Pediatric neuromuscular diseases encompass all disorders with onset in childhood and where the primary area of pathology is in the peripheral nervous system. These conditions are largely genetic in ...etiology, and only those with a genetic underpinning will be presented in this review. This includes disorders of the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot–Marie–Tooth disease), the neuromuscular junction (e.g., congenital myasthenic syndrome), and the muscle (myopathies and muscular dystrophies). Historically, pediatric neuromuscular disorders have uniformly been considered to be without treatment possibilities and to have dire prognoses. This perception has gradually changed, starting in part with the discovery and widespread application of corticosteroids for Duchenne muscular dystrophy. At present, several exciting therapeutic avenues are under investigation for a range of conditions, offering the potential for significant improvements in patient morbidities and mortality and, in some cases, curative intervention. In this review, we will present the current state of treatment for the most common pediatric neuromuscular conditions, and detail the treatment strategies with the greatest potential for helping with these devastating diseases.
Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for ...disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap. Whole-genome sequencing is one potential strategy, but it currently has variant-interpretation challenges, particularly for non-coding changes. In this study we focus on transcriptome analysis, specifically total RNA sequencing (RNA-seq), by using monogenetic neuromuscular disorders as proof of principle. We examined a cohort of 25 exome and/or panel “negative” cases and provided genetic resolution in 36% (9/25). Causative mutations were identified in coding and non-coding exons, as well as in intronic regions, and the mutational pathomechanisms included transcriptional repression, exon skipping, and intron inclusion. We address a key barrier of transcriptome-based diagnostics: the need for source material with disease-representative expression patterns. We establish that blood-based RNA-seq is not adequate for neuromuscular diagnostics, whereas myotubes generated by transdifferentiation from an individual’s fibroblasts accurately reflect the muscle transcriptome and faithfully reveal disease-causing mutations. Our work confirms that RNA-seq can greatly improve diagnostic yield in genetically unresolved cases of Mendelian disease, defines strengths and challenges of the technology, and demonstrates the suitability of cell models for RNA-based diagnostics. Our data set the stage for development of RNA-seq as a powerful clinical diagnostic tool that can be applied to the large population of individuals with undiagnosed, rare diseases and provide a framework for establishing minimally invasive strategies for doing so.
Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely ...unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). Furthermore, we demonstrate preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia. Using a previously undescribed approach involving single guide RNA, we successfully removed large genome rearrangement in primary cells of an individual with an X chromosome duplication including MECP2. Moreover, removal of a duplication of DMD exons 18–30 in myotubes of an individual affected by DMD produced full-length dystrophin. Our findings establish the far-reaching therapeutic utility of CRISPR/Cas9, which can be tailored to target numerous inherited disorders.
•LAMB2 gene disorders present with different phenotypes but neuromuscular junction abnormalities represented as congenital myasthenic syndrome (CMS) is very rare phenotype.•CMS can be presented with ...LAMB2 gene disorder as evidenced by abnormal repetitive nerve stimulation or weakness.•Salbutamol could be a potential medication but its effect is still illusive for this specific gene disorder.
LAMB2 gene disorders present with different phenotypes. Pierson syndrome (PS) is a common phenotype associated with LAMB2 variants. Neuromuscular phenotype has been reported including hypotonia and developmental delay. However, neuromuscular junction abnormalities represented as congenital myasthenic syndrome (CMS) was reported in one adult patient only. Here, in this paper, we present two pediatric cases with a severe presentation of PS and have CMS so expanding the knowledge of LAMB2 related phenotypes. The first patient had hypotonia and global developmental delay. Targeted genetic testing panel demonstrated homozygous pathogenic variant in the LAMB2 gene (c.5182C>T, pGln1728*) which was reported by Maselli et al. 2009. Repetitive nerve stimulation (RNS) showed a decremental response at low frequency of 3 Hz. On the other hand, the second patient had profound weakness since birth. Tri-Whole exome sequencing showed homozygous pathogenic variant in the LAMB2 gene c.2890C>T, pArg964*. A trial of salbutamol did not improve the symptoms. Both patients passed away from sequala of PS. The spectrum of phenotypic changes associated with LAMB2 mutations is still expanding, and further investigation into the various clinical and morphologic presentations associated with these mutations is important to better identify and manage affected individuals.
X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss of expression/function mutations in the myotubularin (MTM1) gene. Much of what is ...known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO). Despite this understanding, and the identification of potential therapies, much remains to be understood about XLMTM disease pathomechanisms, and about the normal functions of MTM1 in muscle development. To lay the groundwork for addressing these knowledge gaps, we performed a natural history study of Mtm1 KO mice. This included longitudinal comparative analyses of motor phenotype, transcriptome and proteome profiles, muscle structure, and targeted molecular pathways. We identified age associated changes in gene expression, mitochondrial function, myofiber size, and key molecular markers including DNM2. Importantly, some molecular and histopathologic changes preceded overt phenotypic changes, while others, such as triad structural alternations, occurred coincidentally with the presence of severe weakness. In total, this study provides a comprehensive longitudinal evaluation of the murine XLMTM disease process, and thus provides a critical framework for future investigations.
Background
Spinal muscular atrophy type 1 (SMA1) is a neuromuscular disorder with a natural history of chronic respiratory failure and death during infancy without ventilation. Recently, ...disease‐modifying therapies such as nusinersen have improved disease trajectory. However, objective data on the trajectory of polysomnography outcomes, the relationship between motor scores and respiratory parameters, respiratory technology dependence and healthcare utilization in children with SMA1 remain to be elucidated.
Methods
This was a retrospective observational study of children with SMA1 receiving nusinersen between October 2016 and February 2021 at two tertiary care hospitals in Canada. Baseline polysomnography data, motor scores, respiratory technology, and unanticipated healthcare utilization were examined.
Results
Eleven children (five females, two SMN2 copies each) were included. Median (interquartile range IQR) age at diagnosis was 3.6 (2.8–5.0) months and age at diagnostic polysomnogram following nusinersen initiation was 9.4 (5.3–14.0) months. Nusinersen was initiated at a median (IQR) age of 5.4 (3.4–7.6) months and 8/11 children had respiratory symptoms at that time. Diagnostic polysomnography data showed a median (IQR) central apnea‐hypopnea index (AHI) of 4.1 (1.8–10.0) and obstructive AHI of 2.2 (0–8.0) events/h. We observed an inverse relationship between motor scores and central apnea‐hypopnea indices. All children required ventilatory support at the end of the study period.
Conclusion
This study showed abnormal polysomnography parameters and need for ventilation despite nusinersen suggesting ongoing need for regular monitoring with polysomnography. Understanding the respiratory disease trajectory of children undergoing treatment with nusinersen will inform decision‐making regarding optimal timing of ventilatory support initiation.
The genetics of congenital myopathies Gonorazky, Hernan D; Bönnemann, Carsten G; Dowling, James J
Handbook of clinical neurology,
2018, Letnik:
148
Journal Article
Recenzirano
Congenital myopathies are a clinically and genetically heterogeneous group of conditions that most commonly present at or around the time of birth with hypotonia, muscle weakness, and (often) ...respiratory distress. Historically, this group of disorders has been subclassified based on muscle histopathologic characteristics. There has been an explosion of gene discovery, and there are now at least 32 different genetic causes of disease. With this increased understanding of the genetic basis of disease has come the knowledge that the mutations in congenital myopathy genes can present with a wide variety of clinical phenotypes and can result in a broad spectrum of histopathologic findings on muscle biopsy. In addition, mutations in several genes can share the same histopathologic features. The identification of new genes and interpretation of different pathomechanisms at a molecular level have helped us to understand the clinical and histopathologic similarities that this group of disorders share. In this review, we highlight the genetic understanding for each subtype, its pathogenesis, and the future key issues in congenital myopathies.
•Amongst patients with neuromuscular disorders transitioning from paediatric to adult care there was a broad range of disorders, with myopathy being the most common inherited disorder and myasthenia ...gravis in acquired.•A definite genetic diagnosis was achieved in a large proportion of patients.•Cardiac and respiratory transitioning was performed in more than a third of patients and there was a strong correlation between scoliosis and the presence of respiratory abnormality.•A wide range of systemic issues required the services of endocrinology, gastroenterology, speech and language pathology and psychiatry.•A multidisciplinary clinical care model where all aspects of neuromuscular disease are addressed may provide optimal care for patients undergoing transition.
Transition in paediatric health care refers to the planned process of shifting to an adult model of care and is highly individualised, patient focussed and requires a coordinated effort from different health care professionals. Through this retrospective study, we describe the spectrum of neuromuscular diseases evaluated through a paediatric to adult neuromuscular transition program in a tertiary academic centre in Canada, and also the speciality supports needed for these patients. 126 patients were transitioned during the study period. The most common clinical diagnosis was muscle disease (44.4%), followed by neuropathy (27.8%), neuromuscular junction disorders (15.9%) and motor neuron disease (MND) (10.3%). The majority of cases were inherited neuromuscular disorders (66.6%); 58.3% had a genetically confirmed diagnosis. Cardiac and respiratory abnormalities were encountered in 8.7% and 27.7% and transitioning was required for 39.8% and 35.7% respectively. Scoliosis was seen in 30.2% of patients; 9.5% underwent spine surgery. Patients with MND had maximum requirements for self-care (46.2% of MND) and a mobility device for ambulation was required in 69.2% of MND. We observed a wide range of systemic issues requiring the services of endocrinology, gastroenterology, speech and language pathology and psychiatry. A multidisciplinary clinical care model may provide optimal care for patients transitioning from paediatric to adult care health systems.
Background and ObjectivesThe introduction of spinal muscular dystrophy (SMA)-modifying therapies, such as antisense oligonucleotide therapy, has changed the natural history of SMA. Most reports on ...treatment outcomes have focused on motor scores and respiratory function. The objective of this study is to document the development and progression of scoliosis in patients with SMA1 treated with nusinersen. MethodsA descriptive single-center study was conducted in patients with SMA1 who were treated with nusinersen before 6 months of age. Data were collected on patients who met criteria, including age at the first nusinersen dose, number of nusinersen doses, degree of scoliosis, respiratory parameters, feeding route, and motor scores at baseline and follow-up. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) was subanalyzed using axial (AxS) and appendicular motor (ApS) scores to evaluate a possible correlation between scoliosis and axial muscle strength. ResultsFrom our cohort, 31 percent (11/35) of patients had a diagnosis of SMA1. Sixty-three percent (7/11) met the inclusion criteria. All patients (7/7) showed initial improvement in their CHOP-INTEND scores in correlation with improvement on the ApS. Despite this, most patients did not show improvement in the AxS. Subsequently, all patients developed scoliosis in the first year of life with Cobb angles that ranged between 18° and 60°. Furthermore, total CHOP-INTEND scores had dropped in 2 patients alongside the development of a Cobb angle of >40°. DiscussionDespite the significant improvement in functional motor assessment in patients with SMA1, there is a progression of significant scoliosis despite treatment. Subsequently, lack or minimal improvement on the axial CHOP-INTEND scores may predict worsening on the total motor scores.
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