Current advancements in therapy for Niemann-Pick disease: progress and pitfalls.

INTRODUCTION: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder. To combat the progressive neurodegeneration in NPC, disease-modifying treatment needs to be introduced early in the course of the disease. The only approved, disease-modifying treatment is a substrate-reduction treatment, miglustat. Given miglustat's limited efficacy, new compounds are under development, including gene therapy; however, many are still far from clinical use. Moreover, the phenotypic heterogeneity and variable course of the disease can impede the development and approval of new agents. AREAS COVERED: Here, we offer an expert review of these therapeutic candidates, with a broad scope not only on the main pharmacotherapies, but also on experimental approaches, gene therapies, and symptomatic strategies. The National Institute of Health (NIH) database PubMed has been searched for the combination of the words 'Niemann-Pick type C'+ 'treatment' or 'therapy' or 'trial.' The website clinicaltrials.gov has also been consulted. EXPERT OPINION: We conclude a combination of treatment strategies should be sought, with a holistic approach, to improve the quality of life of affected individuals and their families.

Cost-effectiveness of miglustat versus symptomatic therapy of Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a progressive neurodegenerative disorder with early infantile (< 2 years), late infantile (2-6 years), juvenile (7-15 years) and adolescent (> 15 years) onset. The mainstay of therapy for NP-C patients with neurological symptoms is miglustat, a drug that may modify the course of the disease. AIM: Our aim was to evaluate the cost-effectiveness of miglustat in comparison to symptomatic therapy in patients with NP-C in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy. METHOD: The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was eighty years. The main outcomes of the study were quality-adjusted life years gained with miglustat and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Discrete-Event Simulation model. The model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients. RESULTS: Treatment with miglustat was not cost-effective when compared with symptomatic therapy and was associated with negative values of net monetary benefit regardless of the onset of neurological manifestations (- 110,447,627.00 ± 701,614.00 RSD, - 343,871,695.00 ± 2,577,441.00 RSD, - 1,397,908,502.00 ± 23,084,235.00 RSD and - 2,953,680,879.00 ± 33,297,412.00 RSD) for early infantile, late infantile, juvenile and adolescent cohorts, respectively). CONCLUSION: When traditional pharmacoeconomic evaluation is employed, miglustat is not a cost-effective option in comparison to symptomatic therapy for the treatment of NP-C. However, given the proven efficacy of miglustat, there is a need to find ways to make this drug available to all patients with NP-C.

Niemann-Pick type C: contemporary diagnosis and treatment of a classical disorder.

Niemann-Pick type C is an uncommon neurodegenerative lysosomal storage disorder that can cause a progressive neuropsychiatric syndrome associated with supranuclear vertical gaze palsy and a movement disorder. There have been recent developments in testing that make diagnosis easier and new therapies that aim to stabilise the disease process. A new biochemical test to measure serum cholesterol metabolites supersedes the skin biopsy and is practical and robust. It is treatable with miglustat, a drug that inhibits glycosphingolipid synthesis. We describe a patient, aged 22 years, with juvenile-onset Niemann-Pick type C who presented with seizures and a label of 'cerebral palsy'. We describe the approach to this syndrome in general, and highlight the classical features and red flags that should alert a neurologist to this treatable condition.

Long-term therapy with miglustat and cognitive decline in the adult form of Niemann-Pick disease type C: a case report.

Niemann-Pick disease type C (NPC) is a recessive lysosomal lipid storage disorder characterized by central nervous system involvement. Miglustat treatment might improve or stabilize neurological manifestations but there is still limited data on the long-term efficacy. The aim of our study was to report a four-year clinical, neuropsychological and electrophysiological follow-up of two sisters under treatment with miglustat. We report data at basal (T0) and after 4 years (T4) of treatment with miglustat from two sisters (P1 and P2) affected by NPC disease. During the follow-up period, P1 was not adherent to treatment. Both patients underwent neurological evaluation, neuropsychological assessment, nerve conduction study and motor (MEP), visual (VEP), somatosensory, and brainstem auditory evoked potentials. In the patient P2, neurological and electrophysiological evaluations at T4 were stable. Instead, the patient P1, with poor adherence to therapy, developed spasticity, psychiatric disturbances, and alterations of MEP and VEP. Neuropsychological examination showed in both patients a worsening of cognitive impairment. Our findings suggest that long-term therapy with miglustat does not arrest cognitive decline; otherwise, it stabilizes other neurological manifestations.

Patient with Niemann-Pick disease type C: over 20 years' follow-up.

We report a 37-year-old woman with Niemann-Pick disease type C (NPC) 1. At the age of 8 years, she presented slow running followed by both fingers dystonia at the age of 10 years. At the age of 16 years, she developed declined scholastic achievement. On her first visit at the age of 17 years, she showed dystonia, ataxic gait and vertical supranuclear gaze palsy. We suspected it was NPC. She presented atrophies in the frontal lobes, brainstem and cerebellum in a brain MRI. She presented hepatomegalies and splenomegalies in an abdominal CT. At the age of 26 years, she undertook perpetually tracheal fistula because of recurrent aspiration pneumonia. Diagnosis of NPC1 was made by filipin staining and existence of foamy cells in the bone marrow and NPC1 gene analysis. We obtained informed consent of genetic analysis. Miglustat therapy was started at the age of 32 years. Improvements in swallowing capacity and in muscle tonus were seen.

Complete recovery from psychosis upon miglustat treatment in a juvenile Niemann-Pick C patient.

Niemann-Pick disease type C is a rare lipid trafficking disorder characterized by the accumulation of cholesterol and glycosphingolipids in the brain and viscera. Perinatal, early infantile, late infantile, juvenile and adult forms are distinguished based on the age of manifestation. In the juvenile form, patients in their early years are usually, but not always, symptom free, but present with neurodegeneration later in their lives. These include clumsiness, ataxia, seizures, motor and intellectual decline. Psychiatric manifestations may occur at any stage of the disease. These manifestations include schizophrenia, presenile dementia, depression or psychosis. In 2009, miglustat was approved for the therapy of the disease. We present a case of a patient with juvenile Niemann-Pick C disease whose psychosis was reversed completely by miglustat treatment. Based on our clinical experience we suggest considering Niemann-Pick C in cases of therapy-resistant psychosis and encourage the introduction of miglustat in Niemann-Pick C patients even in the most advanced cases, with respect to psychiatric illness.

Efficacy of miglustat in Niemann-Pick C disease: a single centre experience.

Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by progressive neurological degeneration. Miglustat is the first approved specific therapy and its efficacy in stabilizing or slowing disease progression has been demonstrated in previous studies. We evaluated data from 10 NPC patients treated with Miglustat in a single study centre. All disease manifestations were assessed and patients were stratified according to age at onset of neurological symptoms. Neurological data were recorded by using a modified version of the NP-C disability scale; a "composite score" and a "mean annual change" were calculated to evaluate disease progression. We observed a mean annual change of the composite score of 0.04 in our cohort, indicating slower progression of neurological symptoms if compared with the natural history of the disease. The evidence of slower disease evolution in patients treated with Miglustat suits with previous data and here it is also emphasized by the comparison between disease progression in two early-infantile onset patients receiving different Miglustat dosages. Evaluation of the mean annual change for individual subgroups of patients evidenced minor values in juvenile patients, highlighting better response in such class of patients. Among individual neurological parameters, swallowing showed the minor mean annual change (0.02), indicating better response to therapy. We underline the importance of using a standardized disability scale to quantify and compare neurological features and their evolution over time.

Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling.

Niemann-Pick type C (NPC)1 is a rare neurodegenerative disease for which treatment options are limited. A major barrier to development of effective treatments has been the lack of validated biomarkers to monitor disease progression or serve as outcome measures in clinical trials. Using targeted metabolomics to exploit the complex lipid storage phenotype that is the hallmark of NPC1 disease, we broadly surveyed Npc1(-/-) mouse tissues and identified elevated species across multiple sphingolipid classes that increased with disease progression. There was a striking accumulation of sphingoid bases, monohexosylceramides (MCs), and GM2 gangliosides in liver, and sphingoid bases and GM2 and GM3 gangliosides in brain. These lipids were modestly decreased following miglustat treatment, but markedly decreased in response to treatment with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), two drugs that have shown efficacy in NPC1 animal models. Extending these studies to human subjects led to identification of sphingolipid classes that were significantly altered in the plasma of NPC1 patients. Plasma MCs and ceramides were elevated, whereas sphingoid bases were reduced in NPC1 subjects. Intervention with miglustat in NPC1 patients was accompanied by striking alterations in plasma (reductions in GM1 and GM3 gangliosides) and cerebrospinal fluid (CSF) (increased MCs) sphingolipids. Similar alterations were observed in the CSF from the NPC1 feline model following HP-ß-CD treatment. Our findings suggest that these lipid biomarkers may prove useful as outcome measures for monitoring efficacy of therapy in clinical trials.

A case report of 'variant' biochemical phenotype of Niemann-Pick C disease and a discussion of therapeutic options.

Niemann-Pick disease type C is a rare hereditary disorder caused by mutation-disrupted metabolism of cholesterol and low-density lipoprotein (LDL). In most patients, symptoms begin in childhood with severe clinical progression. We present a patient with heterozygote mutations 3001A>G and 3019C>G with late onset of the disease and positive response to treatment with miglustat. Behaviour and educational problems in childhood were probably related to the disease diagnosed later.

Neuroimaging findings in a brain with Niemann-Pick type C disease.

Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disorder caused by impaired cellular functions in processing and transporting low-density lipoprotein-cholesterol. In this report, we present magnetic resonance imaging (MRI), magnetic resonance spectrography (MRS) and 18-fluoro-2-deoxyglucose positron emission tomography (PET) imaging results for a 22-year-old male NPC patient. The patient's two MRI studies (at age 19 years and 22 years) demonstrated progressive changes of brain atrophy that were more prominent at the frontal lobes, and hyperintense signals in bilateral parietal-occipital periventricular white matter. MRS (at age 19 years) revealed no significant decrease in N-acetyl aspartate/choline ratio in the left frontal central white matter. PET (at age 22 years) showed significant bilateral hypometabolism in the prefrontal cortex and dorsomedial thalamus, and hypermetabolism in the parietal-occipital white matter, lenticular nucleus of the basal ganglia, cerebellum and pons. The imaging findings noted by MRI, MRS and 18-fluoro-2-deoxyglucose PET offered a possible supplementary explanation for the clinical neurological symptoms of this NPC patient.

Treatment of a child diagnosed with Niemann-Pick disease type C with miglustat: a case report in Brazil.

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder that leads to variable symptoms that include cognitive decline, ataxia, dystonia, cataplexy, vertical supranuclear gaze palsy, and seizures. Currently, there is no specific treatment for NPC other than palliative care. Substrate reduction therapy represents a potential strategy for treating this debilitating neurodegenerative disorder. Miglustat (Zavesca) is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyses the first step in the biosynthesis of most glycosphingolipids. Miglustat has pharmacokinetic properties that allow it to cross the blood-brain barrier, thus making it a potential therapeutic agent for treating neurological symptoms in NPC patients. We present here a case report of a Brazilian child treated with miglustat. Before treatment, the patient presented with difficulties walking and swallowing, slurred speech, moderate cognitive impairments, ataxia, ptosis, and vertical supranuclear ophthalmoplegia. On a disability scale, the patient obtained a score of 15 before treatment and 8 after treatment. Following 12 months of treatment, the patient remained stable with improvements in speech, ptosis, ophthalmoplegia, ataxia, hypotonia and seizures. The Child Behavior Checklist (CBCL) was used to assess psychopathological, behavioural and social problems before and after treatment. The CBCL showed that indices for depression, affective and attention problems were all in the normal range following treatment. Thus, for this individual miglustat was an effective, well-tolerated and efficacious medication for treatment of NPC symptoms. Follow-up maintenance studies are vital to establish whether both the efficacy and safety of miglustat persist with time.