Genetic features of patients with MPS type IIIB: Description of five pathogenic gene variations.

BACKGROUND: There are four distinct forms of Sanfilippo syndrome (MPS type III), each of which is an autosomal lysosomal storage disorder. These forms are caused by abnormalities in one of four lysosomal enzymes. This study aimed to identify possible genetic variants that contribute to Sanfilippo IIIB in 14 independent families in Southwest Iran. METHODS: Patients were included if their clinical features and enzyme assay results were suggestive. The patients were subsequently subjected to Sanger Sequencing to screen for Sanfilippo-related genes. Additional investigations have been conducted using various computational analyses to determine the probable functional effects of diagnosed variants. RESULTS: Five distinct variations were identified in the NAGLU gene. This included two novel variants in two distinct families and three previously reported variants in 12 distinct families. All of these variations were recognized as pathogenic using the MutationTaster web server. In silico analysis showed that all detected variants affected protein structural stability; four destabilized protein structures, and the fifth variation had the opposite effect. CONCLUSION: In this study, two novel variations in the NAGLU gene were identified. The results of this study positively contribute to the mutation diversity of the NAGLU gene. To identify new disease biomarkers and therapeutic targets, precision medicine must precisely characterize and account for genetic variations. New harmful gene variants are valuable for updating gene databases concerning Sanfilippo disease variations and NGS gene panels. This may also improve genetic counselling for rapid risk examinations and disease surveillance.

Molecular determination of glutaric aciduria type I in individuals from southwest Iran.

BACKGROUND: Glutaric Aciduria type 1 (GA1) is a metabolic inborn error and is characterized by increasing excursion of glutaric acid and its derivates, presented in microcephaly and dystonia. The disease is resulted from mutational inactivation in the GCDH gene encoding the glutaryl-CoA dehydrogenase. The defective enzyme causes the accumulation of an excessive level of intermediate breakdown products that leads to the brain damage. In spite of the clinical features, diagnosis of GAI has been often confusing, because of variability in the clinical manifestations of patients. Early diagnosis and treatment can though prevent irreversible disease progression and consequent brain damage; otherwise the affected individuals will die in their first decade of lives. METHODS: The GCDH gene was also analyzed to (detect or identify) disease causing mutations using gene amplification and direct sequencing in 18 patients. RESULTS: Among 18 patients, 10 patients (55.5%) were homozygous or compounded heterozygous for the recurrent mutation E181Q, three patients (16.7%) were homozygous for the known mutation R402Q and one patient (5.6%) was compound heterozygous for S255L. All three detected missense mutations are pathogenic, which cause structural changes in the binding site and tetramerization or functional deficiency. Four other individuals (22.2%) with a preliminary diagnosis of GAI were negative for any pathogenic mutations. CONCLUSION: Most GA1 affected persons in southwest Iran are with Persian ethnicity and the most common mutation in Khuzestan Province is prominent in comparison to  previous reports from Iran.