Niemann–Pick type C disease with a novel intronic mutation: three Turkish cases from the same family

Abstract

Objectives Niemann–Pick type C (NPC) disease is a rare progressive neurodegenerative condition that is characterized by the accumulation of cholesterol, glycosphingolipids, and sphingosine in lysosomes. Patients have various systemic and neurological findings depending on their age at onset. This disease is caused by the autosomal recessive transmission of mutations in the NPC1 and NPC2 genes; patients have mutations mainly in the NPC1 gene (95%) and the majority of them are point mutations located in the exonic regions. Case presentation Here, we presented three cousins with hepatosplenomegaly and progressive neurodegeneration who were diagnosed with visceral-neurodegenerative NPC disease. Their parents were relatives, and they had a history of sibling death with similar complaints. Bone marrow smear showed foamy cells in patient 1. Vertical supranuclear gaze palsy was not present in all cases. Sphingomyelinase (SM) activities were almost normal to exclude NPA or NPB. Filipin staining was performed in patient 2 and showed a massive accumulation of unesterified cholesterol The NPC1 gene analysis of the three patients showed a novel homozygous c.1553+5G>A intronic mutation. cDNA analysis was performed from the patient 3 and both parents. It was observed that exon 9 was completely skipped in the homozygous mutant baby. Both the normal and the exon 9-skipped transcripts have been detected in the parents. Conclusions When combined with the filipin staining and the patients’ clinical outcomes, this mutation is likely to be deleterious. Moreover, cDNA sequencing supports the pathogenicity of this novel variant.

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

“…Notably, vertical supranuclear gaze palsy was not consistently observed across all cases. Through molecular diagnosis, a homozygous c.1553+5 G > A intronic mutation in NPC1 was identified, resulting in exon 9 skipping and the production of an aberrant NPC1 protein 58 .…”

Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications

“…However, the data must be interpreted with care [ 86 ] as cholesterol diffusion can lead to dissociation of the complex. It has also been used to detect Niemann–Pick type C disease [ 13 ] which is an autosomal recessive lysosomal storage disorder due to mutations in the NPC1 or NPC2 gene that can lead to a fatal disease in neonatal infants or chronic neurodegeneration in adults [ 87 ]. Filipin, similar to other polyenes, has been used to construct semi-synthetic derivatives searching to increase safety [ 88 ].…”

“…The phenomenon of the interaction of polyenes with the lipid membrane has been studied for decades. Polyenes are quite small molecules, for biological standards, but present a wide variety of phenomena depending on concentration [ 2 , 3 ], solvent [ 4 , 5 , 6 , 7 ], pH [ 8 , 9 , 10 , 11 ], oxidation [ 12 , 13 , 14 , 15 , 16 ], and membrane properties [ 17 , 18 , 19 , 20 ]. Pertinent studies have advanced our understanding of the interaction between molecules and membranes.…”