5/15/2007 Case 3: 3-hydroxyisobutyric aciduria

Presented by: Dr. Chandrakant Rao

Clinical History:

This 4 year old boy presented to the KCHC- ER with tachypnea, fever, and growth and developmental retardation. He had contractures of both lower extremities and carried a diagnosis of cerebral palsy. He had bushy eye brows with synophrys, thus also carrying a diagnosis of Cornelia De Lange syndrome. He has been in and out of this institution several times for episodes of tachypnea and metabolic acidosis. In the ER he was found to be poorly responsive to stimuli, tachypnic, and in respiratory distress. Blood gas analysis showed severe metabolic acidosis which did not improve with therapy. He developed Kussmaul respirations and died 3 days after admission.

Diagnostic Notes:

The submitted slide was of cerebral hemispheric tissue with leptomeninges, cortex, and white matter. The principal finding was multifocal white matter degeneration, with gliosis, rarefaction, and focal frank cavitation. The cortex was, in contrast, relatively well preserved, and there was no inflammation in the meninges, cortex, or white matter. There were no vascular anomalies or vasculitis. There were relatively few macrophages in the cavities, and these did not have any particular content as seen in the H&E
stained section.

Dr Rao provided additional history: A CT scan showed agenesis of the corpus callosum at age 1 year, and also showed "cystic lesions" in the basal ganglia, thought to account for the diagnosis from age 6 months of "cerebral palsy". At autopsy the brain was only 587 g, had some wide sulci but was not grossly severely atrophic. Cut surfaces of the brain had gray discolored lesions with focal cystic cavities in the white matter, sparing the arcuate zones; a small caudal portion of the corpus callosum was present at autopsy, otherwise the agenesis was confirmed. While the patient was alive urinalysis showed elevated levels of 3 hydroxyisobutyric acid, leading to the final diagnosis: the rare condition of 3-hydroxyisobutyric aciduria. The metabolic acidosis and episodes of respiratory difficulty mentioned in the history were the major
clinical clues, plus of course the biochemical findings in the urine. Dr Rao said that there were 14 cases of this condition currently in the literature.

One case of this genetic metabolic abnormality with severe cystic brain lesions similar to those seen in this case was reported by Sasaki et al (Brain & Devel 2001, 23:241-254), and with additional details from the same group in the same journal in 2006. One earlier report about this organic aciduria, but without neuropathological findings, came from Ko et al (Pediatr Res 1991, 30:322-326), and one of a set of twins with severe brain malformations including lissencephaly, polymicrogyria, and, notably for this KCMC case, agenesis of the corpus callosum was described by Chitayat et al (J Pediatr 1992, 121:86-89). Additional biochemical investigations in three patients,
including the one reported by Sasaki et aI, were described by Loupatty et al (Molec Genetics & Metabolism 2005, 87:243-248), and clinical findings in two siblings were reported by Shield et al (Clinical Dysmorphology 2001, 10:189- 191).

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