Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Abstract

Here we demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein as well as increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients homozygous for the p.Ala253GlnfsTer27 mutation compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a potentially treatable cause in a significant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families

“…Of note, GARS was one of the most common causative genes of dHMN in North China and England and AARS has also been reported (4,(10)(11)(12), suggesting that ARS-related dHMN might account for a large part of dHMN. Recently, Cortese et al identified homozygous or compound heterozygous c.757delG variant in SORD from 38 CMT2/dHMN families, suggesting a mutation in SORD as the most frequent cause of the recessive form of hereditary neuropathy (23). Here, we detected the homozygous c.757delG mutation in SORD in two sporadic cases with childhood disease onset and mild phenotype.…”

Distal hereditary motor neuropathies: Mutation spectrum and genotype–phenotype correlation

“…Because one of the series involved patients from across the entire Valencian community, we could calculate a minimum prevalence in this geographic region of 2.3 per 100,000 individuals, which is very similar to that recently calculated in the north of England (2.14 per 100,000 individuals) [18]. A thorough genetic screening including the recently identified causative gene, SORD [15], was performed on our patients, and a molecular diagnosis was achieved in 47.8% (78/163) of patients and 34.2% (37/108) of families. These rates of diagnosis are similar to the most recent published series studied by NGS techniques [18,30], which highlights the fact that the majority of patients with dHMN remain without genetic diagnosis.…”

Evaluation of SORD mutations as a novel cause of Charcot‐Marie‐Tooth disease

“…Previous research has shown that the accumulation of sorbitol in the sciatic nerve induced neuropathy in a diabetic mouse model 12 . More recently, the effects of SORD deficiency on neurodegeneration were investigated in an Sodh2 MB01265/MB01265 drosophila model 5 . However, more evidence is necessary to definitively elucidate the neuropathic mechanisms associated with SORD mutation.…”

“…Very recently, biallelic mutations in the sorbitol dehydrogenase ( SORD) gene were identified as a novel and common genetic cause for autosomal‐recessive CMT. The discovery of the gene may resolve the genetic diagnosis of a significant proportion of CMT patients 5 …”