Maternal obesity, interpregnancy weight changes and congenital heart defects in the offspring: a nationwide cohort study.

OBJECTIVE: To evaluate the association between maternal BMI and congenital heart defects (CHDs) in the offspring when including live births, stillbirths, aborted and terminated pregnancies and to investigate if maternal interpregnancy weight changes between the first and second pregnancy influences the risk of foetal CHDs. METHODS: A nationwide cohort study of all singleton pregnancies in Denmark from 2008 to 2018. Data were retrieved from the Danish Foetal Medicine Database, which included both pre- and postnatal diagnoses of CHDs. Children or foetuses with chromosomal aberrations were excluded. Odds ratios were calculated with logistic regression models for CHDs overall, severe CHDs and five of the most prevalent subtypes of CHDs. RESULTS: Of the 547 105 pregnancies included in the cohort, 5 442 had CHDs (1.0%). Risk of CHDs became gradually higher with higher maternal BMI; for BMI 25-29.9 kg/m2, adjusted odds ratio (aOR) 1.17 (95% CI 1.10-1.26), for BMI 30-34.9 kg/m2, aOR 1.21 (95% CI 1.09-1.33), for BMI 35-39.9 kg/m2, aOR 1.29 (95% CI 1.11-1.50) and for BMI ≥ 40 kg/m2, aOR 1.85 (95% CI 1.54-2.21). Data was adjusted for maternal age, smoking status and year of estimated due date. The same pattern was seen for the subgroup of severe CHDs. Among the atrioventricular septal defects (n = 231), an association with maternal BMI ≥ 30 kg/m2 was seen, OR 1.67 (95% CI 1.13-2.44). 109 654 women were identified with their first and second pregnancies in the cohort. Interpregnancy BMI change was associated with the risk of CHDs in the second pregnancy (BMI 2 to < 4 kg/m2: aOR 1.29, 95% CI 1.09-1.53; BMI ≥ 4 kg/m2: aOR 1.36, 95% CI 1.08-1.68). CONCLUSION: The risk of foetal CHDs became gradually higher with higher maternal BMI and interpregnancy weight increases above 2 BMI units were also associated with a higher risk of CHDs.

The impact of the COVID-19 lockdown on birthweight among singleton term birth in Denmark.

In Denmark, a nationwide COVID-19 lockdown was implemented on March 12, 2020 and eased on April 14, 2020. The COVID-19 lockdown featured reduced prevalence of extremely preterm or extremely low birthweight births. This study aims to explore the impact of this COVID-19 lockdown on term birthweights in Denmark. We conducted a nationwide register-based cohort study on 27,870 live singleton infants, born at term (weeks 37-41), between March 12 and April 14, 2015-2020, using data from the Danish Neonatal Screening Biobank. Primary outcomes, corrected for confounders, were birthweight, small-for-gestational-age (SGA), and large-for-gestational-age (LGA), comparing the COVID-19 lockdown to the previous five years. Data were analysed using linear regression to assess associations with birthweight. Multinomial logistic regression was used to assess associations with relative-size-for-gestational-age (xGA) categories. Adjusted mean birthweight was significantly increased by 16.9 g (95% CI = 4.1-31.3) during the lockdown period. A dip in mean birthweight was found in gestational weeks 37 and 38 balanced by an increase in weeks 40 and 41. The 2020 lockdown period was associated with an increased LGA prevalence (aOR 1.13, 95% CI = 1.05-1.21). No significant changes in proportions of xGA groups were found between 2015 and 2019. The nationwide COVID-19 lockdown resulted in a small but significant increase in birthweight and proportion of LGA infants, driven by an increase in birthweight in gestational weeks 40 and 41.

SARS-CoV-2 placentitis and severe pregnancy outcome after maternal infection: A Danish case series.

INTRODUCTION: SARS-CoV-2 infection during pregnancy may cause viral inflammation of the placenta, resulting in fetal demise even without fetal or newborn infection. The impact of timing of the infection and the mechanisms that cause fetal morbidity and mortality are not well understood. MATERIAL AND METHODS: To describe placental pathology from women with confirmed SARS-CoV-2 infection during pregnancy, a SARS-CoV-2 immunohistochemistry-positive placenta and late miscarriage, stillbirth, neonatal death, or medically indicated birth due to fetal distress. RESULTS: The triad of trophoblastic necrosis, inflammatory intervillous infiltrates, and increased perivillous fibrinoid deposition was present in all 17 placentas; the pregnancies resulted in eight stillbirths, two late miscarriages (19 and 21 weeks' gestation), and seven liveborn children, two of which died shortly after delivery. The severity of maternal COVID-19 was not reflected by the extent of the placental lesions. In only one case, SARS-CoV-2 was detected in lung tissue samples from the fetus. The majority events (miscarriage, stillbirth, fetal distress resulting in indicated birth, or livebirth, but neonatal death) happened shortly after maternal SARS-CoV-2 infection was diagnosed. Seven of eight sequenced cases were infected with the Delta (B.1.617.2) virus strain. CONCLUSION: We consolidate findings from previous case series describing extensive SARS-CoV-2 placentitis and placental insufficiency leading to fetal hypoxia. We found sparse evidence to support the notion that SARS-CoV-2 virus had infected the fetus or newborn.

Risk factors for and pregnancy outcomes after SARS-CoV-2 in pregnancy according to disease severity: A nationwide cohort study with validation of the SARS-CoV-2 diagnosis.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark. MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers. RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs < 22: RR 3.53, 95% CI 1.75-7.10). SARS-CoV-2-infected women more frequently had hypertensive disorders in pregnancy (adjusted hazard ratio [aHR] 1.31, 95% CI 1.04-1.64), early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88), preterm delivery before gestational age 28 (aHR 2.31, 95% CI 1.01-5.26), iatrogenically preterm delivery before gestational age 37 (aHR 1.49, 95% CI 1.01-2.19) and small-for-gestational age children (aHR 1.28, 95% CI 1.05-1.54). The associations were stronger among women admitted to hospital for any reason. The validity of the SARS-CoV-2 diagnosis in relation to pregnancy in the registers compared with medical records showed a negative predictive value of 99.9 (95% CI 99.9-100.0) and a positive predictive value of 82.1 (95% CI 80.4-83.7). CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

Preterm birth, stillbirth and early neonatal mortality during the Danish COVID-19 lockdown.

Using provisional or opportunistic data, three nationwide studies (The Netherlands, the USA and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, none of the studies accounted for perinatal deaths. To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be the result of an increase in perinatal deaths and to assess the impact of extended COVID-19 restrictions, we performed a nationwide Danish register-based prevalence proportion study. We examined all singleton pregnancies delivered in Denmark during the COVID-19 strict lockdown calendar periods (March 12-April 14, 2015-2020, N = 31,164 births) and the extended calendar periods of COVID-19 restrictions (February 27-September 30, 2015-2020, N = 214,862 births). The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period in 2020, while perinatal mortality was not significantly different. During the extended period of restrictions in 2020, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.Conclusion: Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support the design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes. What is Known: • The aetiologies of preterm birth and stillbirth are multifaceted and linked to a wide range of socio-demographic, medical, obstetric, foetal, psychosocial and environmental factors. • The COVID-19 lockdown saw a reduction in extremely preterm births in Denmark and other high-income countries. An urgent question is whether this reduction can be explained by increased perinatal mortality. What is New: • The reduction in extremely preterm births during the Danish COVID-19 lockdown was not a consequence of increased perinatal mortality, which remained unchanged during this period. • The stillbirth rate was reduced throughout the extended period of COVID-19 restrictions.

The perinatal health challenges of emerging and re-emerging infectious diseases: A narrative review.

The world has seen numerous infectious disease outbreaks in the past decade. In many cases these outbreaks have had considerable perinatal health consequences including increased risk of preterm delivery (e.g., influenza, measles, and COVID-19), and the delivery of low birth weight or small for gestational age babies (e.g., influenza, COVID-19). Furthermore, severe perinatal outcomes including perinatal and infant death are a known consequence of multiple infectious diseases (e.g., Ebola virus disease, Zika virus disease, pertussis, and measles). In addition to vaccination during pregnancy (where possible), pregnant women, are provided some level of protection from the adverse effects of infection through community-level application of evidence-based transmission-control methods. This review demonstrates that it takes almost 2 years for the perinatal impacts of an infectious disease outbreak to be reported. However, many infectious disease outbreaks between 2010 and 2020 have no associated pregnancy data reported in the scientific literature, or pregnancy data is reported in the form of case-studies only. This lack of systematic data collection and reporting has a negative impact on our understanding of these diseases and the implications they may have for pregnant women and their unborn infants. Monitoring perinatal health is an essential aspect of national and global healthcare strategies as perinatal life has a critical impact on early life mortality as well as possible effects on later life health. The unpredictable nature of emerging infections and the potential for adverse perinatal outcomes necessitate that we thoroughly assess pregnancy and perinatal health implications of disease outbreaks and their public health interventions in tandem with outbreak response efforts. Disease surveillance programs should incorporate perinatal health monitoring and health systems around the world should endeavor to continuously collect perinatal health data in order to quickly update pregnancy care protocols as needed.

Maternal obesity and metabolic disorders associate with congenital heart defects in the offspring: A systematic review.

BACKGROUND: Congenital heart defects (CHDs) are the most common congenital malformations. The aetiology of CHDs is complex. Large cohort studies and systematic reviews and meta-analyses based on these have reported an association between higher risk of CHDs in the offspring and individual maternal metabolic disorders such as obesity, diabetes, hypertension, and preeclampsia, all conditions that can be related to insulin resistance or hyperglycaemia. However, the clinical reality is that these conditions often occur simultaneously. The aim of this review is, in consequence, both to evaluate the existing evidence on the association between maternal metabolic disorders, defined as obesity, diabetes, hypertension, preeclampsia, dyslipidaemia and CHDs in the offspring, as well as the significance of combinations, such as metabolic syndrome, as risk factors. METHODS: A systematic literature search of papers published between January 1, 1990 and January 14, 2021 was conducted using PubMed and Embase. Studies were eligible if they were published in English and were case-control or cohort studies. The exposures of interest were maternal overweight or obesity, hypertension, preeclampsia, diabetes, dyslipidaemia, and/or metabolic syndrome, and the outcome of interest was CHDs in the offspring. Furthermore, the studies were included according to a quality assessment score. RESULTS: Of the 2,250 identified studies, 32 qualified for inclusion. All but one study investigated only the individual metabolic disorders. Some disorders (obesity, gestational diabetes, and hypertension) increased risk of CHDs marginally whereas pre-gestational diabetes and early-onset preeclampsia were strongly associated with CHDs, without consistent differences between CHD subtypes. A single study suggested a possible additive effect of maternal obesity and gestational diabetes. CONCLUSIONS: Future studies of the role of aberrations of the glucose-insulin homeostasis in the common aetiology and mechanisms of metabolic disorders, present during pregnancy, and their association, both as single conditions and-particularly-in combination, with CHDs are needed.

Danish premature birth rates during the COVID-19 lockdown.

To explore the impact of COVID-19 lockdown on premature birth rates in Denmark, a nationwide register-based prevalence proportion study was conducted on all 31 180 live singleton infants born in Denmark between 12 March and 14 April during 2015-2020.The distribution of gestational ages (GAs) was significantly different (p=0.004) during the lockdown period compared with the previous 5 years and was driven by a significantly lower rate of extremely premature children during the lockdown compared with the corresponding mean rate for the same dates in the previous years (OR 0.09, 95% CI 0.01 to 0.40, p<0.001). No significant difference between the lockdown and previous years was found for other GA categories.The reasons for this decrease are unclear. However, the lockdown has provided a unique opportunity to examine possible factors related to prematurity. Identification of possible causal mechanisms might stimulate changes in clinical practice.

Moderate-intensity aerobic exercise improves physical fitness in bethlem myopathy.

INTRODUCTION: Bethlem myopathy is caused by dysfunctional collagen VI assembly, leading to varying degrees of hyperlaxity, contractures and muscle weakness. Previous studies demonstrate that cardiovascular training is safe and beneficial in patients with myopathies. However, exercise exacerbates the dystrophic phenotype in collagen VI-knockout mice. METHODS: Six men with Bethlem myopathy were included (4 training; 2 controls). After training, 2 patients detrained. Patients performed 10 weeks of home-based, moderate-intensity exercise monitored by a pulse-watch. The primary outcome was change in peak oxygen uptake (VO2peak ). Secondary outcomes were performances in functional tests. RESULTS: VO2peak improved in the training group (16%, P = 0.017). Detraining led to regression of VO2peak toward baseline values (-8%; P = 0.03). No change was seen in the control group (-7%; P = 0.47). Performance in functional tests did not change significantly. Creatine kinase values were stable during the study. CONCLUSIONS: Moderate-intensity exercise seems to safely improve oxidative function in patients with Bethlem myopathy. Muscle Nerve 60: 183-188, 2019.

Muscle contractility of leg muscles in patients with mitochondrial myopathies.

BACKGROUND: The primary disease mechanism underlying mitochondrial myopathies (MM) is impaired energy generation to support muscle endurance. Little is known about muscle contractility before energy becomes deficient during muscle contractions. We investigated muscle contractility in MM to uncover potentially fixed weakness aspects of the disorders. METHODS: Contractility of calf and thigh muscles was investigated by comparing strength with contractile cross-sectional area (CCSA) of the used muscles, as measured by stationary dynamometry and MRI, respectively. RESULTS AND DISCUSSION: Our findings suggest reduced contractile properties in thigh and calf muscles of patients with MM.

L-Carnitine Improves Skeletal Muscle Fat Oxidation in Primary Carnitine Deficiency.

Context: Primary carnitine deficiency (PCD) is an inborn error of fatty acid metabolism. Patients with PCD are risk for sudden heart failure upon fasting or illness if they are not treated with daily l-carnitine. Objective: To investigate energy metabolism during exercise in patients with PCD with and without l-carnitine treatment. Design: Interventional study. Setting: Hospital exercise laboratories and department of cardiology. Participants: Eight adults with PCD who were homozygous for the c.95A>G (p.N32S) mutation and 10 healthy age- and sex-matched controls. Intervention: Four-day pause in l-carnitine treatment. Main outcome measures: Total fatty acid and palmitate oxidation rates during 1-hour submaximal cycle ergometer exercise assessed with stable isotope method (U13C-palmitate and 2H2-d-glucose) and indirect calorimetry with and without l-carnitine. Results: Total fatty acid oxidation rate was higher in patients with l-carnitine treatment during exercise than without treatment [12.3 (SD, 3.7) vs 8.5 (SD, 4.6) µmol × kg-1 × min-1; P = 0.008]. However, the fatty acid oxidation rate was still lower in patients treated with l-carnitine than in the healthy controls [29.5 (SD, 10.1) µmol × kg-1 × min-1; P < 0.001] and in the l-carnitine group without treatment it was less than one third of that in the healthy controls (P < 0.001). In line with this, the palmitate oxidation rates during exercise were lower in the no-treatment period [144 (SD, 66) µmol × kg-1 × min-1] than during treatment [204 (SD, 84) µmol × kg-1 × min-1; P = 0.004) . Conclusions: The results indicate that patients with PCD have limited fat oxidation during exercise. l-Carnitine treatment in asymptomatic patients with PCD may not only prevent cardiac complications but also boost skeletal muscle fat metabolism during exercise.

Progressive fat replacement of muscle contributes to the disease mechanism of patients with single, large-scale deletions of mitochondrial DNA.

Muscle dysfunction in mitochondrial myopathy is predominantly caused by insufficient generation of energy. We hypothesise that structural changes in muscles could also contribute to their pathophysiology. The aims of this study were to determine fat fractions and strength in selected muscles in patients with chronic progressive external ophthalmoplegia (CPEO), and compare progression of muscle fat fraction with age in individuals with CPEO vs. healthy controls and patients with the m.3243A>G mutation of mitochondrial DNA (mtDNA). Seventeen patients with CPEO and single large-scale deletions of mtDNA, 52 healthy controls, and 12 patients carrying the m.3243A>G mtDNA mutation were included. Muscle fat fractions were measured from cross-sections of paraspinal and leg muscles. Peak muscle strength was assessed from a static dynamometer. There was a direct correlation between age and fat fraction in all muscle groups in CPEO patients and healthy controls (p < 0.05). Analysis of covariance showed a higher progression rate of fat replacement in CPEO patients vs. healthy controls in studied muscle groups (p < 0.05). Patients with the m.3243A>G mutation had slower progression rates of fat replacement. Muscle strength decreased with increasing muscular fat fraction in CPEO patients, no correlation was seen in other groups. This indicates that structural muscle changes contribute to the phenotype of older patients affected by CPEO and large-scale deletions. It should therefore be considered, along with known energy deficiencies, as the cause of exercise intolerance.

The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study.

Mexiletine is the only drug with proven effect for treatment of non-dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non-dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non-dystrophic myotonias. In this, randomized double-blind, placebo-controlled, two-period cross-over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8-week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013-003309-24). We included 26 patients (10 females, 16 males, age: 19-74 years) from 13 November 2013 to 6 July 2015. Twenty-two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5-1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2-1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient-related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment-naive patients with non-dystrophic myotonias.

Skeletal muscle metabolism during prolonged exercise in Pompe disease.

OBJECTIVE: Pompe disease (glycogenosis type II) is caused by lysosomal alpha-glucosidase deficiency, which leads to a block in intra-lysosomal glycogen breakdown. In spite of enzyme replacement therapy, Pompe disease continues to be a progressive metabolic myopathy. Considering the health benefits of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. METHODS: Seven adults with Pompe disease were matched to a healthy control group (1:1). We determined (1) peak oxidative capacity (VO2peak) and (2) carbohydrate and fatty acid metabolism during submaximal exercise (33 W) for 1 h, using cycle-ergometer exercise, indirect calorimetry and stable isotopes. RESULTS: In the patients, VO2peak was less than half of average control values; mean difference -1659 mL/min (CI: -2450 to -867, P = 0.001). However, the respiratory exchange ratio increased to >1.0 and lactate levels rose 5-fold in the patients, indicating significant glycolytic flux. In line with this, during submaximal exercise, the rates of oxidation (ROX) of carbohydrates and palmitate were similar between patients and controls (mean difference 0.226 g/min (CI: 0.611 to -0.078, P = 0.318) and mean difference 0.016 µmol/kg/min (CI: 1.287 to -1.255, P = 0.710), respectively). CONCLUSION: Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes.

Fat Replacement of Paraspinal Muscles with Aging in Healthy Adults.

PURPOSE: The aims of this study were to investigate the age-related changes in fatty replacement and cross-sectional area (CSA) of cervical, thoracic, and lumbar paraspinal muscles versus leg muscles in healthy adults and to test for association between muscle fat fraction and lifestyle factors. METHODS: Fifty-three healthy adults (24-76 yr) were included. Dixon magnetic resonance imaging technique was used to determine CSA and to quantify the fat fraction of paraspinal and leg muscles. Muscle CSA and fat fractions were tested for association with age and muscle strength. The fat fractions were also tested for association with sex, body mass index (BMI), physical activity, and lower back pain. RESULTS: Both paraspinal and leg fat fractions correlated directly with age (P < 0.0001). At all ages, fat fraction was higher in paraspinal than leg muscles. The age-related increase in fat fraction was higher in paraspinal muscles than leg muscles (P < 0.0001). The CSA of the muscles did not correlate with age. Knee extension strength correlated with fat fraction (P < 0.05), and the muscle strength of hip muscles, thigh muscles, and anterior calf muscles correlated with CSA (P < 0.05). Sex was associated with lumbar paraspinal fat fraction (P < 0.05) and BMI with thigh fat fraction (P < 0.001). There was no association between fat fraction and physical activity or lower back pain. CONCLUSION: The paraspinal muscles were more susceptible to age-related changes than leg muscles. Further, men had significantly lower fat fractions in lumbar paraspinal muscles, and BMI was positively associated with thigh, but not paraspinal, fat fraction.

Dysphagia is prevalent in patients with CPEO and single, large-scale deletions in mtDNA.

BACKGROUND: The aim of this study was to assess the frequency of subjective and objective dysphagia in patients with chronic progressive external ophthalmoplegia (CPEO) due to single, large-scale deletions (LSDs) of mitochondrial DNA (mtDNA). METHODS: Sixteen patients with CPEO and single LSDs of mtDNA were included in the study and compared to a control group of 12 patients with the m.3243A>G mtDNA mutation. Patients had to drink 80ml of water at 4°C as fast as they could (cold-water test) and fill out a standardized questionnaire about dysphagia. RESULTS: Eight patients (50%) with CPEO and single LSDs of mtDNA had a prolonged cold-water test, including one with a PEG-tube, who was unable to perform the test, and nine patients reported subjective swallowing problems (56.3%). All mitochondrial myopathy patients in the control group had a normal duration of the cold-water test. CONCLUSIONS: The study shows that dysphagia is a common problem in patients with CPEO and LSDs of mtDNA. Dysphagia seems to be progressive with age as abnormal swallowing occurred preferentially in persons ≥45years. The study shows that increased awareness of this symptom should be given to address appropriate treatment interventions and avoid complications such as social isolation, malnutrition and aspiration pneumonia.

Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I.

We investigated whether a linear relationship between muscle strength and cross-sectional area (CSA) is preserved in calf muscles of patients with Becker muscular dystrophy (BMD, n = 14) and limb-girdle type 2I muscular dystrophy (LGMD2I, n = 11), before and after correcting for muscle fat infiltration. The Dixon magnetic resonance imaging technique was used to quantify fat and calculate a fat-free contractile CSA. Strength was assessed by dynamometry. Muscle strength/CSA relationships were significantly lower in patients versus controls. The strength/contractile-CSA relationship was still severely lowered in BMD, but was almost normalized in LGMD2I. Our findings suggest close to intact contractile properties in LGMD2I, which are severely disrupted in BMD. Ann Neurol 2016;80:466-471.

Aerobic Training in Patients with Congenital Myopathy.

INTRODUCTION: Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and beneficial in patients with CM. METHODS: Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at 70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy. RESULTS: Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range, 6-25%; 95% CI 7-20; p < 0.001) in the seven patients who completed training, and tended to decrease in a non-intervention group (n = 7; change -3.5%; range, -11-3%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine patients dropped out of the training program. Fatigue was the major single reason. CONCLUSIONS: Ten weeks of endurance training is safe and improves fitness in patients with congenital myopathies. The training did not cause sarcomeric injury, even though sarcomeric function is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to improve in those who train. TRIAL REGISTRATION: The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2-2013-066 and ClinicalTrials.gov H2-2013-066.

Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III.

OBJECTIVE: Glycogen storage disease type IIIa (GSDIIIa) is classically regarded as a glycogenosis with fixed weakness, but we hypothesized that exercise intolerance in GSDIIIa is related to muscle energy failure and that oral fructose ingestion could improve exercise tolerance in this metabolic myopathy. METHODS: We challenged metabolism with cycle-ergometer exercise and measured substrate turnover and oxidation rates using stable isotope methodology and indirect calorimetry in 3 patients and 6 age-matched controls on 1 day, and examined the effect of fructose ingestion on exercise tolerance in the patients on another day. RESULTS: Total fatty acid oxidation rates during exercise were higher in patients than controls, 32.1 (SE 1.2) vs 20.7 (SE 0.5; range 15.8-29.3) µmol/kg/min (p = 0.048), and oxidation of carbohydrates was lower in patients, 1.0 (SE 5.4) vs 38.4 (SE 8.0; range 23.0-77.1) µmol/kg/min (p = 0.024). Fructose ingestion improved exercise tolerance in the patients. CONCLUSION: Similar to patients with McArdle disease, in whom muscle glycogenolysis is also impaired, GSDIIIa is associated with a reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation, and fructose ingestion improves exercise tolerance. Our results indicate that GSDIIIa should not only be viewed as a glycogenosis with fixed skeletal muscle weakness, but should also be considered among the glycogenoses presenting with exercise-related dynamic symptoms caused by muscular energy deficiency. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ingestion of fructose improves exercise tolerance in patients with GSDIIIa.