SORD – Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 8

The sorbitol dehydrogenase gene (SORD) encodes a key enzyme in the polyol pathway with high expression in neuronal tissues. Biallelic variants in SORD have been identified as a novel cause of autosomal recessive inherited neuropathies including Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy, collectively referred to as neuronopathy, distal hereditary motor, autosomal recessive 8 (neuronopathy, distal hereditary motor, autosomal recessive 8). The initial case described a 72-year-old man with long-standing progressive lower limb weakness found homozygous for c.757del (p.Ala253GlnfsTer27) via genome sequencing ([PMID:37622199]). This diagnosis resolved a 45-year clinical odyssey and associated extreme sorbitol accumulation with SORD deficiency. Exome sequencing in other cohorts has corroborated this association across diverse populations. Functional studies in patient samples and cellular models have provided mechanistic insight into enzyme loss.

To date, at least 20 unrelated probands have been reported in five independent cohorts ([PMID:37622199], [PMID:33314640], [PMID:33397963], [PMID:37584201], [PMID:38915017]). All cases display autosomal recessive inheritance with biallelic SORD variants identified. Segregation data include confirmation of homozygosity or compound heterozygosity in affected individuals with parental carriers. No de novo occurrences have been documented. A high recurrence of the frameshift variant c.757del (p.Ala253GlnfsTer27) suggests a founder effect in multiple populations. Carrier frequency estimates indicate SORD variants may underlie a significant proportion of undiagnosed recessive distal motor neuropathies.

The SORD variant spectrum comprises loss-of-function and missense changes. Recurrent LoF alleles include c.757del (p.Ala253GlnfsTer27) and c.625C>T (p.Arg209Ter) ([PMID:33314640]). Novel missense variants such as c.210T>G (p.His70Gln) and c.361G>C (p.Ala121Pro) have been reported in homozygous or compound heterozygous states ([PMID:37584201], [PMID:38915017]). Deep-intronic or splice-site variants like c.908+1G>C further expand the pathogenic repertoire ([PMID:33397963]). No large structural rearrangements have been described to date. This range of variant classes supports a consistent loss-of-function mechanism.

Functional assays confirm that SORD mutations abrogate enzyme activity through multiple mechanisms. Ex vivo cDNA analysis demonstrated aberrant transcript splicing for c.908+1G>C, leading to exon skipping ([PMID:33397963]). In vitro expression of p.Ala153Asp resulted in protein aggregation and reduced solubility ([PMID:33397963]). Enzyme assays quantify markedly reduced or absent sorbitol dehydrogenase activity in patient cells. Affected individuals exhibit a mean serum sorbitol increase of 88-fold over controls, confirming functional loss ([PMID:37584201]). These results provide moderate functional evidence consistent with disease pathology.

Clinically, patients present with symmetric distal muscle weakness and atrophy, primarily affecting the lower limbs (HP:0009830, HP:0001324). Electrophysiological studies reveal chronic axonal motor neuropathy with reduced compound muscle action potentials. Subclinical muscle involvement is common, including mild creatine kinase elevations and MRI-detected muscle edema ([PMID:37584201]). Age at onset ranges from adolescence to late adulthood, reflecting variable expressivity. No significant sensory involvement is reported, distinguishing SORDD from demyelinating neuropathies. Serum sorbitol and CK serve as accessible biomarkers to support molecular diagnosis.

Collectively, the robust identification of 20 probands, recurrent LoF alleles, and concordant functional data support a Strong ClinGen gene–disease validity classification. Genetic evidence meets the criteria for a ClinGen Strong tier based on case count and recurrent variants. Functional assays provide Moderate-level support for a loss-of-function mechanism. No conflicting evidence has been reported to date. Incorporation of SORD into diagnostic gene panels and measurement of sorbitol levels can streamline diagnosis and enable clinical trial enrollment. Key take-home: Biallelic SORD loss-of-function variants cause AR neuronopathy, distal hereditary motor, enabling precise diagnosis and biomarker-guided management.

References

• American journal of medical genetics. Part A • 2023 • A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency. PMID:37622199
• Annals of clinical and translational neurology • 2021 • Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth disease. PMID:33314640
• NPJ genomic medicine • 2021 • Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy. PMID:33397963
• Journal of the peripheral nervous system : JPNS • 2023 • Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement. PMID:37584201
• BMC medical genomics • 2024 • A novel mutation in SORD gene associated with distal hereditary motor neuropathies. PMID:38915017

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