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

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.

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'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.

MetaboRank: network-based recommendation system to interpret and enrich metabolomics results.

Motivation: Metabolomics has shown great potential to improve the understanding of complex diseases, potentially leading to therapeutic target identification. However, no single analytical method allows monitoring all metabolites in a sample, resulting in incomplete metabolic fingerprints. This incompleteness constitutes a stumbling block to interpretation, raising the need for methods that can enrich those fingerprints. We propose MetaboRank, a new solution inspired by social network recommendation systems for the identification of metabolites potentially related to a metabolic fingerprint. Results: MetaboRank method had been used to enrich metabolomics data obtained on cerebrospinal fluid samples from patients suffering from hepatic encephalopathy (HE). MetaboRank successfully recommended metabolites not present in the original fingerprint. The quality of recommendations was evaluated by using literature automatic search, in order to check that recommended metabolites could be related to the disease. Complementary mass spectrometry experiments and raw data analysis were performed to confirm these suggestions. In particular, MetaboRank recommended the overlooked α-ketoglutaramate as a metabolite which should be added to the metabolic fingerprint of HE, thus suggesting that metabolic fingerprints enhancement can provide new insight on complex diseases. Availability and implementation: Method is implemented in the MetExplore server and is available at www.metexplore.fr. A tutorial is available at https://metexplore.toulouse.inra.fr/com/tutorials/MetaboRank/2017-MetaboRank.pdf. Supplementary information: Supplementary data are available at Bioinformatics online.

Targeted versus untargeted omics - the CAFSA story.

BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.

High-dose biotin therapy leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin interference.

BACKGROUND: High-dose biotin therapy is beneficial in progressive multiple sclerosis (MS) and is expected to be adopted by a large number of patients. Biotin therapy leads to analytical interference in many immunoassays that utilize streptavidin-biotin capture techniques, yielding skewed results that can mimic various endocrine disorders. We aimed at exploring this interference, to be able to remove biotin and avoid misleading results. METHODS: We measured free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), parathyroid homrone (PTH), 25-hydroxyvitamin D (25OHD), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, C-peptide, cortisol (Roche Diagnostics assays), biotin and its main metabolites (liquid chromatography tandem mass spectrometry) in 23 plasmas from MS patients and healthy volunteers receiving high-dose biotin, and in 39 biotin-unsupplemented patients, before and after a simple procedure (designated N5) designed to remove biotin by means of streptavidin-coated microparticles. We also assayed fT4, TSH and PTH in the 23 high-biotin plasmas using assays not employing streptavidin-biotin binding. RESULTS: The biotin concentration ranged from 31.7 to 1160 µg/L in the 23 high-biotin plasmas samples. After the N5 protocol, the biotin concentration was below the detection limit in all but two samples (8.3 and 27.6 µg/L). Most hormones results were abnormal, but normalized after N5. All results with the alternative methods were normal except two slight PTH elevations. In the 39 biotin-unsupplemented patients, the N5 protocol did not affect the results for any of the hormones, apart from an 8.4% decrease in PTH. CONCLUSIONS: We confirm that most streptavidin-biotin hormone immunoassays are affected by high biotin concentrations, leading to a risk of misdiagnosis. Our simple neutralization method efficiently suppresses biotin interference.

Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a neurological complication observed in patients with liver disease and/or porto-systemic shunt. The proportion of cirrhotic patients developing overt HE is about 20%, and 60-80% of cirrhotic patients exhibit mild cognitive impairment potentially related to minimal HE. However, the pathophysiological mechanisms of HE remain poorly understood. In this context, metabolomics was used to highlight dysfunction of metabolic pathways in cerebrospinal fluid (CSF) samples of patients suffering from HE. METHODS: CSF samples were collected in 27 control patients without any proven neurological disease and 14 patients with symptoms of HE. Plasma samples were obtained from control patients, and from cirrhotic patients with and without HE. Metabolomic analysis was performed using liquid chromatography coupled to high-resolution mass spectrometry. RESULTS: Concentrations of 73 CSF metabolites, including amino acids, acylcarnitines, bile acids and nucleosides, were altered in HE patients. Accumulation of acetylated compounds, which could be due to a defect of the Krebs cycle in HE patients, is reported for the first time. Furthermore, analysis of plasma samples showed that concentrations of metabolites involved in ammonia, amino-acid and energy metabolism are specifically and significantly increased in CSF samples of HE patients. Lastly, several drugs were detected in CSF samples and could partially explain worsening of neurological symptoms for some patients. CONCLUSION: By enabling the simultaneous monitoring of a large set of metabolites in HE patients, CSF metabolomics highlighted alterations of metabolic pathways linked to energy metabolism that were not observed in plasma samples. LAY SUMMARY: CSF metabolomics provides a global picture of altered metabolic pathways in CSF samples of HE patients and highlights alterations of metabolic pathways linked to energy metabolism that are not observed in plasma samples.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

BACKGROUND: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. OBJECTIVE: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. METHODS: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. RESULTS: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. CONCLUSION: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.

Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study.

Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3ß,5α,6ß-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18-90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3ß,5α,6ß-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.

A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.

OBJECTIVE: Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations. DESIGN: Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG(+/-) group) or two POLG alleles (POLG(+/+) group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG(+/+) and patients without POLG mutation. RESULTS: High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy. CONCLUSIONS: Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.

A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression.

A growing number of long nuclear-retained non-coding RNAs (ncRNAs) have recently been described. However, few functions have been elucidated for these ncRNAs. Here, we have characterized the function of one such ncRNA, identified as metastasis-associated lung adenocarcinoma transcript 1 (Malat1). Malat1 RNA is expressed in numerous tissues and is highly abundant in neurons. It is enriched in nuclear speckles only when RNA polymerase II-dependent transcription is active. Knock-down studies revealed that Malat1 modulates the recruitment of SR family pre-mRNA-splicing factors to the transcription site of a transgene array. DNA microarray analysis in Malat1-depleted neuroblastoma cells indicates that Malat1 controls the expression of genes involved not only in nuclear processes, but also in synapse function. In cultured hippocampal neurons, knock-down of Malat1 decreases synaptic density, whereas its over-expression results in a cell-autonomous increase in synaptic density. Our results suggest that Malat1 regulates synapse formation by modulating the expression of genes involved in synapse formation and/or maintenance.

Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations.

OBJECTIVE: The Suspicion Index (SI) screening tool was developed to identify patients suspected of having Niemann-Pick disease type C (NP-C). The SI provides a risk prediction score (RPS) based on NP-C manifestations within and across domains (visceral, neurological, and psychiatric). The aim of these subanalyses was to further examine the discriminatory power of the SI by age and manifestation-associations by NP-C suspicion-level and leading manifestations. METHODS: The original retrospectively collected data were split into three patient age groups, where NP-C-positive cases were >16 years (n = 30), 4-16 years (n = 18), and <4 years (n = 23), and patients' RPS were analyzed by logistic regression. Co-occurrence of manifestations within groups of suspicion level (low, medium, high) and leading manifestations (presence/absence of ataxia, cognitive decline, psychosis, and splenomegaly) were analyzed descriptively. RESULTS: NP-C-positive cases versus controls showed strong discriminatory power of RPS. Area under the receiver operating characteristic curve was 0.964 (>16 years) and 0.981 (4-16 years) but weaker 0.562 for infants (<4 years). Patients with RPS <70 were characterized by a lack of psychiatric manifestations and low levels of neurological involvement, suggestive of a preneurological phase of the disease. In patients >4 years, prominent leading manifestation-associations were ataxia with dystonia, dysarthria/dysphagia, and cognitive decline. Psychosis was associated with dysarthria/dysphagia but also with cognitive decline and treatment-resistant psychiatric symptoms. CONCLUSIONS: The SI tool maintains strong discriminatory power in patients >4 years but is not as useful for infants <4 years. The SI is also informative regarding the association and co-occurrence of manifestations in patients with NP-C.

Psychiatric manifestations of treatable hereditary metabolic disorders in adults.

Detecting psychiatric disorders of secondary origin is a crucial concern for the psychiatrist. But how can this reliably be done among a large number of conditions, most of which have a very low prevalence? Metabolic screening undertaken in a population of subjects with psychosis demonstrated the presence of treatable metabolic disorders in a significant number of cases. The nature of the symptoms that should alert the clinician is also a fundamental issue and is not limited to psychosis. Hereditary metabolic disorders (HMD) are a rare but important cause of psychiatric disorders in adolescents and adults, the signs of which may remain isolated for years before other more specific organic signs appear. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists. However, it is important to identify HMDs in order to refer patients to specialist centres for appropriate management, disease-specific treatment and possible prevention of irreversible physical and neurological complications. Genetic counselling can also be provided. This review focuses on three HMD categories: acute, treatable HMDs (urea cycle abnormalities, remethylation disorders, acute intermittent porphyria); chronic, treatable HMDs (Wilson's disease, Niemann-Pick disease type C, homocystinuria due to cystathionine beta-synthase deficiency, cerebrotendinous xanthomatosis); and chronic HMDs that are difficult to treat (lysosomal storage diseases, X-linked adrenoleukodystrophy, creatine deficiency syndrome). We also propose an algorithm for the diagnosis of HMDs in patients with psychiatric symptoms.

Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.

OBJECTIVE: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder, progressive spastic gait, and peripheral neuropathy. Polyglucosan bodies accumulate in the central and peripheral nervous systems and are often associated with glycogen branching enzyme (GBE) deficiency. To improve clinical diagnosis and enable future evaluation of therapeutic strategies, we conducted a multinational study of the natural history and imaging features of APBD. METHODS: We gathered clinical, biochemical, and molecular findings in 50 APBD patients with GBE deficiency from Israel, the United States, France, and the Netherlands. Brain and spine magnetic resonance images were reviewed in 44 patients. RESULTS: The most common clinical findings were neurogenic bladder (100%), spastic paraplegia with vibration loss (90%), and axonal neuropathy (90%). The median age was 51 years for the onset of neurogenic bladder symptoms, 63 years for wheelchair dependence, and 70 years for death. As the disease progressed, mild cognitive decline may have affected up to half of the patients. Neuroimaging showed hyperintense white matter abnormalities on T2 and fluid attenuated inversion recovery sequences predominantly in the periventricular regions, the posterior limb of the internal capsule, the external capsule, and the pyramidal tracts and medial lemniscus of the pons and medulla. Atrophy of the medulla and spine was universal. p.Y329S was the most common GBE1 mutation, present as a single heterozygous (28%) or homozygous (48%) mutation. INTERPRETATION: APBD with GBE deficiency, with occasional exceptions, is a clinically homogenous disorder that should be suspected in patients with adult onset leukodystrophy or spastic paraplegia with early onset of urinary symptoms and spinal atrophy.

Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review.

Krabbe disease usually presents as a severe leukodystrophy in early infancy and childhood. From a series of 11 patients and 30 cases previously reported in the literature we describe the clinical, radiological, electrophysiological and genetic features of adult Krabbe disease. Patients diagnosed after the age of 16 years were included in this study. They were further divided into three groups depending on age at symptoms onset: (1) childhood onset cases (n = 7); (2) adolescence onset cases (n = 6) and adult onset cases (n = 28). Overall, 96 % of patients in the adult-onset group presented with signs of pyramidal tracts dysfunction. Spastic paraparesis or tetraparesis became prominent in all cases. A peripheral neuropathy was present in 59 % of cases and was most often demyelinating (80 %). Other clinical signs encompassed dysarthria (31 %), cerebellar ataxia (27 %), pes cavus (27 %), deep sensory signs (23 %), tongue atrophy (15 %), optic neuropathy (12 %), cognitive decline (12 %). Cerebrospinal fluid protein concentration was moderately increased in 54 % of patients. Patients in the adolescent- and childhood-onset groups had similar presentations but were more likely to display optic neuropathy (33 % and 57 %) and cerebellar ataxia (50 % and 57 %). In the adult-onset group, the disease progressed slowly over more than 10 years, but a rapid course was observed in two patients. Abnormalities of brain MRI was similar in the three groups and included high signals of cortico-spinal tracts (94 % of cases), hyper-intensities of optic radiations (89 %) and hyper-intensities or atrophy of the posterior part of the corpus callosum (60 %). No clear genotype-phenotype relationship could be demonstrated.

A Retrospective Self-Controlled Study Evaluating the Prophylactic Effects of CACIPLIQ20 on Postsurgical Scars.

Background: CACIPLIQ20 (OTR3, Paris, France) is a medical device used for the treatment of chronic skin ulcers. It contains a heparan sulfate mimetic that accelerates tissue healing by stabilizing matrix proteins and protecting heparin-binding growth factors. In humans, an open self-controlled study suggested that the topical application of CACIPLIQ20 optimizes skin healing following surgery. Objectives: To expand previous findings using a different CACIPLIQ20 administration regimen. Methods: Twenty-four females were referred for breast-reduction surgery. Each patient had their own control with 1 CACIPLIQ20-treated and 1 saline-treated control breast. The treated side (right or left) was randomly assigned by the operating surgeon. Scar appearance was assessed by 6 independent raters using a global visual scar comparison scale based on scar photographs. All raters were blinded toward the CACIPLIQ20-treated side. Results: The follow-up period following surgery ranged from 1 to 12 months with a median follow-up of 6 months. Overall, there was a mean improvement of 15.2% (SD = 26.7) in favor of CACIPLIQ20 (P = .016). On the CACIPLIQ20-treated side, the mean score per patient was above 20% in 11 patients and above 30% improvement in 8 cases. In contrast, only 3 patients were considered improved by at least 20% on the control side and only 1 above 30%. A comparison of different application regimens suggested that the best trend was obtained with a single administration of CACIPLIQ20 at Day 0. Conclusions: In conclusion, CACIPLIQ20 could represent an interesting scar prophylactic therapy, based on a single administration at the time of surgery, and without any known adverse effects.

Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.

Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues. Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy. Epileptic seizures are also common in affected patients. Typically, neurological disease onset occurs during childhood, although an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations. Categorization of patients according to age at onset of neurological manifestations (i.e. early-infantile, late-infantile, juvenile and adolescent/adult-onset) can be useful for the evaluation of disease course and treatment responses. The first international guidelines for the clinical management of NP-C in children and adults were published in 2009. Since that time a significant amount of data regarding the epidemiology, detection/diagnosis, and treatment of NP-C has been published. Here, we report points of consensus among experts in the diagnosis and treatment of NP-C based on a follow-up meeting in Paris, France in September 2011. This article serves as an update to the original guidelines providing, among other things, further information on detection/diagnostic methods, potential new methods of monitoring disease progression, and therapy. Treatment goals and the application of disease-specific therapy with miglustat are also re-evaluated.

Myoclonus and dystonia in cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an inherited neurometabolic disorder. The main neurological manifestations of the disease are pyramidal syndrome, ataxia, peripheral neuropathy, cognitive impairment, epilepsy, and psychiatric disturbances. Myoclonic dystonia has been reported on in the setting of various neurometabolic diseases. Anecdotal reports describe movement disorders associated with CTX, but no dystonia with myoclonic events. METHODS: We collected clinical, biochemical, electrophysiological, neuroradiological, and genetic data of 6 patients with myoclonus and mild dystonia associated with CTX. From a systematic literature review, we analyzed 31 patients with movement disorders secondary to CTX. RESULTS: Our 6 patients presented distal myoclonus with mild dystonia of the upper limbs. Myoclonus was of subcortical origin, based on neurophysiological recordings, and differed from oromandibular myoclonus previously described in CTX patients. CONCLUSIONS: These results expand the phenotype of CTX and suggest that myoclonus and/or dystonia are underdiagnosed. In keeping with our findings, tremors previously observed in CTX patients might actually correspond to myoclonic events. We hypothesize that a dysfunction of the dentate nuclei-basal ganglia pathway may be involved.

Treatable metabolic psychoses that go undetected: what Niemann-Pick type C can teach us.

OBJECTIVE: The objective of this review is to raise awareness of the prevalence of inborn errors of metabolism, in particular NP-C, in psychiatric populations. METHODS: This review summarises research presented at a satellite symposium held on 28 August 2010 at the 23rd European College of Neuropsychopharmacology (ECNP) meeting. RESULTS AND CONCLUSION: Organic causes of psychoses may have an unrecognised yet notable prevalence, particularly in adolescent or adult patients. Several inherited metabolic disorders can present with psychiatric signs. In some disorders, such as Niemann-Pick type C (NP-C), the disease may remain unrecognised for many years due to a heterogeneous and subtle clinical presentation. In patients presenting with psychoses, subtle signs such as vertical supranuclear gaze palsy, ataxia and splenomegaly should raise the suspicion of NP-C. Miglustat is so far the only approved treatment for NP-C. Miglustat can stabilise neurological disease, particularly in adolescent or adult-onset patients who are detected as early as possible, before irreversible neurological damage occurs.