👤 Mika Laine

CLN3 disease, also called Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease, is an ultra‑rare, neurodegenerative lysosomal storage disorder generally affecting individuals during the first decade of life. There can be a delay in diagnosis or misdiagnosis due to a lack of awareness, and when the most common presenting symptom of visual loss is attributed to more common conditions affecting vision. We used a previously published Expert Mapping Tool (EMT) to identify multidisciplinary professionals with diagnostic or clinical management expertise, as well as patient advocates with experience of CLN3 disease. A systematic literature review of published evidence using the Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidance was conducted independently and simultaneously to develop key clinical care statements. Each statement was based on the strength of the evidence. The statements formed the basis of an international modified-Delphi consensus process using a virtual meeting platform (Within3). Experts were asked to agree or disagree with each statement and suggest any changes. Statements that reached a consensus of 75% or over are the guiding statements within this manuscript. The processes and manuscript have been independently assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria. Thirty‑nine international experts from eight specialities were identified, including a patient advocate. Fifty‑three recommendation statements were developed covering eleven domains: General statements, Diagnostics, Clinical Recommendations and Management, Assessments, Social Considerations, Ocular Management, Epilepsy/Seizures, Nutrition, Respiratory Health, Sleep and Rest, and End-of-Life Care. Consensus was reached after one round of voting for all except three statements. The overall AGREE II score for developing these recommendations was 6.4, where 1 represents the lowest and 7 is the highest quality. Currently, there are no comprehensive clinical recommendations for CLN3 disease. These recommendations provide a comprehensive, evidence- and consensus‑based tool that can be used by all healthcare professionals involved in the management of CLN3 disease and other similar neurodegenerative conditions. The goal is to address the unmet clinical need for CLN3 disease management and complement other information available. The online version contains supplementary material available at 10.1186/s13023-026-04298-2. Show less

While a growing body of literature exists on initial word-to-meaning mapping and retrieval of fully lexicalized words, our understanding on the consolidation that occurs between these two stages remains limited. The current study investigated the neural correlates of retrieving newly learned word using oscillatory brain dynamics. Participants learned to associate new words with unknown objects and performed overt and covert naming tasks during the first and last days of a five-day training period. Behavioral results showed improved overt naming on Day 5 compared to Day 1. Selecting only words that were successfully produced in the overt naming task, we examined oscillatory activity associated with word retrieval while participants produced new words covertly, both pre- (Day 1) and post (Day 5) learning. The results showed a robust alpha (8-12 Hz) and lower beta (13-25 Hz) power decrease during covert naming after learning. We hypothesize that this alpha-beta power decrease indexes successful word retrieval following consolidation. Show less

Plasma lipids are mainly carried in apolipoprotein B (apoB) containing lipoproteins. High levels of these lipoproteins are associated with several metabolic diseases and lowering their plasma levels is associated with reduced incidence of atherosclerotic cardiovascular disease. MicroRNAs (miRs) are small non-coding RNAs that reduce the protein expression of their target mRNAs and are potential therapeutic agents. Here, we identified a novel miR-615-3p that interacts with human 3'-UTR of apoB mRNA, induces post-transcriptional mRNA degradation, and reduces cellular and secreted apoB100 in human hepatoma Huh-7 cells. Reducing cellular miR-615-3p levels by CRISPR-sgRNA increased cellular and secreted apoB100 indicating endogenous miR regulates apoB expression. Overexpression of miR-615-3p along with or without palmitic acid treatment decreased cellular and media apoB and increased cellular triglyceride levels without inducing endoplasmic reticulum stress. These studies have identified miR-615-3p as a negative regulator of apoB expression in human liver-derived cells. It is likely that there are more miRs that regulate apoB-containing lipoprotein assembly and secretion. Discovery of additional miRs may uncover novel mechanisms that control lipoprotein assembly and secretion. Show less

This manuscript has not been published before and is not currently being considered for publication elsewhere. Increased septal convexity of left ventricle has been described in subjects with hypertrophic cardiomyopathy (HCM) -causing mutations without left ventricular hypertrophy (LVH). Our objective was to study septal convexity by cardiac magnetic resonance (CMR) in subjects with the Finnish founder mutation Q1016X in the myosin-binding protein C gene (MYBPC3). Septal convexity was measured in end-diastolic 4-chamber CMR image in 67 study subjects (47 subjects with the MYBPC3-Q1061X mutation and 20 healthy relatives without the mutation). Septal convexity was significantly increased in subjects with the MYBPC3-Q1061X mutation and LVH (n = 32) compared to controls (11.4 ± 4.3 vs 2.7 ± 3.2 mm, P < 0.001). In mutation carriers without LVH, there was a trend for increased septal convexity compared to controls (4.9 ± 2.5 vs 2.7 ± 3.2 mm, P = 0.074). When indexed for BSA, septal convexity in mutation carriers without LVH was 2.8 ± 1.4 mm/m Show less

The sensitivity and specificity of the conventional 12-lead ECG to identify carriers of hypertrophic cardiomyopathy (HCM) - causing mutations without left ventricular hypertrophy (LVH) has been limited. We assessed the ability of novel electrocardiographic parameters to improve the detection of HCM mutation carriers. We studied 140 carriers (G+) of the TPM1-Asp175Asn or MYBPC3-Gln1061X pathogenic variants for HCM: The G+/LVH+ group (n = 98) consisted of mutation carriers with LVH and the G+/LVH- group (n = 42) without LVH. The control group consisted of 30 subjects. The standard 12-lead ECG was comprehensively analyzed and two novel ECG variables were introduced: RV1RV3 and septal remodeling. A subset of 65 individuals underwent cardiac magnetic resonance imaging and 2D strain echocardiography. Conventional major ECG criteria were sensitive (90%) and specific (97%) in identifying G+/LVH+ subjects. RV1RV3 and septal remodeling were more prevalent in the G+/LVH- subjects compared to the control group (33% vs 3%, p = 0.005 and 45% vs 3%, p < 0.001, respectively). The combination of RV1RV3 and Q waves and repolarization abnormalities (QR) differentiated between the G+/LVH- subjects and the control group with a sensitivity of 52% and specificity of 97%. The combination of septal remodeling and QR differentiated between G+/LVH- subjects and the control group with a sensitivity of 64% and specificity of 97%. The novel ECG-parameters RV1RV3 and septal remodeling were effective in identifying G+/LVH- subjects and could be useful in the diagnostics of new suspected HCM patients and in the screening and follow-up of HCM families. Show less

Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. HCM patients with either the MYBPC3-Q1061X or TPM1-D175N mutation (n = 46) and control subjects without mutation and hypertrophy (n = 35) were studied with 24-hr ambulatory ECG recordings by measuring time intervals of rate-adapted QT (QTe), maximal QT, and T-wave apex to wave end (TPE) intervals and the QTe/RR slope. Findings were correlated to specified echocardiographic and cardiac magnetic resonance imaging (CMRI) findings. Rate-adapted QTe interval was progressively longer in HCM patients with decreasing heart rates compared to control subjects (p = 0.020). The degree of hypertrophy correlated with measured QTe values. HCM patients with maximal wall thickness higher than the mean (20.6 mm) had longer maximum QTe and median TPE intervals compared to control subjects and HCM patients with milder hypertrophy (p < 0.001 and p = 0.014, respectively). HCM patients with late gadolinium enhancement (LGE) on CMRI had steeper QTe/RR slopes compared to HCM patients without LGE and control subjects (p = 0.044 and p = 0.001, respectively). LGE was an independent predictor of QTe/RR slope (p = 0.023, B = 0.043). Dynamics of ventricular repolarization in HCM are affected by hypertrophy and fibrosis. LGE may confer an independent effect on QT dynamics which may increase the arrhythmogenic potential in HCM. Show less

Previous data suggest that mitral valve leaflets are elongated in hypertrophic cardiomyopathy (HCM), and mitral valve leaflet elongation may constitute a primary phenotypic expression of HCM. Our objective was to measure the length of mitral valve leaflets by cardiovascular magnetic resonance (CMR) in subjects with HCM caused by a Finnish founder mutation in the myosin-binding protein C gene (MYBPC3-Q1061X), carriers of the same mutation without left ventricular hypertrophy, as well as in unselected consecutive patients with HCM, and respective controls. Anterior mitral valve leaflet (AML) and posterior mitral valve leaflet (PML) lengths were measured by CMR in 47 subjects with the Q1061X mutation in the gene encoding MYBPC3 and in 20 healthy relatives without the mutation. In addition, mitral valve leaflet lengths were measured by CMR in 80 consecutive non-genotyped patients with HCM in CMR and 71 age- and gender-matched healthy subjects. Of the subjects with the MYBPC-Q1016X mutation, 32 had left ventricular hypertrophy (LVH, LV maximal wall thickness ≥ 13 mm in CMR) and 15 had no hypertrophy. PML was longer in patients with the MYBPC3-Q1061X mutation and LVH than in controls of the MYBPC group (12.8 ± 2.8 vs 10.6 ± 1.9 mm, P = 0.013), but the difference between the groups was not statistically significant when PML was indexed for BSA (P = 0.066), or when PML length was adjusted for BSA, age, gender, LV mass and ejection fraction (P = 0.195). There was no significant difference in the PML length in mutation carriers without LVH and controls (11.1 ± 3.4 vs 10.6 ± 1.9, P = 0.52). We found no difference in AML lengths between the MYBPC mutation carriers with or without hypertrophy and controls. In 80 consecutive non-genotyped patients with HCM, there was no difference either in AML or PML lengths in subjects with HCM compared to respective control subjects. In subjects with HCM caused by the Q1061X mutation in the MYBPC3 gene, the posterior mitral valve leaflets may be elongated, but mitral valve elongation does not constitute primary phenotypic expression of the disease. Instead, elongated mitral valve leaflets seem to be associated with body size and left ventricular remodeling. Show less

We assessed the value of speckle tracking two-dimensional (2D) strain echocardiography (2DSE) measured mechanical dispersion (MD) with other imaging and electrocardiographic parameters in differentiating hypertrophic cardiomyopathy (HCM) patients with and without nonsustained ventricular tachycardia (NSVT) on 24-h ambulatory ECG monitoring. We studied 31 patients with HCM caused by the Finnish founder mutation MYBPC3-Q1061X and 20 control subjects with comprehensive 2DSE echocardiography and cardiac magnetic resonance imaging (CMRI). The presence of NSVT was assessed from ambulatory 24-h ECG monitoring. NSVT episodes were recorded in 11 (35%) patients with HCM. MD was significantly higher in HCM patients with NSVT (93 ± 41 ms) compared to HCM patients without NSVT (50 ± 18 ms, p = 0.012) and control subjects (41 ± 16 ms, p < 0.001). MD was the only variable independently associated with the presence of NSVT (OR: 1.60, 95% CI: 1.05-2.45, p = 0.030). Assessed by ROC curves, MD performed best in differentiating between HCM patients with and without NSVT (AUC = 0.81). Increased mechanical dispersion was associated with NSVT in HCM patients on 24-h ambulatory ECG monitoring. Key messages The prediction of sudden cardiac death in hypertrophic cardiomyopathy remains a challenge and novel imaging methods are required to identify individuals at risk of malignant ventricular arrhythmias. Mechanical dispersion by speckle tracking echocardiography is associated with NSVT on 24-h ambulatory ECG monitoring in patients with hypertrophic cardiomyopathy. Show less

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters. 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle. Show less