Three novel FHL1 variants cause a mild phenotype of Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary muscle disease, characterized by the clinical triade of early-onset joint contractures, progressive muscle weakness, and cardiac involvement. Pathogenic variants in FHL1 can cause a rare X-linked recessive form of EDMD, type 6. We report three men with novel variants in FHL1 leading to EDMD6. The onset of muscle symptoms was in late adulthood and muscle weakness was not prominent in either of the patients. All patients had hypertrophic cardiomyopathy and one of them also had cardiac arrhythmias. Western blot performed on muscle biopsies from two of the patients showed no FHL1 protein expression. We predict that the variant in the third patient also leads to the absence of FHL1 protein. Complete loss of all FHL1 isoforms combined with mild muscle involvement supports the hypothesis that loss of all FHL1 isoforms is more benign than the cytotoxic effects of expressed FHL1 protein with pathogenic missense variants.

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.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

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.

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.

Cardiac Involvement in Women With Pathogenic Dystrophin Gene Variants.

Objective: To determine the frequency and extent of cardiac involvement in female carriers of pathogenic variants in DMD, 53 women were examined through an observational, cross-sectional study. Methods: Genetically verified female carriers of pathogenic DMD variants were examined by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement, echocardiography, 24-h Holter monitoring, ECG, and blood concentrations of skeletal and cardiac muscle biomarkers. Results: Fifty-three female carriers of pathogenic DMD variants (mean age 49.6 years, 33 associated with DMD, and 20 with BMD) were included in the study. Sixty-two percent had cardiac dysfunction on echocardiography. On CMR, 49% had myocardial fibrosis, 35% had dilated left ventricles, and 10% had left ventricular hypertrophy. ECGs were abnormal in 72%, and abnormal Holter monitoring was found in 43%. Age did not correlate with myocardial fibrosis or cardiac dysfunction. Myocardial fibrosis was more frequent in carriers of pathogenic variants associated with DMD vs. BMD (61 vs. 28%, p = 0.02). Conclusion: This study shows that cardiac involvement, affecting both structure and function of the heart, is found in over 2/3 of women with a pathogenic DMD variant. The study supports early cardiac screening, including ECG, Holter, and cardiac imaging, in this group of carriers, so that symptoms related to pathogenic variants in DMD can be recognized, and relevant treatment can be initiated. Longitudinal studies are needed to assess morbidity and mortality related to single, pathogenic DMD variants in women.

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.

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.

Growth and differentiation factor 15 as a biomarker for mitochondrial myopathy.

OBJECTIVE: We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with mitochondrial myopathy from patients with other myopathies. METHODS: Serum GDF-15 was measured in 28 patients with mitochondrial disease, 24 with metabolic myopathies, 27 with muscular dystrophy and 21 healthy controls. RESULTS AND CONCLUSIONS: Our findings indicate that elevated GDF-15 can distinguish patients with mitochondrial myopathy from other myopathies, including metabolic myopathies. This suggests that increases in GDF-15 is specific to respiratory chain dysfunction rather than general metabolic dysfunction or muscle defect.

BAG3 myopathy is not always associated with cardiomyopathy.

Bag3opathy is a rare myofibrillar myopathy (MFM) caused by a mutation in the Bcl-2 associated-athanogene-3 gene. Less than twenty patients have been described, almost all with severe cardiac involvement. We present a 26-year-old man with a c.626C>T (p.Pro209Leu) mutation in the Bcl-2 associated-athanogene-3 gene (BAG3). Our patient presented with problems running before he turned 10 and rapidly progressing, proximal muscle weakness and rigidity of the neck and back. Muscle biopsy showed Z-disc streaming, vacuoles, which is typical findings of Bag3opathy, as well as accumulation of filamentous materials. He rapidly developed respiratory insufficiency necessitating assisted ventilation, and became wheelchair bound by age 13. The progression of his muscle disease is characteristic of Bag3opathy, but unlike other reported cases, he had no evidence of cardiac involvement at age 25 years, despite serial Holter monitoring, ECG and echocardiographs. This case illustrates that counseling of patients with BAG3 myopathy should not predict an inevitable occurrence of cardiomyopathy.