Phenotype and pathology of the dilated cardiomyopathy with ataxia syndrome in children.

The dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive mitochondrial disease caused by mutations in the DnaJ heat shock protein family (Hsp40) member C19 (DNAJC19) gene. DCMA or 3-methylglutaconic aciduria type V is globally rare, but the largest number of patients in the world is found in the Hutterite population of southern Alberta in Canada. We provide an update on phenotypic findings, natural history, pathological findings, and our clinical experience. We analyzed all available records for 43 patients diagnosed with DCMA between 2005 and 2015 at the Alberta Children's Hospital. All patients studied were Hutterite and homozygous for the causative DNAJC19 variant (c.130-1G>C, IVS3-1G>C) and had elevated levels of 3-methyglutaconic acid. We calculated a birth prevalence of 1.54 cases per 1000 total births in the Hutterite community. Children were small for gestational age at birth and frequently required supplemental nutrition (63%) or surgical placement of a gastrostomy tube (35%). Early mortality in this cohort was high (40%) at a median age of 13 months (range 4-294 months). Congenital anomalies were common as was dilated cardiomyopathy (50%), QT interval prolongation (83%), and developmental delay (95%). Tissue pathology was analyzed in a limited number of patients and demonstrated subendocardial fibrosis in the heart, macrovesicular steatosis and fibrosis in the liver, and structural abnormalities in mitochondria. This report provides clinical details for a cohort of children with DCMA and the first presentation of tissue pathology for this disorder. Despite sharing common genetic etiology and environment, the disease is highly heterogeneous for reasons that are not understood. DCMA is a clinically heterogeneous systemic mitochondrial disease with significant morbidity and mortality that is common in the Hutterite population of southern Alberta.

Aerobic training as an adjunctive therapy to enzyme replacement in Pompe disease.

BACKGROUND: Aerobic exercise may be used in conjunction with enzyme replacement therapy (ERT) to attenuate cardiovascular deconditioning, skeletal muscle wasting, and loss of motor function in Pompe disease (glycogen storage disease type II; GSDII), but the effects on lysosomal glycogen content and macroautophagy have not been defined to date. PURPOSE: The main objectives of this study were to determine if acute aerobic exercise enhances 24-h uptake of recombinant human enzyme (rhGAA; Myozyme® [aim 1]) and if endurance training improves disease pathology when combined with ERT [aim 2] in Pompe mice. METHODS: For the first aim in our study, Pompe mutant mice (6(neo)/6(neo)) were grouped into ERT (Myozyme® injection only [40 mg/kg]) and ERT+EX (Myozyme® injection followed by 90 min treadmill exercise) cohorts, and enzyme uptake was assessed in the heart and quadriceps 24h post injection. For the second aim of our study, mutant mice were randomized into control, endurance-trained, enzyme-treated, or combination therapy groups. Exercised animals underwent 14 weeks of progressive treadmill training with or without biweekly Myozyme® injections (40 mg/kg) and tissues were harvested 1 week post last treatment. RESULTS: Myozyme® uptake (GAA activity) was not improved in ERT+EX over ERT alone at 24-h post injection. Endurance exercise training, with or without ERT, improved aerobic capacity and normalized grip strength, motor function, and lean mass (P<0.05), but did not reduce glycogen content or normalize macroautophagy beyond traditional enzyme replacement therapy. CONCLUSIONS: Endurance training is beneficial as an adjunctive therapy to ERT in Pompe disease, although it works by mechanisms independent of a reduction in glycogen content.

Validation of the visual acuity iPad app Eye Chart Pro compared to the standard Early Treatment Diabetic Retinopathy Study chart in a low-vision population.

INTRODUCTION: A low-vision assessment (LVA) is central to developing a vision rehabilitation plan. However, access to LVAs is often limited by the quantity and geographic distribution of low-vision providers, as well as patient-centred transportation challenges. A tablet-based LVA tool kit, delivered virtually, has the potential to overcome many of these barriers. The purpose of this research was to validate a key component of the tablet-based tool kit - a commercially available iPad visual acuity (VA) test (Eye Chart Pro) iPad app - in a low-vision population. METHODS: Participants with low vision (n = 26) and those who were normally sighted (n = 25) underwent VA testing with both the iPad VA test application and the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The VA data were compared using a t-test, linear regression and Bland-Altman analysis. RESULTS: There was no significant difference in the mean absolute difference in VA (log of minimum angle of resolution (logMAR)=0.11; p = 0.82). Eye Chart Pro and Standard ETDRS Chart measures were also not significantly different (p = 0.98). However, there were significant differences between test methods in the low-vision group and the normally sighted group (p > 0.0001 and p = 0.007, respectively). The Bland-Altman analysis showed a mean bias (difference) of -0.0005 logMAR between methods, and 95% limits of agreement of 0.298 and -0.299 logMAR. DISCUSSION: The ETDRS chart function on the Eye Chart Pro application can reliably measure VA across a range, from normally sighted patients to those with low vision.

Validation of a portable, remotely delivered refraction approach compared to standard in-clinic refraction in a low-vision population.

INTRODUCTION: A low-vision assessment (LVA) is critical in developing a vision rehabilitation plan. A remotely delivered LVA that replicates a standard in-clinic assessment may bridge the gap for patients not accessing care due to the limited quantity and distribution of low-vision providers. Within an LVA, an accurate and consistent assessment of refraction error is an essential component. No system has currently been validated for the purposes of a remote LVA. The purpose of this study was to validate a commercially available portable refraction approach in a low-vision population. METHODS: Low-vision patients (n = 26) or normally sighted patients (n = 25) underwent a refraction assessment using the Adaptica® 2WIN autorefractor, adaptor scope (Kaleidos) and VisionFit phoropter portable refraction devices, as well as a standard autorefractor (Huvitz) and phoropter (Haag-Streit). Refraction data between systems and populations were compared using intraclass correlations. Bland-Altman plots were used to assess the differences between devices. RESULTS: Spherical equivalent values were found to be reproducible between standard and experimental autorefraction devices (intraclass correlation coefficient (ICC) > 0.8) in both low-vision and normally sighted groups. Similarly, manifest refraction was highly consistent (ICC > 0.8) between devices in all groups. The Bland-Altman plots showed clinically acceptable mean differences of 0.701 between autorefraction methods and -0.116 between manifest refraction methods. DISCUSSION: The 2WIN/VisionFit system can reliably generate refraction values across a spectrum of errors in normally sighted and visually impaired people, and would be feasible to deliver remotely.

Addition of Digoxin Improves Cardiac Function in Children With the Dilated Cardiomyopathy With Ataxia Syndrome: A Mitochondrial Cardiomyopathy.

BACKGROUND: The dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare mitochondrial disorder characterized by progressive cardiomyopathy, prolonged QT interval and early death in childhood related to intractable heart failure. We present a case series of 9 children with DCMA who demonstrated functional improvement and favourable left ventricular remodeling only after digoxin was added to their medical therapy. METHODS: A retrospective review of 46 patients with DCMA followed at the Alberta Children's Hospital from 2005 to 2017 identified 9 patients who were treated with digoxin and had serial echocardiography data. For each subject, we calculated the difference between baseline and follow-up for left ventricular ejection fraction (LVEF), end-diastolic dimension (LVEDD), and end-systolic dimension (LVESD) as determined by echocardiography. RESULTS: Patients were on average 45.6 ± 59 months of age when digoxin was started with a mean LVEF of 40% ± 11% when digoxin was started. Seven patients were on angiotensin-converting enzyme inhibitors (ACEIs) at the time of initiation of digoxin, and all were on ß-receptor antagonists (BB). After being on digoxin for a mean of 11.7 ± 10.9 months, average LVEF improved to 55% ± 10% (P = 0.0005), and there were significant decreases in the Z-scores for LVEDD (+2.1 ± 1.9 to +0.65 ± 1.4, P = 0.02) and LVESD (+3.83 ± 2.07 to +1.79 ± 1.76, P = 0.01). CONCLUSIONS: In children with DCMA, we report that digoxin seems to have additive beneficial properties when combined with ACEI and BB therapy. This novel observation may have implications for the medical treatment of mitochondrial cardiomyopathies.

Comparison of Cardiac Magnetic Resonance Imaging and Echocardiography in Assessment of Left Ventricular Hypertrophy in Fabry Disease.

BACKGROUND: Cardiac hypertrophy in Fabry disease can be assessed using the left ventricular mass index (LVMI) with either echocardiography (LVMI-ECHO) or magnetic resonance imaging (LVMI-CMR). METHODS: A retrospective case series of patients with Fabry disease in Alberta involved a cross-sectional analysis of 32 patients and a longitudinal analysis of 14 of these patients with at least 4 serial CMR measurements. RESULTS: The cross-sectional analysis showed the mean LVMI-ECHO was 97.8 ± 26.0 g/m2, which was higher compared with LVMI-CMR at 81.1 ± 26.9 g/m2 with a mean bias of 16.7 g/m2 (P < 0.001). In the longitudinal analysis, LVMI-ECHO was higher, with an estimated marginal mean of 96.21 ± 6.13 (mean ± standard error of the mean [SEM]) compared with 71.18 ± 5.99 for LVMI-CMR (P < 0.01; generalized estimating equations). There was an association between an increase in LVMI-CMR over time with the presence of cardiac fibrosis, and patients treated with enzyme replacement therapy (ERT) had slower increases than those without therapy. LVMI-ECHO failed to detect these associations owing to the higher variability and tendency to overestimate the LVMI. CONCLUSIONS: We propose the preferred method for measuring LVMI is CMR in patients with Fabry disease.