Objective Riboflavin 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. Methods We 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. Results Adult 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%). Interpretation Whereas 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.
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a promising treatment in relapsing B-cell lymphoma but is frequently associated with acute neurotoxicity. Neurologic long-term safety has not been thoroughly assessed.All patients with consecutive refractory lymphoma admitted in our center for CAR T-cell therapy underwent neurologic examination, extensive neuropsychological assessment, and brain MRI (except 1 patient) and completed self-administrated questionnaires at baseline. The patients who remained disease-free at 2 years were re-evaluated similarly. All neurologic assessments were conducted by senior neurologists.None of the 19 disease-free patients developed new neurologic deficits or MRI changes when compared with baseline. There was no difference in cognitive performances before and 2 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 the patients at 2 years. We observed a reduction in HADS anxiety scores 2 years after treatment when compared with baseline (median score: 7/21 vs 4/21, p = 0.01).In conclusion, no significant neurocognitive or neurologic disorders were observed in this cohort of patients, 2 years after treatment with anti-CD19 CAR T cells.
Abstract BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the landscape of cancer treatment, particularly in haematological malignancies, and while these therapies have demonstrated significant efficacy against malignancies, they are associated with a spectrum of side effects. Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are unique to CAR-T cell therapy and distinguish it from other forms of autoimmune toxicity. Predicting which patients will develop neurotoxicity remains a challenge. The pattern of ICANS is cognitive dysfunction, suggesting a plausible relationship between cognitive status and neurotoxicity. Understanding the interplay between cognitive function and neurotoxicity may provide valuable insights for early detection. The primary endpoint of this study was to investigate whether the cognitive performance of patients at the time of leukapheresis is associated with the subsequent development of ICANS. MATERIAL AND METHODS We report here on a prospective study of an adult patient population with aggressive B-cell lymphoma treated with CAR-T cell therapy at our centre between May 2020 and November 2023. All patients underwent neurological examination, cerebral MRI and global cognitive assessment using the Montreal Cognitive Assessment (MoCA) test with a cut-off of less than 26 points. We retrospectively recorded total metabolic tumour volume (TMTV) and International Prognostic Index (IPI) at lymphodepletion. Biological data including lactate dehydrogenase (LDH), albumin, ferritin and C-reactive protein (CRP) were also collected at the time of treatment. A retrospective analysis of pre-infusion serum neurofilament light chain (NfL) levels at the time of the decision to proceed with CAR-T cell therapy and at the time of treatment was performed. RESULTS 156 patients, median age 64 years (range 21 to 79 years), 55 females / 101 males, all treated for lymphoma, were included in this study. The mean MoCA score was 26 (range 12 to 30 points), 63 patients (40%) had a MoCA test below the cut-off at baseline. Following infusion of CAR T cells, 32% of patients developed ICANS within 6 days (grade 1-2: 72%; grade 3-4: 30%). The most common sign of neurotoxicity was cognitive impairment. In univariate analyses, the occurrence of ICANS was not significantly associated with baseline cognitive performance (p 0.58). As the study is ongoing, an update on the results will be available at the EANO meeting. CONCLUSION Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This study does not suggest an association between the occurrence of ICANS and baseline cognitive performance. Despite progress in understanding the mechanisms underlying neurotoxicity, predicting its occurrence remains a challenge.
Abstract 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.
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.
