Clinical, Laboratory, Molecular Data and Miglustat Outcome in 8 Iranian patients affected of Niemann Pick Type C

Introduction: Niemann Pick type C(NP-C)disease is a rare neurodegenerative lysosomal storage disorder with autosomal recessive inheritance characterized by impaired intracellular lipid trafficking leading to accumulation of cholesterol and glycosphingolipids in various tissues (1-12).It is a progressive irreversible disease caused by mutation in NPC1 gene located on chromosome 18q11-12(95% of cases or NPC2 located on chromosome14q24.3 (4% of cases) (4-8).The exact NPC1 &NPC2 protein functions are unknown and mechanism leading to abnormal storage and cellular malfunction and neurodegeneration are not to date fully described(2,8) Different studies showed to affect 1/120000 to 1/150000 live births in Western Europe and overall 1/100000 in the world.(9-12).Wassif et al predicted a prevalence as high as 1/19000 to1/36000 based on exome sequencing.(6)Its true incidence is underestimated due to under recognition and misdiagnosis(2).NP-C is very heterogeneous in its presentation, age of onset, clinical feature(visceral, neurological& psychiatric) and also progresses in different rates, so delay of diagnosis is common(2-4).Until recently filipin staining of skin fibroblasts was principal of diagnosis but was costy and time consuming(3).In recent years advances in mass spectrometry identified sensitive plasma biomarkers elevated in NP-C(eg.cholestan triol, bile acids, and lysosphyngomyelin isoforms)which together with genetic enables a rapid correct diagnosis.(1) There is no curative treatment for NP-C.(5,8)Miglustat(Zavesca , Actelion Pharmaceuticals)by inhibiting glucosylceramide synthase enzyme is approved for improvement of neurological manifestations(1-12.Several studies have been published on short term (up to 26 months) follow up of miglustat in NP-C patients .Here we have described our NP-C patients’ treated with zavesca from 2010 to 2017.Materials & Methods: A retrospective descriptive study was done on patients referred and treated in research unit of Iranian National Society for Study on Inborn Errors of Metabolism from 2010 to2017.Diagnosis was done in suspected cases by filipin staining of skin fibroblasts or plasma measurement of lysosphyngomyelin(Lyso 509) and confirmed via genetic testing of NPC1 and NPC2 genes with NGS method .Miglustat treatment at the dose of 220-300 mg/m2 body surface area was started after genetic confirmation and every 6 months follow up was done with physical examination and laboratory studies. Data were extracted and analyzed from clinic patients’ records with their consentsResults: 8 patients(1♀&7♂)of 8 consanguineous families;8/8uneventful pregnancy and delivery(4NVD&4C/Sec);Mean Birth Body Weight:3120grams(range:2500-3800);Mean Birth Head Circumference:34.4 cm(range:33-38); Mean age at onset:8.5 months (range:1-18); Mean age at diagnosis: 4.5 years(range:1.33-14); Symptoms&Signs: 7/8 neurodevelopmental delay ;1/8 circumcision location bleeding;,2/8 cholestatic Jaundice;7/8 Ataxia,2/8 Ptosis;5/8 Gelastic cataplexy; 6/8 hepatosplenomegaly;1/8 kidneys microlithiasis;1/8 Sensorineural hearing loss, 1/8 Cherry red spots in ophthalmoscopy;4/8 seizure; 7/8 Dysphagia ;7/8 Dysarthria;6/8prolonged neonatal Jaundice leading to admission;1/8 pigmented retinopathy on ophthalmoscopy;6/8 supravertical gaze palsy .Mean Acid Phosphatase level:11.9 (NLC;c.926G> A;c.1096C> T ; c.762delA.1/8 had four heterozygote mutations in NPC1 gene. Mean Follow up duration after treatment: 3.1 years (range: 0.5-8); 4/8 experienced adverse drug reactions which were controlled with special food regimes. Symptoms & signs: 4/8 improved; 2/8 unchanged; 2/8 deteriorated after treatment.1/8 died one month after parents discontinued miglustat without advice.Conclusion & discussion: Miglustat was effective in stabilization and improvement of neurologic manifestations in half of our patients but was effective in decreasing their mortality .Further study on long term follow up of miglustat treated Iranian NP-C patients together with genotype correlation is recommended

کلیدواژه ها:

NPC ، molecular ، clinical ، niemman pick C