Biological biomarkers in muscle diseases relevant for follow-up and evaluation of treatment.

Muscle diseases cover a diverse group of disorders that in most cases are hereditary. The rarity of the individual muscle diseases provides a challenge for researchers when wanting to establish natural history of the conditions and when trying to develop diagnostic tools, therapies, and outcome measures to evaluate disease progression. With emerging molecular therapies in many genetic muscle diseases, as well as biological therapies for the immune-mediated ones, biological biomarkers play an important role in both drug development and evaluation.

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.

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.

Energy metabolism during exercise in patients with β-enolase deficiency (GSDXIII).

Aim: To investigate the in vivo skeletal muscle metabolism in patients with β-enolase deficiency (GSDXIII) during exercise, and the effect of glucose infusion.

Methods: Three patients with GSDXIII and 10 healthy controls performed a nonischemic handgrip test as well as an incremental cycle ergometer test measuring maximal oxidative consumption (VO) and a 1-hour submaximal cycle test at an intensity of 65% to 75% of VO. The patients repeated the submaximal exercise after 2 days, where they received a 10% iv-glucose supplementation.

Myopathy can be a key phenotype of membrin (GOSR2) deficiency.

T1-weighted, cross-sectional MR images showing shoulder girdle, abdominal, paraspinal, gluteal and thigh muscles almost completely replaced by fat, whereas lower leg muscles are almost unaffected i a patient who is compound heterozygous for pathogenic variants in GOSR2.

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC).

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed.

Results of an open label feasibility study of sodium valproate in people with McArdle disease.

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy.

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.

No effect of triheptanoin on exercise performance in McArdle disease.

Objective: To study if treatment with triheptanoin, a 7-carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and glycogen-dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease.

Fat oxidation is impaired during exercise in lipin-1 deficiency.

Objective: To investigate substrate metabolism during exercise in an adult with lipin-1 deficiency, an inherited defect in lipid homeostasis, and to study the effect of glucose supplementation on his exercise tolerance.

Methods: We studied a 48-year-old man with lipin-1 deficiency and 2 healthy men. The patient has exercise intolerance and monthly episodes of rhabdomyolysis.

Impaired fat oxidation during exercise in multiple acyl-CoA dehydrogenase deficiency.

We investigated the in vivo skeletal muscle metabolism in patients with multiple acyl-CoA dehydrogenase deficiency (MADD) during exercise, and the effect of a glucose infusion. Two adults with MADD on riboflavin and l-carnitine treatment and 10 healthy controls performed an incremental exercise test measuring maximal oxidative capacity (VO) and a submaximal exercise test (≤1 hour) on a cycle ergometer. During submaximal exercise, we studied fat and carbohydrate oxidation, using stable isotope tracer methodology and indirect calorimetry.

Impaired Fat Oxidation During Exercise in Long-Chain Acyl-CoA Dehydrogenase Deficiency Patients and Effect of IV-Glucose.

Context: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) affects oxidation of long-chain fatty acids (FAO) and is associated with risk of metabolic crises and episodic rhabdomyolysis.

Case Description: We present the cases of two patients with LCHADD. Patient 1 (male, 26 years old) was severely affected by muscle weakness and neuropathy.

Muscle glycogen synthesis and breakdown are both impaired in glycogenin-1 deficiency.

Objective: To study fat and carbohydrate metabolism during exercise in patients with glycogenin-1 (GYG1) deficiency, and to study whether IV glucose supplementation can alleviate exercise intolerance in these patients.

Methods: This is a case-control study with 4 patients with GYG1 deficiency and 4 healthy controls. Patients performed 1 hour of cycling at 50% of their maximal workload capacity, while controls cycled at the same absolute workloads as patients.