Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency

Abstract

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency. Analysis of X-inactivation ratios by DNA methylation-based assays showed remarkable intra-organ variation ranging from 46:54 to 82:18 (average 70:30, n = 37), in favor of the active X chromosome carrying the mutation c.583G>C (p.G195R), in the first patient and from 75:25 to 90:10 (average 82:18, n = 20) in favor of the active X chromosome carrying the splicing mutation c.663+1G>A in the second patient. The X-inactivation ratios in liver samples correlated highly with the proportions of OTC-positive hepatocytes calculated from high-resolution image analyses of the immunohistochemically detected OTC in frozen sections that was performed on total area > 5 cm. X-inactivation ratios in blood in both female patients corresponded to the lower limit of the liver values. Our data indicate that the proportion of about 20-30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X-inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver.

Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency

“…Approximately 20% of heterozygous females present some neurocognitive disorders due to unfavorable random X-inactivation. However, the clinical picture of carrier females is highly diverse because of the extent of X-inactivation in hepatocytes [7]. The OTCD clinical phenotypes can generally be divided into two groups, namely early-onset (onset age ≤ 30 days), and late-onset (onset age > 30 days) or asymptomatic.…”

The Application of Next-Generation Sequencing (NGS) in Neonatal-Onset Urea Cycle Disorders (UCDs): Clinical Course, Metabolomic Profiling, and Genetic Findings in Nine Chinese Hyperammonemia Patients

“…However, our cohort also revealed phenotypic heterogeneity within the same family: an OTC-deficient male (P9) was characterized by a hyperammonemia crisis after birth and died at the third day of age; his heterozygous mother developed vomiting and altered consciousness during pregnancy, and successful management of her prenatal and postpartum blood ammonia level was achieved after the administration of pharmacologic nitrogen scavengers and protein limitation; his grandmother, heterozygous for the same mutation remained asymptomatic until then. Musalkova et al [ 26 ] advocated that the heterogeneity of a group of female OTC carriers might be due to variable X-chromosome inactivation and environmental variables such as causes of catabolic stress as well.…”

Clinical and Molecular Characteristics of 69 Chinese Patients with Ornithine Transcarbamylase Deficiency

“…LT has emerged as a de nitive treatment for the risk of metabolic decompensation in urea cycle disorders, including OTCD, with excellent post-transplant survival rates and good metabolic outcomes [26]. LT should be considered early in neonatal cases and those considered refractory to optimal medical therapy.…”