Neuropathology of 3-Hydroxyisobutyric Aciduria, an Autopsy Case Report

3-hydroxyisobutyric aciduria (3-HiB-uria), a rare disorder of valine metabolism, results from tissue accumulation and significant elevation of urinary excretion of 3-hydroxyisobutyric acid.To date, 14 cases of 3-HiB-uria have been reported, the majority of which were male patients, including two sets of male twins, two brothers, and a brother-and-sister pair.[1][2][3][4][5][6][7] The clinical course varies, from mild attacks of vomiting with normal brain and cognitive development, 3,5 to failure to thrive with profound mental impairment and early death.2,4 Dysmorphic facial features and brain malformation have been described in patients with 3-HiB-uria.[1][2][3][4]6,8 Of the 14 reported cases, there were only two autopsies from four deaths.No gross or microscopic images exist.In this report, we document the post-mortem neuropathological findings in a 3-HiB-uria case with photographs for the first time. CASE REPORTThis four-year-old Trinidadian boy was the first baby born to healthy unrelated parents.At birth, the infant weighed 5lbs with lethargy, feeding difficulties and poor cry.Family history was not contributory.The patient's developmental and mental retardation and dysmorphic facial features initially lead to misdiagnoses of cerebral palsy and Cornelia de Lange syndrome.When he presented to our institution at the age of three years, he was found to have organic acidemia, recurrent episodes of ketoacidosis and lactic academia, and severe failure to thrive.Repeated urine organic acid tests revealed persistent high 3hydroxyisobutyrate levels, and diagnosis of 3-HiB-uria was made.Other acids were elevated including: 3-hydroxybutyrate and acetoacetate (consistent with ketosis); lactate, 4hydroxyphenyl lactate, 2-hydroxybutyrate, and pyruvate (consistent with lactic acidosis); and 2-hydroxyisovalerate and 3hydroxy-2-ethhylpropionate (products secondary to ketosis or lactic acidosis).The levels of 3-hydroxypropionate, methylcitrate, and methylmalonate were all within normal range.Patient was placed on carnitine supplement with high-calorielow-protein diet without success and died seven months after the diagnosis.At autopsy, severe growth retardation and wasting was noted.The body weighed 8.95kg, and measured 67cm.Dysmorphic facial features included: microcephaly, persistent anterior fontanel, prominent occiput, bushy eyebrows, flat nasal bridge, epicanthal folds, discolored hypoplastic teeth, and micrognathia (Figure 1).Additional autopsy findings included: severe thyroid and adrenal atrophy, marantic degeneration of mitral valve, testicular atrophy, cryptorchism, neurogenic muscular atrophy, and bronchopneumonia in the left lung.

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