Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

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.

Figure 1

Diagnostic approach for a patient (<18 years) with a motor neuron disorder (MND). ALS: amyotrophic lateral sclerosis; CK: creatinine kinase; dHMN: distal hereditary motor neuropathy; GBS: Guillain-Barre syndrome; MND: motor neuron disorder; MRI: magnetic resonance imaging; NGS: next generation sequencing. ^∗genomic testing by panel; WES or WGS may be an option depending on local availability.

Figure 2

Clinical pictures of SMA plus syndrome. (a) EMG demonstrating a large-amplitude polyphasic motor unit characteristic of reinnervation. (b) H&E magnification ×200 showing small round denervated muscle fibers^∗ and large hypertrophic muscle fibers^∗∗. (c) Distal leg atrophy. (d) CXR showing diaphragm eventration in spinal muscular atrophy with respiratory distress (SMARD. (e) Tongue atrophy seen in Brown-Vialetto-Van Laere syndrome. (f) Hand wasting with contractures seen in Brown-Vialetto-Van Laere syndrome.

Figure 3

Clinical pictures of paediatric multisystem disorders with motor neuron disease. (a) Interictal EEG showing diffuse spike and slow wave complexes in infantile neuroaxonal dystrophy (INAD). (b) MRI brain in the sagittal plane showing cerebellar atrophy seen in INAD. (c) Barium swallow demonstrating dilated oesophagus and tapering in keeping with achalasia in AAA syndrome.

Figure 4

Pathogenic mechanisms underlying motor neuron disease in children of these genetic variants associated with paediatric motor neuron diseases relate to disordered regulation of autophagy/protein quality control (ASAH1, UBE1,UBQLN1, LYST, ATXN3, and SCP2), RNA processing (VRK1, EXOSC3, EXOSC8, TSEN54, SLC254A6, MORC2, SMN1, TRIP4, ASCC1, UBA1, GLE1, ERBB3, IGHMBP2, and RBM28), and cytoskeletal dynamics (ASAH1, BICD2, and DYNC1H1). Functional connections between pathways occur. Additional mechanisms include structural and functional abnormalities of mitochondria (SOC2, TK2, DGUOK, and PLAG26), molecular transport by cation channeling (TRPV4 and SCN1A), and vitamin uptake (SLC52A3 and SLC52A2).