Evolution of structural neuroimaging biomarkers in a series of adult patients with Niemann-Pick type C under treatment

International audienceBackground: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by a wide clinical spectrum and non-specific conventional magnetic resonance imaging (MRI) signs. As substrate reduction therapy with miglustat is now used in almost all patients, its efficacy and the course of the disease are sometimes difficult to evaluate. Neuroimaging biomarkers could prove useful in this matter. We first performed a retrospective analysis of volumetric and diffusion tensor imaging (DTI) data on 13 adult NPC patients compared to 13 controls of similar age and sex. Eleven NPC patients were then studied using the same neuroimaging modalities over a mean of 5 years. The NPC composite score was used to evaluate disease severity.ResultsNPC patients showed atrophy in basal ganglia – pallidum (p = 0.029), caudate nucleus (p = 0.022), putamen (p = 0.002) and thalamus (p < 0.001) – cerebral peduncles (p = 0.003) and corpus callosum (p = 0.006), compared to controls. NPC patients also displayed decreased fractional anisotropy (FA) in several regions of interest – corona radiata (p = 0.015), internal capsule (p = 0.007), corpus callosum (p = 0.032) and cingulate gyrus (p = 0.002) – as well as a broad increase in radial diffusivity (p < 0.001), compared to controls. Over time, 3 patients worsened clinically, including 2 patients who interrupted treatment, while 8 patients remained stable. With miglustat, no significant volumetric change was observed but FA improved after 2 years in the corpus callosum and the corona radiata of NPC patients (n = 4; p = 0.029) – although that was no longer observed at further time points.ConclusionThis is the first study conducted on a series of adult NPC patients using two neuroimaging modalities and followed under treatment. It confirmed that NPC patients displayed cerebral atrophy in several regions of interest compared to controls. Furthermore, miglustat showed an early effect on diffusion metrics in treated patients. DTI can detect brain microstructure alterations caused by neurometabolic dysfunction. Its potential as a biomarker in NPC shall be further evaluated in upcoming therapeutic trials

Niemann-Pick disease type C symptomatology: an expert-based clinical description

Niemann-Pick disease type C (NP-C) is a rare, progressive, irreversible disease leading to disabling neurological manifestations and premature death. The estimated disease incidence is 1:120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. NP-C is characterised by visceral, neurological and psychiatric manifestations that are not specific to the disease and that can be found in other conditions. The aim of this review is to provide non-specialists with an expert-based, detailed description of NP-C signs and symptoms, including how they present in patients and how they can be assessed. Early disease detection should rely on seeking a combination of signs and symptoms, rather than isolated findings. Examples of combinations which are strongly suggestive of NP-C include: splenomegaly and vertical supranuclear gaze palsy (VSGP); splenomegaly and clumsiness; splenomegaly and schizophrenia-like psychosis; psychotic symptoms and cognitive decline; and ataxia with dystonia, dysarthria/dysphagia and cognitive decline. VSGP is a hallmark of NP-C and becomes highly specific of the disease when it occurs in combination with other manifestations (e.g. splenomegaly, ataxia). In young infants (<2 years), abnormal saccades may first manifest as slowing and shortening of upward saccades, long before gaze palsy onset. While visceral manifestations tend to predominate during the perinatal and infantile period (2 months–6 years of age), neurological and psychiatric involvement is more prominent during the juvenile/adult period (>6 years of age). Psychosis in NP-C is atypical and variably responsive to treatment. Progressive cognitive decline, which always occurs in patients with NP-C, manifests as memory and executive impairment in juvenile/adult patients. Disease prognosis mainly correlates with the age at onset of the neurological signs, with early-onset forms progressing faster. Therefore, a detailed and descriptive picture of NP-C signs and symptoms may help improve disease detection and early diagnosis, so that therapy with miglustat (Zavesca®), the only available treatment approved to date, can be started as soon as neurological symptoms appear, in order to slow disease progression.The authors thank Dominique Spirig and Andrew Smith of PHOCUS Services\ud Ltd, a member of the Fishawack Group of Companies, who provided\ud medical writing support funded by Actelion Pharmaceuticals Ltd.\ud The manuscript preparation was funded by a support grant from Actelion\ud Pharmaceuticals Ltd, Allschwil, Switzerland. All authors agreed to submit the\ud manuscript for publication and can confirm the content of the manuscript\ud has not been influenced by the funding body

Orientation diagnostique devant une leucoencéphalopathie de l adulte (validation d une grille de lecture en IRM)

Le terme de leucoencéphalopathie regroupe des affections ayant en commun une atteinte sélective ou prédominante de la substance blanche encéphalique. La plupart de ces maladies peuvent être classées en trois catégories principales : inflammatoire, vasculaire, ou métabolique. Différencier les leucoencéphalopathies selon leur mécanisme est une tache difficile en pratique clinique, d autant qu il n existe pas à ce jour de critères radiologiques validés.L' objectif est de définir des critères IRM afin de différencier les trois principaux types de leucoencéphalopathies. Le Materiel et les méthodes sont : les IRM de 75 patients ayant une leucoencéphalopathie au diagnostic établi avec certitude, ont été examinées de façon rétrospective, en aveugle par 3 lecteurs indépendants, à l aide d une grille de lecture comprenant 14 items. Le pouvoir discriminant et la concordance inter observateurs de ces 14 critères ont été évalués.Résultats: les analyses statistiques ont démontré que la présence de lésions ovoïdes, une atteinte en chapeau autour des cornes ventriculaires temporales orientent vers un mécanisme inflammatoire. Une distribution symétrique et fasciculaire des hypersignaux ainsi qu une intensité de signal modérée à faible sont des critères discriminants en faveur d une atteinte métabolique. La présence d hypersignaux centropontiques, de lacunes ou d un état criblé est un élément décisif pour le diagnostic de leucoencéphalopathie vasculaire. Donc : nous avons défini pour la première fois des critères IRM spécifiques et concordants pour différencier les leucoencéphalopathies de l adulte selon leur mécanisme. Ces critères devront être évalués de façon prospective.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

La forme de l adulte de la maladie de Niemann-Pick de type C

La maladie de Niemann-Pick de type C (NPC) est une forme fatale de neurolipidose, de transmission autosomique récessive, liée à un trouble du transport intracellulaire du cholestérol et des glycolipides. Deux gènes, NPC1 et NPC2 sont impliqués dans la survenue de la maladie. Le spectre clinique de la maladie s étend des formes néonatales, rapidement létales, aux formes chroniques de l adulte. Par l étude de 13 cas personnels et de 55 cas publiés, nous avons étudié les caractéristiques cliniques, radiologiques, biochimiques et génotypiques de la forme de l adulte. L âge moyen de début (+-DS) était de 25+-9,7 ans. L âge moyen au décès était de 38+-10,2 ans. Les principaux signes cliniques étaient l ataxie cérébelleuse (76%), l ophtalmoplégie supranucléaire de la verticalité (75%), la dysarthrie (63%), les troubles cognitifs (61%), les mouvements anormaux (58%), la splénomégalie (54%) et les troubles psychiatriques (45%). Pendant l évolution de la maladie, les signes pouvaient être classés en signes viscéraux (hépatomégalie, splénomégalie), corticaux (troubles cognitifs, psychiatriques, épilepsie) ou cérébraux profonds (ataxie, ophtalmoplégie supranucléaire, mouvements anormaux), qui suivaient des profils évolutifs distincts. Des signes viscéraux et corticaux discrets étaient parfois observés dans l enfance. Les signes cérébraux profonds étaient souvent à l origine du décès. Le phénotype biochimique variant était surreprésenté dans la forme de l adulte. Le gène muté était NPC1 dans 33 des 34 familles étudiées.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study

Abstract Background We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. Methods Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. Results The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. Conclusions Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. Trial registration ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05

A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.

This case expands the phenotypic spectrum of 3-phosphoglycerate dehydrogenase deficiency. Plasma amino acid chromatography should be added to the list of investigations performed in patients with Charcot-Marie-Tooth–like polyneuropathy, especially if it is associated with psychomotor delay and congenital cataracts

High Dose Pharmaceutical Grade Biotin (MD1003) Accelerates Differentiation of Murine and Grafted Human Oligodendrocyte Progenitor Cells In Vivo

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother&rsquo;s milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials