Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have recently been found to be one of the most frequent causes of autosomal recessive axonal Charcot-Marie-Tooth (CMT2) and distal hereditary motor neuropathy (dHMN). This study was performed to explore the frequency of SORD mutations and correlations of the phenotypic-genetic spectrum in a relatively large Chinese cohort. In this study, we screened a cohort of 485 unrelated Chinese patients with hereditary neuropathy by using Sanger sequencing, next generation sequencing, or whole exome sequencing after PMP22 duplication was initially excluded. SORD mutation was identified in five out of 78 undiagnosed patients. Two individuals carried the previously reported homozygous c.757 delG (p.A253Qfs*27) variant, and three individuals carried the heterozygous c.757delG (p.A253Qfs*27) variant together with a second novel likely pathogenic variant, including c.731 C>T (p.P244L), c.776 C>T (p.A259V), or c.851T>C (p.L284P). The frequency of SORD variants was calculated to be 6.4% (5/78) in unclarified CMT2 and dHMN patients. All patients presented with distal weakness and atrophy in the lower limb, two of whom had minor clinical sensory abnormalities and small fiber neuropathy. Our study provides further information on the genotype and phenotype of patients with SORD mutations.

EPIDEMIOLOGICAL CHARACTERISTICS OF HEREDITARY MOTOR AND SENSORY NEUROPATHY IN THE KHARKOV REGION

Hereditary motor and sensory neuropathies are one of the most common diseases among monogenic hereditary diseases of the nervous system. Hereditary motor and sensory neuropathies are the group of clinically and genetically heterogeneous diseases characterized by peripheral nerve damage. Hereditary motor and sensory neuropathies have little effect on life expectancy, and this leads to their significant accumulation in individual families and in populations as a whole. The most common form of this disorder is hereditary motor and sensory neuropathy with an autosomal dominant type of inheritance - type 1A, caused by a mutation in the gene of peripheral myelin protein 22 (PMP22) on chromosome 17p11.2-12. According to various researches, the frequency of all hereditary motor and sensory neuropathies in the general population is 1:2500. The prevalence of hereditary motor and sensory neuropathies in different populations varies widely, therefore, the most appropriate at the initial stage of the genetic-epidemiological study of hereditary motor and sensory neuropathies is to determine the population frequency of this mutation in a specific region. The research of the territorial and ethnic distribution of hereditary motor and sensory neuropathies in the Kharkiv region was not carried out. That is why the aim of the research was to study and analyze the prevalence rates of hereditary motor and sensory neuropathies in the Kharkiv region in the context of administrative and territorial units and individual ethnic groups of the population. The epidemiological study of hereditary motor and sensory neuropathies in the Kharkiv region was carried out in the period from 2015 to 2020. The diagnosis of hereditary motor and sensory neuropathy was established in accordance with the recommendations of the WHO Research Group on neuromuscular diseases on the basis of diagnostic criteria.The prevalence rate of hereditary motor and sensory neuropathy was calculated both for various administrative and territorial units of the Kharkiv region and for individual ethnic groups of the population and expressed as the number of cases per 100,000 people. The results of the research showed that the prevalence rate of all forms of hereditary motor and sensory neuropathies in the Kharkiv region is 5.56 per 100,000 population and this indicator is unevenly distributed. The reason for the uneven distribution of hereditary motor and sensory neuropathies in the Kharkiv region may be the "effect of small samples" due to differences in population size both in individual administrative regions and in some ethnic groups of the population. In the Kharkiv region, the part of registered patients with hereditary motor and sensory neuropathies among the urban population (55.3%) is higher than among residents of country areas (44.7%). The heterogeneity of the prevalence rate of hereditary motor and sensory neuropathies in various ethnic groups of the Kharkiv region is due to the non-representativeness of these groups to the corresponding ethnic populations and such indicators cannot be transferred to the entire population as a whole. The high prevalence of hereditary motor and sensory neuropathies among certain ethnic groups is most likely due to the presence of ethnic isolates with a high degree of inbred members of the group.

Temporal manipulation of KCC3 expression in juvenile or adult mice suggests irreversible developmental deficit in hereditary motor sensory neuropathy with agenesis of the corpus callosum

Hereditary motor sensory neuropathy (HMSN/ACC) with agenesis of the corpus callosum (ACC) has been documented in the French-derived populations of Charlevoix and Saguenay/Lac St. Jean in Quebec, Canada, as well as a few sporadic families throughout the world. HMSN/ACC occurs because of loss-of-function mutations in the potassium-chloride cotransporter 3 (KCC3). In HMSN/ACC, motor deficits occur early in infancy with rapid and continual deterioration of motor and sensory fibers into juvenile and adulthood. Genetic work in mice has demonstrated that the disease is caused by loss of KCC3 function in neurons and particularly parvalbumin (PV)-expressing neurons. Currently, there are no treatments or cures for HMSN/ACC other than pain management. As genetic counseling in Quebec has increased as a preventative strategy, most individuals with HSMN/ACC are now adults. The onset of the disease is unknown. In particular, it is unknown if the disease starts early during development and whether it can be reversed by restoring KCC3 function. In this study, we used two separate mouse models that when combined to the PV-CreERT2 tamoxifen-inducible system allowed us to 1) disrupt KCC3 expression in adulthood or juvenile periods; and 2) reintroduce KCC3 expression in mice that first develop with a nonfunctional cotransporter. We show that disrupting or reintroducing KCC3 in the adult mouse has no effect on locomotor behavior, indicating that expression of KCC3 is critical during embryonic development and/or the perinatal period and that once the disease has started, reexpressing a functional cotransporter fails to change the course of HMSN/ACC.

Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy

Sorbitol dehydrogenase gene (SORD) has been identified as a novel causative gene of recessive forms of hereditary neuropathy, including Charcot–Marie–Tooth disease type 2 and distal hereditary motor neuropathy (dHMN). Our findings reveal two novel variants (c.404 A > G and c.908 + 1 G > C) and one known variant (c.757delG) within SORD in four Chinese dHMN families. Ex vivo cDNA polymerase chain reaction confirmed that c.908 + 1 G > C variant was associated with impaired splicing of the SORD transcript. In vitro cell functional studies showed that c.404 A > G variant resulted in aggregate formation of SORD and low protein solubility, confirming the pathogenicity of SORD variants. We have provided more evidence to establish SORD as a causative gene for dHMN.