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. 2012 Jan 25:7:9.
doi: 10.1186/1750-1172-7-9.

Clinical and neurocognitive outcome in symptomatic isovaleric acidemia

Sarah C Grünert  1 , Udo Wendel, Martin Lindner, Michael Leichsenring, K Otfried Schwab, Jerry Vockley, Willy Lehnert, Regina Ensenauer
Affiliations

Clinical and neurocognitive outcome in symptomatic isovaleric acidemia

Sarah C Grünert et al. Orphanet J Rare Dis. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Figures

Figure 1
Figure 1
Study design. Sixteen of a total of 21 study patients with symptomatic isovaleric acidemia (IVA) were evaluated not only by use of a questionnaire and/or medical records (step I) but also by cross-sectional clinical, biochemical, and neurocognitive assessments (step II). IQ = intelligence quotient.
Figure 2
Figure 2
Triggering factors of catabolic episodes in symptomatic isovaleric acidemia (IVA). Moderate and severe catabolic episodes (n = 69) in 21 study patients with symptomatic IVA were analyzed as documented in the medical records and/or questionnaires. No specific focus of infection was evident in febrile illnesses.
Figure 3
Figure 3
Clinical signs and laboratory findings at catabolic episodes in symptomatic isovaleric acidemia (IVA). Prevalence of clinical signs and laboratory findings during moderate and severe catabolic episodes (n = 69) of 21 study patients with symptomatic IVA were analyzed as documented in the medical records and/or questionnaires. A) General clinical signs; B) neurological findings; C) clinical chemical and hematologic abnormalities measured in blood and urine at the time of episodes. * Neurologic abnormalities included hyperexcitability, dyscoordination, decreased tendon reflexes.
Figure 4
Figure 4
Proportion of patients with an unremarkable neurocognitive outcome in symptomatic isovaleric acidemia. The percentage of patients with normal cognitive abilities (intelligence quotient [IQ] scores) including academic performance (absence of learning disabilities) is presented for the group of study patients (n = 20). In the group of patients reported in the literature (n = 108), neurocognitive outcome was defined as normal if reported as "normal" or "excellent" and/or normal IQ scores were available. Patients were subdivided into an early diagnosis group (defined as a diagnosis made within the first 5 weeks of life) and a late diagnosis group (defined as a diagnosis made thereafter). Of 20 study patients, 11 were diagnosed early and nine were diagnosed late (median 3.7 years; range 1.6-6.5 years). Of 108 patients in whom information on neurocognitive outcome was available in the literature, 46 were diagnosed early and 62 were diagnosed late.
Figure 5
Figure 5
Survival data of 155 patients with symptomatic isovaleric acidemia reported in the literature. Early diagnosis was defined as a diagnosis made within the first 5 weeks of life (n = 81), late diagnosis was defined as a diagnosis made thereafter (n = 74).
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