Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.

Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation.

Congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) result from impaired neuromuscular transmission and are due to genetic mutations in one of several genes involved in the development, function, or maintenance of the neuromuscular junction (NMJ). The clinical presentation, age of onset, and prognosis can vary significantly depending on the underlying genetic defect. Since therapeutic management should be tailored to the specific causative mutation, achieving an accurate diagnosis is essential for optimal patient care.

Estimating the Prevalence of GNE Myopathy Using Population Genetic Databases.

GNE myopathy (GNEM) is a rare autosomal recessive disorder characterized by progressive skeletal muscle wasting starting in early adulthood. The prevalence of GNEM is estimated to range between one and nine cases per million individuals, but the accuracy of these estimates is limited by underdiagnosis, misdiagnosis, and bias introduced by founder allele frequencies. As GNEM is a recessive disorder, unaffected carriers of single damaging variants can be expected to be found in the healthy population, providing an alternative method for estimating prevalence.

Serum Proteomic and Metabolomic Signatures of High Versus Low Physical Function in Octogenarians.

Physical function declines with aging, yet there is considerable heterogeneity, with some individuals declining very slowly while others experience accelerated functional decline. To gain insight into mechanisms promoting high physical function with aging, we performed proteomics, targeted metabolomics, and targeted kynurenine-focused metabolomic analyses on serum specimens from three groups of octogenarians: High-functioning master athletes (HF, n = 16), healthy normal-functioning non-athletes (NF, n = 12), and lower functioning non-athletes (LF, n = 11). Higher performance status was associated with evidence consistent with: Lower levels of circulating proinflammatory markers, as well as unperturbed tryptophan metabolism, with the normal function of the kynurenic pathway; higher circulating levels of lysophosphatidylcholines that have been previously associated with better mitochondrial oxidative capacity; lower activity of the integrated stress response; lower levels of circulating SASP protein members; and lower levels of proteins that reflect neurodegeneration/denervation.

Dominant rhabdomyolysis linked to a recurrent ATP2A2 variant reducing SERCA2 function in muscle.

Rhabdomyolysis is an acute failure of cellular homeostasis resulting in muscle breakdown, triggered by trauma, infection, drugs or strenuous exercise. Recurrent rhabdomyolysis is often associated with genetic and metabolic defects of skeletal muscle. The sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), encoded by the ATP2A2 gene, is an intracellular pump located in the sarcoplasmic and endoplasmic reticulum that is essential for maintaining intracellular calcium (Ca2+) homeostasis and is highly expressed in slow-twitch muscle.

Development of a riboflavin-responsive model of riboflavin transporter deficiency in zebrafish.

Riboflavin transporter deficiency (RTD) is a rare and progressive neurodegenerative disease resulting from the disruption of RFVT2- and RFVT3- mediated riboflavin transport caused by biallelic mutations in SLC52A2 and SLC52A3, respectively. The resulting impaired mitochondrial metabolism leads to sensorimotor neurodegeneration and symptoms including muscle weakness, respiratory difficulty, and sensorineural deafness. Although over 70% of patients with RTD improve following high-dose riboflavin supplementation, remaining patients either stabilise or continue to deteriorate.

Ion Mobility QTOF-MS Untargeted Lipidomics of Human Serum Reveals a Metabolic Fingerprint for GNE Myopathy.

GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP--acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/-acetylmannosamine kinase (ManNAc kinase) gene (), clinically resulting in the loss of ambulation within 10-20 years from the onset of the initial symptoms. The disease's mechanism is poorly understood and non-invasive biomarkers are lacking, hindering effective therapy development.

A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).

The neuromuscular junction (NMJ) is the site where the motor neuron innervates skeletal muscle, enabling muscular contraction. Congenital myasthenic syndromes (CMS) arise when mutations in any of the approximately 35 known causative genes cause impaired neuromuscular transmission at the NMJ, resulting in fatigable muscle weakness. A subset of five of these CMS-causative genes are associated with protein glycosylation.

Partial loss of desmin expression due to a leaky splice site variant in the human DES gene is associated with neuromuscular transmission defects.

Recessive desminopathies are rare and often present as severe early-onset myopathy. Here we report a milder phenotype in three unrelated patients from southern India (2 M, 1F) aged 16, 21, and 22 years, who presented with childhood-onset, gradually progressive, fatigable limb-girdle weakness, ptosis, speech and swallowing difficulties, without cardiac involvement. Serum creatine kinase was elevated, and repetitive nerve stimulation showed decrement in all.

Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes.

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics.

Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease.

Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes-SLC25A1 and TEFM-have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ).

Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models.

Presynaptic congenital myasthenic syndromes (CMS) are a group of genetic disorders affecting the presynaptic side of the neuromuscular junctions (NMJ). They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft. Other proteins involved in presynaptic endplate development and maintenance can also be impaired.

Periostin as a blood biomarker of muscle cell fibrosis, cardiomyopathy and disease severity in myotonic dystrophy type 1.

Background And Purpose: Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy and is caused by an repeat expansion [r(CUG)] located in the 3' untranslated region of the DMPK gene. Symptoms include skeletal and cardiac muscle dysfunction and fibrosis. In DM1, there is a lack of established biomarkers in routine clinical practice.

Unbiased proteomics, histochemistry, and mitochondrial DNA copy number reveal better mitochondrial health in muscle of high-functioning octogenarians.

Background: Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.

Methods: We performed muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochondrial DNA (mtDNA) copy number, and proteomics by liquid-chromatography mass spectrometry.

Collagen VI Regulates Motor Circuit Plasticity and Motor Performance by Cannabinoid Modulation.

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 VI (COL6A3) C-terminal domain (CTD).

Mitochondrial Content, but Not Function, Is Altered With a Multimodal Resistance Training Protocol and Adequate Protein Intake in Leucine-Supplemented Pre/Frail Women.

Frailty is a clinical condition associated with loss of muscle mass and strength (sarcopenia). Mitochondria are centrally implicated in frailty and sarcopenia. Leucine (Leu) can alter mitochondrial content in myocytes, while resistance training (RT) is the strongest stimulus to counteract sarcopenia and may enhance mitochondrial biogenesis.

Modulation of the Acetylcholine Receptor Clustering Pathway Improves Neuromuscular Junction Structure and Muscle Strength in a Mouse Model of Congenital Myasthenic Syndrome.

Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). CMS often present early with fatigable weakness and can be fatal through respiratory complications. The gene is one of over 30 genes known to harbor mutations causative for CMS.

Advances in the diagnosis of inherited neuromuscular diseases and implications for therapy development.

Advances in DNA sequencing technologies have resulted in a near doubling, in under 10 years, of the number of causal genes identified for inherited neuromuscular disorders. However, around half of patients, whether children or adults, do not receive a molecular diagnosis after initial diagnostic workup. Massively parallel technologies targeting RNA, proteins, and metabolites are being increasingly used to diagnose these unsolved cases.

Modulation of Agrin and RhoA Pathways Ameliorates Movement Defects and Synapse Morphology in MYO9A-Depleted Zebrafish.

Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by impaired function of the neuromuscular junction (NMJ). This is due to defects in one of the many proteins associated with the NMJ. In three patients with CMS, missense mutations in a gene encoding an unconventional myosin protein, MYO9A, were identified as likely causing their disorder.

Fidelity of muscle fibre reinnervation modulates ageing muscle impact in elderly women.

Key Points: Susceptibility to age-related muscle atrophy relates to the degree of muscle denervation and the capacity of successful reinnervation. However, the specific role of denervation as a determinant of the severity of muscle aging between populations with low versus high physical function has not been addressed. We show that prefrail/frail elderly women exhibited marked features of muscle denervation, whereas world class octogenarian female master athletes showed attenuated indices of denervation and greater reinnervation capacity.

Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome.

The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies. Here, we investigated the effect of salbutamol treatment on the neuromuscular junction in the ColQ deficient mouse, a model of end-plate acetylcholinesterase deficiency.

Reduced Mitochondrial Content, Elevated Reactive Oxygen Species, and Modulation by Denervation in Skeletal Muscle of Prefrail or Frail Elderly Women.

Denervation and mitochondrial impairment are implicated in age-related skeletal muscle atrophy and may play a role in physical frailty. We recently showed that denervation modulates muscle mitochondrial function in octogenarian men, but this has not been examined in elderly women. On this basis, we tested the hypothesis that denervation plays a modulating role in mitochondrial impairment in skeletal muscle from prefrail or frail elderly (FE) women.

Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C.

The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities.

SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human.

Background: Marinesco-Sjögren Syndrome (MSS) is a rare neuromuscular condition caused by recessive mutations in the SIL1 gene resulting in the absence of functional SIL1 protein, a co-chaperone for the major ER chaperone, BiP. As BiP is decisive for proper protein processing, loss of SIL1 results in the accumulation of misshaped proteins. This accumulation likely damages and destroys cells in vulnerable tissues, leading to congenital cataracts, cerebellar ataxia, vacuolar myopathy and other MSS phenotypes.