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

BACKGROUND AND OBJECTIVES: Primary 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. METHODS: In 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. RESULTS: We 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. DISCUSSION: The study demonstrates that HypoPP can be a progressive myopathy in both patients with and without attacks of paralysis.

Axial muscle involvement in patients with limb girdle muscular dystrophy type R9.

INTRODUCTION/AIMS: Limb girdle muscular dystrophy type R9 (LGMDR9) is characterized by progressive weakness of the shoulder and hip girdles. Involvement of proximal extremity muscles is well-described whereas information about axial muscle involvement is lacking. It is important to recognize the involvement of axial muscles to understand functional challenges for the patients. The aim of this study was to investigate the involvement of axial and leg muscles in patients with LGMDR9. METHODS: This observational, cross-sectional study investigated fat replacement of axial and leg muscles in 14 patients with LGMDR9 and 13 matched, healthy controls using quantitative MRI (Dixon technique). We investigated paraspinal muscles at three levels, psoas major at the lumbar level, and leg muscles in the thigh and calf. Trunk strength was assessed with stationary dynamometry and manual muscle tests. RESULTS: Patients with LGMDR9 had significantly increased fat replacement of all investigated axial muscles compared with healthy controls (P < .05). Trunk extension and flexion strength were significantly reduced in patients. Extension strength correlated negatively with mean fat fraction of paraspinal muscles. Fat fractions of all investigated leg muscles were significantly increased versus controls, with the posterior thigh muscles being the most severely affected. DISCUSSION: Patients with LGMDR9 have severe involvement of their axial muscles and correspondingly have reduced trunk extension and flexion strength. Our findings define the axial muscles as some of the most severely involved muscle groups in LGMDR9, which should be considered in the clinical management of the disorder and monitoring of disease progression.

Quantitative Muscle MRI and Clinical Findings in Women With Pathogenic Dystrophin Gene Variants.

Objective: To explore fat replacement, muscle strength, and clinical features in women heterozygous for a pathogenic DMD variant, we prospectively examined 53 women, assuming that some of these women-despite of the recessive X-linked inheritance-manifested clinical symptoms. Methods: We performed a cross-sectional observational study using MRI and stationary dynamometry of lower extremities, extracted blood muscle biomarkers, and investigated subjective complaints. Results were compared with 19 healthy women. Results: DMD variant carriers were weaker and had higher fat fractions than controls in all investigated muscle groups (p < 0.02). Fat fractions were 18% in carriers vs. 11% in controls in thighs (p = 0.008), and 15 vs. 11% in calf muscles (p = 0.032). Seventy-two percent had fat fractions deviating from controls by two standard deviations (SDs) in one or more of the 16 investigated muscle groups. On strength testing, 40% of the carriers had results deviating from control muscle strength by two SDs in one or more dynamometry assessments. Forty-three carriers (81%) had either reduced muscle strength (<2 SDs from control mean) and/or elevated muscle fat fraction (>2 SDs from control mean). Thirty of these had subjective symptoms. Blood creatine kinase and myoglobin were elevated in 57% of the carriers. Conclusion: Using quantitative methods, this study shows that both clinically symptomatic and asymptomatic women with pathogenic DMD variants show a high prevalence of muscle affection. Longitudinal studies in female carriers of pathogenic DMD variants are needed to follow the evolution of these changes.

Evaluation of inflammatory lesions over 2 years in facioscapulohumeral muscular dystrophy.

OBJECTIVE: We followed up patients with facioscapulohumeral muscular dystrophy (FSHD) with sequential examinations over 2 years to investigate whether inflammatory lesions always precede fat replacement, if inflammation can be resolved without muscle degeneration, and if inflammatory lesions in muscle are always followed by fat replacement. METHODS: In this longitudinal study of 10 sequential MRI assessments over 2.5 years, we included 10 patients with FSHD. We used MRI with short TI inversion recovery to identify regions of interest (ROIs) with hyperintensities indicating muscle inflammation. Muscle T2 relaxation time mapping was used as a quantitative marker of muscle inflammation. Dixon sequences quantified muscle fat replacement. Ten healthy controls were examined with a magnetic resonance scan once for determination of normal values of T2 relaxation time. RESULTS: We identified 68 ROIs with T2 elevation in the patients with FSHD. New ROIs with T2 elevation arising during the study had muscle fat content of 6.4% to 33.0% (n = 8) and 47.0% to 78.0% lesions that resolved (n = 6). ROIs with T2 elevation had a higher increase in muscle fat content from visits 1 to 10 (7.9 ± 7.9%) compared to ROIs with normal muscle T2 relaxation times (1.7 ± 2.6%; p < 0.0001). Severe T2 elevations were always followed by an accelerated replacement of muscle by fat. CONCLUSIONS: Our results suggest that muscle inflammation starts in mildly affected muscles in FSHD, is related to a faster muscle degradation, and continues until the muscles are completely fat replaced. CLINICALTRIALSGOV IDENTIFIER: NCT02159612.

Contractile properties are impaired in congenital myopathies.

The ratio between muscle strength and muscle cross-sectional area is called the specific force. Fatty replacement of muscles is seen in many myopathies, affecting the specific force, without necessarily affecting the ability of the remaining muscle fibers to contract. This ability is called the contractility and is the ratio between muscle strength and the lean muscle cross-sectional area, i.e. the contractile cross-sectional area. We hypothesized that contractility is disrupted in patients with congenital myopathy, because of defects in contractile proteins of the sarcomere. Peak torque across ankle and knee joints was measured by isokinetic dynamometry in 16 patients with congenital myopathy and 13 healthy controls. Five patients only participated partially in the dynamometer measurements due to severe muscle weakness. Dixon MRI technique was used to quantify muscle fat fractions and calculate cross-sectional area. Patients with congenital myopathy had lower cross-sectional area in all muscle groups (P<0.01), higher fat fraction (P<0.01) and less strength (P<0.005) in all studied muscle groups. Their fat content was more than doubled and peak torque lower than half that in healthy controls. Muscle contractility was reduced (P<0.01) in three of four patient muscle groups. In conclusion, muscle contractility was reduced in patients with congenital myopathy, across different diagnoses, and was independent of the level of muscle fat fraction, suggesting that intrinsic defects of the myocyte are responsible for reduced contractility.

Permanent muscle weakness in hypokalemic periodic paralysis.

OBJECTIVE: To map the phenotypic spectrum in 55 individuals with mutations in CACNA1S known to cause hypokalemic periodic paralysis (HypoPP) using medical history, muscle strength testing, and muscle MRI. METHODS: Adults with a mutation in CACNA1S known to cause HypoPP were included. Medical history was obtained. Muscle strength and MRI assessments were performed. RESULTS: Fifty-five persons were included. Three patients presented with permanent muscle weakness and never attacks of paralysis. Seventeen patients presented with a mixed phenotype of periodic paralysis and permanent weakness. Thirty-one patients presented with the classical phenotype of periodic attacks of paralysis and no permanent weakness. Four participants were asymptomatic. Different phenotypes were present in 9 of 18 families. All patients with permanent weakness had abnormal replacement of muscle by fat on MRI. In addition, 20 of 35 participants with no permanent weakness had abnormal fat replacement of muscle on MRI. The most severely affected muscles were the paraspinal muscles, psoas, iliacus, the posterior muscles of the thigh and gastrocnemius, and soleus of the calf. Age was associated with permanent weakness and correlated with severity of weakness and fat replacement of muscle on MRI. CONCLUSIONS: Our results show that phenotype in individuals with HypoPP-causing mutations in CACNA1S varies from asymptomatic to periodic paralysis with or without permanent muscle weakness or permanent weakness as sole presenting picture. Variable phenotypes are found within families. Muscle MRI reveals fat replacement in patients with no permanent muscle weakness, suggesting a convergence of phenotype towards a fixed myopathy with aging.

A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity.

Recessively inherited limb girdle muscular dystrophy (LGMD) type 2A is the most common LGMD worldwide. Here, we report the first single missense variant in CAPN3 causing dominantly inherited calpainopathy. A 43-year-old proband, his father and two sons were heterozygous for a c.1715G>C p.(Arg572Pro) variant in CAPN3. Affected family members had at least three of the following; muscle pain, a LGMD2A pattern of muscle weakness and wasting, muscle fat replacement on magnetic resonance imaging, myopathic muscle biopsy, and elevated creatine kinase. Total calpain 3 protein expression was 4 ± 3% of normal. In vitro analysis of c.1715G>C and the previously described c.643_663del variant indicated that the mutant proteins lack autolytic and proteolytic activity and decrease the quantity of wild-type CAPN3 protein. Our findings suggest that dominantly inherited calpainopathy is not unique to the previously reported c.643_663del mutation of CAPN3, and that dominantly inherited calpainopathy should be considered for other single variations in CAPN3.

MRI in Neuromuscular Diseases: An Emerging Diagnostic Tool and Biomarker for Prognosis and Efficacy.

There is an unmet need to identify biomarkers sensitive to change in rare, slowly progressive neuromuscular diseases. Quantitative magnetic resonance imaging (MRI) of muscle may offer this opportunity, as it is noninvasive and can be carried out almost independent of patient cooperation and disease severity. Muscle fat content correlates with muscle function in neuromuscular diseases, and changes in fat content precede changes in function, which suggests that muscle MRI is a strong biomarker candidate to predict prognosis and treatment efficacy. In this paper, we review the evidence suggesting that muscle MRI may be an important biomarker for diagnosis and to monitor change in disease severity. ANN NEUROL 2020;88:669-681.

Characteristic muscle signatures assessed by quantitative MRI in patients with Bethlem myopathy.

Using MRI, the main aim was to (1) map the pattern of muscle involvement by assessing fat fraction and (2) investigate frequency of target and sandwich signs in 42 muscles of patients with Bethlem myopathy (BM). Fifteen BM patients were included. Results were compared to findings in 8 healthy controls and 50 patients with four other types of muscular dystrophies. All muscles, except one, showed higher fat fraction in BM patients vs healthy controls (p < 0.05) with an overall proximal muscle affection, resembling a limb girdle-like pattern. In moderate patients, the specificity was 90% for the sandwich sign and 98% for the target sign. Sensitivity for both signs was 100%. Twelve BM patients had sandwich sign in other muscles than the vastus lateralis. Muscle strength correlated with fat fraction. Mean fat fraction in the psoas major was 39% in BM patients, which was considerably higher than in 3 of the 4 muscular dystrophy control diseases. The presence of signs in conjunction with severe affection of the psoas major muscle can serve as a diagnostic tool in BM. The high level of STIR lesions in muscles of BM patients warrants further investigations.

A quantitative method to assess muscle edema using short TI inversion recovery MRI.

Muscle inflammation is an important component of disease pathophysiology in several muscular dystrophies. Hyperintensities on MRI sequences with short TI inversion recovery (STIR) reflect edema, or inflammation (STIR+). Conventionally, STIR evaluation has been done by visual inspection. In this study, we developed a quantitative STIR method, and tested its ability to identify STIR+ lesions in healthy controls and patients with Facioscapulohumeral muscular dystrophy and compared the results with visual STIR evaluation and quantitative T2 relaxation time mapping. The method was based on pixel-by-pixel histograms of the distribution of signal intensities from muscles. Signal intensities from healthy control muscles were averaged and used to define an upper reference limit. Muscles with >2.5% pixels above the limit were defined as being STIR+. The new method showed agreement with T2 relaxation time mapping in 95% of muscles. The visual STIR method only showed agreement with the quantitative STIR method and T2 relaxation time mapping in 88 and 84%, respectively. STIR sequences are available on most MR scanners and the post-processing used in the new quantitative method can be performed using free software. We therefore believe that the new method can play an important role in identifying STIR+ lesions in patients with neuromuscular diseases.

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints.

OBJECTIVE: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years. METHODS: Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups. RESULTS: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies. INTERPRETATION: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

Muscle contractility in spinobulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is caused by a trinucleotide repeat expansion in the androgen receptor gene on the X chromosome. There is a toxic effect of the mutant receptor on muscle and neurons resulting in muscle weakness and atrophy. The weakness can be explained by wasting due to loss of muscle cells, but it is unknown whether weakness also relates to poor muscle contractility of the remaining musculature. In this study, we investigated the muscle contractility in SBMA. We used stationary dynamometry and quantitative MRI to assess muscle strength and absolute and fat-free, cross-sectional areas. Specific muscle force (strength per cross-sectional area) and contractility (strength per fat-free cross-sectional area) were compared with healthy controls and their relation to walking distance and disease severity was investigated. Specific force was reduced by 14-49% in SBMA patients compared to healthy controls. Contractility was reduced by 22-39% in elbow flexion, knee extension, ankle dorsi- and plantarflexion in SBMA patients. The contractility decreased with increasing muscle fat content in muscles with affected contractility in SBMA. The decreased muscle contractility in SBMA may relate to motor neuron degeneration and changed fibre type distribution and muscle architecture.

Relationship between muscle inflammation and fat replacement assessed by MRI in facioscapulohumeral muscular dystrophy.

OBJECTIVE: Unlike most muscular dystrophies that progress symmetrically at a constant rate, facioscapulohumeral muscular dystrophy (FSHD) is characterized by stepwise, asymmetric progression of muscle wasting, and weakness. Muscle tissue is progressively replaced by fat; however, its relation to preceding inflammation is unclear. In this longitudinal study of FSHD, we assessed muscle inflammation and fat replacement and their relation quantitatively. We also investigated whether fat replacement in muscle varies along its length. METHODS: Forty-five patients with FSHD were evaluated twice, 14 months apart. Using MRI sequences with short TI inversion recovery (STIR), we quantified the degree of STIR hyperintensity in muscles (≥ 2 SD above control intensity). STIR hyperintensities (STIR+) suggest edema or inflammation. We used Dixon MRI to quantify fat content. RESULTS: Of 370 thigh muscles, 83 were STIR+ at baseline and 103 at follow-up. The highest frequency of STIR+ was seen in muscles with inter-mediate fat content (40-60% fat). The progression of fat replacement was higher in STIR+ muscles (5.0 ± 4.0%) vs. STIR- muscles [2.3 ± 3.3% (P < 0.0001)]. In addition, muscles with severe STIR+ at baseline had a higher fat replacement progression than muscles with milder STIR+ (R = 0.39, P = 0.001). The fat content was higher in the distal part vs. proximal part of most muscles (P < 0.05). However, the progression of the fat replacement was uniform along the length of all the muscles. CONCLUSION: Muscles with STIR+, indicating inflammation, have a faster progression of fat replacement than STIR- muscles, and the fat replacement progression correlated with the severity of STIR+.

Refining the spinobulbar muscular atrophy phenotype by quantitative MRI and clinical assessments.

OBJECTIVE: To investigate the phenotypic features, with emphasis on muscle, in 40 patients with spinobulbar muscular atrophy (SBMA) using quantitative MRI, stationary dynamometry, questionnaires, and functional tests. METHODS: Patients with genetically confirmed SBMA were included. MRI was used to describe muscle involvement and quantify muscle fat fractions of arm, back, and leg muscles. Muscle strength was assessed with a stationary dynamometer. All patients were evaluated with the SBMA functional rating scale and the 6-minute walk test among others. MRI and muscle strength results were compared with healthy controls. RESULTS: Forty patients with SBMA were included. The muscle fat content was significantly higher in patients with SBMA than in controls: paraspinal fat fraction was 45% vs 33% in controls, thigh fat fraction 36% vs 14%, calf fat fraction 37% vs 15%, upper arm fat fraction 20% vs 8%, and forearm fat fraction was 20% vs 9%. Muscle strength in patients was reduced to approximately half of that in controls in all muscles. Muscle fat content correlated with muscle strength, SBMA functional rating scale score, and 6-minute walk test distance. CONCLUSIONS: Our results show that there is a diffuse muscle involvement pattern in SBMA. Leg muscles are more vulnerable than arm muscles, especially the posterior flexor muscles. The muscle fat content correlates with muscle function and disease severity.

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.

Disease progression and outcome measures in spinobulbar muscular atrophy.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive disease with weakness of bulbar and extremity muscles. There is no curative treatment for the disease, but several clinical trials have been conducted over the past years. The results from these trials have uncovered a great need to develop quantitative, reliable outcome measures. In this study, we prospectively investigated disease progression over 18 months in 29 patients with genetically confirmed SBMA, using quantitative outcome measures, including Dixon magnetic resonance imaging (MRI). METHODS: We used MRI to assess changes in muscle fat content and stationary dynamometry to assess changes in muscle strength. Disease progression was also investigated with the SBMA functional rating scale, bulbar rating scale, 6-minute walk test, and blood samples, among others. RESULTS: Mean muscle fat content, muscle strength in knee extensors, handgrip strength, walking distance, and creatinine levels changed significantly. Mean muscle fat content increased by 2 ± 1.25%, and knee extension strength decreased from 83 ± 60 to 76 ± 56Nm, handgrip strength from 31 ± 13 to 29 ± 13kg, walking distance from 362 ± 216 to 336 ± 219m, and creatinine level from 58 ± 21 to 54 ± 20 µmol/l. Functional rating scores did not change. INTERPRETATION: The present study demonstrates a slow and steady disease progression in SBMA. Dixon MRI detected increases in muscle fat content in all investigated muscles and is therefore a suitable candidate for an outcome measure in natural history or treatment studies in SBMA. The 6-minute walk test and handgrip strength also seem to be reliable outcome measures for SBMA. Ann Neurol 2018;84:762-773.

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.

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.

Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency.

OBJECTIVE: To describe the variability of muscle symptoms in patients carrying mutations in the GYG1 gene, encoding glycogenin-1, an enzyme involved in the biosynthesis of glycogen, and to discuss genotype-phenotype relations. METHODS: We describe 9 patients from 5 families in whom muscle biopsies showed vacuoles with an abnormal accumulation of glycogen in muscle fibers, partially α-amylase resistant suggesting polyglucosan bodies. The patients had either progressive early-onset limb-girdle weakness or late-onset distal or scapuloperoneal muscle affection as shown by muscle imaging. No clear definite cardiac disease was found. Histologic and protein analysis investigations were performed on muscle. RESULTS: Genetic analyses by direct or exome sequencing of the GYG1 gene revealed 6 different GYG1 mutations. Four of the mutations were novel. They were compound heterozygous in 3 families and homozygous in 2. Protein analysis revealed either the absence of glycogenin-1 or reduced glycogenin-1 expression with impaired glucosylation. CONCLUSIONS: Our report extends the genetic and clinical spectrum of glycogenin-1-related myopathies to include scapuloperoneal and distal affection with glycogen accumulation.

MRI as outcome measure in facioscapulohumeral muscular dystrophy: 1-year follow-up of 45 patients.

There is no effective treatment available for facioscapulohumeral muscular dystrophy type 1 (FSHD1), but emerging therapies are under way that call for a better understanding of natural history in this condition. In this prospective, longitudinal study, we used quantitative MRI to assess yearly disease progression in patients with FSHD1. Ambulatory patients with confirmed diagnosis of FSHD1 (25/20 men/women, age 20-75 years, FSHD score: 0-12) were tested with 359-560-day interval between tests. Using the MRI Dixon technique, muscle fat replacement was evaluated in paraspinal, thigh, and calf muscles. Changes were compared with those in FSHD score, muscle strength (hand-held dynamometry), 6-minute-walk-distance, 14-step-stair-test, and 5-time-sit-to-stand-test. Composite absolute fat fraction of all assessed muscles increased by 0.036 (CI 0.026-0.046, P < 0.001), with increases in all measured muscle groups. The clinical severity FSHD score worsened (10%, P < 0.05), muscle strength decreased over the hip (8%), neck (8%), and back (17%) (P < 0.05), but other strength measures, 6-minute-walk-distance, 5-times-sit-to-stand-test, and 14-step-stair-test were unchanged. Changes in muscle strength, FSHD score, and fat fraction did not correlate. This first study to systemically monitor quantitative fat replacement longitudinally in FSHD1 shows that MRI provides an objective measure of disease progression, often before changes can be appreciated in strength and functional tests. The study indicates that quantitative MRI can be a helpful end-point in follow-up and therapeutic trials of patients with FSHD1.