On this page
SORD
sorbitol dehydrogenase
SORD encodes sorbitol dehydrogenase, an enzyme that converts sorbitol to fructose in the polyol pathway, with variants linked to hereditary neuropathy. The SORD gene provides instructions for making sorbitol dehydrogenase, an enzyme involved in processing sorbitol within cells.
SORD is located on the long (q) arm of chromosome 15, at band 15q21.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 15 in the library →Overview
SORD encodes sorbitol dehydrogenase, an enzyme that catalyses the conversion of sorbitol to fructose in the polyol metabolic pathway. This pathway represents an alternative route for glucose metabolism, particularly active in tissues such as peripheral nerves, the lens of the eye, and the kidney. The SORD protein functions as part of cellular carbohydrate handling, ensuring that sorbitol does not accumulate to levels that might disrupt cellular function. Pathogenic variants in SORD have been recognised as a cause of autosomal recessive hereditary neuropathy, a condition affecting the peripheral nerves that carry signals between the central nervous system and the rest of the body. Understanding SORD's role has clinical relevance for individuals with unexplained progressive neuropathy and their families.
What the gene does
Sorbitol dehydrogenase catalyses the oxidation of sorbitol to fructose, using NAD+ as a cofactor. This reaction represents the second step in the polyol pathway, which begins with the reduction of glucose to sorbitol by aldose reductase. Under normal circumstances, this pathway accounts for a small proportion of glucose metabolism, but it becomes more active when glucose concentrations rise or in tissues with limited insulin-dependent glucose uptake.
The enzyme's activity is particularly important in peripheral nerve tissue, where it helps prevent sorbitol accumulation. Sorbitol is an osmotically active sugar alcohol that does not readily cross cell membranes. When sorbitol dehydrogenase function is impaired, sorbitol can build up within cells, potentially drawing water into the cell and disrupting normal cellular processes. In nerve cells, this may interfere with axonal transport, myelin maintenance, and overall nerve conduction. The enzyme operates as a homodimer and requires zinc ions for structural stability, contributing to its catalytic efficiency within the cytoplasm.
Video: Genetics 101
Chromosome location
SORD is located on chromosome 15 at position 15q21.1, a region on the long arm of chromosome 15. The gene spans approximately 14 kilobases of genomic DNA and contains nine exons. Its position places it among a cluster of metabolic genes on chromosome 15, though SORD itself operates independently of neighbouring genes in terms of regulation and function.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein, though structural predictions based on related enzymes suggest characteristic features. The SORD protein comprises 357 amino acids and functions as a member of the medium-chain dehydrogenase/reductase superfamily. Structural studies of related enzymes suggest that sorbitol dehydrogenase likely adopts a characteristic fold featuring a nucleotide-binding domain that accommodates the NAD+ cofactor and a substrate-binding pocket that positions sorbitol for catalysis. The protein operates as a homodimer, with each subunit contributing to catalytic activity. Zinc-binding sites are thought to play a structural role, stabilising the overall conformation required for enzymatic function.
Key variants
Pathogenic variants in SORD typically result in reduced or absent enzyme activity, leading to impaired sorbitol metabolism. The majority of disease-associated changes identified to date are loss-of-function variants, including missense substitutions that disrupt the protein's catalytic site or structural integrity, as well as nonsense and frameshift variants that produce truncated, non-functional proteins. Inheritance follows an autosomal recessive pattern, meaning that a person must inherit two pathogenic variants (one from each parent, which may be the same variant or two different variants) for clinical manifestation of neuropathy.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.458C>A | p.Ala153Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.757del | p.Ala253fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.776C>T | p.Ala259Val | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronopathy, distal hereditary motor, autosomal recessive 8 |
c.112dup | p.Arg38fs | Pathogenic | ★☆☆☆ | not provided |
c.298C>T | p.Arg100Ter | Pathogenic | ★☆☆☆ | not provided |
c.908+1G>C | - | Pathogenic | ★☆☆☆ | not provided |
c.731C>T | p.Pro244Leu | Pathogenic | - | Neuronopathy, distal hereditary motor, autosomal recessive 8 |
c.851T>C | p.Leu284Pro | Pathogenic | - | Neuronopathy, distal hereditary motor, autosomal recessive 8 |
c.895C>T | p.Arg299Ter | Pathogenic | - | Neuronopathy, distal hereditary motor, autosomal recessive 8 |
c.73_88del | p.Tyr25fs | Likely pathogenic | ★☆☆☆ | Neuronopathy, distal hereditary motor, autosomal recessive 8 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in SORD are associated with hereditary neuropathy, a progressive disorder affecting the peripheral nerves. Individuals with SORD-related neuropathy often develop symptoms in childhood or early adulthood, though onset age varies, including sensory loss in the feet and hands, muscle weakness, and difficulties with balance and coordination. The condition progresses gradually, and severity can vary among affected individuals. Some people experience predominantly sensory features, whilst others develop more significant motor impairment affecting mobility and fine motor tasks. The underlying mechanism is thought to involve sorbitol accumulation in peripheral nerve cells, which may interfere with normal nerve structure and function over time.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SORD variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SORD is included on the NHS Genomic Medicine Service's Hereditary Neuropathy panel and the Hereditary Neuropathy or Pain Disorder panel, both with green classification status. This indicates that there is robust evidence supporting SORD's role in hereditary neuropathy, and genetic testing for variants in this gene is considered clinically appropriate for individuals presenting with relevant neurological features. The green status on both panels reflects established evidence, with the pain disorder panel representing a broader phenotypic context in which SORD-related neuropathy may present. Inclusion on these panels means that SORD analysis may be offered through NHS genomic testing pathways when hereditary neuropathy is suspected based on clinical assessment.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
There are currently no specific lifestyle modifications with established evidence for SORD-related neuropathy. Management focuses on supportive care as directed by healthcare professionals, which may include physiotherapy, mobility aids, and monitoring for progression of neurological features. Research into metabolic interventions is ongoing, but no specific recommendations can currently be made outside of clinical trial settings.
Supplement considerations
There are currently no specific supplements with established evidence for SORD-related neuropathy. Management focuses on supportive care as directed by healthcare professionals. Research into metabolic interventions is ongoing, but no specific recommendations can currently be made outside of clinical trial settings.
Frequently asked questions
What does the SORD gene do?
SORD provides instructions for making sorbitol dehydrogenase, an enzyme that converts sorbitol to fructose in the polyol metabolic pathway. This enzyme helps prevent sorbitol from accumulating in cells, particularly in peripheral nerve tissue.
How are SORD variants inherited?
SORD variants are inherited in an autosomal recessive pattern. This means a person must inherit a pathogenic variant from both parents to develop SORD-related neuropathy. Individuals with one variant are carriers and typically do not show symptoms.
Can genetic testing identify SORD variants?
Yes, genetic testing can identify pathogenic variants in SORD. Testing is available through NHS genomic testing pathways for individuals with clinical features of hereditary neuropathy, and SORD is included on relevant clinical panels used in the UK.