PRDX1 – Methylmalonic Aciduria and Homocystinuria Type cblC

Methylmalonic aciduria and homocystinuria type cblC (cblC disease) is an autosomal recessive inborn error of cobalamin metabolism caused by loss of MMACHC function. An epigenetic subtype, termed epi-cblC, arises from aberrant antisense transcription and cis-hypermethylation of the MMACHC promoter secondary to splicing variants in the adjacent PRDX1 gene, expanding the molecular spectrum of cblC disease (PMID:34215320).

A cohort of 11 unrelated patients with clinical and biochemical features of cblC disease but inconclusive MMACHC sequencing were investigated. All 11 probands were found to harbor the PRDX1 c.515-1G>T epimutational allele, either homozygously or in trans with a MMACHC genetic variant (PMID:34215320).

One patient exhibited a bi-allelic MMACHC epimutation due to homozygous PRDX1 c.515-1G>T transmission from unaffected parents, while the remaining ten carried a mono-allelic PRDX1 c.515-1G>T epimutation in combination with a single MMACHC coding variant. Epi-cblC accounted for approximately 13% of cblC cases diagnosed by newborn screening in Tuscany and Umbria since 2001 (PMID:34215320).

Autosomal recessive segregation was confirmed by transmission of PRDX1 c.515-1G>T to the homozygous patient from both heterozygous parents, with no additional affected relatives reported. This supports a classic recessive inheritance model for the epigenetic mechanism.

Functional analyses including genome-wide DNA methylation profiling and patient fibroblast studies demonstrated that bi-allelic PRDX1 c.515-1G>T causes complete cis-hypermethylation of the MMACHC promoter and silencing of MMACHC expression, establishing a clear mechanistic link between the PRDX1 splicing defect and cblC pathogenesis (PMID:34215320).

These genetic and functional data support a Moderate clinical validity classification for the PRDX1–cblC association. Incorporation of MMACHC epimutation and PRDX1 variant analysis into routine diagnostics is warranted for all patients presenting with combined methylmalonic aciduria (HP:0005587) and homocystinuria (HP:0002141). Key Take-home: PRDX1 c.515-1G>T–mediated MMACHC epimutation is an underrecognized but actionable cause of cblC disease, accounting for ~13% of cases on newborn screening.

References

• Clinical Epigenetics • 2021 • PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. PMID:34215320

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