A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. This underlines the importance of genetic diagnosis. Here, we report on cases with genetically proven CMS from Turkey. We retrospectively reviewed our experience of all patients with CMS, referred over a 5-year period (2011–2016) to the Child Neurology Department of Dokuz Eylül University, Izmir, Turkey. In addition, PubMed was searched for published cases of genetically proven CMS originating from Turkey. In total, we identified 43 (8 new patients, 35 recently published patients) cases. Defects in the acetylcholine receptor (n=15; 35%) were the most common type, followed by synaptic basal-lamina associated (n=14; 33%) and presynaptic syndromes (n=10; 23%). We only had 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n=1; 2%). Knowledge on CMS and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.

show abstract

“…This patient initially presented with a cervical myopathy and developed ptosis and ocular findings during the course of disease. 10 …”

Section: Discussionmentioning

confidence: 99%

“…Clinical findings also resemble DOK7 deficiency. 10 MYO9A is the one of the newest genes described in the literature. It has been described in three patients, two of whom were siblings.…”

Section: Discussionmentioning

confidence: 99%

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Similarly, patients with mutations in AGRN also present with neonatal stridor and are nonresponsive to pyridostigmine but have been shown to improve with ephedrine and recently also with salbutamol treatment …”

Section: Clinical Presentation Of Lg‐cms Patientsmentioning

confidence: 99%

Clinical and research strategies for limb‐girdle congenital myasthenic syndromes

O’Connor

Töpf

Zahedi

et al. 2018

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Congenital myasthenic syndromes (CMS) are a group of rare disorders that cause fatigable muscle weakness due to defective signal transmission at the neuromuscular junction, a specialized synapse between peripheral motor neurons and their target muscle fibers. There are now over 30 causative genes that have been reported for CMS. Of these, there are 10 that are associated with a limb-girdle pattern of muscle weakness and are thus classed as LG-CMS. Next-generation sequencing and advanced methods of data sharing are likely to uncover further genes that are associated with similar clinical phenotypes, contributing to better diagnosis and effective treatment of LG-CMS patients. This review highlights clinical and pathological hallmarks of LG-CMS in relation to the underlying genetic defects and pathways. Tailored animal and cell models are essential to elucidate the exact function and pathomechanisms at the neuromuscular synapse that underlie LG-CMS. The integration of genomics and proteomics data derived from these models and patients reveals new and often unexpected insights that are relevant beyond the rare genetic disorder of LG-CMS and may extend to the functioning of mammalian synapses in health and disease more generally.

show abstract

“…Agrin is further capable of inducing postnatal maturation and handling stability of the NMJ later in life (Samuel et al, ). Several distinct mutations have been identified in the AGRN gene, causing CMS8 and affecting specific muscle groups with diverse disease pathologies, which can be severe (Huze et al, ; Karakaya et al, ; Zhang et al, ). Interestingly, one of these mutations has been found to cause serious myasthenic symptoms by bringing about molecular characteristics similar to those of non‐neural agrin (Maselli et al, ).…”

Section: Introductionmentioning

confidence: 99%

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Heikkinen

Härönen

Norman

et al. 2019

The Anatomical Record

View full text Add to dashboard Cite

Alongside playing structural roles, the extracellular matrix (ECM) acts as an interaction platform for cellular homeostasis, organ development, and maintenance. The necessity of the ECM is highlighted by the diverse, sometimes very serious diseases that stem from defects in its components. The neuromuscular junction (NMJ) is a large peripheral motor synapse differing from its central counterparts through the ECM included at the synaptic cleft. Such synaptic basal lamina (BL) is specialized to support NMJ establishment, differentiation, maturation, stabilization, and function and diverges in molecular composition from the extrasynaptic ECM. Mutations, toxins, and autoantibodies may compromise NMJ integrity and function, thereby leading to congenital myasthenic syndromes (CMSs), poisoning, and autoimmune diseases, respectively, and all these conditions may involve synaptic ECM molecules. With neurotransmission degraded or blocked, muscle function is impaired or even prevented. At worst, this can be fatal. The article reviews the synaptic BL composition required for assembly and function of the NMJ molecular machinery through the lens of studies primarily with mouse models but also with human patients. In‐depth focus is given to collagen XIII, a postsynaptic‐membrane‐spanning but also shed ECM protein that in recent years has been revealed to be a significant component for the NMJ. Its deficiency in humans causes CMS, and autoantibodies against it have been recognized in autoimmune myasthenia gravis. Mouse models have exposed numerous details that appear to recapitulate human NMJ phenotypes relatively faithfully and thereby can be readily used to generate information necessary for understanding and ultimately treating human diseases. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

show abstract

A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop

Cited by 23 publications

References 10 publications

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights

Clinical and research strategies for limb‐girdle congenital myasthenic syndromes

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Contact Info

Product

Resources

About