Thesis (Ph.D.) - Cairo University - Faculty of Science - Department of Biochemistry

Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2 in the remaining cases. It is characterized by an impaired intracellular lipid trafficking leading to the aggregation of unesterified cholesterol and various sphingolipids in different body organs such as the liver, spleen, and brain. The estimated incidence of NPC is 1/100000. Although early disease diagnosis is very crucial for proper initiation of treatment and inhibition of disease progression, proper diagnosis at the early stages of the disease is difficult due to its wide heterogeneous clinical presentation. In our study, we aimed at the molecular diagnosis of NPC in Egyptian patients and investigate certain NPC1 mutations hotspots residues (855{u2013}1098) and (1038{u2013}1253) in the NPC1 gene. This study included 15 Egyptian patients derived from 15 families. Consanguinity was certain in 12 families (80%). They were 9 males (60%) and 6 females (40%) and their age ranged from 6 months to 10 years. The onset of disease varied from early infantile to juvenile form. Accordingly, our patients were classified into early infantile (<2 years) in 7 patients (46.7%), late-infantile (2{u2013}5 years) in 4 patients (26.7%), juvenile (5{u2013}16 years) in 1 patient (6.7%). Assessment of peripheral leukocytic Ý-glucocerebrosidase and peripheral leukocytic acid sphingomyelinase enzymes showed normal values in all patients, while a remarkable elevated level in the chitotriosidase assay was observed for all patients in compared to control. Molecular analysis of the 9 exons of NPC1 (exons 17-25) confirmed 6 different mutations (15 mutant alleles out of 30 studied alleles). They are distributed as follows, two homozygous missense novel mutations in the amino acid residue (1038-1253)

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