Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann–Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report

Abstract

BackgroundNiemann–Pick disease type C is a rare inherited neurodegenerative disease involving impaired intracellular lipid trafficking and accumulation of glycolipids in various tissues, including the brain. Miglustat, a reversible inhibitor of glucosylceramide synthase, has been shown to be effective in the treatment of progressive neurological manifestations in pediatric and adult patients with Niemann–Pick disease type C, and has been used in that indication in Europe since 2010.Case presentationWe describe the case of a 16-year-old white French boy with late-infantile-onset Niemann–Pick disease type C who had the unusual presentation of early-onset behavioral disturbance and learning difficulties (aged 5) alongside epileptic seizures. Over time he developed characteristic, progressive vertical ophthalmoplegia, ataxic gait, and cerebellar syndrome; at age 10 he was diagnosed as having Niemann–Pick disease type C based on filipin staining and genetic analysis (heterozygous I1061T/R934X NPC1 mutations). He was commenced on miglustat therapy aged 11 and over the course of approximately 3 years he showed a global improvement as well as improved cognitive and ambulatory function. During this period he remained seizure free on antiepileptic therapy, using valproate and lamotrigine.ConclusionsMiglustat improved the neurological status of our patient, including seizure control. Based on our findings in this patient and previous published data, we discuss the importance of effective seizure control in neurological improvement in Niemann–Pick disease type C, and the relevance of cerebellar involvement as a possible link between these clinical phenomena. Thus the therapeutic efficacy of miglustat could be hypothesized as a substrate reduction effect on Purkinje cells.

Neurodegeneration in Niemann–Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment

“…Although the pathophysiological basis is still poorly understood, NPC patients show hyperexcitability among their main symptoms, with consequent epileptic manifestations [ 66 , 67 ]. The cause of this phenomenon has been attributed to the dynamic loss of lipid rafts enriched in cholesterol and sphingolipids, which occurs because of an imbalance in lipid trafficking [ 68 ].…”

Activation of PKC triggers rescue of NPC1 patient specific iPSC derived glial cells from gliosis

“…Currently, there is only one, by the European Medicines Agency (EMA) approved, therapy for NPC1 disease, using Miglustat, a reversible inhibitor of glucosylceramide synthase. Miglustat was approved to treat Gaucher disease Type 1, but also improves neurological symptoms in NPC1-patients, whereby the hypothesized mode of action is substrate reduction effect [ 7 , 8 ]. Further potential therapy approaches are discussed containing the use of cyclodextrins, histone deacetylase inhibitors and chaperons [ 9 , 10 ].…”

Stylistic features of case reports as a genre of medical discourse

“…Hence, MCRs are notable for their use of active sentences in the simple past tense (309 cases) [ 3 , 5 – 18 ]: “We maintained anesthesia with inhaled desflurane at 5% and intravenously administered remifentanil at 0.2 μg/kg/min in a fraction of inspired oxygen of 0.45 (…) At that moment, we administered 20 mg ephedrine, 300 μg phenylephrine, and 0.03 μg/kg/min norepinephrine to maintain adequate blood pressure (…) We did not detect any problems with his respiratory parameters (…) His systolic blood pressure remained at 40 mmHg for 10 min; we performed chest compressions to maintain his blood pressure” [ 5 ]; “We did not find cases with such an evolution in the literature, but we found some cases of spontaneous expulsion of ileal lipoma per rectum” [ 6 ]; “We found electrogram amplitude to be normal throughout the right ventricle (…) In this case we used cryoablation to avoid the pain associated with radiofrequency delivery” [ 7 ]; “An extraoral examination revealed a diffuse swelling of her left nasal alar base without tenderness” [ 8 ]; “Two patients with EHPVO presented with micrognathia, restricted mouth openings, and facial asymmetry” [ 9 ]; “Brain magnetic resonance imaging (MRI) did not identify any abnormalities, but an ophthalmic examination revealed vertical supranuclear gaze palsy (VSGP), and analysis of peripheral blood and bone marrow biopsies identified vacuolated histiocytes” [ 10 ]; “…we considered electroconvulsive therapy; clinicians may opt for electroconvulsive therapy at an earlier stage in similar psychiatric emergencies (…) We hypothesized that our patient’s poor clinical response was from a genetic polymorphism in the drug-metabolizing activity of cytochrome P450 enzymes” [ 11 ].…”