ArticleClinical epigenetics2021
PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations.
Article in Clinical epigenetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 17 citations in OpenAlex.
- Late-onset epi-cblC methylmalonic aciduria with tissue-variable MMACHC promoter methylation due to a stop retained PRDX1 variant.Clinical epigenetics · 2026Article
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- First pathogenic non-coding variant in MMACHC: a functional deletion in the 5'-UTR associated with cobalamin C deficiency.Molecular biology reports · 2025Article
- Review
- Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease.Journal of inherited metabolic disease · 2025Article
- Improved biochemical and neurodevelopmental profiles with high-dose hydroxocobalamin therapy in cobalamin C defect.Journal of inherited metabolic disease · 2025Article
- Newborn Screening by DNA-First: Systematic Evaluation of the Eligibility of Inherited Metabolic Disorders Based on Treatability.International journal of neonatal screening · 2024Article
- Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry.International journal of neonatal screening · 2024Article
- Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease.iScience · 2022Review
- Epimutation in inherited metabolic disorders: the influence of aberrant transcription in adjacent genes.Human genetics · 2022Review
- Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin BClinical epigenetics · 2022Article
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23 authors at 6 institutions in 2 countries.
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Abstract
backgroundThe role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported.
methodsWe report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients.
resultsAll patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients.
conclusionsWe provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.
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