Biomarkers and outcome parameters: A global natural history study on SORD neuropathy Biallelic loss-of-function mutations in SORD lead to the accumulation of sorbitol and to the development of neuropathy. The underlying polyol-pathway involving the enzymes aldose reductase and sorbitol dehydrogenase, the latter encoded by SORD, has been studied already in the context of diabetes mellitus and diabetic neuropathies. Therapeutically, this can be used to specifically reduce the production of sorbitol. To define valid outcome measures for clinical trials, we have been conducting a global natural history study on SORD neuropathy, which will help us to understand phenotype patterns and disease dynamics. At the time of the ICNMD meeting, our study will be closed, and we will be able to present the first statistically significant results. Through an international network of collaborators, we have so far enrolled 150 patients carrying biallelic SORD mutations. Detailed clinical data, collected following a standardised protocol, are so far available from 101 patients. Out of these, 73 carry the most common c.753delG; p.Ala253GlnfsTer27 variant in a homozygous state. Further 27 patients have the c.753delG variant in compound-heterozygosity with a second missense or nonsense variant, including c.458C>A; p.Ala153Asp, which appears to be the second most common mutation in this cohort (n=18). Patient phenotypes were classified as axonal Charcot-Marie-Tooth disease (CMT2) in 64%, as distal hereditary motor neuropathy (dHMN) in 31%, and intermediate CMT in 5%. The mean age of symptom onset, mostly manifested through difficulty walking and running, was 17±10 years (range 3-51 years). Foot dorsal and plantar flexion strengths were reduced in 96% and 79% of patients, respectively, while sensation was preserved in over 60% of the cases. According to the CMTES score, the neuropathy was mild in two thirds of cases. MRC scores of foot dorsiflexion correlated inversely with the subjects' age and declined significantly over 1 year, while CMTES did not (n=23). Analyzing fasting sorbitol levels in patient serum, we found a significant elevation (14.2±2.7 gr/L, n.v.<0.25) without differences between genotypes. With these preliminary data at hand, we conclude that foot dorsi- and plantar flexion are prominently involved in patients with SORD neuropathy. Especially the former seems to be a promising outcome measure to be considered for future clinical trials. Sensory symptoms were less severe and less frequently reported, so that the leading phenotype was motor predominant axonal CMT. Fasting serum sorbitol is a reliable biomarker that can functionally validate a variant's pathogenicity within the expanding genotype spectrum of the disease. SORD neuropathy is probably (one of) the most common autosomal recessive inherited neuropathy(/ies), and with clinical trials in preparation, it might become the first treatable CMT subform in the near future.
Biomarkers and outcome parameters: A global natural history study on SORD neuropathy
Francesca Cavalcanti;
2022
Abstract
Biomarkers and outcome parameters: A global natural history study on SORD neuropathy Biallelic loss-of-function mutations in SORD lead to the accumulation of sorbitol and to the development of neuropathy. The underlying polyol-pathway involving the enzymes aldose reductase and sorbitol dehydrogenase, the latter encoded by SORD, has been studied already in the context of diabetes mellitus and diabetic neuropathies. Therapeutically, this can be used to specifically reduce the production of sorbitol. To define valid outcome measures for clinical trials, we have been conducting a global natural history study on SORD neuropathy, which will help us to understand phenotype patterns and disease dynamics. At the time of the ICNMD meeting, our study will be closed, and we will be able to present the first statistically significant results. Through an international network of collaborators, we have so far enrolled 150 patients carrying biallelic SORD mutations. Detailed clinical data, collected following a standardised protocol, are so far available from 101 patients. Out of these, 73 carry the most common c.753delG; p.Ala253GlnfsTer27 variant in a homozygous state. Further 27 patients have the c.753delG variant in compound-heterozygosity with a second missense or nonsense variant, including c.458C>A; p.Ala153Asp, which appears to be the second most common mutation in this cohort (n=18). Patient phenotypes were classified as axonal Charcot-Marie-Tooth disease (CMT2) in 64%, as distal hereditary motor neuropathy (dHMN) in 31%, and intermediate CMT in 5%. The mean age of symptom onset, mostly manifested through difficulty walking and running, was 17±10 years (range 3-51 years). Foot dorsal and plantar flexion strengths were reduced in 96% and 79% of patients, respectively, while sensation was preserved in over 60% of the cases. According to the CMTES score, the neuropathy was mild in two thirds of cases. MRC scores of foot dorsiflexion correlated inversely with the subjects' age and declined significantly over 1 year, while CMTES did not (n=23). Analyzing fasting sorbitol levels in patient serum, we found a significant elevation (14.2±2.7 gr/L, n.v.<0.25) without differences between genotypes. With these preliminary data at hand, we conclude that foot dorsi- and plantar flexion are prominently involved in patients with SORD neuropathy. Especially the former seems to be a promising outcome measure to be considered for future clinical trials. Sensory symptoms were less severe and less frequently reported, so that the leading phenotype was motor predominant axonal CMT. Fasting serum sorbitol is a reliable biomarker that can functionally validate a variant's pathogenicity within the expanding genotype spectrum of the disease. SORD neuropathy is probably (one of) the most common autosomal recessive inherited neuropathy(/ies), and with clinical trials in preparation, it might become the first treatable CMT subform in the near future.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
