCM group and the DCM with left ventricular hypertrabeculation group (both P>0.05). In terms of CMR characteristics, the left ventricular end-diastolic volume (126 (105, 158) ml vs. 146 (114, 185) ml), left ventricular global longitudinal strain ((-8.15±3.17)% vs. (-8.56±3.76)%), and left ventricular LGE extent (11.4 (4.3, 26.6)% vs. 12.3 (5.4, 20.2)%) in the isolated DCM group were lower than those in the DCM with left ventricular hypertrabeculation group, while the left ventricular ejection fraction was higher than that in the DCM with left ventricular hypertrabeculation group (29 (23, 35)% vs. 27 (20, 39)%). However, there were no statistically significant differences in the above CMR parameters between the two groups (all P>0.05). For prognosis, during a follow-up of 368 (146, 652) days, 25 patients (22%) experienced outcome events, including 4 cases (4%) of cardiovascular death, 22 cases (19%) of heart failure hospitalization, and 1 case (1%) of malignant arrhythmia. Cox regression analysis showed that left ventricular hypertrabeculation was not associated with the occurrence of outcome events in DCM patients (HR=0.682, 95%CI 0.301-1.540, P=0.358), while left ventricular LGE extent was associated with the prognosis of DCM patients (HR=6.589, 95%CI 1.064-40.794, P=0.043). Kaplan-Meier curves showed that there was no statistically significant difference in the cumulative incidence of outcome events between the isolated DCM group and the DCM with left ventricular hypertrabeculation group (log-rank P=0.355); however, DCM patients with left ventricular LGE extent ≥7.5% had a higher risk of adverse prognosis than those with left ventricular LGE extent <7.5% (log-rank P=0.032). Conclusion: There are no significant differences in CMR characteristics between DCM patients with left ventricular hypertrabeculation and those with isolated DCM, and left ventricular hypertrabeculation had no impact on the prognosis of DCM patients. In contrast, left ventricular LGE extent was a risk factor affecting the prognosis of DCM patients.

A 50-year-old man with the rare McLeod syndrome, associated with glomerular lesion to the end stage of chronic renal failure and death, is reported. McLeod syndrome is an X-linked recessive disorder on the basis of abnormal expression of the Kell blood group antigens and absence of erythrocyte surface Kx antigen. Most often the clinical and pathological findings are retinitis pigmentosa to blindness, progressive chronic neuropathy, cortical atrophy, dilated cardiomyopathy, and glomerular lesion with chronic renal failure. Among the laboratory parameters the most important are very low level of cholesterol and triglycerides, then various numbers of acanthocytes in peripheral blood smears and sometimes in urine (as in our case).

The goal of this study was to evaluate the accuracy of gated single photon emission computed tomography (SPECT) in the assessment of left ventricular (LV) end-diastolic/end-systolic volumes (EDV, ESV) and ejection fraction (LVEF) in patients with dilated cardiomyopathy, using cardiac magnetic resonance imaging (MRI) as the reference method. Furthermore, software-specific characteristics of Quantitative Gated SPECT (QGS), Emory Cardiac Toolbox (ECTB) and 4D-MSPECT were analysed. Thirty-six patients with dilated cardiomyopathy who underwent gated (99m)Tc-methoxyisobutylisonitrile SPECT and cardiac MRI were included. LV EDV, ESV and LVEF values of gated SPECT were calculated using QGS, ECTB and 4D-MSPECT. The correlation between the results of gated SPECT and cardiac MRI was excellent for EDV [R = 0.872 (QGS), R = 0.879 (ECTB), R = 0.869 (4D-MSPECT)], ESV [R = 0.908 (QGS), R = 0.897 (ECTB), R = 0.880 (4D-MSPECT)] and LVEF [R = 0.794 (QGS), R = 0.763 (ECTB), R = 0.710 (4D-MSPECT)]. EDV and ESV assessed by QGS did not differ significantly from those assessed by cardiac MRI (all p = NS), whereas EDV and ESV were overestimated by ECTB and 4D-MSPECT compared with cardiac MRI (all p < 0.05). LVEF was overestimated by QGS, ECTB and 4D-MSPECT compared with cardiac MRI (all p < 0.05). The correlation between gated SPECT and cardiac MRI is excellent for LV volume and LVEF values calculated by QGS, ECTB and 4D-MSPECT in patients with dilated cardiomyopathy. However, algorithm-varying over- or underestimation of LV volumes and LVEF should be accounted for in the clinical context.