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

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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).

ß-Galactosidase deficiency in the GLB1 spectrum of lysosomal storage disease can present with severe muscle weakness and atrophy.

Deficiency of the enzyme ß-galactosidase due to variants in the GLB1-gene is associated with metabolic disorders: Morquio B and GM1-gangliosidosis. Here, we report a case compound heterozygous for variants in the GLB1-gene and a severe muscular phenotype. Full body T1-w MRI was conducted for muscular involvement. Biopsy was stained with hematoxylin and eosin for histopathological evaluation. EDTA blood-sample was subjected to whole exome sequencing. Metabolic analysis included residual enzyme activity and evaluation urinary substrate secretion. Additionally, electroneurography, echocardiography, forced volume capacity and biochemistry were evaluated. Examination showed severe proximal weakness (MRC: hip flexion 2, hip extension 2, and shoulder rotation 2), Gower's sign, no extrapyramidal symptoms and normal creatine kinase levels. MRI showed severe muscle wasting of the thigh and shoulder girdle. Muscle biopsy showed mild myopathic changes. ß-galactosidase activity was reduced to 28%-34%. Urinary glycosaminoglycan was elevated by 5.9-8.6 mg/mmol (ref.:0-5.1 mg/mmol). Electrophoresis indicated excess keratan sulfate. Exome sequencing revealed two missense variants in the GLB1 gene. Clinical features, genetic testing and laboratory findings indicate a case of ß-galactosidase-deficiency with a muscular phenotype.