OBJECTIVES: Phosphoribosylpyrophosphate synthetase (PRPS1) superactivity is an X-linked disorder characterized by urate overproduction Online Mendelian Inheritance in Man (OMIM) gene reference 300661. This condition is thought to rarely affect women, and when it does, the clinical presentation is mild. We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction. Family history included a mother with tophaceous gout who developed end-stage kidney disease due to nephrolithiasis and an affected sister with polyarticular gout. The main aim of this study was to describe the clinical manifestations of PRPS1 superactivity in women. METHODS: Whole exome sequencing was performed in affected females and their fathers. RESULTS: Mutational analysis revealed a new c.520 G > A (p.G174R) mutation in the PRPS1 gene. The mutation resulted in decreased PRPS1 inhibition by ADP. CONCLUSION: Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5 (4.1) mg/dl [506 (247) μmol/l] and a high prevalence of gout. These findings indicate that all women in families with PRPS1 superactivity should be genetically screened for a mutation (for clinical management and genetic counselling). In addition, women with tophaceous gout, gout presenting in childhood, or a strong family history of severe gout should be considered for PRPS1 mutational analysis.

• MeSH
• Arthritis, Gouty etiology   genetics   MeSH
• Adult MeSH
• Genetic Diseases, X-Linked diagnosis   genetics   MeSH
• Humans MeSH
• Adolescent MeSH
• Molecular Structure MeSH
• Mutation MeSH
• Nephrolithiasis etiology   genetics   MeSH
• Purine-Pyrimidine Metabolism, Inborn Errors complications   diagnosis   genetics   MeSH
• Ribose-Phosphate Pyrophosphokinase genetics   metabolism   MeSH
• Pedigree MeSH
• Whole Genome Sequencing methods   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• PRPS1 protein, human MeSH Browser
• Ribose-Phosphate Pyrophosphokinase MeSH

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 cm2. 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.

• Keywords
• Glutamine synthetase, Glycogen storage, Liver, Liver zonation, Ornithine transcarbamylase, X chromosome inactivation,
• MeSH
• Biopsy MeSH
• Genotype MeSH
• Glutamate-Ammonia Ligase genetics   metabolism   MeSH
• Heterozygote MeSH
• X Chromosome Inactivation * MeSH
• Liver enzymology   MeSH
• Humans MeSH
• Chromosomes, Human, X genetics   MeSH
• Ornithine Carbamoyltransferase Deficiency Disease genetics   MeSH
• Ornithine Carbamoyltransferase genetics   metabolism   MeSH
• Sex Characteristics MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Glutamate-Ammonia Ligase MeSH
• Ornithine Carbamoyltransferase MeSH

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.

• MeSH
• Alleles MeSH
• Child MeSH
• Exons MeSH
• Phenotype * MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Association Studies * MeSH
• Genotype * MeSH
• X Chromosome Inactivation MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Child, Preschool MeSH
• Methyl-CpG-Binding Protein 2 genetics   MeSH
• Rett Syndrome diagnosis   genetics   MeSH
• Nucleic Acid Amplification Techniques MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Methyl-CpG-Binding Protein 2 MeSH