Abstract
BackgroundNiemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse.MethodsThe study population consisted of two Greek NPC patients and their extended pedigree. Patients’ clinical, biochemical, molecular profiles and the possible correlations are presented. Genotyping was performed by direct sequencing. Mutations’ origin was investigated through selected exonic NPC1 polymorphisms encountered more frequently in a group of 37 Greek patients with clinical suspicion of NPC disease and in a group of 90 healthy Greek individuals, by the use of Haplore software.ResultsTwo novel NPC1 mutations, [IVS23 + 3insT (c.3591 + 3insT) and p. K1057R (c.3170A > C)] were identified and each mutation was associated with a specific haplotype. One of the patients was entered to early treatment with miglustat and has presented no overt neurological impairment after 11.5 years.ConclusionsThe splicing mutation IVS23 + 3insT was associated in homozygocity with a severe biochemical and clinical phenotype. A possible founder effect for this mutation was demonstrated in the Greek Island, as well as a different origin for each novel mutation. Longitudinal follow-up may contribute to clarify the possible effect of early miglustat therapy on the patient compound heterozygous for the two novel mutations.
Highlights
Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2
Data from clinical trials and observational studies mainly suggest that miglustat treatment does not prevent, but can at least decelerate the progression of some neurological manifestations, in juvenile and adult onset forms that received the treatment from the very beginning of neurological impairment [6, 9, 10]
We describe the clinical, biochemical and molecular profiles of two Greek NPC patients; a 12-year old female (Patient 1) with two novel NPC1 mutations
Summary
Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Niemann-Pick type C disease (NPC) (OMIM257220) is a rare lethal lysosomal storage disorder characterised by impaired lipid trafficking and subsequent intracellular accumulation of a wide spectrum of lipids, including unesterified cholesterol, several glycosphingolipids, Bountouvi et al BMC Medical Genetics (2017) 18:51 with declining prevalence pertaining to increasing age of inaugural neurological signs [6, 7]. Except in a small subset of patients with a severe systemic perinatal rapidly fatal form, clinical course and prognosis correlate with the age of entering neurological symptomatology. Data from clinical trials and observational studies mainly suggest that miglustat treatment does not prevent, but can at least decelerate the progression of some neurological manifestations, in juvenile and adult onset forms that received the treatment from the very beginning of neurological impairment [6, 9, 10]. 2-hydroxypropyl-ß-cyclodextrin (NCT01747135), which has shown significant promise in preclinical studies [12], and Arimoclomol (NCT02435030), a heat-shock protein 70/90 co-inducer in cells under stress [13], are currently on clinical trials
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