Jackie Imrie

The natural history of Niemann–Pick disease type C in the UK

SummaryNiemann–Pick disease type C (NPC) is an autosomal recessive, neurovisceral lipid storage disorder. Mutations in two genes (NPC1 and NPC2) produce indistinguishable clinical phenotypes by biochemical mechanisms that have not yet been entirely clarified. The wide spectrum of clinical presentations of NPC includes hepatic and pulmonary disease as well as a range of neuropsychiatric disorders. Late-onset disease has been increasingly recognized as the biochemical diagnosis of NPC has been more widely applied in adult neurology clinics. The clinical presentation and follow-up of 94 patients with NPC is described, 58 of whom were still alive at the time this report was prepared. The age at diagnosis ranged from the prenatal period (with hydrops fetalis) up to 51 years. This review of NPC patients in the UK confirms the phenotypic variability of this inherited lipid storage disorder reported elsewhere. Although a non-neuronopathic variant has been described, most patients in this series who survived childhood inevitably suffered neurological and in some cases neuropsychiatric deterioration. While symptomatic treatment, such as anticholinergic and antiepileptic drugs, can alleviate some aspects of the disease, there is a clear need to develop a specific treatment for this progressively debilitating neurodegenerative disorder.

Niemann-Pick disease type C in adults

Although it is often perceived as a paediatric disorder, significant numbers of patients with Niemann–Pick disease type C present for the first time in adult life or survive into adult life. The presentation in these patients differs from that seen in the classical juvenile form of the disease. Adult patients are often referred to clinicians with psychosis or other major psychiatric problems. The dystonia with preserved intellectual functioning can be mistaken for other basal ganglia disorders such as Wilson disease. The presence of vertical gaze palsy is an important clinical clue and, in the presence of a modest increase in plasma chitotriosidase activity, can be very helpful in the differential diagnosis. The diagnosis should be confirmed in suspected cases by filipin staining of cultured fibroblasts, as well as cholesterol esterification studies and DNA mutation analysis.

New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Zavesca®), a reversible inhibitor of glycosphingolipid synthesis, has recently been authorized in the European Union, Brazil and South Korea for the treatment of progressive neurological symptoms in adult and pediatric patients, and represents the first specific treatment for NP-C. Here we review current data on the pharmacology, efficacy, safety and tolerability of miglustat in patients with NP-C, based on findings from a prospective clinical trial, preclinical and retrospective studies, and case reports. Findings demonstrated clinically relevant beneficial effects of miglustat on neurological disease progression in adult, juvenile and pediatric patients with NP-C, particularly those diagnosed in late childhood (6–11 years) and in juveniles and adults (12 years and older), compared with those diagnosed in early childhood (younger than 6 years). Miglustat therapy was well-tolerated in all age groups. With the approval of miglustat, treatment of patients with NP-C can now be aimed toward stabilizing neurological disease, which is likely the best attainable therapeutic goal for this disorder.

Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: Systematic literature review and evidence from studies with miglustat

Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological deterioration and premature death, and has an estimated birth incidence of 1:120,000. Mutations in the NPC1 gene (in 95% of cases) and the NPC2 gene (in approximately 4% of cases) give rise to impaired intracellular lipid metabolism in a number of tissues, including the brain. Typical neurological manifestations include vertical supranuclear gaze palsy, saccadic eye movement abnormalities, cerebellar ataxia, dystonia, dysmetria, dysphagia and dysarthria. Oropharyngeal dysphagia can be particularly problematic as it can often lead to food or fluid aspiration and subsequent pneumonia. Epidemiological data suggest that bronchopneumonia subsequent to food or fluid aspiration is a major cause of mortality in NP-C and other neurodegenerative disorders. These findings indicate that a therapy capable of improving or stabilising swallowing function might reduce the risk of aspiration pneumonia, and could have a positive impact on patient survival. Miglustat, currently the only approved disease-specific therapy for NP-C in children and adults, has been shown to stabilise key neurological manifestations in NP-C, including dysphagia. In this article we present findings from a systematic literature review of published data on bronchopneumonia/aspiration pneumonia as a cause of death, and on the occurrence of dysphagia in NP-C and other neurodegenerative diseases. We then examine the potential links between dysphagia, aspiration, pneumonia and mortality with a view to assessing the possible effect of miglustat on patient lifespan.

Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.

Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1

Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model, we found the frequency of NK cells was altered and phenocopied S1P5-deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicity due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK-cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.

Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases.

BACKGROUND Acid sphingomyelinase deficiency (ASMD), [Niemann-Pick Disease Types A and B (NPD A and B)], is an inherited metabolic disorder resulting from deficiency of the lysosomal enzyme acid sphingomyelinase. Accumulation of sphingomyelin in hepatocytes, reticuloendothelial cells, and in some cases neurons, results in a progressive multisystem disease that encompasses a broad clinical spectrum of neurological and visceral involvement, including: infantile neurovisceral ASMD (NPD A) that is uniformly fatal by 3years of age; chronic neurovisceral ASMD (intermediate NPD A/B; NPD B variant) that has later symptom onset and slower neurological and visceral disease progression; and chronic visceral ASMD (NPD B) that lacks neurological symptoms but has significant disease-related morbidities in multiple organ systems. The purpose of this study was to characterize disease-related morbidities and causes of death in patients with the chronic visceral and chronic neurovisceral forms of ASMD. METHODS Data for 85 patients who had died or received liver transplant were collected by treating physicians (n=27), or abstracted from previously published case studies (n=58). Ages at symptom onset, diagnosis, and death; cause of death; organ involvement, and morbidity were analyzed. RESULTS Common disease-related morbidities included splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%). The overall leading causes of death were respiratory failure and liver failure (27.7% each) irrespective of age. For patients with chronic neurovisceral ASMD (31.8%), progression of neurodegenerative disease was a leading cause of death along with respiratory disease (both 23.1%) and liver disease (19.2%). Patients with chronic neurovisceral disease died at younger ages than those with chronic visceral disease (median age at death 8 vs. 23.5years). CONCLUSIONS The analysis emphasizes that treatment goals for patients with chronic visceral and chronic neurovisceral ASMD should include reducing splenomegaly and improving liver function and respiratory status, with the ultimate goal of decreasing serious morbidity and mortality.

Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C.

Invariant natural killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α‐galactosylceramide, a non‐mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann‐Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or NPC2, resulting in the storage of multiple lipids, including glycosphingolipids. In the NPC1 mouse model, iNKT cells are virtually undetectable, which is likely due to the inability of CD1d to be loaded with the selecting ligand due to defective lysosomal function and/or CD1d trafficking. However, in this study we have found that in NPC1 patients iNKT cells are present at normal frequencies, with no phenotypic or functional differences. In addi‐tion, antigen‐presenting cells derived from NPC1 patients are functionally competent to present several different CD1d/iNKT‐cell ligands. This further supports the hypothesis that there are different trafficking requirements for the development of murine and human iNKT cells, and a functional lysosomal/late‐endosomal compartment is not required for human iNKT‐cell development.

Developmental outcome post allogenic bone marrow transplant for Niemann Pick Type C2.

Niemann Pick Type C2 (NPC2) is a rare autosomal recessive disease caused by mutations in the NPC2 gene (OMIM 601015). Clinically, NPC2 presents in most cases in the neonatal period with inflammatory lung disease, which may lead to death in the first year. If patients survive the neonatal period, they may develop a severe neurological disease. Here we present the developmental and neurological follow up at 5 years of age of a child with NPC2 successfully treated with allogenic bone marrow transplantation (BMT) at the age of 16 months. A homozygous p.E20X sequence variation previously associated with a severe phenotype was identified. In contrast to the previously reported patients with the same mutations, our patient has no respiratory compromise and has made some developmental progress (especially gross motor), though is significantly delayed (particularly in speech and language). Haematopoietic stem cell transplantation (HSCT) could be considered for patients with this mutation as long as performed early in the course of the disease.

Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials

BackgroundNiemann-Pick disease type C (NPC) is a lysosomal storage disease with a heterogeneous neurodegenerative clinical course. Multiple therapies are in clinical trials and inclusion criteria are currently mainly based on age and neurological signs, not taking into consideration differential individual rates of disease progression.ResultsIn this study, we have evaluated a simple metric, denoted annual severity increment score (ASIS), that measures rate of disease progression and could easily be used in clinical practice. We show that ASIS is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria. In addition, we show that ASIS has prognostic value and demonstrate that treatment with an experimental therapy - acetyl-DL-leucine - is associated with a reduction in ASIS scores.ConclusionASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy.