Patterson, Marc C.

Abstract Background Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients’ and caregivers’ quality of life (QOL) and reduces the patient’s life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients’ and caregivers’ daily lives to understand the burden of disease.Results A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months – 65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients’ and caregivers’ activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL.Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients’ and caregivers’ HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers).ConclusionsAmbulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.Trial registrationNCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129

Rapidly progressive non-traumatic paraplegia in a child is uncommonly encountered in clinical practice, but is an important presentation to consider given the potential for significant morbidity. We present the case of an 11-year-old girl who was found to have hyperacute paraplegia due to spinal cord infarction. We discuss the appropriate workup, differential diagnosis in children and how this relates to adults; and describe the prognosis and current state of management options for spinal cord infarction.

Abstract BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937). ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.

AbstractInborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell‐and gene‐based therapies have become available. Inherent to the rare nature of the single conditions, generating high‐quality evidence for these treatments in clinical trials and under real‐world conditions has been challenging. Guidelines developed with standardized methodologies have contributed to improve the practice of care and long‐term clinical outcomes. Adaptive trial designs allow for changes in sample size, group allocation and trial duration as the trial proceeds. n‐of‐1 studies may be used in small sample sized when participants are clinically heterogeneous. Multicenter observational and registry‐based clinical trials are promoted via international research networks. Core outcome and standard data element sets will enhance comparative analysis of clinical trials and observational studies. Patient‐centered outcome‐research as well as patient‐led research initiatives will further accelerate the development of therapies for IEM.

Secondary narcolepsy occurs as a consequence of lesions involving the hypothalamic region that subserve wakefulness. Although observations on the characteristics of secondary narcolepsy have been published in adults, information on this topic in children is sparse. This is a retrospective study of characteristics and outcome of secondary narcolepsy in children. The medical records of 10 children with this condition at Mayo Clinic, Rochester, were reviewed. Characteristics of the underlying neurologic disorder, narcolepsy subtype, multiple sleep latency tests, medications used and outcome were extracted. Age at diagnosis of narcolepsy was between 6 and 17 years. Five of 10 patients had onset of excessive sleepiness within 1 year of diagnosis of the primary neurologic disorder. Six of 10 patients had type 1 narcolepsy (with cataplexy) whereas 4/10 had type 2 (without cataplexy). The clinical course was variable, with 8/10 continuing to require treatment for sleepiness at a mean period 6.6±6.2 years after diagnosis. One patient with narcolepsy type 1 due to Niemann Pick type C disease had died. One patient with narcolepsy type 2 due to craniopharyngioma had spontaneous remission of sleepiness. The 5/10 patients surviving with narcolepsy type 1 have continued to require pharmacotherapy for both sleepiness and cataplexy. This study draws attention to an important chronic sequel of childhood brain lesions that has variable, etiology-specific outcome. The rare occurrence of spontaneous resolution of childhood narcolepsy symptoms, not previously described, is also discussed.

Abstract Background (+)‐Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)‐EPI in pediatric subjects with Friedreich's ataxia (FRDA). Methods This was a phase II, open‐label, baseline‐controlled single‐center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)‐EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8‐m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. Results Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8‐m walk in 3/9 (33%), 9‐peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks ( P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks ( P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks ( P = .031). There were no serious adverse events. Conclusion (+)‐EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes. Synopsis A (+)‐epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle‐regeneration biomarker follistatin.

Abstract BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937).ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.Trial Registration: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030; EudraCT 2014-005194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE. OR-REL-NPC-01: Unregistered.

AbstractMiglustat has been indicated for the treatment of Niemann‐Pick disease type C (NP‐C) since 2009. The aim of this observational study was to assess the effect of miglustat on long‐term survival of patients with NP‐C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Miglustat‐treated and untreated patients overall and within sub‐groups according to age‐at‐neurological‐onset, that is, early infantile‐onset (<2 years), late infantile‐onset (2 to <6 years), juvenile‐onset (6 to <15 years), and adolescent/adult‐onset (≥15 years) were analysed and compared. Survival was analysed from the time of first neurological manifestation (Neurological onset group, comprising 669 patients) and from diagnosis (Diagnosis group, comprising 590 patients) using a Cox proportional hazard model adjusted for various covariates. Overall, 384 (57.4%) patients in the Neurological onset group and 329 (55.8%) in the Diagnosis group were treated with miglustat. Miglustat treatment was associated with a significant reduction in risk of mortality in both groups (entire Neurological onset group, Hazard ratio [HR] = 0.51; entire Diagnosis group, HR = 0.44; both P < .001). The effect was observed consistently in all age‐at‐neurological‐onset sub‐groups (HRs = 0.3 to 0.7) and was statistically significant for late infantile‐onset patients in both groups (Neurological onset group, HR = 0.36, P < .05; Diagnosis group, HR = 0.32, P < .01), and juvenile‐onset patients in the Diagnosis group only (HR = 0.30, P < .05). Despite the limitations of the data that urge cautious interpretation, the findings are consistent with a beneficial effect of miglustat on survival in patients with NP‐C.