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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, <jats:italic>cblC<\/jats:italic> type (<jats:italic>cblC<\/jats:italic> disease), and it has been named <jats:italic>epi-cblC<\/jats:italic>. <jats:italic>Epi-cblC<\/jats:italic> has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the <jats:italic>MMACHC<\/jats:italic> locus, which is secondary to a splicing variant (c.515-1G\u2009&gt;\u2009T or c.515-2A\u2009&gt;\u2009T) at the adjacent <jats:italic>PRDX1<\/jats:italic> gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the <jats:italic>MMACHC<\/jats:italic> gene promotor with subsequent silencing. Until now, only nine <jats:italic>epi-cblC<\/jats:italic> patients have been reported.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We report clinical\/biochemical assessment, <jats:italic>MMACHC<\/jats:italic>\/<jats:italic>PRDX1<\/jats:italic> gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive <jats:italic>MMACHC<\/jats:italic> gene testing. We also compare clinical phenotype of <jats:italic>epi-cblC<\/jats:italic> patients with that of canonical <jats:italic>cblC<\/jats:italic> patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>All patients turned out to have the <jats:italic>epi-cblC<\/jats:italic> disease. One patient had a bi-allelic <jats:italic>MMACHC<\/jats:italic> epimutation due to the homozygous <jats:italic>PRDX1<\/jats:italic>:c.515-1G\u2009&gt;\u2009T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of <jats:italic>MMACHC<\/jats:italic> in the patient\u2019s fibroblasts. The remaining ten patients had a mono-allelic <jats:italic>MMACHC<\/jats:italic> epimutation, due to the heterozygous <jats:italic>PRDX1<\/jats:italic>:c.515-1G\u2009&gt;\u2009T, in association with a mono-allelic <jats:italic>MMACHC<\/jats:italic> genetic variant. <jats:italic>Epi-cblC<\/jats:italic> disease has accounted for about 13% of <jats:italic>cblC<\/jats:italic> cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of <jats:italic>epi-cblC<\/jats:italic> patients is similar to that of canonical <jats:italic>cblC<\/jats:italic> patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We provide evidence that <jats:italic>epi-cblC<\/jats:italic> is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of <jats:italic>epi-cblC<\/jats:italic> due to a bi-allelic <jats:italic>MMACHC<\/jats:italic> epimutation. <jats:italic>MMACHC<\/jats:italic> epimutation\/<jats:italic>PRDX1<\/jats:italic> mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13148-021-01117-2","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T19:03:25Z","timestamp":1625252605000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations"],"prefix":"10.1186","volume":"13","author":[{"given":"Catia","family":"Cavicchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abderrahim","family":"Oussalah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Falliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Ferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Gozzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Gasperini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Motta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Rigoldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Parenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albina","family":"Tummolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Meli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Menni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Furlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Daniotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Malvagia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"la Marca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Chery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Emmanuel","family":"Morange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Tregouet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Alice","family":"Donati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-8179","authenticated-orcid":false,"given":"Amelia","family":"Morrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,2]]},"reference":[{"issue":"2","key":"1117_CR1","first-page":"53","volume":"41","author":"M Fuller","year":"2020","unstructured":"Fuller M. 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