Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case

Molecular Genetics and Metabolism
Steven F DobrowolskiJerry Vockley

Abstract

Methylmalonate semialdehyde dehydrogenase deficiency (MMSDD; MIM 614105) is a rare autosomal recessive defect of valine and pyrimidine catabolism. Four prior MMSDD cases are published. We present a fifth case, along with functional and metabolomic analysis. The patient, born to non-consanguineous parents of East African origin, was admitted at two weeks of age for failure to thrive. She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia. Gastroesophageal reflux occurred with feeding. Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate, while urine amino acid analysis identified elevated concentrations of β-aminoisobutyrate and β-alanine. Plasma amino acids showed an elevated concentration of β-aminoisobutyrate with undetectable β-alanine. ALDH6A1 gene sequencing identified a homozygous variant of uncertain significance, c.1261C > T (p.Pro421Ser). Management with valine restriction led to reduced concentration of abnormal analytes in blood and urine, improved growth, and reduced gastroesophageal reflux. Western blotting of patient fibroblast extracts demonstrated a large reduction of methylmalonate semialdehyde dehydrogenase (MMSD) protein. Patient cells displayed compro...Continue Reading

References

Aug 18, 2000·Journal of Inherited Metabolic Disease·K L ChamblissK M Gibson
Apr 8, 2006·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Jerry Vockley, Regina Ensenauer
Aug 25, 2011·Journal of Inherited Metabolic Disease·Jörn Oliver SassLaurie D Smith
May 10, 2017·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Jan D QuellGabi Kastenmüller
Oct 17, 2017·Molecular Genetics and Metabolism·Parith WongkittichoteKimberly A Chapman

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Citations

Feb 20, 2021·Molecular Genetics and Metabolism·Steven F DobrowolskiHarry C Blair

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