Susd2 et Susd4 sont deux nouveaux gènes codant pour des protéines avec domaines CCP (Complement Control Protein) jouant un rôle dans plusieurs étapes du développement des circuits neuronaux au sein de cultures d'hippocampe de rat

During brain development, several steps precisely coordinated lead to establishment of a functional neuronal network. Many molecules participate to this process, including adhesion proteins mediating interactions between neurons and their environment. Involvement of numerous genes coding for adhesion proteins in neuropsychiatric diseases such as autism argue for usefulness of identifying new ones. During my PhD, I characterized two new genes, Sud2 and Susd4, coding for proteins containing CCP domains (Complement Control Protein), classically described in proteins involved in Complement regulation system. Recently, in mammals, CCP containing proteins were shown to be involved in neuronal development. Identification of several predicted CCP containing proteins without a known function prompted me to characterize Susd2 and Susd4 which are part of them.Susd2 is expressed in neurons from hippocampal cell cultures. Its peak of expression takes place in early post natal period, suggesting a developmental function. Susd2 recombinant protein has a diffuse neuronal localization, but is particularly enriched in excitatory synapses. Decreased expression of Susd2 leads to decreased axonal growth, increased dendritic growth, and specific inhibition of excitatory synaptogenesis. Susd4 is also expressed in neurons, with a peak of expression during embryonic development, and seems to act as a regulator of dendritic growth.Le développement cérébral est une succession d'étapes aboutissant à l'établissement d'un réseau neuronal. Il fait intervenir de nombreuses molécules comme des protéines d'adhésion permettant l'interaction des neurones avec leur environnement. L'implication de nombreux gènes codant des protéines d'adhésion dans la physiopathologie de maladies neuropsychiatriques comme l'autisme souligne l'intérêt à en identifier de nouveaux. Pendant ma thèse, j'ai pu caractériser deux nouveaux gènes, Susd2 et Susd4, codant des protéines contenant des domaines CCP (Complement Control Protein), classiquement connus pour leur présence dans les protéines participant à la régulation du système du Complément. Récemment, des protéines à domaines CCP ont été décrites chez la souris comme ayant une fonction dans le développement neuronal. L'existence de nombreuses protéines prédites à domaines CCP sans fonction connue m'ont conduit à tenter de caractériser Susd2 et Susd4 qui en font partie.Susd2 est exprimé dans les neurones au sein de cultures de cellules d'hippocampe de rat. Son expression atteint un pic à un stade post natal précoce, suggérant une fonction développementale. La protéine Susd2 recombinante a une localisation neuronale diffuse, mais est particulièrement enrichie dans les synapses excitatrices. La diminution de l'expression de Susd2 a pour conséquences un défaut de croissance axonale, une augmentation de la croissance dendritique, et une inhibition spécifique de la synaptogénèse excitatrice. Susd4 est également exprimé dans les neurones, avec un pic d'expression au stade embryonnaire, et semble jouer un rôle de régulation du développement dendritique

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

Bone Marrow Transplant

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy

Emerging neuronal functions for CCP (Complement Control Protein) containing proteins : characterization of SUSD2 and SUSD4

Le développement cérébral est une succession d'étapes aboutissant à l'établissement d'un réseau neuronal. Il fait intervenir de nombreuses molécules comme des protéines d'adhésion permettant l'interaction des neurones avec leur environnement. L'implication de nombreux gènes codant des protéines d'adhésion dans la physiopathologie de maladies neuropsychiatriques comme l'autisme souligne l'intérêt à en identifier de nouveaux. Pendant ma thèse, j'ai pu caractériser deux nouveaux gènes, Susd2 et Susd4, codant des protéines contenant des domaines CCP (Complement Control Protein), classiquement connus pour leur présence dans les protéines participant à la régulation du système du Complément. Récemment, des protéines à domaines CCP ont été décrites chez la souris comme ayant une fonction dans le développement neuronal. L'existence de nombreuses protéines prédites à domaines CCP sans fonction connue m'ont conduit à tenter de caractériser Susd2 et Susd4 qui en font partie.Susd2 est exprimé dans les neurones au sein de cultures de cellules d'hippocampe de rat. Son expression atteint un pic à un stade post natal précoce, suggérant une fonction développementale. La protéine Susd2 recombinante a une localisation neuronale diffuse, mais est particulièrement enrichie dans les synapses excitatrices. La diminution de l'expression de Susd2 a pour conséquences un défaut de croissance axonale, une augmentation de la croissance dendritique, et une inhibition spécifique de la synaptogénèse excitatrice. Susd4 est également exprimé dans les neurones, avec un pic d'expression au stade embryonnaire, et semble jouer un rôle de régulation du développement dendritique.During brain development, several steps precisely coordinated lead to establishment of a functional neuronal network. Many molecules participate to this process, including adhesion proteins mediating interactions between neurons and their environment. Involvement of numerous genes coding for adhesion proteins in neuropsychiatric diseases such as autism argue for usefulness of identifying new ones. During my PhD, I characterized two new genes, Sud2 and Susd4, coding for proteins containing CCP domains (Complement Control Protein), classically described in proteins involved in Complement regulation system. Recently, in mammals, CCP containing proteins were shown to be involved in neuronal development. Identification of several predicted CCP containing proteins without a known function prompted me to characterize Susd2 and Susd4 which are part of them.Susd2 is expressed in neurons from hippocampal cell cultures. Its peak of expression takes place in early post natal period, suggesting a developmental function. Susd2 recombinant protein has a diffuse neuronal localization, but is particularly enriched in excitatory synapses. Decreased expression of Susd2 leads to decreased axonal growth, increased dendritic growth, and specific inhibition of excitatory synaptogenesis. Susd4 is also expressed in neurons, with a peak of expression during embryonic development, and seems to act as a regulator of dendritic growth

Susd2 et Susd4 sont deux nouveaux gènes codant pour des protéines avec domaines CCP (Complement Control Protein) jouant un rôle dans plusieurs étapes du développement des circuits neuronaux au sein de cultures d'hippocampe de rat

During brain development, several steps precisely coordinated lead to establishment of a functional neuronal network. Many molecules participate to this process, including adhesion proteins mediating interactions between neurons and their environment. Involvement of numerous genes coding for adhesion proteins in neuropsychiatric diseases such as autism argue for usefulness of identifying new ones. During my PhD, I characterized two new genes, Sud2 and Susd4, coding for proteins containing CCP domains (Complement Control Protein), classically described in proteins involved in Complement regulation system. Recently, in mammals, CCP containing proteins were shown to be involved in neuronal development. Identification of several predicted CCP containing proteins without a known function prompted me to characterize Susd2 and Susd4 which are part of them.Susd2 is expressed in neurons from hippocampal cell cultures. Its peak of expression takes place in early post natal period, suggesting a developmental function. Susd2 recombinant protein has a diffuse neuronal localization, but is particularly enriched in excitatory synapses. Decreased expression of Susd2 leads to decreased axonal growth, increased dendritic growth, and specific inhibition of excitatory synaptogenesis. Susd4 is also expressed in neurons, with a peak of expression during embryonic development, and seems to act as a regulator of dendritic growth.Le développement cérébral est une succession d'étapes aboutissant à l'établissement d'un réseau neuronal. Il fait intervenir de nombreuses molécules comme des protéines d'adhésion permettant l'interaction des neurones avec leur environnement. L'implication de nombreux gènes codant des protéines d'adhésion dans la physiopathologie de maladies neuropsychiatriques comme l'autisme souligne l'intérêt à en identifier de nouveaux. Pendant ma thèse, j'ai pu caractériser deux nouveaux gènes, Susd2 et Susd4, codant des protéines contenant des domaines CCP (Complement Control Protein), classiquement connus pour leur présence dans les protéines participant à la régulation du système du Complément. Récemment, des protéines à domaines CCP ont été décrites chez la souris comme ayant une fonction dans le développement neuronal. L'existence de nombreuses protéines prédites à domaines CCP sans fonction connue m'ont conduit à tenter de caractériser Susd2 et Susd4 qui en font partie.Susd2 est exprimé dans les neurones au sein de cultures de cellules d'hippocampe de rat. Son expression atteint un pic à un stade post natal précoce, suggérant une fonction développementale. La protéine Susd2 recombinante a une localisation neuronale diffuse, mais est particulièrement enrichie dans les synapses excitatrices. La diminution de l'expression de Susd2 a pour conséquences un défaut de croissance axonale, une augmentation de la croissance dendritique, et une inhibition spécifique de la synaptogénèse excitatrice. Susd4 est également exprimé dans les neurones, avec un pic d'expression au stade embryonnaire, et semble jouer un rôle de régulation du développement dendritique

Cognitive impairment profile in adult patients with Niemann pick type C disease

Abstract Background Cognitive impairment is one of the core symptoms of Niemann Pick type C (NPC) disease, but few data concerning the neuropsychological profile of NPC patients are available. The aim of our study was to characterize cognitive impairments in NPC disease and to assess the evolution of these symptoms and the impact of miglustat on cognitive follow-up. Methods We conducted a retrospective study of 21 adult patients diagnosed with NPC disease. Neuropsychological data (global cognitive efficiency, language, attention, executive functions, praxis, and visuoconstructive functions tests) were retrieved to describe the cognitive profile of patients. Cognitive impairment scores over time were assessed under treatment by miglustat. Results The majority of patients (90%) were impaired in one or more cognitive function. Executive functions and attention were the most impaired cognitive functions. Conversely, storage in the episodic memory was preserved in 61.5% of cases. Mean neuropsychological scores were stable during the period under miglustat (mean of 3.8 years). Conclusions This study is one of the first to assess the cognitive profile of adult NPC patients. This profile is not specific to attention and executive dysfunctions; however, the preservation of storage in the episodic memory is promising for cognitive remediation. Further studies are needed to confirm the role of miglustat on cognition, but in this study, patients were stable under this treatment

Natural history of cerebrotendinous xanthomatosis: a paediatric disease diagnosed in adulthood

International audienceCerebrotendinous xanthomatosis (CTX) is among the few inherited neurometabolic disorders amenable to specific treatment. It is easily diagnosed using plasma cholestanol. We wished to delineate the natural history of the most common neurological and non-neurological symptoms in thirteen patients with CTX. Diarrhea almost always developed within the first year of life. Cataract and school difficulties usually occurred between 5 and 15 years of age preceding by years the onset of motor or psychiatric symptoms. The median age at diagnosis was 24.5 years old. It appears critical to raise awareness about CTX among paediatricians in order to initiate treatment before irreversible damage occurs

Adolescence/adult onset MTHFR deficiency may manifest as isolated and treatable distinct neuro-psychiatric syndromes

Abstract 5,10-Methylene-tetrahydrofolate reductase (MTHFR) deficiency is a genetic disorder that can occur at any age and can be easily detected by increased homocysteinemia. In adolescence/adult onset forms, the clinical picture is often complex with association of various neurological features and thrombosis. Here we report the cases of two adult siblings who experienced focal epilepsy at 18 years old as a first disease manifestation, without other symptom during several years. Upon diagnosis, both patients received metabolic treatment comprising B9, B12 and betaine which has stopped the occurrence of seizures, allowing discontinuation of anti-epileptic drugs. Among 24 reviewed adolescent/adult onset patients with MTHFR deficiency in the literature, clinical manifestations included gait disorder (96%, from motor central or peripheral origin), cognitive decline (74%), epileptic syndromes (50%), encephalopathy (30%), psychotic symptoms (17%), and thrombotic events (21%). A total of 41% presented a single neurological manifestation that could stay isolated during at least 3 years, delaying achievement of the diagnosis. Brain MRI showed a mostly periventricular white matter changes in 71% of cases. All patients stabilized or improved following metabolic treatment. Despite being rare, adolescence/adult onset MTHFR deficiency can nevertheless be successfully treated. Therefore, homocysteinemia should be tested in various unexplained neuro-psychiatric syndromes like epilepsy or spastic paraparesis, even if isolated, since waiting for completion of the clinical picture is likely to increase the risk of irreversible neurological damage

Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C?

Abstract Background Rare and ultra-rare diseases (URDs) are often chronic and life-threatening conditions that have a profound impact on sufferers and their families, but many are notoriously difficult to detect. Niemann-Pick disease type C (NP-C) serves to illustrate the challenges, benefits and pitfalls associated with screening for ultra-rare inborn errors of metabolism (IEMs). A comprehensive, non-systematic review of published information from NP-C screening studies was conducted, focusing on diagnostic methods and study designs that have been employed to date. As a key part of this analysis, data from both successful studies (where cases were positively identified) and unsuccessful studies (where the chosen approach failed to identify any cases) were included alongside information from our own experiences gained from the planning and execution of screening for NP-C. On this basis, best-practice recommendations for ultra-rare IEM screening are provided. Twenty-six published screening studies were identified and categorised according to study design into four groups: 1) prospective patient cohort and family-based secondary screenings (18 studies); 2) analyses of archived ‘biobank’ materials (one study); 3) medical chart review and bioinformatics data mining (five studies); and 4) newborn screening (two studies). NPC1/NPC2 sequencing was the most common primary screening method (Sanger sequencing in eight studies and next-generation sequencing [gene panel or exome sequencing] in five studies), followed by biomarker analyses (usually oxysterols) and clinical surveillance. Conclusions Historically, screening for NP-C has been based on single-patient studies, small case series, and targeted cohorts, but the emergence of new diagnostic methods over the last 5–10 years has provided opportunities to screen for NP-C on a larger scale. Combining clinical, biomarker and genetic diagnostic methods represents the most effective way to identify NP-C cases, while reducing the likelihood of misdiagnosis. Our recommendations are intended as a guide for planning screening protocols for ultra-rare IEMs in general