Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases

Abstract

Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement. Their cumulative estimated prevalence is 2.14/100 000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive,and X-linked inheritance. Despite the advances of next generation sequencing, more than 60% of patients with HMN remain genetically uncharacterized. Of note, we are increasingly aware of the broad range of phenotypes caused by pathogenic variants in the same gene and of the considerable clinical and genetic overlap between HMN and other conditions, such as Charcot-Marie-Tooth type 2 (axonal), spinal muscular atrophy with lower extremities predominance, neurogenic arthrogryposis multiplex congenita and juvenile amyotrophic lateral sclerosis. Considering that most HMN present during childhood, in this review we primarily aim to summarize key clinical features of paediatric forms, including recent data on novel phenotypes, to help guide differential diagnosis and genetic testing. Second, we describe newly identified causative genes and molecular mechanisms, and discuss how the discovery of these is changing the paradigm through which we approach this group of conditions.

Keywords: HMN; SMA-LED; dHMN; distal SMA; paediatric neuronopathies.

Figure 1

Diagnostic clues based on age of onset (A) and relevant clinical features (B). Relevant clinical features (B) may or may not be present due to disease spectrum or stage at assessment. Genes are listed in alphabetical order and according to mode of inheritance: autosomal dominant (AD) pattern, bold font and red; autosomal recessive (AR), regular font and blue; X-linked in black (LAS1L and ATP7A). Asterisk indicates when more than one mode of inheritance has been associated with the same gene. EMG = electromyography; MCD = malformation of cortical development.

Figure 2

Schematic representation of molecular mechanism involved in neuronopathies. The top section includes a central schematic of motor nerve structure and its interaction with skeletal muscle fibres. Genes associated with neuronopathies, grouped according to their main function, are mentioned in panels surrounding the schematic. (A–D) Aim to show the physiological role of genes recently implicated in these disorders and their presumed pathological mechanism. (A) Mutations in the extracellular protein VWA, that in its wild-type state connects collagen VI and perlecan, affect both axonal elongation and branching. (B) Mutant GARS and AARS tRNA synthetases are thought to impede the release of neurotrophic signals by binding NRP1 protein and thus altering Nrp1/VEGF signalling. (C) The increase of intracellular calcium resulting from the mutant TRPV4 channel activates CAMKII ad RhoA signalling, leading to the formation of cytoplasmic actin stress fibers. (D) A defective BICD2 protein impairs both the release of muscle neurotrophins and the neuronal vesicles retrograde transport, resulting in abnormal development of the motor unit and neuronal degeneration.

Figure 3

Clinical and radiological features of neuronopathies. (A) Distal leg thinning in a patient with MFN2 variant; (B) lower leg atrophy and foot deformities in a patient with BICD2 variant; (C) lower leg atrophy and foot posture in a patient with DYNC1H1 variant. (D) Foot posture in a young adult with TRPV4 variant; (E) photo of hand atrophy (split-hand sign) in a patient with GARS variant; (F) thigh muscle MRI showing islands of muscle, a finding strongly suggestive of neuronopathy; (G) X-ray showing diaphragmatic paralysis in SMARD1 (arrow).