Muscle Fat Replacement Research Articles

Lessons for future clinical trials in adults with Becker muscular dystrophy: Disease progression detected by muscle magnetic resonance imaging, clinical and patient-reported outcome measures.

Because Becker muscular dystrophy (BMD) is a heterogeneous disease and only few studies have evaluated adult patients, it is currently still unclear which outcome measures should be used in future clinical trials. Muscle magnetic resonance imaging, patient-reported outcome measures and a wide range of clinical outcome measures, including motor function, muscle strength and timed-function tests, were evaluated in 21 adults with BMD at baseline and at 9 and 18 months of follow-up. Proton density fat fraction increased significantly in 10/17 thigh muscles after 9 months, and in all thigh and lower leg muscles after 18 months. The 32-item Motor Function Measurement (MFM-32) scale (-1.3%, p = 0.017), North Star Ambulatory Assessment (-1.3 points, p = 0.010) and patient-reported activity limitations scale (-0.3 logits, p = 0.018) deteriorated significantly after 9 months. The 6-min walk distance (-28.7 m, p = 0.042), 10-m walking test (-0.1 m/s, p = 0.032), time to climb four stairs test (-0.03 m/s, p = 0.028) and Biodex peak torque measurements of quadriceps (-4.6 N m, p = 0.014) and hamstrings (-5.0 N m, p = 0.019) additionally deteriorated significantly after 18 months. At this timepoint, domain 1 of the MFM-32 was the only clinical outcome measure with a large sensitivity to change (standardized response mean 1.15). It is concluded that proton density fat fraction imaging of entire thigh muscles is a sensitive outcome measure to track progressive muscle fat replacement in patients with BMD, already after 9 months of follow-up. Finally, significant changes are reported in a wide range of clinical and patient-reported outcome measures, of which the MFM-32 appeared to be the most sensitive to change in adults with BMD.

Contractile properties and magnetic resonance imaging-assessed fat replacement of muscles in myotonia congenita.

Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients. Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole-body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross-sectional area (PT/CCSA). Muscle contractility was compared with clinical data. Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0-14.3% vs. 5.3-9.6%, PT/CCSA = 1.1-4.9 Nm/cm2 vs. 1.9-5.8 Nm/cm2 [p < 0.05]). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm2 vs. 3.2 Nm/cm2 [p < 0.05]). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms. Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms.

Hypokalemic periodic paralysis: a 3-year follow-up study

Background and objectivesPrimary hypokalemic periodic paralysis (HypoPP) is an inherited channelopathy most commonly caused by mutations in CACNA1S. HypoPP can present with different phenotypes: periodic paralysis (PP), permanent muscle weakness (PW), and mixed weakness (MW) with both periodic and permanent weakness. Little is known about the natural history of HypoPP.MethodsIn this 3-year follow-up study, we used the MRC scale for manual muscle strength testing and whole-body muscle MRI (Mercuri score) to assess disease progression in individuals with HypoPP-causing mutations in CACNA1S.ResultsWe included 25 men (mean age 43 years, range 18–76 years) and 12 women (mean age 42 years, range 18–76 years). Two participants were asymptomatic, 21 had PP, 12 MW, and two PW. The median number of months between baseline and follow-up was 42 (range 26–52). Muscle strength declined in 11 patients during follow-up. Four of the patients with a decline in muscle strength had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. Fat replacement of muscles increased in 27 patients during follow-up. Eight of the patients with increased fat replacement had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis.DiscussionThe study demonstrates that HypoPP can be a progressive myopathy in both patients with and without attacks of paralysis.

Muscle magnetic resonance imaging of a large cohort of distal hereditary motor neuropathies reveals characteristic features useful for diagnosis

Distal motor neuropathies (dHMN) are an heterogenous group of diseases characterized by progressive muscle weakness affecting predominantly the distal muscles of the lower and upper limbs. Our aim was to study the imaging features and pattern of muscle involvement in muscle magnetic resonance imaging (MRI) in dHMN patients of suspected genetic origin (dHMN). We conducted a retrospective study collecting clinical, genetic and muscle imaging data. Muscle MRI included T1-weighted and T2 weighted Short Tau Inversion Recovery images (STIR-T2w) sequences. Muscle replacement by fat was quantified using the Mercuri score. Identification of selective patterns of involvement was performed using hierarchical clustering. Eighty-four patients with diagnosis of dHMN were studied. Fat replacement was predominant in the distal lower leg muscles (82/84 cases), although also affected thigh and pelvis muscles. Asymmetric involvement was present in 29% of patients. The superficial posterior compartment of the leg, including the soleus and gastrocnemius muscles, was the most affected area (77/84). We observed a reticular pattern of fatty replacement progressing towards what is commonly known as “muscle islands” in 79.8%. Hyperintensities in STIR-T2w were observed in 78.6% patients mainly in distal leg muscles. Besides features common to all individuals, we identified and describe a pattern of muscle fat replacement characteristic of BICD2, HSPB1 and DYNC1H1 patients. We conclude that muscle MRI of patients with suspected dHMN reveals common features helpful in diagnosis process.

Muscle fat replacement and contractility in patients with skeletal muscle sodium channel disorders

Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74–4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75–3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14–27% (p < 0.05). Despite greater fat fraction and less contractility, absolute strength was not significantly less. This study quantitatively documents greater fat fraction and additionally describes difference in muscle contractility in a large cohort of patients with skeletal muscle sodium channel disorders. The clinical impact of these abnormal findings is likely limited as muscle hypertrophy in the patients served to preserve absolute muscle strength. Subgroup analysis indicated significant difference in phenotype by genotype, however these findings lack statistical significance and serve as inspiration for future researchers to probe into the geno- phenotype relationship in these disorders.Trial registration: The study was registered at http://clinicaltrials.gov (identifier: NCT04808388).

Reader Response: Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures.

De Wel et al. conducted a prospective study to evaluate prognosis in 24 patients with limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12).1 They prepared 24 healthy controls by way of an age- and sex-matching procedure. Biodex(R) isometric dynamometry showed a significant decrease of muscle strength in the right quadricep muscles for all patients after 1 year. In contrast, outcomes from the 6-minute walk distance, 10-meter walk test, and Medical Research Council sum scores did not change significantly, even after 2 years. The authors recognized that thigh muscle proton density fat fraction imaging was a sensitive indicator to track progressive muscle fat replacement.

Quantitative vs qualitative muscle MRI: Imaging biomarker in patients with Oculopharyngeal Muscular Dystrophy (OPMD)

Oculopharyngeal muscular dystrophy (OPMD) is a genetic muscle disease causing ptosis, severe swallowing difficulties and progressive limb weakness, although atypical presentations may be difficult to diagnose. Sensitive biomarkers of disease progression in OPMD are needed to enable more effective clinical trials. This study was designed to test the feasibility of using MRI to aid OPMD diagnosis and monitor OPMD progression. Twenty-five subjects with Dixon whole-body muscle MRI were enrolled: 10 patients with genetically confirmed OPMD, 10 patients with non-OPMD muscular dystrophies, and 5 controls. Using the MRI Dixon technique, muscle fat replacement was evaluated in the tongue, serratus anterior, lumbar paraspinal, adductor magnus, and soleus muscles using quantitative and semi-quantitative rating methods. Changes were compared with muscle strength testing, dysphagia severity, use of gait aids, and presence of dysarthria. Quantitative MRI scores of muscle fat replacement in the tongue could differentiate OPMD from other muscular dystrophies and from controls. Moreover, fat fraction in the tongue correlated with clinical severity of dysphagia. This study provides preliminary support for the use of Dixon-based quantitative MRI images as outcome measures for monitoring disease progression in clinical trials and provides rationale for future prospective studies aimed at methodological refinement and covariate identification.

FP.19 Quantification of glycogen distribution in late-onset Pompe patients using 7 Tesla C13 NMR spectroscopy

Pompe disease is an autosomal recessive disorder, caused by acid alpha-glucosidase deficiency, which limits the lysosomal breakdown of glycogen, causing accumulation in muscle tissue. Pompe patients suffer from fat replacement of muscle tissue and muscle atrophy, leading to muscle weakness. MRI studies have shown a characteristic pattern with fat replacement of the axial muscles (latissimus dorsi, paraspinal muscles and psoas) and the hamstrings (especially semimembranosus), while distal muscles, and muscles of the anterior thigh compartment are less affected. The aim of this study is to investigate if higher levels of muscle glycogen precede the fat replacement of muscles in Pompe disease. We used C13 NMR spectroscopy at 7 Tesla, to measure the total glycogen value in four muscle groups; the lumbar muscles, the anterior compartment of the thigh, the hamstrings and the calf. The fat-free muscle volume was found using T1 and Dixon sequences and the glycogen concentrations were determined as the total glycogen levels divided by the fat-free muscle volume of distribution. Young Pompe patients with relatively preserved muscles and healthy controls were included. Preliminary results from the first two patients show a higher glycogen concentration in the lumbar and hamstring muscles than in the anterior compartment of the thigh and the calf. Compared to the calf, the glycogen concentration was about fifty percent higher in the lumbar muscles, and twice as high in the hamstrings. Hamstrings had twice as high glycogen levels compared to the anterior compartment of the thigh. Compared to eight healthy controls, the glycogen concentration was 2-3 times higher in all muscle groups of the patients. No clear pattern of muscle glycogen distribution was seen in the control group. These preliminary results indicate a link between high levels of glycogen accumulation in muscle tissue and the subsequent late pattern of fat replacement in Pompe diseases. This is important for the understanding of pathogenesis of muscle wasting in Pompe disease, but could also be an important biomarker for treatment success.

FP.09 Analysis of muscle MRI of a large cohort of chronic motor neuropathy/neuronopathy patients reveals characteristic features useful for diagnosis

Chronic motor neuropathy/neuronopathy (CMNs) encompass a group of rare diseases characterized by muscle weakness mainly affecting distal muscles of the limbs. Muscle magnetic resonance imaging (MRI) can be a useful tool for the diagnostic workup but has not been explored systematically in these patients. This is a retrospective study collecting clinical, genetic and imaging data. Muscle MRI included T1-weighted and Short Tau Inversion Recovery (STIR) sequences. Fat replacement was quantified using the Mercuri score. Identification of patterns was performed using hierarchical clustering. We included 76 patients with a clinical and electrophysiological diagnosis of CMN. A pathogenic gene variant was identified in 29 subjects, a VUS was identified in 15 and 32 subjects remained without molecular diagnosis. We collected 25 whole-body and 51 lower limb (LL) MRIs. All patients but one had pathological findings. We identified features common to all patients regardless of the genetic diagnosis. Muscle fat replacement was predominant in the LL distal muscles (75/76 cases), but also affected the thigh in 59, the pelvis in 18 and the trunk/upper limb muscles in seven. The posterior compartment of the leg, including soleus and gastrocnemius, was the most affected (71/76) followed by the peronei (63/76). Asymmetric involvement was found in 19 patients. A distal to proximal gradient of fat replacement was observed in 39 patients (52%). Texture analysis showed a reticular pattern or "muscle islets" in 63 patients (83%). Hyperintensities on STIR were observed in 49/59 and were predominantly located in the distal LL muscles. A distal to proximal gradient in STIR was observed in 25 subjects. Besides features common to all individuals, we identified a pattern of muscle fat replacement characteristic of BICD2 and HSPB1 patients. We did not identify a correlation between fat content and age, disease duration or motor functionality. Muscle MRI of CMN patients reveals common features that could be helpful for the diagnosis of patients. We have observed a pattern of MRI involvement characteristic of patients with mutations in specific genes. There was no correlation between fat content and functional status or time of disease progression.

Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures.

Limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12) is a rare hereditary muscular dystrophy for which outcome measures are currently lacking. We evaluated quantitative MRI and clinical outcome measures to track disease progression to determine which tests could be useful in future clinical trials to evaluate potential therapies. We prospectively measured the following outcome measures in all participants at baseline and after 1 and 2 years: 6-minute walk distance (6MWD), 10-meter walk test (10MWT), the Medical Research Council (MRC) sum scores, Biodex isometric dynamometry, serum creatine kinase, and 6-point Dixon MRI of the thighs. We included 24 genetically confirmed, adult patients with LGMDR12 and 24 age-matched and sex-matched healthy controls. Patients with intermediate-stage thigh muscle fat replacement at baseline (proton density fat fraction [PDFF] 20%-70%) already showed an increase in PDFF in 8 of the 14 evaluated thigh muscles after 1 year. The standardized response mean demonstrated a high responsiveness to change in PDFF for 6 individual muscles over 2 years in this group. However, in patients with early-stage (<20%) or end-stage (>70%) muscle fat replacement, PDFF did not increase significantly over 2 years of follow-up. Biodex isometric dynamometry showed a significant decrease in muscle strength in all patients in the right and left hamstrings (-6.2 Nm, p < 0.002 and -4.6 Nm, p < 0.009, respectively) and right quadriceps muscles (-9 Nm, p = 0.044) after 1 year of follow-up, whereas the 6MWD, 10MWT, and MRC sum scores were not able to detect a significant decrease in muscle function/strength even after 2 years. There was a moderately strong correlation between total thigh PDFF and clinical outcome measures at baseline. Thigh muscle PDFF imaging is a sensitive outcome measure to track progressive muscle fat replacement in selected patients with LGMDR12 even after 1 year of follow-up and correlates with clinical outcome measures. Biodex isometric dynamometry can reliably capture the loss of muscle strength over the course of 1 year in patients with LGMDR12 and should be included as an outcome measure in future clinical trials as well.

P 89 Evaluating correlations of muscle MRI derived fat fractions of leg muscles and clinical outcome measurements in patients with LGMD2A

1. Introduction: Quantitative MRI (qMRI) techniques like Dixon fat fraction (FF) are a promising non-invasive tool in the evaluation of neuromuscular diseases [1]. Increase of FF has been shown to precede clinical deterioration of muscle function in different longitudinal studies [2]. In this study we aimed to analyse Dixon fat fraction of calf and thigh muscles in a cohort of patients with genetically confirmed LGMD Type 2A and to correlate the quantitative values FF with clinical findings and daily life activities assessed by questionnaires. 2. Methods: In total, 19 individuals with genetically confirmed LGMD2A (10 females, mean age 39.8 ± 13.4 years) and 19 age- and gender-matched healthy volunteers (10 females, mean age 39.2 ± 12.6 years) participated in this study. Clinical assessments included Quick Motor Function Measure (QMFM), the 6-Minute Walk Test (6-MWT), time to walk 10 meters (T10m) and timed up- and-go test (TUG) and the assessments of daily life activities by the ACTIVLIM and the Neuromuscular Symptom Score [3]. All participants underwent a 3T MRI acquiring Dixon sequences of both legs. Fat fractions of quadriceps, hamstrings, dorsi extensors and plantar flexors were calculated. Pearson and Spearman rank correlation coefficients were calculated between FF and clinical outcome measurements in both groups and daily life activities in LGMD group. 3. Results: We found significant moderate to strong correlations between FF and gait measurements for all muscle groups (r ≥ 0.646, p < 0.001) and moderate to high correlation of daily activities and FF (r ≥ 0.550, p < 0.001). An ANOVA revealed significant differences of FF between LGMD and healthy control group (Main Effect: p < 0.001). 4. Discussion: Advanced qMRI techniques like Dixon FF can offer quantitative information about fat infiltration and inflammation. In this study FF in all muscle groups correlated strongly with clinical findings. Those findings are in line with the results of a previous study by Arrigoni in thigh muscles [4]. We conclude that Dixon fat fraction should be considered a non-invasive biomarker in LGMD2A. 5. Citations: [1] Aivazoglou LU et al. MR imaging of inherited myopathies: a review and proposal of imaging algorithms. Eur Radiol. Epub 21/04/2021. doi:10.1007/s00330-021-07931-9. [2] Burakiewicz J et al. Quantifying fat replacement of muscle by quantitative MRI in muscular dystrophy. J Neurol. 2017; 264(10):2053-2067. doi:10.1007/s00415-017-8547-3. [3] Vandervelde L et al. ACTIVLIM: A Rasch-built measure of activity limitations in children and adults with neuromuscular disorders. Neuromuscul Disord . 2007;17(6):459-469. doi:10.1016/j.nmd.2007.02.013. [4] Arrigoni F et al. Multiparametric qMRI assessment of thigh muscles in LGMD 2A and 2B. Muscle and Nerve . 2018;58(4):550-558. doi:10.1002/mus.26189.

High prevalence of paraspinal muscle involvement in adults with McArdle disease.

Very few studies analyzing the pattern of muscle involvement in magnetic resonance imaging (MRI) of patients with McArdle disease have been reported to date. We aimed to examine the pattern of muscle fat replacement in patients with McArdle disease. We performed a retrospective study including all patients with genetically confirmed McArdle disease followed in our center from January 2010 to March 2021. Clinical data were collected from the medical record. Whole-body MRI was performed as part of the diagnostic evaluation. The distribution of muscle fat replacement and its severity were analyzed. Nine patients were included. Median age at onset was 7 y (range, 5-58) and median age at the time when MRI was performed was 57.3y (range, 37.2-72.8). At physical examination, four patients had permanent weakness: in three the weakness was limited to paraspinal muscles, whereas in one the weakness involved the paraspinal and proximal upper limb muscles. Muscle MRI showed abnormalities in six of the seven studied patients. In all of them, fat replacement of paravertebral muscles was found. Other muscles frequently affected were the tongue in three, subscapularis in three, and long head of biceps femoris and semimembranosus in two. Our findings suggest that paraspinal muscle involvement is common in McArdle disease and support the need to include this disease in the differential diagnosis of the causes of paraspinal muscle weakness. Involvement of the tongue and subscapularis are also frequent in McArdle disease.

Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort

LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). 27 patients (2-62years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

IMAGING: EP.334 Using MRI to review contractile properties and fat replacement of muscles in patients with myotonia congenita

IMAGING: EP.334 Using MRI to review contractile properties and fat replacement of muscles in patients with myotonia congenita

IMAGING: EP.337 Different approaches to analyze muscle fat replacement with dixon MRI

IMAGING: EP.337 Different approaches to analyze muscle fat replacement with dixon MRI

Muscle architecture is associated with muscle fat replacement in Duchenne and Becker muscular dystrophies.

Introduction/AimsDuchenne and Becker muscular dystrophies (DMD and BMD, respectively) are characterized by fat replacement of different skeletal muscles in a specific temporal order. Given the structural role of dystrophin in skeletal muscle mechanics, muscle architecture could be important in the progressive pathophysiology of muscle degeneration. Therefore, the aim of this study was to assess the role of muscle architecture in the progression of fat replacement in DMD and BMD.MethodsWe assessed the association between literature‐based leg muscle architectural characteristics and muscle fat fraction from 22 DMD and 24 BMD patients. Dixon‐based magnetic resonance imaging estimates of fat fractions at baseline and 12 (only DMD) and 24 months were related to fiber length and physiological cross‐sectional area (PCSA) using age‐controlled linear mixed modeling.ResultsDMD and BMD muscles with long fibers and BMD muscles with large PCSAs were associated with increased fat fraction. The effect of fiber length was stronger in muscles with larger PCSA.DiscussionMuscle architecture may explain the pathophysiology of muscle degeneration in dystrophinopathies, in which proximal muscles with a larger mass (fiber length × PCSA) are more susceptible, confirming the clinical observation of a temporal proximal‐to‐distal progression. These results give more insight into the mechanical role in the pathophysiology of muscular dystrophies. Ultimately, this new information can be used to help support the selection of current and the development of future therapies.

Different Approaches to Analyze Muscle Fat Replacement With Dixon MRI in Pompe Disease

Quantitative MRI is an increasingly used method to monitor disease progression in muscular disorders due to its ability to measure changes in muscle fat content (reported as fat fraction) over a short period. Being able to objectively measure such changes is crucial for the development of new treatments in clinical trials. However, the analysis of the images involved continues to be a daunting task because of the time needed. Whether a more specific analysis selecting individual muscles or a global one analyzing the whole thigh or compartments could be a suitable alternative has only been marginally studied. In our study we compare three methods of analysis of 2-point-dixon images in a cohort of 34 patients with late onset Pompe disease followed over a period of one year. We measured fat fraction on MRIs obtained at baseline and at year 1, and we calculated the increment of fat fraction. We correlated the results obtained with the results of muscle function tests to investigate whether the three methods of analysis were equivalent or not. We observed significant differences between the three methods in the estimation of the fat fraction at both baseline and year 1, but no difference was found in the increment in fat fraction between baseline and year 1. When we correlated the fat fraction obtained with each method and the muscle function tests, we found a significant correlation with most tests in all three methods, although in most comparisons the highest correlation coefficient was found with the analysis of individual muscles. We conclude that the fastest strategy of analysis assessing compartments or the whole thigh could be reliable for certain cohorts of patients where the variable to study is the fat increment. In other sorts of studies, an individual muscle approach seems the most reliable technique.

Regional variation of thigh muscle fat infiltration in patients with neuromuscular diseases compared to healthy controls.

Chemical shift encoding-based water-fat magnetic resonance imaging (CSE-MRI) measures a quantitative biomarker: the proton density fat fraction (PDFF). The aim was to assess regional and proximo-distal PDFF variations at the thigh in patients with myotonic dystrophy type 2 (DM2), limb-girdle muscular dystrophy type 2A (LGMD2A), and late-onset Pompe disease (LOPD) as compared to healthy controls. Seven patients (n=2 DM2, n=2 LGMD2A, n=3 LOPD) and 20 controls were recruited. A 3D-spoiled gradient echo sequence was used to scan the thigh musculature. Muscles were manually segmented to generate mean muscle PDFF. In all three disease entities, there was an increase in muscle fat replacement compared to healthy controls. However, within each disease group, there were patients with a shorter time since symptom onset that only showed mild PDFF elevation (range, 10% to 20%) compared to controls (P≤0.05), whereas patients with a longer period since symptom onset showed a more severe grade of fat replacement with a range of 50% to 70% (P<0.01). Increased PDFF of around 5% was observed for vastus medialis, semimembranosus and gracilis muscles in advanced compared to early DM2. LGMD2A_1 showed an early disease stage with predominantly mild PDFF elevations over all muscles and levels (10.9%±7.1%) compared to controls. The quadriceps, gracilis and biceps femoris muscles showed the highest difference between LGMD2A_1 with 5 years since symptom onset (average PDFF 11.1%±6.9%) compared to LGMD2A_2 with 32 years since symptom onset (average PDFF 66.3%±6.3%). For LOPD patients, overall PDFF elevations were observed in all major hip flexors and extensors (range, 25.8% to 30.8%) compared to controls (range, 1.7% to 2.3%, P<0.05). Proximal-to-distal PDFF highly varied within and between diseases and within controls. The intra-reader reliability was high (reproducibility coefficient ≤2.19%). By quantitatively measuring muscle fat infiltration at the thigh, we identified candidate muscles for disease monitoring due to their gradual PDFF elevation with longer disease duration. Regional variation between proximal, central, and distal muscle PDFF was high and is important to consider when performing longitudinal MRI follow-ups in the clinical setting or in longitudinal studies.

Correlation Between Respiratory Accessory Muscles and Diaphragm Pillars MRI and Pulmonary Function Test in Late-Onset Pompe Disease Patients.

Objectives: Pompe disease is a rare genetic disease produced by mutations in the GAA gene leading to progressive skeletal and respiratory muscle weakness. T1-weighted magnetic resonance imaging is useful to identify fatty replacement in skeletal muscles of late-onset Pompe disease (LOPD) patients. Previous studies have shown that replacement by fat correlates with worse results of muscle function tests. Our aim was to investigate if fat replacement of muscles involved in the ventilation process correlated with results of the spirometry and predicted respiratory muscle impairment in LOPD patients over time.Materials and Methods: We studied a cohort of 36 LOPD patients followed up annually in our center for a period of 4 years. We quantified muscle fat replacement using Mercuri score of the thoracic paraspinal and abdominal muscles and the pillars of the diaphragm. We correlated the combined Mercuri scores of these areas with spirometry results and the need of respiratory support.Results: We found a statistically significant correlation (Spearman test, p < 0.05; coefficient of correlation > 0.6) between forced vital capacity seated and lying and fat fraction score of all muscle groups studied. The group of patients who needed respiratory support had higher fat fraction scores than patients not requiring ventilatory support. Higher fat replacement in these areas correlated with worse progression in spirometry values over time.Conclusions: Fat replacement of paraspinal, abdominal, and trunk muscles correlates with results of spirometry and is able to predict worsening in respiratory muscle function tests that could lead to an emerging ventilatory dysfunction. Therefore, the identification of fat replacement in these muscle groups should lead to a closer monitorization of patients. Radiologic evaluation of diaphragm pillars in T1-weighted imaging axial sequences could also be helpful to predict respiratory insufficiency.

Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency

Reversible infantile respiratory chain deficiency is a severe neonatal mitochondrial myopathy that resolves spontaneously. It is caused by the homoplasmic m.14674T>C mtDNA mutation and additional nuclear variants in genes interacting with mt-tRNAGlu have been detected in some patients. We present detailed clinical, imaging, and muscle biopsy findings in a boy and a girl with neonatal hypotonia, feeding difficulties, lactic acidosis, and ragged red fibers. Both patients show fat replacement on muscle imaging, which was mild in the boy, but severe in the girl, affecting mostly the posterior leg muscles. In addition to the homoplasmic m.14674T>C, both patients carried heterozygous variants in QRSL1 (c. 686T>G; p.Val299Gly) and EARS2 (c.358C>T; p.Arg120Trp), respectively. It is very important to recognize the clinical and morphological signs of reversible infantile respiratory chain deficiency as patients should receive intensive supportive care in the first 6 months of life. Understanding the mechanism of the spontaneous recovery may lead to novel therapeutic perspectives in other mitochondrial diseases.