Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy.

Hooi Ling Teoh,David Mowat,Michelle Farrar,Tony Roscioli,Hugo Sampaio,Kate Carey

doi:10.1155/2017/6509493

Abstract

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.

Highlights

Motor neuron diseases (MND) are a heterogeneous group of progressive disorders resulting in difficulties walking, moving, breathing, and swallowing, with onset ranging from birth to adulthood
The most common motor neuronopathy in children is attributable to picornavirus infections, including coxsackievirus, enterovirus 68 and 71, echovirus, and polio, presenting with an acute flaccid paralysis that may occur in outbreaks [1, 2]
We have included “spinal muscular atrophy (SMA) plus” syndromes in which motor neuron dysfunction is the primary but not the sole feature, juvenile amyotrophic lateral sclerosis, and multisystem disorders in which amyotrophy related to lower motor neuron degeneration is evident

Summary

Introduction

Motor neuron diseases (MND) are a heterogeneous group of progressive disorders resulting in difficulties walking, moving, breathing, and swallowing, with onset ranging from birth to adulthood. We have included “SMA plus” syndromes in which motor neuron dysfunction is the primary but not the sole feature, juvenile amyotrophic lateral sclerosis (jALS), and multisystem disorders in which amyotrophy related to lower motor neuron degeneration is evident. We provide an overview of NGS technologies that may be utilised in molecular genetic diagnostic approaches These are currently transforming clinical practice and may provide a method to establish a timely cost-effective diagnosis, critical to enabling therapy at the earliest possible stage for these devastating groups of disorders. NGS technologies are transforming clinical practice and increasingly being used as a first-tier diagnostic test to provide a timely diagnosis (Figure 1) This is reinforcing the importance of accurate clinical evaluation together with knowledge of the diverse clinical and genetic phenotypes to be able to provide molecular genetic diagnoses

SMA Plus Syndromes

Paediatric Multisystem Disorders Including Motor Neuron Disease

Genetic Insights into Pathophysiology

Findings

Conclusions