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

Abstract

Despite recent scientific advances, most rare genetic diseases - including most neuro-muscular 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.

Figure 1.. Localization of CMS types and therapeutic strategies.

CMS types are stratified according to the location of the genetic defect into presynaptic, synaptic, and basal lamina-associated, postsynaptic and other, and then further stratified by genetic and functional defect. Therapeutic strategies act on different parts of the NMJ and are effective in different types.

Figure 2.. Systematic review flow chart.

Flow diagram showing the literature evaluation process for the systematic review.

Figure 3.. Mock-up of integration of treatabolome into the analysis system.

(A) A section of the current analysis results interface in the RD-Connect Genome-Phenome Analysis Platform, which includes a range of variant-level information that helps the user to assess which of the candidate variants is most likely causative. (B) The way it would be possible to incorporate an additional column into the results interface to show the clinical end-user that one of the variants they are assessing has a potential treatment associated, enabling them to evaluate the evidence base to decide whether it is appropriate for the patient in question.