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]).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.