A.4 A Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

A young woman with multiple acyl-CoA dehydrogenase deficiency (MADD)

A 31-year-old female hairdresser whose parents were first degree cousins complained of episodic attacks of headache, vomiting, and dizziness for the past eight years after an uneventful childhood and adolescence. Four years ago, she developed progressive weakness, muscle pain and difficulties walking and lifting her arms that she could not work in her profession anymore. She lost hair, weight and became amenorrhoic. Finally, her muscle weakness required intensive care. Early on her CK was mildly elevated to 237 U/l (normal < 167), but later to 900 and 1800. By MRI, skeletal muscles showed minimal contrast enhancement.The clinically suspected diagnosis of myositis prompted repeated muscle biopsies, which disclosed non-specific myopathic changes, scattered necrotic muscle fibers without inflammation, protein aggregation, or vacuolation by light microscopy, but abnormally structured mitochondria with inclusions by electron microscopy, and treatment with steroids without any clinical improvement.A panel of 1131 mitochondrial genes revealed a homozygous mutation in the ETFDH gene.LEARNING OBJECTIVESThis presentation will enable the learner to: 1.Discuss MADD as a mitochondrial and lipid storage disease2.Recognize the myopathology of MADD

Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation?

Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult.Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients.Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis.

MICROSTRUCTURAL INDICATORS OF MUSCLE TISSUE WITH VARYING DEGREES OF SEVERITY OF MYOPATHY SIGNS IN FASTGROWING PIGS

The article presents the criteria for determining the severity of myopathy by assessing the morphological features of muscle tissue. Since it is known that hybrid pigs are most susceptible to stress, which further leads to the development of dystrophic (myopathic) changes in the structure of muscle tissue, which subsequently reduce the quality of pork.

Three Individuals with PURA Syndrome in a Cohort of Patients with Neuromuscular Disease

Pur-α protein (PURA) syndrome manifests in early childhood with core features such as neurodevelopmental and speech delay, feeding difficulties, epilepsy, and hypotonia at birth. We identified three cases with PURA syndrome in a cohort of patients with unexplained muscular weakness, presenting with a predominantly neuromuscular and ataxic phenotype. We further characterize the clinical presentation of PURA syndrome including myopathic facies and muscular weakness as the main clinical symptoms in combination with elevated serum creatine kinase levels. Furthermore, we report two novel variants located in the conservative domains PUR-I and PUR-II. For the first time, we present the muscle biopsies of PURA syndrome patients, showing myopathic changes, fiber size variability, and fast fiber atrophy as the key features. PURA syndrome should be taken into consideration as a differential diagnosis in pediatric patients with unexplained muscle weakness.

Effect of modelled stress and adaptogens on microstructural characteristics of pork from fast-growing hybrid animals

This research aimed to study the effect of modelled technological stress and the introduction of selenium and dihydroquercetin (DHQ) into pig diets on the microstructure of M. longissimus dorsi muscle tissue. The in vivo experiment was carried out on 36 hybrid young barrows (Large White x Landrace) x Duroc) with an initial live weight of 34 – 36 kg until they reached a weight of not less than 110 kg. The animals were divided into four groups: 1 (C-) – pigs did not receive adaptogens and were not subjected to modelled technological stress; 2 (C+) – pigs did not receive adaptogens but were subjected to stress via relocation of animals; 3 (С+Se) – pigs were subjected to stress and received 0.2 mg Se.kg-1 feed as selenium proteinate in addition to their diet; 4 (С+DHQ) – pigs were subjected to stress and received 32 mg DHQ.kg-1 feed in addition to their diet. The best results regarding the muscle tissue condition were recorded in the musle L. dorsi samples were taken from the carcasses of group 4 (С+DHQ). Analysis of variance using the Fisher–Snedecor test confirmed that addition of adaptogens led to an improvement of the pH24 value (at p = 0.05, f observed = 5.90 >fcritical = 4.17) and moisture-holding capacity (at p = 0.05, f observed = 3.04 >fcritical = 2.92). The effect of long-term addition of DHQ to pig diets (78 days) on the condition of muscle tissue was studied for the first time, which allowed us to conclude its role in the prevention of myopathic changes in the muscle fibre structure.

Muscle biopsy: what and why and when?

Skeletal muscle biopsy remains an important investigative tool in the diagnosis of a variety of muscle disorders. Traditionally, someone with a limb-girdle muscle weakness, myopathic changes on electrophysiology and raised serum creatine kinase (CK) would have a muscle biopsy. However, we are living through a genetics revolution, and so do all such patients still need a biopsy? When should we undertake a muscle biopsy in patients with a distal, scapuloperoneal or other patterns of muscle weakness? When should patients with myositis, rhabdomyolysis, myalgia, hyperCKaemia or a drug-related myopathy have a muscle biopsy? What does normal muscle histology look like and what changes occur in neurogenic and myopathic disorders? As with Kipling’s six honest serving men, we hope that by addressing these issues we can all become more confident about when to request a muscle biopsy and develop clearer insights into muscle pathology.