Sural biopsy to detect the axonal cytoskeleton defects in KIF5A-related Charcot-Marie-Tooth disease type 2

Kinesins are microtubule-associated motor proteins involved in in regulating microtubule dynamics in neuronal and non-neuronal cells. However, the axonal cytoskeleton-related pathological changes in peripheral nerve have never been described in patients with KIF5A mutation. This study aims to report sural biopsy to detect axonal cytoskeleton abnormalities in a patient with KIF5A-related Charcot-Marie-Tooth disease type 2 (CMT2). We screened for the variants of CMT or related pathogenic genes using next-generation sequencing in a Chinese family with CMT2. The proband was a 13-year-old girl who presented with severe weakness and wasting of distal muscles of limbs starting at early childhood. The disease rapidly progressed, and the girl lost ambulation. Her mother showed absence of deep tendon reflexes in the lower limbs. Nerve conduction studies disclosed a more pronounced axonal sensory-motor neuropathy in the proband. The girl and her mother had a heterozygous p.E755K mutation of the KIF5A gene, which was previously reported only in hereditary spastic paraplegia and amyotrophic lateral sclerosis. Sural biopsy revealed loss of both myelinated and unmyelinated nerve fibers. Closely packed, irregularly oriented neurofilaments were observed in axons of unmyelinated nerve fibers. Another important finding was ubiquitous presence of elongated mitochondria with vacuole in the myelinated and unmyelinated axons. This study suggested the p.E755K mutation of KIF5A was a cause of early-onset CMT2 with defective axonal transport, and emphasized sural biopsy could be an important tool to detect axonal cytoskeleton defects in KIF5A related CMT2.