ORIGINAL ARTICLE Combined malonic and methylmalonic aciduria due to ACSF3 mutations: benign clinical course in an unselected cohort Alina Levtova 1,2 & Paula J. Waters 3 & Daniela Buhas 4,5 & Sébastien Lévesque 3 & Christiane Auray-Blais 3 & Joe T. R. Clarke 3 & Rachel Laframboise 6 & Bruno Maranda 3,6 & Grant A. Mitchell 2 & Catherine Brunel-Guitton 2 & Nancy E. Braverman 4,5 Received: 11 March 2018 /Revised: 17 April 2018 /Accepted: 4 May 2018 # SSIEM 2018 Abstract Background The clinical significance of combined malonic and methylmalonic aciduria due to ACSF3 deficiency (CMAMMA) is controversial. In most publications, affected patients were identified during the investigation of various complaints. Methods Using a cross-sectional multicenter retrospective natural history study, we describe the course of all known CMAMMA individuals in the province of Quebec. Results We identified 25 CMAMMA patients (6 months to 30 years old) with a favorable outcome regardless of treatment. All but one came to clinical attention through the Provincial Neonatal Urine Screening Program (screening on day 21 of life). Median methylmalonic acid (MMA) levels ranged from 107 to 857 mmol/mol creatinine in urine (<10) and from 8 to 42 μmol/L in plasma (<0.4); median urine malonic acid (MA) levels ranged from 9 to 280 mmol/ mol creatinine (<5). MMA was consistently higher than MA. These findings are comparable to those previously reported in CMAMMA. Causal ACSF3 mutations were identified in all patients for whom genotyping was performed (76% of cases). The most common ACSF3 mutations in our cohort were c.1075G > A (p.E359K) and c.1672C > T (p.R558W), representing 38.2 and 20.6% of alleles in genotyped families, respectively; we also report several novel mutations. Conclusion Because our province still performs urine newborn screening, our patient cohort is the only one free of selection bias. Therefore, the favorable clinical course observed suggests that CMAMMA is probably a benign condi- Alina Levtova and Paula J. Waters contributed equally to this work. Communicated by: Bruce A Barshop Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10545-018-0197-9) contains supplementary material, which is available to authorized users. * Alina Levtova alina.levtova.chum@ssss.gouv.qc.ca * Paula J. Waters Paula.J.Waters@USherbrooke.ca Daniela Buhas daniela.buhas@muhc.mcgill.ca Sébastien Lévesque Sebastien.a.levesque@USherbrooke.ca Christiane Auray-Blais Christiane.Auray-Blais@USherbrooke.ca Joe T. R. Clarke joeclarke@sympatico.ca Rachel Laframboise rachel.laframboise@crchudequebec.ulaval.ca Bruno Maranda Bruno.Maranda@USherbrooke.ca Grant A. Mitchell grant.mitchell@recherche-ste-justine.qc.ca Catherine Brunel-Guitton catherine.brunel-guitton.hsj@ssss.gouv.qc.ca Nancy E. Braverman nancy.braverman@mcgill.ca Extended author information available on the last page of the article Journal of Inherited Metabolic Disease https://doi.org/10.1007/s10545-018-0197-9