Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome

Abstract Despite recent scientific advances, most rare genetic diseases — including most neuromuscular diseases — do not currently have curative gene-based therapies available. However, in some cases, such as vitamin, cofactor or enzyme deficiencies, channelopathies and disorders of the neuromuscular junction, a confirmed genetic diagnosis provides guidance on treatment, with drugs available that may significantly alter the disease course, improve functional ability and extend life expectancy. Nevertheless, many treatable patients remain undiagnosed or do not receive treatment even after genetic diagnosis. The growth of computer-aided genetic analysis systems that enable clinicians to diagnose their undiagnosed patients has not yet been matched by genetics-based decision-support systems for treatment guidance. Generating a ‘treatabolome’ of treatable variants and the evidence for the treatment has the potential to increase treatment rates for treatable conditions. Here, we use the congenital myasthenic syndromes (CMS), a group of clinically and genetically heterogeneous but frequently treatable neuromuscular conditions, to illustrate the steps in the creation of a treatabolome for rare inherited diseases. We perform a systematic review of the evidence for pharmacological treatment of each CMS type, gathering evidence from 207 studies of over 1000 patients and stratifying by genetic defect, as treatment varies depending on the underlying cause. We assess the strength and quality of the evidence and create a dataset that provides the foundation for a computer-aided system to enable clinicians to gain easier access to information about treatable variants and the evidence they need to consider.

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

Journal of Child Neurology ◽

10.1177/0883073817705252 ◽

2017 ◽

Vol 32 (8) ◽

pp. 759-765 ◽

Cited By ~ 10

Author(s):

Uluç Yiş ◽

Kerstin Becker ◽

Semra Hız Kurul ◽

Gökhan Uyanik ◽

Erhan Bayram ◽

...

Keyword(s):

Cholinesterase Inhibitors ◽

Neuromuscular Disorders ◽

Genetic Diagnosis ◽

Common Type ◽

Child Neurology ◽

Novel Mutations ◽

Congenital Myasthenic Syndromes ◽

Genetic Landscape ◽

Prompt Diagnosis ◽

Myasthenic Syndromes

Congenital myasthenic syndromes 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, the authors report on cases with genetically proven congenital myasthenic syndromes from Turkey. The authors retrospectively reviewed their experience of all patients with congenital myasthenic syndromes, 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 congenital myasthenic syndromes originating from Turkey. In total, the authors 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%). The authors had only 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n = 1; 2%). Knowledge on congenital myasthenic syndromes and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.

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The Increasing Genetic and Phenotypical Diversity of Congenital Myasthenic Syndromes

Neuropediatrics ◽

10.1055/s-0037-1602832 ◽

2017 ◽

Vol 48 (04) ◽

pp. 294-308 ◽

Cited By ~ 29

Author(s):

Angela Abicht ◽

Teresinha Evangelista ◽

Sally Spendiff ◽

Hanns Lochmüller ◽

Grace McMacken

Keyword(s):

Therapeutic Intervention ◽

Genetic Diagnosis ◽

Muscular Dystrophies ◽

Diverse Group ◽

Peripheral Neuropathies ◽

Critical Importance ◽

Congenital Myasthenic Syndromes ◽

Pathologic Features ◽

Myasthenic Syndromes

AbstractThe congenital myasthenic syndromes (CMS) are a diverse group of diseases, which result in an increasing range of phenotypes, but which are all due to inherited defects at the neuromuscular junction (NMJ). Although some patients remain genetically undiagnosed, our ability to identify the causative genes has shed new light on the role of previous uncharacterized proteins at the NMJ. Securing the genetic diagnosis can be challenging, but it is of critical importance to allow rational therapeutic intervention. In this review, we summarize the key clinical and pathologic features of the CMS subtypes, outline diagnostic clues, and challenges, and describe the recent advances that have highlighted the overlap between CMS and the muscular dystrophies and peripheral neuropathies.

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Neurophysiological testing in congenital myasthenic syndromes: A systematic review of published normal data

Muscle & Nerve ◽

10.1002/mus.23929 ◽

2013 ◽

Vol 48 (5) ◽

pp. 711-715 ◽

Cited By ~ 5

Author(s):

Ana Kosac ◽

Erika Gavillet ◽

Roger G. Whittaker

Keyword(s):

Systematic Review ◽

Congenital Myasthenic Syndromes ◽

Myasthenic Syndromes

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Disease monitoring programs of rare genetic diseases: transparent data sharing between academic and commercial stakeholders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01687-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Hanns Lochmüller ◽

Antonio Nino Ramirez ◽

Emil Kakkis

Keyword(s):

Conflicts Of Interest ◽

Genetic Diseases ◽

Neuromuscular Diseases ◽

Disease Monitoring ◽

Concept Of Disease ◽

Monitoring Programs ◽

Rare Genetic Diseases ◽

Post Marketing ◽

Current Compliance

AbstractIt has recently been suggested that registries for rare neuromuscular diseases should be formed and governed exclusively by physicians and patients in an effort to limit conflicts of interest. Enacting such an approach would not only be challenging logistically and financially, but it would also exclude the involvement of sponsors, who are an integral component of drug development within the current compliance framework. Therefore, as an alternative to traditional registries, we propose the use of a better collaborative model for post-marketing follow-up that includes all stakeholders. We developed the concept of Disease Monitoring Programs (DMPs), which are designed to monitor disease manifestations over a 10-year period whether on a sponsored drug or not, and ensure consistent collection, ownership sharing and governance of data.

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Opportunities and pitfalls of social media research in rare genetic diseases: a systematic review

Genetics in Medicine ◽

10.1038/s41436-021-01273-z ◽

2021 ◽

Author(s):

Emily G. Miller ◽

Amanda L. Woodward ◽

Grace Flinchum ◽

Jennifer L. Young ◽

Holly K. Tabor ◽

...

Keyword(s):

Systematic Review ◽

Social Media ◽

Genetic Diseases ◽

Rare Genetic Diseases ◽

Media Research ◽

Social Media Research

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La diagnosi pre-impiantatoria Lo stato dell’arte scientifico e gli interrogativi etici - Parte I

Medicina e Morale ◽

10.4081/mem.2007.317 ◽

2007 ◽

Vol 56 (3) ◽

Author(s):

Jacques Suaudeau

Keyword(s):

Preimplantation Genetic Diagnosis ◽

Chromosomal Abnormalities ◽

Late Onset ◽

Genetic Diseases ◽

Genetic Defect ◽

Genetic Diagnosis ◽

Human Embryos ◽

The Social ◽

Selection Of

La diagnosi genetica pre-impiantatoria (Preimplantation genetic diagnosis o PGD) è una tecnica nella quale gli embrioni umani prodotti in vitro per le tecniche di fecondazione artificiale, vengono selezionati, nelle prime fasi di sviluppo, dal punto di vista genetico, tramite lo studio di uno o due blastomeri prelevati con una biopsia. Gli embrioni non affetti da malattie vengono poi trasferiti nell’utero. La PGD è stata introdotta agli inizi degli anni ’90 in alternativa alla diagnosi prenatale per coppie per le quali fosse alto il rischio di trasmettere un difetto genetico. Negli anni successivi è stata adoperata per altre indicazioni come l’individuazione delle anomalie cromosomiche, la ricerca delle aneuploidie, la selezione “sociale” del sesso, la selezione degli embrioni secondo il tipo di Human Leukocit Antigen (HLA) e l’individuazione di malattie genetiche ad esordio tardivo. Dai reports relativi all’uso della PGD nel mondo emergono, tuttavia, tre punti critici: il primo riguarda l’esattezza diagnostica, con la presenza di falsi positivi e falsi negativi; la seconda, la notevole perdita di embrioni umani nel processo; la terza, i risultati della PGD in termini di nascita di bambini sani. ---------- The preimplantation genetic diagnosis (PGD) is a technique in which early human embryos, obtained in vitro for artificial fertilization techniques, are genetically screened for selection, through study of one or two blastomeres taken by biopsy. The embryos, that are healthy, are transferred to uterus. The PGD has been introduced in the early 1990s as an alternative to prenata1 diagnosis for couples at high risk of transmitting a genetic defect. It has been subsequently extended to other indications as the individualization of chromosomal abnormalities, the research of the aneuploidies, the “social selection of sex”, the selection of the embryos according to the type of Human Leukocit Antigen (HLA) and the individualization of late-onset genetic diseases. But the reports concerning with the use of PGD in the world make clear that there are three critical points: the first deals with the diagnostic accuracy, with the presence of false positives and false negatives; the second, with the wide loss of embryos during the process; the third, with the outcomes of the PGD in terms of birth of healthy babies.

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Results of clinical and genetic diagnosis of rare diseases in the Eastern region of Hungary (2007–2013)

Orvosi Hetilap ◽

10.1556/oh.2014.29690 ◽

2014 ◽

Vol 155 (9) ◽

pp. 348-357 ◽

Cited By ~ 1

Author(s):

Katalin Szakszon ◽

Erzsébet Balogh ◽

Anikó Ujfalusi ◽

Beáta Bessenyei ◽

Gabriella P. Szabó ◽

...

Keyword(s):

Rare Diseases ◽

Congenital Anomalies ◽

Genetic Diseases ◽

Genetic Diagnosis ◽

International Standards ◽

Time Interval ◽

Clinical Genetics ◽

Eastern Region ◽

Rare Genetic Diseases ◽

International Data

Introduction: 80% of rare diseases have a genetic origin, and 50% manifest themselves as congenital anomalies. Their adequate health care includes early recognition of genetic anomalies and prevention of recurrence. Aim: The aims of the authors were to provide correct diagnoses to patients with multiple congenital anomalies with or without mental retardation attending to the outpatient clinic of the Clinical Genetics Center at the University of Debrecen in the time interval between August 1, 2007 and March 31, 2013, establish the possibility of prenatal diagnosis, assess the distribution of different genetic mechanisms in the background of rare genetic diseases, compare them with international data, and develop an algorithm for the diagnostic approach of rare genetic diseases applicable in Hungary. Method: Clinical data and genetic results of patients were evaluated, and patients were categorized into one of the ten proposed etiological groups, based on which the distribution of genetic causes was defined. Results: Clinical diagnosis was achieved in 64.3% of patients, confirmed genetic diagnosis in 37.8%, while 35.7% of patients remained undiagnosed. Several dysmorphic syndromes and metabolic disorders were first diagnosed in Hungary, two of which unique in the literature. Conclusions: In the centre of the authors the diagnostic effectiveness of chromosome aberrations exceeds the international standards, that of known microdeletions and dysmorphic syndromes meets international data, and the genetic diagnosis of mendelian disorders and submicroscopic copy number changes remain below international figures. Orv. Hetil., 2014, 155(9), 348–357.

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