Motion analysis of a child with Niemann-Pick disease type C treated with miglustat
ABSTRACT Niemann-Pick disease type C (NPC) is a progressive neurodegenerative disorder for which there is no effective treatment other than supportive therapy. Recently, the oral medication miglustat has been offered as a possible therapy aimed at reducing pathological substrate accumulation. This article describes the use of computerized three-dimensional motion analysis to evaluate a 3-year-old child with NPC treated with miglustat for 12 months. Motion analysis provided quantitative data on the patient's gait. However, dementia and motor dysfunction progressed despite the treatment, and the patient lost the ability to walk between 9 and 12 months of the study. Motion analysis should be considered among the tools for measuring functional outcomes in future therapeutical trials of patients with neurodegenerative diseases. It is not possible to draw conclusions about miglustat therapy in NPC from a single patient experience.
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ABSTRACT: Niemann-Pick disease type C (NP-C) is an inherited neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Different clinical forms have been defined based on patient age at onset: perinatal, early-infantile (EI), late-infantile (Li), juvenile and adult. We evaluated the efficacy and tolerability of miglustat in 16 symptomatic NP-C patients, with comparative reference to one neurologically asymptomatic, untreated patient. All patients were categorized according to age at neurological disease onset, and were assessed using a standardized clinical assessment protocol: disability and cognitive function scales, positron emission tomography (PET), and biochemical markers. PET and disability scale evaluations indicated that cerebral hypometabolism and neurological symptoms were stabilized during treatment in juvenile-onset NP-C patients. EI and Li NP-C patients, who had higher disease severity at baseline (treatment start), showed increased disability scores and progressive cerebral hypometabolism during follow up. Similarly, while cognitive scale scores remained relatively stable in patients with juvenile NP-C, cognition deteriorated in EI and Li patients. Plasma chitotriosidase (ChT) activity was lower in the juvenile NP-C subgroup than in EI and Li patients, and generally increased in patients who discontinued treatment. Plasma CCL18/PARC and ChT activities indicated greater macrophagic activity in EI and Li patients versus juveniles. Miglustat was generally well tolerated; frequent adverse events included diarrhea and flatulence, which were managed effectively by dietary modification and loperamide. Overall, miglustat appeared to stabilize neurological status in juvenile-onset NP-C patients, but therapeutic benefits appeared smaller among younger patients who were at a more advanced stage of disease at baseline.Molecular Genetics and Metabolism 04/2010; 99(4):358-66. DOI:10.1016/j.ymgme.2009.11.007 · 2.83 Impact Factor
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ABSTRACT: 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.Journal of Inherited Metabolic Disease 11/2008; 31 Suppl 2(S2):S357-61. DOI:10.1007/s10545-008-0923-9 · 4.14 Impact Factor
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ABSTRACT: Niemann-Pick C (NPC) is a fatal progressive neurolipidosis. Miglustat, an inhibitor of glycosphingolipid synthesis, has been proposed to treat patients but questions remain regarding its efficacy. A major problem has been the lack of suitable objective efficacy endpoints. Three adults with NPC were treated with miglustat for 24 months. Efficacy of treatment was assessed clinically and using brain magnetic resonance spectroscopy. All patients reported mild clinical improvement or stabilization. Furthermore, a sustained decrease in the choline/creatine ratio was observed in all three patients over time. Although these preliminary results require confirmation on a larger cohort of patients, they suggest that miglustat has some beneficial effect on brain dysfunction in NPC and that MRS could be used routinely as a non invasive surrogate marker of treatment efficacy.Molecular Genetics and Metabolism 02/2009; 96(2-96):55-58. DOI:10.1016/j.ymgme.2008.10.002 · 2.83 Impact Factor