Julia R. Dahlqvist

Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy

Objective: In this study, involvement of paraspinal muscles in 50 patients with facioscapulohumeral dystrophy (FSHD) was evaluated using MRI. Methods: The Dixon MRI technique was used in this observational study to quantify muscle fat content of paraspinal and leg muscles. Muscle strength in the neck, back, and legs was assessed with a handheld dynamometer. All subjects completed the Low Back Pain Rating Scale questionnaire. MRI findings were compared with 31 age-matched controls and correlated to muscle strength, back pain, and MRI findings in lower extremities. Results: The fat fraction in muscles was significantly higher in patients with FSHD than in controls: paraspinal fat fraction was 38% in patients vs 20% in controls, thigh fat fraction was 36% vs 11%, and calf fat fraction was 37% vs 11%. Increased paraspinal fat fraction correlated with D4Z4 repeat size, FSHD severity score, fat fraction of the thigh, and muscle strength in the back. The prevalence of back pain was 3 times higher in patients with FSHD vs controls, but back pain did not correlate with the paraspinal fat fraction. Conclusions: This study shows a prominent involvement of paraspinal muscles in patients with FSHD, which should be considered in the management of this condition.

Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

Objective: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease. Methods: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed. Results: Thirty-two patients were included (16 male, 16 female; age 7–67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation. Conclusions: This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.

Aerobic training and postexercise protein in facioscapulohumeral muscular dystrophy RCT study

Objective: To investigate the effect of regular aerobic training and postexercise protein-carbohydrate supplementation in patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: In this randomized, double-blind, placebo-controlled parallel study, we randomized untrained men (n = 21) and women (n = 20) with FSHD (age 19–65 years) to 2 training groups—training with protein supplement (n = 18) and training with placebo supplement (n = 13)—and a nonintervention control group (n = 10). We assessed fitness, walking speed, muscle strength, questionnaires, and daily activity levels before and after 12 weeks of interventions. Training involved 36 sessions of 30-minute cycle-ergometer training. After each session, patients drank either a protein-carbohydrate or placebo beverage. Results: In the trained participants, fitness, workload, and walking speed improved (10% [confidence interval (CI) 4%–15%], 18% [CI 10%–26%], 7% [CI 4%–11%], respectively, p < 0.001, number needed to treat = 2.1). Self-assessed physical capacity and health (Short Form–36) also improved. Muscle strength and daily activity levels did not change with training. Protein-carbohydrate supplementation did not result in further improvements in any tests compared to training alone. Conclusions: This randomized, controlled study showed that regular endurance training improves fitness, walking speed, and self-assessed health in patients with FSHD without causing muscle damage. Postexercise protein-carbohydrate supplementation does not add any further improvement to training effects alone. Classification of evidence: This study provides Class II evidence that regular aerobic training with or without postexercise protein-carbohydrate supplementation improves fitness and workload in patients with FSHD.

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.

A pilot study of muscle plasma protein changes after exercise

Introduction: Creatine kinase (CK) and myoglobin (Mb) do not possess all good qualities as biomarkers of skeletal muscle damage. We investigated the utility of troponin I (TnI) and telethonin (Tcap) as markers and examined their temporal profiles after skeletal muscle damage. Methods: Plasma profiles were measured before and after exercise in 3 groups: subjects affected by either Becker muscular dystrophy or McArdle disease, and healthy subjects. Results: Mb and TnI appeared early in the blood, and the increase of TnI was only observed in patients with muscle disease. The CK increase was more delayed in plasma. Tcap was not detectable at any time. Conclusions: Our results suggest that TnI is a marker of more severe damage signifying sarcomeric damage, and it could therefore be an important supplement to CK and Mb in clinical practice. Tcap is not useful as a marker for skeletal muscle damage. Muscle Nerve 49: 261–266, 2014

Endocrine function over time in patients with myotonic dystrophy type 1.

Patients with myotonic dystrophy type 1 (DM1) have an increased incidence of endocrine dysfunction. In this study, the temporal evolution of endocrine dysfunction in patients with DM1 was investigated.

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.

Muscle biopsies off-set normal cellular signaling in surrounding musculature.

Studies of muscle physiology and muscular disorders often require muscle biopsies to answer questions about muscle biology. In this context, we have often wondered if muscle biopsies, especially if performed repeatedly, would affect interpretation of muscle morphology and cellular signaling. We hypothesized that muscle morphology and cellular signaling involved in myogenesis/regeneration and protein turnover can be changed by a previous muscle biopsy in close proximity to the area under investigation. Here we report a case where a past biopsy or biopsies affect cellular signaling of the surrounding muscle tissue for at least 3 weeks after the biopsy was performed and magnetic resonance imaging suggests that an effect of a biopsy may persist for at least 5 months. Cellular signaling after a biopsy resembles what is seen in severe limb-girdle muscular dystrophy type 2I with respect to protein synthesis and myogenesis despite normal histologic appearance.

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.

Collagen XII myopathy with rectus femoris atrophy and collagen XII retention in fibroblasts: Findings in Collagen XII Myopathy

Introduction: Mutation in the collagen XII gene (COL12A1) was recently reported to induce Bethlem myopathy. We describe a family affected by collagen XII‐related myopathy in 3 generations. Methods: Systematic interview, clinical examination, skin biopsies, and MRI of muscle were used. Results: The phenotype was characterized by neonatal hypotonia, contractures, and delayed motor development followed by resolution of contractures and a motor performance limited by reduced endurance. DNA analyses revealed a novel donor splice‐site mutation in COL12A1 (c.8100 + 2T>C), which segregated with clinical affection and abnormal collagen XII retention in fibroblasts. MRI disclosed a selective wasting of the rectus femoris muscle. Discussion: COL12A1 mutations should be considered in patients with a mild Bethlem phenotype who present with selective wasting of the rectus femoris, absence of the outside‐in phenomenon on MRI, and abnormal collagen XII retention in fibroblasts. Muscle Nerve 57: 1026–1030, 2018