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.

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Summary Mitochondria are essential in long axons to provide metabolic support and sustain neuron integrity. A healthy mitochondrial pool is maintained by biogenesis, transport, mitophagy, fission, and fusion, but how these events are regulated in axons is not well defined. Here, we show that the Drosophila glutathione S-transferase (GST) Gfzf prevents mitochondrial hyperfusion in axons. Gfzf loss altered redox balance between glutathione (GSH) and oxidized glutathione (GSSG) and initiated mitochondrial fusion through the coordinated action of Mfn and Opa1. Gfzf functioned epistatically with the thioredoxin peroxidase Jafrac1 and the thioredoxin reductase 1 TrxR-1 to regulate mitochondrial dynamics. Altering GSH:GSSG ratios in mouse primary neurons in vitro also induced hyperfusion. Mitochondrial changes caused deficits in trafficking, the metabolome, and neuronal physiology. Changes in GSH and oxidative state are associated with neurodegenerative diseases like Alzheimer’s. Our demonstration that GSTs are key in vivo regulators of axonal mitochondrial length and number provides a potential mechanistic link.

Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these diseases, a diagnostic gap of 30-60% remains. Classic models of genetic causation may be limited to fully close this gap and, thus, we review the current state and future role of alternative, non-Mendelian forms of genetics in CMT. Promising synergies exist to further define the full genetic architecture of inherited neuropathies, including affordable whole-genome sequencing, increased data aggregation and clinical collaboration, improved bioinformatics and statistical methodology, and vastly improved computational resources. Given the recent advances in genetic therapies for rare diseases, it becomes a matter of urgency to diagnose CMT patients with great fidelity. Otherwise, they will not be able to benefit from such therapeutic options, or worse, suffer harm when pathogenicity of genetic variation is falsely evaluated. In addition, the newly identified modifier and risk genes may offer alternative targets for pharmacotherapy of inherited and, potentially, even acquired forms of neuropathies. Genetics of Charcot-Marie-Tooth DiseaseAs with many other Mendelian diseases, the introduction of next generation sequencing (NGS) revolutionized the genetic diagnosis of Charcot-Marie-Tooth disease with now over 90 known genes causing CMT. 1,2 Though CMT can be caused by an overwhelming amount of genetic defects, it is noteworthy that a handful of genes are responsible for the majority of cases. More than half of all CMT cases are caused by five genetic mutations: PMP22 duplication (39.5%), PMP22 point mutation (1.4%), GJB1 (10.8%), MFN2 (2.8%), and MPZ (3.1%). 3 For autosomal dominant (AD) demyelinating CMT (CMT1), the most commonly mutated genes are: GJB1, PMP22, MPZ, EGR2, LITAF, NEFL, or PMP2. 3 Unlike CMT1, AD axonal CMT (CMT2) and autosomal recessive (AR) axonal and/or demyelinating forms (CMT4) are caused by many, individually rare, genes that typically