Clinical features of autosomal recessive Charcot-Marie-Tooth disease 2K

Abstract

Objective To report the clinical and peripheral neuropathological findings in two patients with autosomal recessive Charcot-Marie-Tooth disease 2K(AR-CMT2K). Methods Case one was a nine year-old girl. She had distal weakness of lower limbs for six years, with calf atrophy and contracture of Achilles tendon for three years. Case two was an eight year-old boy. He had distal weakness of lower limbs with contracture of Achilles tendon and calf muscle atrophy for three years, and proximal weakness of low limbs for two years. The motor nerve conduction velocities in median nerves were 48.1 m/s in case one and 47.6 m/s in case two. The compound motor action potential amplitude of median nerves decreased by 46% in case one and 69% in case two. Sural nerve biopsies and gene targeted next-generation sequencing were performed in both patients. Results Density of myelinated fibers was 8 407/mm2 in case one and 7 714/mm2 in case two. The ratio of myelinated fibers with diameter over 8 μm was 2.6% in case one and 0 in case two. Both patients had small regenerating cluster of myelinated fibers. Thin myelinated fibers appeared in case one. In case two, atypical onion bulb formations with focal folded myelin appeared, and electromicroscopy revealed mitochondrial aggregate in axons. Compound heterozygous mutations of ganglioside-induced differentiation associated protein 1 gene were detected in both patients, including c. 767A>G(p.H256R) and c. 466G>A (p.A156T) in case one and c. 767A>G and 845G>A(p.R282H) in case two. Conclusions Contracture of Achilles tendon may appear in early childhood of AR-CMT2K patients. The main pathological changes in sural nerve are loss of large myelinated fibers, mitochondrial aggregate in axons and myelin abnormalities. Key words: Charcot-Marie-Tooth disease; Heredity; Mutation; Peripheral nerve; Ganglioside-induced differentiation associated protein