Genetic axonal neuropathies and neuronopathies of pre‐natal and infantile onset

Abstract

The infantile-onset axonal neuropathies and neuronopathies are an uncommon and heterogeneous group of conditions causing weakness, wasting, and developmental delay in early childhood. Many are associated with central nervous system or other systemic manifestations and cause early mortality. We review the axonal Charcot-Marie-Tooth subtypes with onset in infancy, spinal muscular atrophy, and related syndromes of early infancy, giant axonal neuropathy, infantile neuroaxonal dystrophy, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, early-onset neuropathies associated with mitochondrial disorders, and other less well-delineated clinical entities. Useful clinical and neuropathologic features in the diagnostic work-up of these conditions are also presented.

Autosomal dominant neuropathy of the axonal Charcot–Marie–Tooth type 2

“…Neuropathies caused by mutations of the MFN2 gene [8] are classified as CMT2A and account for 3% of infantile neuropathies [9], and 5-30% of CMT2 cases [10]. Thus CMT2A represents the most frequent autosomal dominantly inherited axonal neuropathy.…”

“…Rapid progression following onset in early childhood and, less commonly, adult onset with slow progression may be seen [10], [15][16][17], occasionally with optic atrophy, pyramidal features, tremor and Parkinsonism [18,19]. The combination of CMT with optic atrophy was previously classified as HMSN VI [10], and that with pyramidal features as HMSN V [20].…”

“…The combination of CMT with optic atrophy was previously classified as HMSN VI [10], and that with pyramidal features as HMSN V [20]. Typically there is distal sensory loss, distal weakness and muscle atrophy, pes cavus, and scoliosis, but nerve conduction velocity (NCV) remains relatively well preserved (electrophysiologically "axonal" type of neuropathy).…”

“…There were no paracrystalline inclusions similar to those seen in muscle fibers in certain mitochondrial myopathies. However, needle-like, crystalline intramitochondrial inclusions (spiculae) were seen in a case of HSMN VI (Hereditary motor and sensory neuropathy type VI, Vizioli; AD with optic atrophy) [24], which would nowadays presumably be classified as CMT2A [10]. In addition swollen, enlarged mitochondria were noted in endoneurial fibroblasts ( Fig.…”

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

“…GAN is an “ultra-rare” disease with tens of patients globally (with many likely to be undiagnosed), but neurologists suspect that some CMT Type 2 patients whose causal gene remains unknown may actually have GAN 15 greatly expanding the patient population. GAN generally appears in early childhood and progresses slowly as the neuronal injury becomes more severe.…”