Background and purpose: Distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders. The purpose of this study was to identify the genetic distribution of dHMNs in a large cohort of Chinese patients and provide insight into the underlying common pathophysiology of dHMNs. Methods: Multi-gene panel testing or whole-exome sequencing was performed in 70 index patients with clinically diagnosed dHMN between January 2007 and December 2018. The clinical features, Charcot-Marie-Tooth (CMT) neuropathy scores and electrophysiological data at diagnosis were recorded. Results: Twenty-four causative mutations were identified in 70 index patients with dHMN (34.3%). Mutation in the HSPB1 gene was the most common cause of dHMN. Some CMT genes (MPZ, SH3TC2, GDAP1) were found to be related to dHMN with minor sensory involvement. Patients with a dHMNplus phenotype (distal motor neuropathy and additional neurological deficits) carried variants in genes related to hereditary spastic paraplegia, amyotrophic lateral sclerosis and spinal muscular atrophy (FUS, KIF5A, KIF1B, ZFYVE26, DNAJB2). Conclusions: Comprehensive genetic testing of dHMN patients allows for identification of the pathogenic mutation in one-third of cases. Pure motor neuropathies and motor neuropathies with minor sensory involvement share many genes with CMT disease. Causes for dHMN-plus phenotypes overlap with motor neuron disease.

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KL-6, one of the MUC1 antigens, is a mucin-like high-molecular-weight glycoprotein, which is strongly expressed on type II pneumocytes. Serum levels of KL-6 have been shown to correlate with activity of interstitial pneumonia (IP). During embryonic development, MUC1 expression coincides with the onset of epithelial sheet and glandular formation. To investigate the potential role of KL-6 in lung morphogenesis, we examined KL-6 expression by immunohistochemistry on autopsied lung tissue specimens of 35 neonates and infants with gestational age from 23 to 40 weeks. Hyaline membranes (HMs) were detected in 13 of 35 cases. Simultaneously, antibody against surfactant protein A (SP-A) was employed in the study which is a distinct marker for type II pneumocytes. In all cases studied with gestational age above 23 weeks, staining for KL-6 was strongly positive in alveolar epithelial cells and in HMs found in 13 cases, whereas immunoreaction for PE10 varied depending on gestational age and duration of postnatal survival. Our findings suggest that KL-6 is expressed earlier in premature lung and may act as an important factor contributing to morphogenesis and function of developing lung in early gestation.

The c.999G>T mutation is a novel mutation of the GARS gene that has not been previously reported. The phenotype of this family is CMT2D, which is first reported in Chinese population.