The second ExoMars mission will be launched in 2020 to target an ancient location interpreted to have strong potential for past habitability and for preserving physical and chemical biosignatures (as well as abiotic/prebiotic organics). The mission will deliver a lander with instruments for atmospheric and geophysical investigations and a rover tasked with searching for signs of extinct life. The ExoMars rover will be equipped with a drill to collect material from outcrops and at depth down to 2 m. This subsurface sampling capability will provide the best chance yet to gain access to chemical biosignatures. Using the powerful Pasteur payload instruments, the ExoMars science team will conduct a holistic search for traces of life and seek corroborating geological context information. Key Words: Biosignatures—ExoMars—Landing sites—Mars rover—Search for life. Astrobiology 17, 471–510.
Neurometabolic diseases are a group of individually rare but numerous and heterogeneous genetic diseases best known to paediatricians. The more recently reported adult forms may present with phenotypes strikingly different from paediatric ones and may mimic other more common neurological disorders in adults. Furthermore, unlike most neurogenetic diseases, many neurometabolic diseases are treatable, with both conservative and more recent innovative therapeutics. However, the phenotypical complexity of this group of diseases and the growing number of specialised biochemical tools account for a significant diagnostic delay and underdiagnosis. We reviewed all series and case reports of patients with a confirmed neurometabolic disease and a neurological onset after the age of 10 years, with a focus on the 36 treatable ones, and classified these diseases according to their most relevant clinical manifestations. The biochemical diagnostic approach of neurometabolic diseases lays on the use of numerous tests studying a set of metabolites, an enzymatic activity or the function of a given pathway; and therapeutic options aim to restore the enzyme activity or metabolic function, limit the accumulation of toxic substrates or substitute the deficient products. A quick diagnosis of a treatable neurometabolic disease can have a major impact on patients, leading to the stabilisation of the disease and cease of repeated diagnostic investigations, and allowing for familial screening. For the aforementioned, in addition to an exhaustive and clinically meaningful review of these diseases, we propose a simplified diagnostic approach for the neurologist with the aim to help determine when to suspect a neurometabolic disease and how to proceed in a rational manner. We also discuss the place of next-generation sequencing technologies in the diagnostic process, for which deep phenotyping of patients (both clinical and biochemical) is necessary for improving their diagnostic yield.
Riboflavin transporter deficiency (RTD) was recently characterized as a cause of genetic recessive childhood‐onset motor neuron disease (MND) with hearing loss, formerly described as Brown‐Vialetto‐Van‐Lear syndrome. We describe a 18‐year‐old woman with probable RTD mimicking juvenile Amyotrophic Lateral Sclerosis (ALS) who presented with an inaugural respiratory failure and moderate distal four limbs weakness. Only one heterozygous SLC52A3 mutation was detected, but presence of a sub‐clinical auditory neuropathy and dramatic improvement under high dose riboflavin argued for a RTD. As RTD probably has a larger phenotypic spectrum than expected, a high dose riboflavin trial should be discussed in young‐onset MND.
ObjectiveRiboflavin transporter deficiencies (RTDs), involving SLC52A3 and SLC52A2 genes, have recently been related to Brown-Vialetto-Van Laere (BVVL) syndrome, a hereditary paediatric condition associating motor neuropathy (MN) and deafness. BVVL/RTD has rarely been reported in adult patients, but is probably underdiagnosed due to poor knowledge and lack of awareness of this form of disease among neurologists. In this study, we aimed to investigate the phenotype and prognosis of RTD patients with late-onset MN.MethodsWe retrospectively collected clinical, biological and electrophysiological data from all French RTD patients with MN onset after 10 years of age (n=6) and extracted data from 19 other similar RTD patients from the literature.ResultsAdult RTD patients with MN had heterogeneous clinical presentations, potentially mimicking amyotrophic lateral sclerosis or distal hereditary motor neuropathy (56%), multinevritis with cranial nerve involvement (16%), Guillain-Barré syndrome (8%) and mixed motor and sensory neuronopathy syndromes (20%, only in SLC52A2 patients). Deafness was often diagnosed before MN (in 44%), but in some patients, onset began only with MN (16%). The pattern of weakness varied widely, and the classic pontobulbar palsy described in BVVL was not constant. Biochemical tests were often normal. The majority of patients improved under riboflavin supplementation (86%).InterpretationWhereas late-onset RTD may mimic different acquired or genetic causes of motor neuropathies, it is a diagnosis not to be missed since high-dose riboflavin per oral supplementation is often highly efficient.
Background and Objectives:Anti-CD19 CAR T-cell therapy is a promising treatment in relapsing B-cell lymphoma, but is frequently associated with acute neurotoxicity. Neurological long-term safety has not been thoroughly assessed.Methods:All consecutive refractory lymphoma patients admitted in our center for CAR T-cell therapy underwent neurological examination, extensive neuropsychological assessment, brain MRI (except one patient) and completed self-administrated questionnaires at baseline. The patients who remained disease-free at 2 years were re-evaluated similarly. All neurological assessments were conducted by senior neurologists.Results:None of the 19 disease-free patients developed new neurological deficits or MRI changes when compared to baseline. There was no difference in cognitive performances before and two years after, even for the 11 patients who had developed acute neurotoxicity after CAR T-cells.In self-questionnaire assessments, cognitive complaint was stable, reported by 32% of patients at 2 years. We observed a reduction in HADS anxiety scores two years after treatment when compared to baseline (median score: 7/21 vs 4/21, p=0.01).Discussion:In conclusion, no significant neurocognitive or neurological disorders were observed in this cohort of patients, two years after treatment with anti-CD19 CAR T-cells.
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