Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency

Abstract

These findings suggest progression of neurochemical events in OTCD, i.e., mI depletion and Gln accumulation followed by Cho depletion, which is reverse of that in hepatic encephalopathy, i.e., Cho depletion followed by mI depletion and Gln accumulation.

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations

“…The diminished concentration inversely correlated with the disease severity score, a measure of previous hyperammonemic episodes. Previous studies, by our group and others [13][14][15][16], shows that relative depletion of brain myoinositol as determined with 1 H MRS is a biomarker of OTCD, including asymptomatic carriers [16]. Here, we found that the concentration of brain myoinositol inversely correlated with clinical phenotype in three female members of a family with a known OTCD mutation that previously was associated with lethal, neonatal onset disease in a hemizygous male infant.…”

“…This neurocognitive profile supports a nonverbal learning disability, characteristic of subcortical white matter dysfunction [12]. 1 H MRS studies have demonstrated elevations in glutamine and decreases in myoinositol and choline in patients who are clinically symptomatic [13][14][15].We recently used 1 HMRS to document a relative depletion of brain myoinositol in females who describe themselves as asymptomatic [16]. We have hypothesized that the decrement of myoinositol might constitute a useful biochemical marker with which to discriminate females with a partial deficiency.…”

“…Here, we found that the concentration of brain myoinositol inversely correlated with clinical phenotype in three female members of a family with a known OTCD mutation that previously was associated with lethal, neonatal onset disease in a hemizygous male infant. We also measured competence of ureagenesis with an in vivo stable isotope study that involved conversion of 15 NH 3 to [ 15 N] urea and [5][6][7][8][9][10][11][12][13][14][15] N]glutamine. Cases 1 and 3 had near normal residual ureagenesis, but 1 H MRS still disclosed a brain metabolic derangement with regard to the myoinositol level.…”

“…We used gas chromatography-mass spectrometry to measure [ 15 N] urea and [5][6][7][8][9][10][11][12][13][14][15] N] glutamine formation after an oral load of 15NH 4 Cl. [10].…”

“…They measured the incorporation of 15 NH 3 into [ 15 N] urea in 11 males and 23 females with OTCD deficiency. The results indicated that asymptomatic carriers formed urea at a normal rate, but that the rate of [5][6][7][8][9][10][11][12][13][14][15] N] glutamine production exceeded the control value, suggesting that nitrogen metabolism was abnormal even in the absence of overt clinical symptomatology. A correlation was observed between genotype and phenotype, with ureagenesis being most compromised in individuals with early-onset disease.…”