Image_2_Different Pattern of Cardiovascular Impairment in Methylmalonic Acidaemia Subtypes.TIF

Methylmalonic acidaemia (MMA) has been reported to be associated with cardiovascular involvement, especially for the combined type with homocystinuria. We have screened 80 control subjects and 99 MMA patients (23 isolated type and 76 combined type) using electrocardiograph and echocardiography. 32 cases (34%) of ECG changes were found including sinus tachycardia (n = 11), prolonged QTc interval (n = 1), I-degree atrioventricular block (n = 1), left axis deviation (n = 5) and T wave change (n = 14). By echocardiography, 8 cases of congenital heart disease were found in 4 combined MMA patients (5.3%) including ventricular septal defect (n = 2), atrial septal defect (n = 3), patent ductus arteriosus (n = 1) and coronary artery-pulmonary artery fistula (n =2). Pulmonary hypertension (n = 2) and hypertrophic cardiomyopathy (n = 1) in combined subtype were also noted. Moreover, echocardiographic parameters were analyzed by multiple regression to clarify the influence of different subtypes on cardiac function. It was found that the left ventricular mass index (LVMI) was significantly reduced only in combined subtype [R = −3.0, 95%CI (−5.4, −0.5), P = 0.017]. For left ventricle, the mitral E' velocity was significantly reduced [isolated type: R = −1.8, 95%CI (−3.3, −0.4), P = 0.016; combined type: R = −2.5, 95%CI (−3.5, −1.5), P < 0.001], the global longitudinal strain (GLS) was the same [isolated type: R = −1.4, 95%CI (−2.3, −0.4), P = 0.007; Combined type: R = −1.1, 95%CI (−1.8, −0.4), P = 0.001], suggesting weakened left ventricular diastolic and systolic functions in both subtypes. For right ventricle, only in combined subtype, the tricuspid E' velocity was significantly reduced [R = −1.4, 95%CI (−2.6, −0.2), P = 0.021], and the tricuspid annular plane systolic excursion (TAPSE) was the same [R = −1.3, 95%CI (−2.3, −0.3), P=0.013], suggesting impaired right ventricular systolic and diastolic function. In conclusion, isolated and combined types showed different pattern of cardiac dysfunction, specifically the former only affected the left ventricle while the latter affected both ventricles. And it is necessary to perform echocardiographic screening and follow up in both MMA subtypes.</p

Image_1_Different Pattern of Cardiovascular Impairment in Methylmalonic Acidaemia Subtypes.TIF

Methylmalonic acidaemia (MMA) has been reported to be associated with cardiovascular involvement, especially for the combined type with homocystinuria. We have screened 80 control subjects and 99 MMA patients (23 isolated type and 76 combined type) using electrocardiograph and echocardiography. 32 cases (34%) of ECG changes were found including sinus tachycardia (n = 11), prolonged QTc interval (n = 1), I-degree atrioventricular block (n = 1), left axis deviation (n = 5) and T wave change (n = 14). By echocardiography, 8 cases of congenital heart disease were found in 4 combined MMA patients (5.3%) including ventricular septal defect (n = 2), atrial septal defect (n = 3), patent ductus arteriosus (n = 1) and coronary artery-pulmonary artery fistula (n =2). Pulmonary hypertension (n = 2) and hypertrophic cardiomyopathy (n = 1) in combined subtype were also noted. Moreover, echocardiographic parameters were analyzed by multiple regression to clarify the influence of different subtypes on cardiac function. It was found that the left ventricular mass index (LVMI) was significantly reduced only in combined subtype [R = −3.0, 95%CI (−5.4, −0.5), P = 0.017]. For left ventricle, the mitral E' velocity was significantly reduced [isolated type: R = −1.8, 95%CI (−3.3, −0.4), P = 0.016; combined type: R = −2.5, 95%CI (−3.5, −1.5), P < 0.001], the global longitudinal strain (GLS) was the same [isolated type: R = −1.4, 95%CI (−2.3, −0.4), P = 0.007; Combined type: R = −1.1, 95%CI (−1.8, −0.4), P = 0.001], suggesting weakened left ventricular diastolic and systolic functions in both subtypes. For right ventricle, only in combined subtype, the tricuspid E' velocity was significantly reduced [R = −1.4, 95%CI (−2.6, −0.2), P = 0.021], and the tricuspid annular plane systolic excursion (TAPSE) was the same [R = −1.3, 95%CI (−2.3, −0.3), P=0.013], suggesting impaired right ventricular systolic and diastolic function. In conclusion, isolated and combined types showed different pattern of cardiac dysfunction, specifically the former only affected the left ventricle while the latter affected both ventricles. And it is necessary to perform echocardiographic screening and follow up in both MMA subtypes.</p

Data_Sheet_1_Different Pattern of Cardiovascular Impairment in Methylmalonic Acidaemia Subtypes.docx

Methylmalonic acidaemia (MMA) has been reported to be associated with cardiovascular involvement, especially for the combined type with homocystinuria. We have screened 80 control subjects and 99 MMA patients (23 isolated type and 76 combined type) using electrocardiograph and echocardiography. 32 cases (34%) of ECG changes were found including sinus tachycardia (n = 11), prolonged QTc interval (n = 1), I-degree atrioventricular block (n = 1), left axis deviation (n = 5) and T wave change (n = 14). By echocardiography, 8 cases of congenital heart disease were found in 4 combined MMA patients (5.3%) including ventricular septal defect (n = 2), atrial septal defect (n = 3), patent ductus arteriosus (n = 1) and coronary artery-pulmonary artery fistula (n =2). Pulmonary hypertension (n = 2) and hypertrophic cardiomyopathy (n = 1) in combined subtype were also noted. Moreover, echocardiographic parameters were analyzed by multiple regression to clarify the influence of different subtypes on cardiac function. It was found that the left ventricular mass index (LVMI) was significantly reduced only in combined subtype [R = −3.0, 95%CI (−5.4, −0.5), P = 0.017]. For left ventricle, the mitral E' velocity was significantly reduced [isolated type: R = −1.8, 95%CI (−3.3, −0.4), P = 0.016; combined type: R = −2.5, 95%CI (−3.5, −1.5), P < 0.001], the global longitudinal strain (GLS) was the same [isolated type: R = −1.4, 95%CI (−2.3, −0.4), P = 0.007; Combined type: R = −1.1, 95%CI (−1.8, −0.4), P = 0.001], suggesting weakened left ventricular diastolic and systolic functions in both subtypes. For right ventricle, only in combined subtype, the tricuspid E' velocity was significantly reduced [R = −1.4, 95%CI (−2.6, −0.2), P = 0.021], and the tricuspid annular plane systolic excursion (TAPSE) was the same [R = −1.3, 95%CI (−2.3, −0.3), P=0.013], suggesting impaired right ventricular systolic and diastolic function. In conclusion, isolated and combined types showed different pattern of cardiac dysfunction, specifically the former only affected the left ventricle while the latter affected both ventricles. And it is necessary to perform echocardiographic screening and follow up in both MMA subtypes.</p

Data_Sheet_1_Novel compound heterozygous CCDC40 mutations in a familial case of primary ciliary dyskinesia.ZIP

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by motile ciliary dysfunction and impaired ultrastructure. Despite numerous studies, the genetic basis for about 30% of PCD cases remains to be elucidated. Here, we present the identification and functional analysis of two novel mutations in the gene encoding coiled-coil domain-containing protein 40 (CCDC40), which are found in a familial case of PCD. These novel CCDC40 mutations, NM_017950.4: c.2236-2delA and c.2042_2046delTCACA, NP_060420.2: p.(Ile681fs), were identified by whole-exome sequencing (WES). Sanger sequencing was then performed to confirm the WES results and determine the CCDC40 gene sequences of the proband’s parents. The c.2042_2046delTCACA mutation disrupts the reading frame of the protein and is therefore predicted to produce a non-functional protein. Using a minigene assay with the pcDNA3.1(+) plasmid, we further investigated the potential pathogenic effects of the c.2236-2delA mutation and found that this mutation leads to formation of a truncated protein via splicing disruption. Thus, in summary, we identified two mutations of the CCDC40 gene that can be considered pathogenic compound heterozygous mutations in a case of familial PCD, thereby expanding the known mutational spectrum of the CCDC40 gene in this disease.</p