👤 Janne Hämäläinen

Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P < 0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually. Show less

In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland. Show less

Hypertrophic cardiomyopathy (HCM) is predominantly caused by a large number of various mutations in the genes encoding sarcomeric proteins. However, two prevalent founder mutations for HCM in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes have previously been identified in eastern Finland. To assess the prevalence of these founder mutations in a large population of patients with HCM from all over Finland. Patients and methods. We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000. The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland. The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM. Show less

Reported here is the 30-year follow-up of a patient, diagnosed with juvenile neuronal ceroid lipofuscinosis, who was compound heterozygous for the common 1-kb deletion and the missense mutation p.Glu295Lys in the CLN3 gene. Visual failure was noticed at 6 years of age, but thereafter disease progression was atypical. Polyneuropathy and cerebellar signs were observed after age 20, and epilepsy and slight mental decline after age 35. From then on, there was rapid deterioration, and the patient died at age 39. This case highlights the importance of exact genotyping for disease course prediction and management. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3) is an inherited lysosomal disease. We used longitudinal MRI, for the first time, to evaluate the rate of brain volume alterations in JNCL. Six patients (mean ages of 12.4 years and 17.3 years) and 12 healthy controls were studied twice with 1.5 T MRI. White matter (WM), gray matter (GM) and CSF volumes were measured from the sets of T1-weighted 3-dimensional MR images using a fully automated image-processing procedure. The brain volume alterations were calculated as percentage change per year. The GM and whole brain volumes decreased and the CSF volume increased significantly more in the patients than in controls (p-values for the null hypothesis of equal means were 0.001, 0.004, and 0.005, respectively). We found no difference in the WM volume change between the populations. In patients, the GM volume decreased 2.4 % (SD 0.5 %, p 0.0001 for the null hypothesis of zero mean change between observations), the whole brain volume decreased 1.1 % (SD 0.5 %, p = 0.003), and the CSF volume increased 2.7 % (SD 1.8 %, p = 0.01) per year. In normal controls, only the mean white matter volume was significantly altered (0.8 % increase, SD 0.7 %, and p = 0.001). We demonstrated by longitudinal MRI that the annual rate of the gray matter loss in adolescent JNCL patients is as high as 2.4 %. Show less

Juvenile neuronal ceroid lipofuscinosis (CLN3) is characterized by progressive cerebral atrophy. The purpose of this study was to re-evaluate the three-dimensional magnetic resonance (3D-MR) images of patients with CLN3 using voxel-based morphometry (VBM) to achieve a detailed understanding of the affected brain regions. T1-weighted 3D-MR images of 15 patients with CLN3 (age range: 12-25 years, mean age 17.6 years) and 15 age- and sex-matched controls were analyzed using VBM. VBM showed strikingly focal alterations in the brains of CLN3 patients: the gray matter volume was significantly decreased in the dorsomedial part of the thalami of CLN3 patients. In addition, the volume of the white matter was significantly decreased in the corona radiata, containing cortical efferents and afferents in the transition between the internal capsule and the subcortical white matter. These data suggest that the dorsomedial part of the thalamus and the corona radiata may have a central, previously unrecognized role in the pathogenesis of CLN3. Show less