Open Access Open Badges Research

Clinical and neurocognitive outcome in symptomatic isovaleric acidemia

Sarah C Grünert1, Udo Wendel2, Martin Lindner3, Michael Leichsenring4, K Otfried Schwab1, Jerry Vockley5, Willy Lehnert1 and Regina Ensenauer6*

Author Affiliations

1 Center for Pediatrics and Adolescent Medicine, Albert-Ludwigs-Universität Freiburg, Germany

2 Department of General Pediatrics, University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany

3 Divison of Inborn Metabolic Diseases, University Children's Hospital, Universität Heidelberg, Germany

4 Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany

5 Department of Pediatrics, University of Pittsburgh School of Medicine and Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA

6 Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Germany

For all author emails, please log on.

Orphanet Journal of Rare Diseases 2012, 7:9  doi:10.1186/1750-1172-7-9

Published: 25 January 2012



Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation.


Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality.


57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days.


Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.

isovaleric acidemia; symptomatic; neurocognitive outcome; mortality