Finally, studies of numerous multiplex families have indicated that mutations either NPC1 or NPC2 appear largely predictive of the neurological course, and not of the systemic disease. What is the diagnostic role of the filipin test in the era of new biomarkers? Statements Filipin test is no longer considered a first line test for the diagnosis of NPC. Until recently, the demonstration of unesterified cholesterol accumulation within the lysosomes by filipin testing was considered to be the gold standard test for the diagnosis of NPC disease [ 11 , 47 , 51 ].
Since this assay needs to be performed on cultured fibroblasts obtained from skin biopsies, it is invasive and has a long turnaround time. Additionally, the assay is technically challenging, labour intensive and is performed only in specialized laboratories [ 51 ]. Due to these drawbacks, and in the light of the recent discovery of several sensitive and specific blood biomarkers, filipin staining is no longer considered as a first line test for the diagnosis of NPC [ 35 ].
However, it is very useful to assess the pathogenicity of novel genetic variants.
In particular, it is important to keep in mind that to date all biomarkers, except bile acids which have not yet been fully validated, do not completely differentiate between heterozygous and affected patients [ 39 , 52 , 53 ]. In these cases, if only one pathogenic mutation is found by molecular analysis of NPC1 and NPC2 , filipin testing should be performed. Consequently, in a few patients, it may not be possible to definitively conclude in spite of comprehensive investigations.
What is the role of brain imaging in the diagnosis and follow-up of NPC? Statements Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. Neuroimaging data gathered primarily from adolescent and adult individuals with NPC show a variable pattern, with some being normal, particularly early in the course of the illness, while most patients will demonstrate cerebellar volume changes, which correlate with measures of ataxia and ocular-motor function [ 54 ].
Reductions in the volume of the hippocampus, basal ganglia and thalamus are also associated with progressive illness [ 55 ]. White matter disease is often widespread, most detectable as changes on diffusion imaging [ 56 ] or visually as atrophy of the corpus callosum [ 57 ]. Increased pontine to mid-brain ratio, much like that seen in progressive supranuclear palsy, is seen, albeit to a lesser degree [ 58 ].
In some patients, brain atrophy may predominantly affect frontal and temporal regions [ 59 ]. However, these changes are often subtle and non-specific, and may be more useful as illness biomarker than as a diagnostic tool. NPC disease is not yet curable but is an eminently treatable condition. The mainstay of therapy is symptom management employing disease modifying agent s when available. Statements Patients with NPC exhibit multisystem disease manifestations and benefit from multidisciplinary follow up from physicians and allied health care professionals with experience in this condition.
Wherever possible, patients identified with NPC should be referred to a centre with expertise in the care of this condition. What symptomatic therapy should be considered for a patient with NPC disease? Statements The growth of children with NPC height, weight and head circumference should be assessed at regular intervals as part of routine health assessments by their primary health care provider.
In addition, their developmental progress should be monitored using age appropriate instruments. Statements Mobility, balance, core stability, trunk control, spasticity, foot posture and strength should be assessed regularly by a suitably qualified physical therapist. A structured and personalized rehabilitation program may prolong mobility and transfer ability. Statements NPC patients should undergo a comprehensive swallowing assessment by a speech and language therapist and nutritional review by a dietician.
Instruction in dietary modification and compensatory postures may be beneficial for individuals with dysphagia. The family should be educated regarding the likely eventual need for assisted feeding, as part of an ongoing process. Statements NPC patients should undergo a comprehensive communication evaluation by a speech and language therapist and receive appropriate treatment.
Statements Individuals with NPC may benefit from assessments for spasticity and incipient or established contracture. Spasticity and spasms should be treated at an early stage, initially by non-pharmacological means. If these are unsuccessful, pharmacological agents including Baclofen, Tizanidine, Benzodiazepines, Dantrolene sodium and botulinum toxin injections may be considered. Statements Co nsider modifying diet and lifestyle to optimize stool consistency and avoid faecal impaction and incontinence.
If required, consider appropriate laxatives to optimize gut transit and stool consistency. Statements Individuals with NPC should have their history reviewed for symptoms suggestive of neurogenic bladder recurrent urinary tract infection, nocturia, incomplete evacuation, dribbling and be referred for urologic evaluation if symptoms are present. Protriptyline, other tricyclic agents or modafanil have been efficacious for cataplexy.
Epilepsy should be treated by a neurologist aware of the disease possibility of aggravation with antiepileptic drugs like carbamazepine and vigabatrin should be considered. Testing should be age and functionally appropriate, using standardised assessment tools. Statements Clinicians, caregivers and individuals with NPC should be aware that there is an increased prevalence of behavioural problems and other psychiatric disorders such as anxiety, depression or psychosis in NPC.
Statements Individuals with NPC should undergo a comprehensive hearing assessment at the time of diagnosis and thereafter annually.
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When appropriate, patients should be offered hearing devices to improve general communication. Miglustat, a substrate reduction therapy, is the only licensed disease modifying medicine in the European Union for the treatment of neurological manifestations of patients with NPC disease. In some patients, miglustat has been shown to halt or attenuate disease progression [ 60 , 61 ]. Statement All patients with a confirmed diagnosis of NPC should be considered for miglustat therapy.
To understand the effects of disease modifying therapy in NPC, information about the natural history of disease progression is required. The rate of progression was 0. The rates of progression correlated with age at diagnosis, the younger patients showing the greatest progression of disease. The study included male and female patients with NPC confirmed by cholesterol esterification and abnormal filipin staining, able to safely ingest a capsule, with normal renal function and not suffering from clinically significant diarrhoea.
Patients with other medical conditions or were on concomitant medications that would render them unsuitable for the study were excluded. Treatment with Miglustat resulted in improvements in the primary end point HSEM compared with standard care. Safety assessments were performed at screening every 3 months and at post screening follow up. Adverse events AEs were recorded at each post-screening visit. Discontinuation was reported in one paediatric patient due to memory impairment and in one adult patient due to confusional state and in one other adult patient due to diarrhoea.
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No deaths were reported. The study concluded that Miglustat was safe and improved or stabilised several clinically relevant markers of NPC [ 61 ]. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit. The month data did not meet the primary end point of improvement in HSEM velocity. Small patient numbers produced wide confidence intervals making the data unreliable; however a modest deterioration in HSEM velocity was noted.
Currently there are limited data on patients with NPC with advanced neurological disease being commenced on miglustat. Miglustat therapy is NOT appropriate for patients who have profound neurological disease, which, in the opinion of the attending physician, would make it difficult to assess for any improvements with therapy. Such symptoms may include but are not limited to:. Swallowing difficulties profound enough to require tube feeding through a per-cutaneous gastrostomy. Whilst there is no evidence in the literature to assess this, most guidelines for other new therapies such as enzyme replacement therapies, and some national guidelines specify the above as an exclusion criteria [ 65 , 66 ].
Although the disease is a disorder of cholesterol trafficking, cholesterol-lowering drugs have not been shown to be effective at altering the course of the disease [ 68 , 69 ]. In addition, a number of other therapeutic modalities in animal and early phase human studies are underway. Statements NPC is a progressive condition and patients require regular follow up.
Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families. Statements Most children with late-infantile and juvenile onset NPC are expected to reach adulthood with complex medical and psychosocial needs. The process of transition from paediatric to adult services should begin early and must include appropriate services in the community to provide a seamless transition from childhood to adult life.
Individuals with NPC may benefit from a detailed assessment identifying barriers to independence. An individual identified as being near the end- of-life may benefit from ongoing access to palliative care services including for symptom control, respite, psychological and spiritual support. Statements 38 : Requests for NPC pre-symptomatic genetic testing are best managed on a case-by-case basis. Pre-symptomatic testing in minors is not permitted in some jurisdictions, and in any case, the risks and benefits from the perspectives of both the child and parents should be carefully discussed in the context of formal counselling from a suitably qualified individual.
All patients identified pre-symptomatically should be referred to specialist centres for surveillance and early detection of neurological manifestations. Statements Prenatal testing for NPC should be offered to all at risk couples and requires careful counselling by clinical geneticists and NPC specialists. Molecular genetic analysis of chorionic villus samples is the strategy of choice, based on mutations identified in the family. These guidelines are the result of an international collaboration of experts in the care of NPC and the evidence gathered to write these guidelines is the best evidence available to the experts.
These guidelines address the management of children and adults affected by NPC and are intended to facilitate optimal care to all NPC patients regardless of their demography and access to health care. In addition, it defines standard of care against which practice can be audited and best practice can be spread. Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis.
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Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis. The clinical spectrum of fetal Niemann-Pick type C. Am J Med Genet A. Niemann-Pick disease type C. Orphanet J Rare Dis. Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Republic: a surprisingly stable diagnostic rate spanning almost 40 years.
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. BMC Neurol. Prevalence of lysosomal storage disorders. The frequency of lysosomal storage diseases in the Netherlands. Hum Genet. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations. JIMD Rep. Genet Med.
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Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study. The adult form of Niemann-Pick disease type C. Niemann-Pick disease type C symptomatology: an expert-based clinical description. The neuropsychiatry of Niemann-Pick type C disease in adulthood. J Neuropsychiatry Clin Neurosci. Niemann-Pick type C: a potentially treatable disorder? Pract Neurol. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C.
Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits. Saccadic eye movement characteristics in adult Niemann-Pick type C disease: relationships with disease severity and brain structural measures. PLoS One. Recommendations for the detection and diagnosis of Niemann-Pick disease type C.
Neurol Clin Pract. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. J Lipid Res. Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Anal Biochem. Clin Chem Lab Med. Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature. Development of a bile acid-based newborn screen for Niemann-Pick disease type C.
Identification of novel bile acids as biomarkers for the early diagnosis of Niemann-Pick C disease. FEBS Lett. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Niemann-Pick C1 disease: the IT substitution is a frequent mutant allele in patients of western European descent and correlates with a classic juvenile phenotype. Niemann-Pick type C1 IT mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding.
Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Vanier MT, Latour P. Laboratory diagnosis of Niemann-Pick disease type C: the filipin staining test. Methods Cell Biol. Rapid diagnosis of 83 patients with Niemann-Pick type C disease and related cholesterol transport disorders by Cholestantriol screening. Comprehensive evaluation of plasma 7-ketocholesterol and cholestan-3beta,5alpha,6beta-triol in an Italian cohort of patients affected by Niemann-Pick disease due to NPC1 and SMPD1 mutations.
Clin Chim Acta. Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C. Subcortical volumetric reductions in adult Niemann-Pick disease type C: a cross-sectional study. White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study.
Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C. Eur J Neurol. Niemann-Pick disease type C1 predominantly involving the frontotemporal region, with cortical and brainstem Lewy bodies: An autopsy case.
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Schiffmann R. From bench to bedside. Type C Niemann-Pick disease: biochemical aspects and phenotypic heterogeneity. Dev Neurosci. Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet. Molecular analysis of 30 Niemann-Pick type C patients from Spain.
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Auditory phenotype of Niemann-Pick disease, type C1. Ear Hear. The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann-Pick disease type C after therapy with miglustat. Eye movement and diffusion tensor imaging analysis of treatment effects in a Niemann-Pick Type C patient. Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat.
Four symposia, held in , , and were designed to gather the most relevant and innovative of the laboratory and field studies concerned with these hereditary disorders. The texts generated by these periodic meetings have mirrored the increasing absorption of the scientific community in the problems of sphingolipid metabolism. The first meeting in consisted of but twelve pre- sentations, the majority emanating from local laboratories.
The current sessions contain 48 scientific presentations by scientists from nine countries and demonstrate the increas- ingly diversified techniques and approaches employed in the study of these diseases.
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Many of the authors, in exploring data on the mucopolysaccharidoses and leucodystrophies, as well as the sphingolipidoses, have given recognition to those biochemical areas held in common by these otherwise diverse disease processes. The problems of prevention and therapy of these diseases have been considered by some of the contributors. Laboratory screening procedures designed to detect carriers of the va- rious lipidoses are now available and the experiences of some laboratories in this area are summarized within this volume. The prospective identification of heterozygotes may indeed become a powerful adjunct in genetic counseling.
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