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FB2026_01
,
released March 12, 2026
This report describes a newly identified disease, sorbitol dehydrogenase deficiency with peripheral neuropathy (SORDD), recently designated neuronopathy, distal hereditary motor, autosomal recessive 8 (HMNR8). Symptoms of HMNR8 overlap those of Charcot-Marie-Tooth disease 2 (FBhh0000073). The gene implicated in this disease is SORD, which encodes a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol. There are two genes orthologous to SORD in Drosophila, Sodh1 and Sodh2. RNAi-targeting constructs and alleles caused by insertional mutagenesis have been for both fly genes; for Sodh2 there is also available a construct that mediates CRISPR/Cas9 sgRNA-targeted mutation in vivo.
The human SORD gene has not been introduced into flies.
Two models of this disease were created in flies: the first using a loss-of-function mutation of Sodh2 and the second using neuron-specific RNAi-mediated knockdown of both Sodh1 and Sodh2. In both models, animals exhibit a normal lifespan, but progressive and age-dependent synaptic degeneration is observed (assayed in adult eyes); progressive locomotor defects are also observed in older adults. Pharmaceutical intervention by feeding the aldose reductase inhibitors, epalrestat and ranirestat, was assessed in the fly models; amelioration of the neurodegenerative and locomotor phenotypes was observed.
[updated Jan. 2024 by FlyBase; FBrf0222196]
[NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 8; HMNR8](https://omim.org/entry/618912)
[SORBITOL DEHYDROGENASE; SORD](https://omim.org/entry/182500)
Autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8), or sorbitol dehydrogenase deficiency with peripheral neuropathy (SORDD), is characterized by onset of distal muscle weakness mainly affecting the lower limbs and resulting in difficulty walking. Onset of symptoms is usually in the first or second decades of life, although later adult onset has been reported; the disorder is slowly progressive. Nerve conduction velocities are most consistent with an axonal process. More variable features include distal sensory impairment, upper limb tremor, and scoliosis. Laboratory studies show increased serum sorbitol (summary by Corese et al., 2020; pubmed:32367058). [from MIM:618912; 2024.02.20]
There is a paralogous pseudogene in human, SORD2P (FBrf0245621 and references cited therein).
Autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8) is caused by homozygous or compound heterozygous mutation in the SORD gene. [from MIM:618912; 2024.02.20]
SORD encodes a polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols. It is a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol, which constitutes an important alternate route for glucose metabolism. The polyol pathway is believed to be involved in the etiology of diabetic complications, such as diabetic neuropathy and retinopathy, induced by hyperglycemia. [Gene Cards, SORD; 2020.08.11]
One to many: 1 human gene to 2 Drosophila genes.
High-scoring ortholog of human SORD (2 Drosophila to 1 human). Dmel\Sodh-1 shares 56% identity and 75% similarity with the human gene.
High-scoring ortholog of human SORD (2 Drosophila to 1 human). Dmel\Sodh-2 shares 55% identity and 73% similarity with the human gene.