Audrey Muller

Disease and patient characteristics in NP-C patients: findings from an international disease registry

BackgroundNiemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterized by progressive neurodegeneration and premature death. We report data recorded at enrolment in an ongoing international NP-C registry initiated in September 2009 to describe disease natural history, clinical course and treatment experience of NP-C patients in clinical practice settings.MethodsThe NPC Registry is a prospective observational cohort study. Participating sites are encouraged to evaluate all consecutive patients with a confirmed diagnosis of NP-C, regardless of their treatment status. All patients undergo clinical assessments and medical care as determined by their physicians. Data are collected through a secure internet-based data collection system.ResultsAs of 19th March, 2012, 163 patients have been enrolled in centres across 14 European countries, Australia, Brazil and Canada. The mean (SD) age at enrolment was 19.6 (13.0) years. In general there was a long lag time between the mean (SD) age at neurological onset (10.9 (9.8) years) and age at diagnosis (15.0 (12.2) years). Among all enrolled patients, 107 were diagnosed based on combined genetic testing and filipin staining. Sixteen (11%) out of 145 patients with available age-at-neurological-onset data had early-infantile neurological onset, 45 (31%) had late-infantile onset; 45 (31%) had juvenile onset and 39 (27%) had adolescent/adult onset. The frequencies of neonatal jaundice, hepatomegaly and/or splenomegaly during infancy were greatest among early-infantile patients, and decreased with increasing age at neurological onset. The most frequent neurological manifestations were: ataxia (70%), vertical supranuclear gaze palsy (VSGP; 70%), dysarthria (66%), cognitive impairment (62%), dysphagia (52%). There were no notable differences in composite NP-C disability scores between age-at-neurological-onset groups. Miglustat therapy at enrolment was recorded in 117/163 (72%) patients.ConclusionsApproximately two-thirds of this NP-C cohort had infantile or juvenile onset of neurological manifestations, while the remaining third presented in adolescence or adulthood. While systemic symptoms were most common among patients with early-childhood onset disease, they were also common among patients with adolescent/adult onset. The profiles of neurological manifestations in this Registry were in line with previous publications.

Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study.

Niemann–Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3β,5α,6β-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18–90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3β,5α,6β-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.

Results from a 9-year Intensive Safety Surveillance Scheme (IS(3) ) in miglustat (Zavesca(®) )-treated patients.

Following approval in the EU in 2002 and the USA in 2003, an Intensive Safety Surveillance Scheme (IS3) was initiated to educate prescribers on the appropriate use of miglustat for the treatment of type I Gaucher disease (GD1), and to actively solicit safety‐relevant information. This report summarises data from all patients enrolled in IS3 between its initiation in 2003 and its closure in October 2012.

1035 The International Registry for Niemann-Pick Disease Type C (NP-C) in Clinical Practice

Background and Aim An international disease registry was started in September 2009 to evaluate the long-term disease course of NP-C in clinical settings. Methods Descriptive data from enrolment are presented for all patients with available data who were included in the Registry as of 19th August 2011. Results 121 patients have been enrolled. The median (range) age at enrolment was 16.9 (0.9−56.6) years, age at onset of neurological manifestations was 8.2 (< 1−48.0) years (n=100), and age at diagnosis was 11.8 (0.1−53.9) years (n=110). A history of neonatal jaundice was recorded in 4/4 evaluable patients with early-infantile (EI) onset of neurological manifestations (at age < 2 years; n=9), 6/21 (29%) with late-infantile (LI) onset (at 2 to < 6 years; n=31), 6/21 (29%) with juvenile (JUV) onset (at 6 to < 15 years; n=31), and 3/20 (15%) with adolescent/adult (AA) onset (at ≥ 15 years; n=29). Miglustat therapy at enrolment was recorded in 88/121 (73%) patients; mean (SD) exposure 1.69 (1.85) years (n=86). Neurological manifestations were observed in 71/84 (85%) patients: ataxia (71%), vertical gaze palsy (68%) and dysarthria (62%) were most frequent. Median (range) disability scores (0=normal; 1=worst) were: 0.0 (0.0–0.94) in EI (n=7), 0.29 (0.0–1.0) in LI (n=28), 0.41 (0.15–0.88) in JUV (n=28), and 0.29 (0.06–0.81) in AA-onset patients (n=26). A low proportion of patients had normal language, manipulation, ambulation, and/or swallowing. Conclusions Over two-thirds of this NP-C cohort had infantile or juvenile onset of neurological manifestations; neonatal jaundice was observed more frequently in these patients versus adolescent/adult-onset patients.