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International audience; Objective: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.Methods: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.Results: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

This thesis examines the pathogenesis of motor neuron diseases in young people. A variety of causes may be considered but the most common motor neuronopathy in children is attributable to picornavirus infections, presenting with an acute flaccid paralysis that may occur in outbreaks. In those with insidious onset and slow progression a genetic basis is frequently considered with spinal muscular atrophy (SMA) being the most common inherited motor neuron disease. In order to examine the pathogenesis, this thesis looked at the acquired and inherited motor neuronopathy of young people. Assessment of the acquired group was focused on non-polio enterovirus, enterovirus 71(EV71). Clinical, neuroimaging, laboratory and pathological characteristics together with treatment administered and functional motor outcomes were assessed during a 2013 outbreak of EV71 in Sydney, Australia. Distinct clinico-radiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of grey matter in the brainstem and/or spinal cord. Assessment of the inherited group focused on children and young people with lower motor neurone (LMN) syndromes. Delineation of SMA and LMN syndromes are important as expansion of effective therapies and clinical trials occur. Our study assessed the ability to better characterise patients with LMN syndromes by integrating next generation sequencing (NGS) with conventional clinical approaches. Clinical assessment and diagnostic investigations were important in endorsing NGS findings. This study identified NGS has shifted the diagnostic paradigm with consequent diagnostic accuracy having a substantial impact on patient management, potentially enabling change of clinical management, genetic counselling with accurate prognosis and also importantly expansion of phenotypes. In a clinic cohort of children and adults with LMN syndrome, the present study confirms the utility of NGS as a rapid, efficacious and useful tool in diagnosis after usual first tier investigations. In conclusion, studies undertaken in this thesis have established that both acquired and inherited causes of motor neurone disease lead to long-term functional morbidity. These insights are important in advancing clinical diagnostic approaches, management and developing novel therapies. Attaining a definitive diagnosis had significant implications for patients and families.

Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.