Expanding the clinicopathological-genetic spectrum of GNE myopathy by a Chinese neuromuscular centre

GNE myopathy is a heterogeneous group of ultrarare neuromuscular disorders caused by mutations in the GNE gene. An estimated prevalence of 1~21/1,000,000 leads to a deficiency of data and a lack of availability of samples to conduct clinical research on this neuromuscular disorder. Although GNE, which is the mutated gene responsible for the disease, is well known as the key enzyme in the biosynthesis pathway of sialic acid, the clinicopathological-genetic spectrum of GNE mutant patients is still unclear and expanding. This study presents ten unrelated patients with GNE myopathy, discovering five novel missense mutations. Clinical, electrophysiological, imaging, pathological and genetic data are presented in a retrospective manner. Interestingly, several patients in the cohort were found to have peripheral neuropathy and inflammatory cell infiltration in muscle biopsies, which have seldom been reported. This study, conducted by a neuromuscular centre in China, is the first attempt to highlight these abnormal clinicopathological features and associate them with genetic mutations in GNE myopathy.     

Scission,a critical step in autophagosome formation

ABSTRACT

A key feature of macroautophagy (hereafter autophagy) is the formation of the phagophore, a double-membrane compartment sequestering cargos and finally maturing into a vesicle termed an autophagosome; however, where these membranes originate from is not clear. In a previous study, researchers from the Rubinsztein lab proposed a model in which the autophagosome can evolve from the RAB11A-positive recycling endosome. In their recent paper, they determine that DNM2 (dynamin 2) functions in scission of the recycling endosome, and the release of the autophagosome precursor. These findings explain how the centronuclear myopathy (CNM) mutation in DNM2 results in the accumulation of immature autophagic structures.     

Association between population structure and allele frequencies of the glycogen synthase 1 mutation in the Austrian Noriker draft horse

The aim of this study was to determine the allele frequency of the glycogen synthase 1 (GYS1) mutation associated with polysaccharide storage myopathy type 1 in the Austrian Noriker horse. Furthermore, we examined the influence of population substructures on the allele distribution. The study was based upon a comprehensive population sample (208 breeding stallions and 309 mares) and a complete cohort of unselected offspring from the year 2014 (1553 foals). The mean proportion of GYS1 carrier animals in the foal cohort was 33%, ranging from 15% to 50% according to population substructures based on coat colours. In 517 mature breeding horses the mutation carrier frequency reached 34%, ranging on a wider scale from 4% to 62% within genetic substructures. We could show that the occurrence of the mutated GYS1 allele is influenced by coat colour; genetic bottlenecks; and assortative, rotating and random mating strategies. Highest GYS1 carrier frequencies were observed in the chestnut sample comprising 50% in foals, 54% in mares and 62% in breeding stallions. The mean inbreeding of homozygous carrier animals reached 4.10%, whereas non‐carrier horses were characterized by an inbreeding coefficient of 3.48%. Lowest GYS1 carrier frequencies were observed in the leopard spotted Noriker subpopulation. Here the mean carrier frequency reached 15% in foals, 17% in mares and 4% in stallions and inbreeding decreased from 3.28% in homozygous non‐carrier horses to 2.70% in heterozygous horses and 0.94% in homozygous carriers. This study illustrates that lineage breeding and specified mating strategies result in genetic substructures, which affect the frequencies of the GYS1 gene mutation.     

Mosaic dysfunction of mitophagy in mitochondrial muscle disease

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Telocytes in neuromuscular spindles

A new cell type named telocyte (TC) has recently been identified in various stromal tissues, including skeletal muscle interstitium. The aim of this study was to investigate by means of light (conventional and immunohistochemical procedures) and electron microscopy the presence of TCs in adult human neuromuscular spindles (NMSs) and lay the foundations for future research on their behaviour during human foetal development and in skeletal muscle pathology. A large number of TCs were observed in NMSs and were characterized ultrastructurally by very long, initially thin, moniliform prolongations (telopodes – Tps), in which thin segments (podomeres) alternated with dilations (podoms). TCs formed the innermost and (partially) the outermost layers of the external NMS capsule and the entire NMS internal capsule. In the latter, the Tps were organized in a dense network, which surrounded intrafusal striated muscle cells, nerve fibres and vessels, suggesting a passive and active role in controlling NMS activity, including their participation in cell‐to‐cell signalling. Immunohistochemically, TCs expressed vimentin, CD34 and occasionally c‐kit/CD117. In human foetus (22–23 weeks of gestational age), TCs and perineural cells formed a sheath, serving as an interconnection guide for the intrafusal structures. In pathological conditions, the number of CD34‐positive TCs increased in residual NMSs between infiltrative musculoaponeurotic fibromatosis and varied in NMSs surrounded by lymphocytic infiltrate in inflammatory myopathy. We conclude that TCs are numerous in NMSs (where striated muscle cells, nerves and vessels converge), which provide an ideal microanatomic structure for TC study.     

Lipomatous muscular ‘dystrophy’ of Piedmontese cattle

Lipomatous myopathy is a degenerative muscle pathology characterized by the substitution of muscle cells with adipose tissue, sporadically reported in cattle, pigs, and rarely in sheep, horses and dogs. This study investigated the pathology of this myopathy in 40 muscle samples collected from regularly slaughtered Piedmontese cattle living in Piedmont region (Italy). None of the animals showed clinical signs of muscular disease. Muscle specimens were submitted to histological and enzymatic investigations. Gross pathology revealed a different grade of infiltration of adipose tissue, involving multiple or single muscles. The most affected regions were the ventral abdomen and the shoulders, especially the cutaneous muscles and the muscles of the thoracic group. Morphological staining revealed an infiltration of adipose tissue varying in distribution and severity, changes in muscle fibre size and increased number of fibres with centrally located nuclei, suggesting muscle degeneration–regeneration. Necrosis and non-suppurative inflammatory cells were also seen. Furthermore, proliferation of connective tissue and non-specific myopathic changes were present. Chemical and physical characteristics of the affected tissue were also evaluated. The authors discuss about the aetiopathogenesis and classification of this muscle disorder whose histological lesions were similar to those reported in human dystrophies.     

A reappraisal of the strength-duration test to assess neuromuscular impairment of critically ill patients

IntroductionNeuromuscular impairment (NMI) affects almost half of critically ill patients. The purpose was to investigate the role of neuromuscular electrical stimulation (NMES) to gain more insight into the nature of the NMI associated with ICU admission. To this aim, we analyzed the strength-duration (S-D) curves of the rectus femoris muscles of ICU patients compared to healthy volunteers.MethodsS-D curves were recorded from 44 healthy volunteers and 29 ICU patients. Three electrophysiological parameters were used to classify the neuromuscular function, from grade 0 (normal function), to grade 3 (no evocable muscle contraction). ICU patients underwent electroneurographic peroneal nerve testing (PENT) to analyze NMI by electroneurography (ENG).ResultsThree patients were classified as Grade 0; nine as mild NMI (Grade 1), 13 as Grade 2, and four showed unexcitable muscles (Grade 3). Mean CMAP amplitudes were 6.1, 3.4, 2.9 and 0.81 mV from Grade 0 to Grade 3, respectively. CMAP was inversely correlated to NMI grade (−1.7 mV, R² = 0.946, p < 0.05).ConclusionsThe normative parameters of the S-D curves obtained by NMES in healthy volunteers allowed identification of NMI in ICU patients. NMES was an affordable tool to evaluate NMI in ICU patients, providing additional information to that obtained by ENG.     

Active oxygen in neuromuscular disorders

Although muscle and nerve are reasonably well protected against active oxygen and related free radicals, environmental or inherited malfunctions can overpower their defences. Active oxygen is involved in many neuropathies and myopathies. In every case the damage is caused by agents which exert effects disproportionately greater than the quantites encountered, through a variety of amplification mechanisms. We can categorize these amplification mechanisms as follows: (a) non-replacement of targets (e.g. loss of genetic information, ataxia telangectasia being an hereditary ataxia in which an oxygen mediated chromosomal instability is apparent), (b) non-removal of unwanted materials (e.g. lipofuscin accumulation in brain and heart), (c) redox cycling, usually involving catalysis by trace-metal ions (e.g. some forms of Parkinsonism), (d) non-redox catalysis (e.g. toxicity in cardiac muscle or brain due to vanadium or aluminium respectively), (e) modification of ion transport (e.g. calcium ionophore or acrylamide induce histopathological changes in muscle, similar in some respects to those seen in Duchenne muscular dystrophy), (f) compromised defences (e.g. muscle and nerve become particularly susceptible to free radical damage after loss of the protective actions of vitamin E), and (g) amplification by inflammatory and immune responses (e.g. multiple sclerosis, reperfusion injury to brain and heart, and traumatic injury to nervous tissue). Unfortunately, a variety of therapeutic agents which might be expected to protect against almost every conceivable form of oxygen mediated damage have proved clinically ineffective in most of these disorders. The reasons for this will be explored with an emphasis on common features, differences, mechanisms, and potential therapeutic approaches.