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The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America

  • Newborn Screening
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Journal of Inherited Metabolic Disease

Abstract

In this work, we review the clinical and genetic data in 14 Latin American propionic acidemia (PA) and 15 methylmalonic aciduria (MMAuria) patients. In the PA patients, we have identified four different changes in the PCCA gene, including one novel one (c.414+5G>A) affecting the splicing process. The PCCB mutational spectrum included two prevalent changes accounting for close to 60% of the mutant alleles studied and one novel change (c.494G>C) which by functional analysis is clearly pathogenic. We have also identified the deep intronic change c.654+462A>G, and the results of the antisense treatment in the patient’s cell line confirmed the functional recovery of PCC activity. All PA patients bearing out-of-frame mutations presented the disease earlier while patients bearing in hemizygous fashion p.E168K and p.R165W presented the disease later. Regarding the MMAuria patients, we have found three novel mutations in the MUT gene (c.1068G>A, c.1587_1594del8 and c.593delA) and one in the MMAB gene (c.349-1 G>C). Two patients with MMAuria with homocystinuria cblC type are carriers of the frequent c.271dupA mutation. All mut 0, cblB and cblC patients presented the symptoms early and in general had more neurological complications, while cblA and mut - patients exhibited a late-onset presentation, and in general the long-term outcome was better. The results presented in this work emphasize the importance of the genetic analysis of the patients not only for diagnostic purposes but also to research into novel therapies based on the genotype.

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Acknowledgements

This work was supported by grants from the Comisión Interministerial de Ciencia y Tecnología (SAF2007-61350), the Fondo de Investigaciones Sanitarias (PI060512) and CIBERER (INTRA/07/720.1). An institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa is gratefully acknowledged. The CIBERER is an initiative of the ISCIII.

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Authors and Affiliations

  1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049, Madrid, Spain

    Belén Pérez, Rocio Sánchez-Alcudia, Begoña Merinero, Celia Pérez-Cerdá, P. Rodríguez-Pombo, Lourdes R. Desviat & Magdalena Ugarte

  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Belén Pérez, Rocio Sánchez-Alcudia, Begoña Merinero, Celia Pérez-Cerdá, P. Rodríguez-Pombo, Lourdes R. Desviat & Magdalena Ugarte

  3. Centro de Estudio de las Metabolopatías Congénitas, CEMECO, Facultad de Ciencias Médicas, Universidad de Córdoba, Hospital de Niños, Córdoba, Argentina

    Celia Angaroni & Raquel Dodelson de Kremer

  4. Cátedra de Genética Bioquímica, Facultad de Ciencias Químicas, Universidad Católica de Córdoba, Córdoba, Argentina

    Celia Angaroni

  5. Unidad de Metabolismo, Hospital de Niños de La Plata, La Plata, Argentina

    N. Specola

  6. Serviço de Genetica Médica, Hospital de Clinicas, Porto Alegre, RS, Brazil

    Moacir Wajner

  7. Laboratorio de Genética y Enfermedades Metabólicas, INTA, Universidad de Chile, Santiago de Chile, Chile

    Verónica Cornejo

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  1. Belén Pérez
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  2. Celia Angaroni
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  3. Rocio Sánchez-Alcudia
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  4. Begoña Merinero
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  5. Celia Pérez-Cerdá
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  6. N. Specola
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  7. P. Rodríguez-Pombo
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  8. Moacir Wajner
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  9. Raquel Dodelson de Kremer
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  10. Verónica Cornejo
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  11. Lourdes R. Desviat
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  12. Magdalena Ugarte
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Corresponding author

Correspondence to Magdalena Ugarte.

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Communicated by: Georg Hoffmann

Competing interest: None declared

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Pérez, B., Angaroni, C., Sánchez-Alcudia, R. et al. The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America. J Inherit Metab Dis 33 (Suppl 2), 307–314 (2010). https://doi.org/10.1007/s10545-010-9116-4

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