The burden of disease in metachromatic leukodystrophy: results of a caregiver survey in the UK and Republic of Ireland.

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disease characterised by the progressive loss of motor function and severe decline in cognitive function. Limited information is available on the burden MLD places on patients and their families and the medical and social support these patients need. Three UK-based MLD patient organisations commissioned an online survey, and follow-up semi-structured interviews to describe and quantify these burdens across MLD subtypes, stage of disease (including end of life) and treatment status (untreated, gene therapy or hematopoietic stem cell transplant [HSCT]). RESULTS: A total of 24 patients were included in the study: thirteen late infantile (LI), six early juvenile (EJ), two late juvenile (LJ) and three adult onset (AO). Six patients had received gene therapy and one had received an HSCT. MLD patients receiving no disease modifying treatment bore a high symptom burden: 94% were wheelchair dependent, 88% required tube feeding, 88% were incontinent, 82% had lost their speech and all the children were either unable to attend education or needed specialist provision. Patients were reliant on numerous medical interventions and assistive equipment. All early-onset patients (LI and EJ) were wheelchair dependent, and tube fed, with all EJ patients having lost all speech. The caregiving responsibilities of parents impacted their employment, finances, relationships and health. Patients treated with gene therapy or HSCT were more mobile and were able to eat normally and two thirds of the children were able to attend mainstream school. CONCLUSIONS: The impact of illness that patients and their caregivers faced was extensive, and the level of care, amount of medication, number of hospital visits and educational support required were substantial. Financial constraints often brought about by inability to work also placed considerable strain on families. The study increases understanding of the burden of MLD on patients and their families, and the level of unmet need in the treatment of the disease.

Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B).

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. METHODS: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. RESULTS: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. CONCLUSION: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).

The importance of early diagnosis and views on newborn screening in metachromatic leukodystrophy: results of a Caregiver Survey in the UK and Republic of Ireland.

Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). MLD causes progressive loss of motor function and severe decline in cognitive function, leading to premature death. Early diagnosis of MLD provides the opportunity to begin treatment before the disease progresses and causes severe disability. MLD is not currently included in newborn screening (NBS) in the UK.This study consisted of an online survey, and follow-up semi-structured interviews open to MLD patients or caregivers, aged 18 years and over. The aims of the study were to understand the importance of early diagnosis and to establish the views of families and caregivers of patients with MLD on NBS.A total of 24 patients took part in the survey, representing 20 families (two families had two children with MLD, one family had three children with MLD). Following on from the survey, six parents participated in the interviews. Our data showed diagnostic delay from first symptoms was between 0 and 3 years, with a median of 1 year (n = 18); during this time deterioration was rapid, especially in earlier onset MLD. In patients with late infantile MLD (n = 10), 50% were wheelchair dependent, 30% were unable to speak, and 50% were tube fed when a diagnosis of MLD was confirmed. In patients with early juvenile MLD (n = 5), over half used a wheelchair some of the time, had uncontrollable crying, and difficulty speaking (all 60%) before or at the time of diagnosis. A high degree of support was expressed for NBS among caregivers, 95% described it as very or extremely important and 86% believed detection of MLD at birth would have changed their child's future. One parent expressed their gratitude for an early diagnosis as a result of familial MLD screening offered at birth and how it had changed their child's future: "It did and it absolutely has I will be forever grateful for his early diagnosis thanks to his older sister."The rapid rate of deterioration in MLD makes it an essential candidate for NBS, particularly now the first gene therapy (Libmeldy™) has been approved by the European Medicines Agency. Libmeldy™ has also been recommended as a treatment option in England and Wales by the National Institute for Health and Care Excellence (NICE) and is being made available to patients in Scotland via the Scottish Medicines Consortium's ultra-orphan pathway.

Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR).

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). METHOD: The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. RESULTS: A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). CONCLUSION: The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study.

Miglustat 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.

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

BACKGROUND: Niemann-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. RESULTS: In 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. CONCLUSION: ASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy.

Consensus clinical management guidelines for Niemann-Pick disease type C.

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.

A Suspicion Index to aid screening of early-onset Niemann-Pick disease Type C (NP-C).

BACKGROUND: Niemann-Pick disease Type C (NP-C) is difficult to diagnose due to heterogeneous and nonspecific clinical presentation. The NP-C Suspicion Index (SI) was developed to identify patients with a high likelihood of NP-C; however, it was less reliable in patients aged <4 years. METHODS: An early-onset NP-C SI was constructed following retrospective chart review of symptom presentation in 200 patients from nine centres comprised of 106 NP-C cases, 31 non-cases and 63 controls. Statistical analyses defined strength of association between symptoms and a diagnosis of NP-C and assigned risk prediction scores to each symptom. RESULTS: Visceral symptoms were amongst the strongest predictors. Except for gelastic cataplexy and vertical supranuclear gaze palsy, central nervous system symptoms were not discriminatory in this population. Performance of the early-onset NP-C SI was superior versus the original NP-C SI in patients aged ≤4 years. CONCLUSIONS: The early-onset NP-C SI can help physicians, especially those with limited knowledge of NP-C, to identify patients aged ≤4 years who warrant further investigation for NP-C.

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.

Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral lipid storage disorder characterised by progressive, disabling neurological symptoms and premature death in most patients. During the last decade, national cohort studies have accrued a great deal of data on the symptomatology and natural history of NP-C. METHODS: In an observational cohort study, we present a substantial update based on the clinical presentation and follow-up of all known UK-based patients with a confirmed diagnosis of NP-C who have been tracked on an electronic database at the Department of Genetic Medicine, University of Manchester, UK. Patients were stratified according to accepted age-at-neurological-onset categories. Data on patients' clinical signs and symptoms, medical history and genetic studies are summarised using descriptive methods. RESULTS: A total of 146 patients with NP-C were included, representing the full known UK NP-C cohort, as observed from database information between 1999 and the end of 2011: 72 patients (49 %) were alive at the end of the observation period. Among a total of 116 patients (79 %) who possessed at least one identified, disease-causing NP-C gene mutation, 114 (98 %) had NPC1 and two (2 %) had NPC2 mutations. Overall, 53/194 (27 %) identified mutations were novel. Six patients (4 %) had an early, non-neurological neonatal onset form of NP-C. The numbers (%) of patients with accepted age-at-neurological onset forms were: 8 (5 %) early-infantile onset, 51 (35 %) late-infantile onset, 42 (29 %) juvenile onset, and 25 (17 %) adolescent/adult onset. Fourteen patients diagnosed based on visceral symptoms and/or sibling history, confirmed in most cases by genetic analysis, did not have any neurological manifestations at last follow up (11 patients with mean [SD] age at last follow up 2.5 [1.8] years: 3 with mean [SD] age at death 20.8 [15.9] years). A total of 51 patients (35 %) received miglustat therapy. The mean (SD) overall treatment duration up to the end of the observation period was 2.6 (2.3) years. CONCLUSIONS: This UK cohort is the largest national NP-C cohort reported to date, and confirms the wide phenotypic variability of the disease, as reported in other countries. Further analyses are required to assess the impact of miglustat therapy on neurological disease progression.

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 Agency­approved 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.

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.

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.

Successful allogeneic bone marrow transplant for Niemann-Pick disease type C2 is likely to be associated with a severe 'graft versus substrate' effect.

Niemann-Pick disease type C2 (NPC2) is caused by the inherited deficiency of a lysosomal cholesterol transport protein, NPC2 protein. Many cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. This disease is theoretically correctable by bone marrow transplantation (BMT), as the NPC2 protein is small and soluble and secreted and recaptured by the mannose-6-phosphate pathway. In this report we describe the first successful allogeneic bone marrow transplantation for this condition in a 16-month-old boy homozygous for the NPC2 p.E20X mutation, which has hitherto been reported to cause disease with a severe phenotype. During BMT there was an initial improvement of the established respiratory illness, with the immune suppression associated with transplant conditioning, but there was subsequent marked deterioration at the time of immune reconstitution and donor cell engraftment. This 'graft versus substrate' reaction was managed with intensive immune suppressant therapy, and it gradually resolved as the substrate was cleared by the engrafted donor macrophages. All immune suppression was withdrawn 18 months after transplantation, and his respiratory illness has resolved. He walked independently at 24 months and is continuing to reach development milestones after receiving his transplant. We conclude that the successful treatment of Niemann-Pick C2 therefore seems likely to be associated with a severe post-transplantation 'graft versus substrate' reaction that requires intense immune suppression before eventual resolution.

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(R)), 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.

Cost of illness associated with Niemann-Pick disease type C in the UK.

OBJECTIVE: Niemann-Pick disease type C (NP-C) is a rare and devastating genetic disorder characterised by a range of progressive neurological symptoms, which imposes a burden on patients, family members, the healthcare system and society overall. The objective of this study was to assess direct and indirect costs associated with NP-C in the UK. METHODS: This was a non-interventional, retrospective, cross-sectional cohort study based on responses from patients and/or their carers/guardians recruited from a UK NP-C database. Resource use and direct medical, direct non-medical and indirect costs were evaluated using data collected via postal survey in October 2007, which included a Medical Resource Use questionnaire. Total annual costs per patient were estimated. RESULTS: In total, 18 Medical Resource Use questionnaires (29% response rate) were received and analysed. The mean total annual cost (SD) of NP-C per patient was 39,168 pounds (50,315 pounds); 46% were direct medical costs, to which home visits and residential care contributed 68% and 15%, respectively. Direct non-medical costs accounted for 24% of the average annual cost per patient, mainly due to specialist education, and indirect costs 30%. If only direct medical costs were considered, the mean annual cost (SD) per patient was reduced to 18,012 pounds (46,536 pounds). CONCLUSIONS: The direct annual per-patient cost of NP-C illness in 2007 appears moderate when compared with other rare and severely disabling diseases. However, cost estimates may be conservative, since findings are limited by a small sample size, low survey response rate and potential recall bias. As demonstrated by this study, a substantial proportion of the cost is shifted from the healthcare system to the patient, family and non-medical providers. These findings highlight the need for treatments that can slow or stop disease progression in NP-C.