Naslov
NIEMANN-PICK TYPE C DISEASE: CLINICAL PRESENTATION AND MUTATIONS OF NPC1 GENE IN CROATIAN SIBLINGS

Autori
Cvitanović-Šojat, Ljerka ; Bielen, Ana ; Malenica, Maša ; Kukuruzović, Monika ; Zigman, Tamara ; Kužnik, Kristina

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
19th Congress of Child Neurologists of Mediterranean

Mjesto i datum
Budva, Crna Gora, 17.10.2013. - 19.10.2013

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Niemann-Pick type C; Croatian siblings

Sažetak
INTRODUCTION: Niemann-Pick disease type C (NP-C, OMIM 257220) is an autosomal recessive disorder caused by mutations in NPC1 (95%) and NPC2 genes. Incidence of NP-C is 1:150, 000 live births. NPC1 is large glycoprotein involved in efflux of cholesterol from late endosomes and lysosomes. Accumulation of unesterified cholesterol is causing various neurovisceral symptoms. Age of onset varies with neonatal, early infantile (2 months-2 years), late infantile (2-6 years), juvenile (6-15 years) and adult forms (>15 years). Major systemic symptoms include foetal ascites/hydrops, neonatal cholestasis and (hepato)splenomegaly. Neurological symptoms are: delay in motor milestones and hypotonia, gait problems, clumsiness, speech delay, cataplexy, school problems, ataxia, seizures, psychiatric problems, ataxia, dystonia, dementia and vertical supranuclear gaze palsy. The diagnosis is confirm by histological, biochemical and genetic tests. CASE STUDY: Two siblings (female born 1987, male born 1992) were born after uneventful pregnancy and delivery. They had neonatal cholestasis, 3 months following birth jaundice was resolved for both of them. Developmental milestones were reached normally. The female had 5 years at the onset of first neurological symptoms: lost of interest and concentration, poor drawing abilities. In the age of 7 years she developed dysrhythmic EEG and slight mental retardation. CT of the brain and laboratory tests were normal. At the age of 9 MR of the brain showed demyelination (in frontal and occipital region). Skin biopsy revealed lipid inclusions in dermal axons and NP-C was confirmed by filipin test (existence of perinuclear vesicles with accumulated unesterified cholesterol). Intractable epilepsy occured, she also had insomnia. At 11 years she was in the vegetative state and gastrostomy had to be applied, she died at 11 years and 10 months. Male sibling had earlier onset and faster progress of the disease. First symptoms of NP-C appeared as very slow speech development, followed by behavioral and cognitive problems (hyperactivity, poor memory, slurred speech). MR revealed demyelination in occipital part of the brain. No lipid inclusions were found in skin biopsy. Filipin test was positive and led to diagnosis. At the age of 6, epilepsy fits started, dysartria and ataxia appeared. He died when he was 9, 5 years old. CONCLUSION: Molecular analysis confirmed that both siblings are compound heterozygotes for two disease-causing mutations in NPC1 gene. NPC1 allele with mutation A3467G in exon 22 codes for defective protein (N1156S), while C2764T in exon 18 causes nonsense mutation (Q922X). This mutation was found only in genomic DNA, while associated cDNA was not detectable. In late childhood when progressive neurological symptoms develope and with previous history of neonatal cholestasis, a classical late infantile type of NP-C must be suspected. Miglustat (N-butyldeoxynojirimycin OGT-918) was under investigation when the famel sibling had a diagnosis of NP-C. Following insufficient informations about the pharmacokinetics, efficacy and safety in NP-C patients, the male sibling did not enter in a clinical trial.

Izvorni jezik
Engleski

Znanstvena područja
Matematika

POVEZANOST RADA