ABSTRACT
Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, lysosomal storage disorder that causes pediatric onset neurodegenerative disease. It is characterized by mutations in the TPP1 gene. Symptoms begin between 2 and 4 years of age with loss of previously acquired motor, cognitive, and language abilities. Cerliponase alfa, a recombinant human TPP1 enzyme, is the only approved therapy. We report the first presymptomatic cerliponase alfa intraventricular treatment in a familial case of CLN2 related to a classical TPP1 variant. Sister 1 presented with motor, cognitive, and language decline and progressive myoclonic epilepsy since the age of 3 years, evolved with severe diffuse encephalopathy, received no specific treatment, and died at 11 years. Sister 2 had a CLN2 presymptomatic diagnosis and has been treated with cerliponase since she was 12 months old. She is now 6 years 8 months and has no CLN2 symptom except one generalized seizure 1 year ago. No serious adverse event has occurred. Repeated Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition standardized index scores are heterogeneous in the extremely low to low average ranges. Mean length of utterances, a global index of sentence complexity, showed a delay, but a gradual improvement. The reported case enhances the major contribution of presymptomatic diagnosis and significant middle-term treatment benefit for patients with CLN2.
Subject(s)
Aminopeptidases , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases , Neuronal Ceroid-Lipofuscinoses , Serine Proteases , Tripeptidyl-Peptidase 1 , Humans , Neuronal Ceroid-Lipofuscinoses/genetics , Neuronal Ceroid-Lipofuscinoses/drug therapy , Neuronal Ceroid-Lipofuscinoses/complications , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Female , Serine Proteases/genetics , Aminopeptidases/genetics , Recombinant Proteins/therapeutic use , Recombinant Proteins/administration & dosage , Child , Enzyme TherapyABSTRACT
AIMS: Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response. METHODS: We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range. RESULTS: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC0-24 between 264 and 549 mg.h.L-1. CONCLUSIONS: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients.
Subject(s)
Anticonvulsants , Models, Biological , Vigabatrin , Humans , Vigabatrin/pharmacokinetics , Vigabatrin/administration & dosage , Vigabatrin/adverse effects , Anticonvulsants/pharmacokinetics , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Retrospective Studies , Child , Child, Preschool , Female , Male , Infant , Adolescent , Dose-Response Relationship, Drug , Spasms, Infantile/drug therapy , Area Under Curve , Treatment Outcome , Epilepsy/drug therapyABSTRACT
BACKGROUND: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy. METHODS: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly. RESULTS: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH2O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation. CONCLUSION: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters.
Subject(s)
Polysomnography , Respiratory Muscles , Humans , Infant , Male , Female , Respiratory Muscles/physiopathology , Prospective Studies , Spinal Muscular Atrophies of Childhood/genetics , Spinal Muscular Atrophies of Childhood/therapy , Spinal Muscular Atrophies of Childhood/physiopathology , Genetic Therapy/methods , Respiratory Function Tests , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/physiopathology , Muscular Atrophy, Spinal/therapy , Biological Products , Recombinant Fusion ProteinsABSTRACT
Gene therapy has brought tremendous hope for patients with severe life-threatening monogenic diseases. Although studies have shown the efficacy of gene therapy, serious adverse events have also emerged, including thrombotic microangiopathy (TMA) following viral vector-based gene therapy. In this review, we briefly summarize the concept of gene therapy, and the immune response triggered by viral vectors. We also discuss the incidence, presentation, and potential underlying mechanisms, including complement activation, of gene therapy-associated TMA. Further studies are needed to better define the pathogenesis of this severe complication of gene therapy, and the optimal measures to prevent it.
ABSTRACT
BACKGROUND: Rituximab (RTX) resistance or early B-cells repopulation were observed in children but only few publications reported the use of Obinutuzumab and no recommendations were made concerning the dosage for children. METHODS: This study was a single-center retrospective cohort study of all the children followed-up in the Pediatric Neurology Department of Necker-Enfants malades Hospital in Paris, France, and treated with obinutuzumab, between November 1, 2019, and November 1, 2021. RESULTS: A total of eight children (three females, median age 4.5 years) were treated. Seven patients presented with autoimmune encephalitis and one with myeloradiculitis. The median delay of B-cell repopulation after a course of RTX was 87 days (range 41 to 160). A switch to obinutuzumab (anti-CD20) was performed for eight children. The median duration between the first RTX infusion and obinutuzumab administration was 6.6 months. The dosage regimen for obinutuzumab was one infusion of 1000 mg/1.73 m2, that is to say 580 mg/m2 (maximum 1000 mg/infusion), by extrapolation from the adult dosage. The median delay of B-cell repopulation after one course of obinutuzumab was 230 days (range 66 to 303 days) vs 87 days after one course of RTX (P < 0.01). None of the patients presented side effects with obinutuzumab treatment. All patients had a favorable evolution at the last-follow up. Median follow-up was 1.6 years. CONCLUSIONS: This study reports the use of obinutuzumab in neurological inflammatory diseases in a pediatric population. Obinutuzumab seems to have a better biological efficacy than RTX with a longer time of B-cell repopulation.
Subject(s)
Antibodies, Monoclonal, Humanized , B-Lymphocytes , Encephalitis , Hashimoto Disease , Immunologic Factors , Rituximab , Humans , Female , Male , Rituximab/administration & dosage , Rituximab/adverse effects , Rituximab/pharmacology , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Child, Preschool , Child , Retrospective Studies , Encephalitis/drug therapy , Encephalitis/chemically induced , B-Lymphocytes/drug effects , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/pharmacology , Hashimoto Disease/drug therapy , Adolescent , InfantABSTRACT
Epilepsy surgery may be a curative therapy for patients with drug-resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely included in many presurgical evaluation programs although recent evidence support that finding a germline genetic mutation could help to better delineate the patient candidacy to surgery and provide valuable information on the expected surgery outcome. In this study, we report nine patients presenting drug-resistant focal epilepsy enrolled in presurgical evaluation. We show how the identification of genetic pathogenic variant in epilepsy known genes led to the interruption of the presurgical work-up and ruled out surgery in 7 of them. We observed that the co-existence of some recurrent clinical characteristics as early seizures' onset, frequent precipitating factors including fever, and developmental delay or intellectual disability may be useful markers for germline genetic pathogenic variants. In this group, genetic assessment should be mandatory during presurgical work up, mainly in patients with negative magnetic resonance imaging (MRI) or doubtful structural lesions. The integration of next generation targeted sequencing into the presurgical evaluation can improve the selection of candidates for resective surgery and fosters a personalized medicine approach with a better outcome. PLAINE LANGUAGE ABSTRACT: Genetic testing is not yet systematically included in the pre-surgical assessment of patients with drug-resistant focal epilepsies. In this study, through the description of nine patients, we underline how the integration of genomics into the presurgical work up can help in evaluating the patient candidacy to surgery and provide valuable information on expected surgery outcome.
Subject(s)
Drug Resistant Epilepsy , Epilepsies, Partial , Genetic Testing , Humans , Epilepsies, Partial/genetics , Epilepsies, Partial/surgery , Female , Male , Child , Drug Resistant Epilepsy/genetics , Drug Resistant Epilepsy/surgery , Child, Preschool , Adolescent , Preoperative Care , Magnetic Resonance ImagingABSTRACT
Background: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. Objective: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. Methods: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Results: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (nâ=â81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. Conclusion: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.
Subject(s)
Biological Products , Muscular Atrophy, Spinal , Recombinant Fusion Proteins , Spinal Muscular Atrophies of Childhood , Infant , Infant, Newborn , Humans , Spinal Muscular Atrophies of Childhood/drug therapy , Prospective Studies , Genetic Therapy , Muscular Atrophy, Spinal/drug therapy , RegistriesABSTRACT
BACKGROUND AND AIMS: Water-soluble vitamins play an essential coenzyme role in the nervous system. Acquired vitamin deficiencies are easily treatable, however, without treatment, they can lead to irreversible complications. This study aimed to provide clinical, laboratory parameters and neuroimaging data on vitamin deficiencies in an attempt to facilitate early diagnosis and prompt supplementation. METHODS: From July 1998 to July 2023, patients at Necker-Enfants-Malades Hospital presenting with acute neurological symptoms attributed to acquired vitamin deficiency were included. Clinical data were extracted from Dr Warehouse database. Neuroimaging, biochemical and electrophysiological data were reviewed. RESULTS: Patients with vitamin B1 deficiency exhibited abnormal eye movements (n = 4/4), fluctuations in consciousness (n = 3/4), and ataxia (n = 3/4). Brain MRI showed alterations of fourth ventricle region (n = 4/4), periaqueductal region (n = 4/4), tectum (n = 3/4), and median thalami (n = 3/4). Patients with vitamin B2 deficiency presented with early onset hypotonia (n = 3/4), hyperlactatemia (n = 4/4), and hyperammonemia (n = 4/4). Plasma acylcarnitines revealed a multiple acyl-coA dehydrogenase deficiency-like profile (n = 4/4). In vitamin B12 deficiency, young children presented with developmental delay (n = 7/7) and older children with proprioceptive ataxia (n = 3/3). Brain MRI revealed atrophy (n = 7/7) and spinal MRI hyperintensity in posterior cervical columns (n = 3/3). Metabolic findings showed elevated methylmalonic acid (n = 6/7) and hyperhomocysteinemia (n = 6/7). Patients with vitamin C deficiency exhibited gait disturbances and muscle weakness (n = 2/2). CONCLUSIONS: Acquired vitamin deficiencies may display reversible clinical symptoms mimicking inherited metabolic disorders. Some situations raise suspicion for diagnosis: concordant clinical presentation, suggestive neuroimaging findings, and/or biochemical evidence. Any acute neurological condition should be treated without waiting for definitive biochemical confirmation.
Subject(s)
Magnetic Resonance Imaging , Neuroimaging , Humans , Male , Female , Child, Preschool , Neuroimaging/methods , Infant , Child , Avitaminosis/complications , Avitaminosis/diagnostic imaging , Brain/diagnostic imaging , Brain/pathology , Adolescent , Retrospective StudiesABSTRACT
Sodium dependent multivitamin transporter (SMVT) deficiency is a very rare autosomal recessive disorder characterized by multisystemic clinical manifestations due to combined biotin, panthotenic acid and lipoic acid deficiency. About 10 families have been described so far. Accurate diagnosis is crucial because of the possibility of a supplementation treatment with proven efficacy. Here we describe 4 new patients (3 additional families) originating from the same world region (Algeria, Maghreb). All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT. RNA study in one family allowed confirming the pathogenic effect of the variation and re-classifying this variant of uncertain significance as pathogenic, opening the possibility of genetic counseling and treatment. The identification of the same variation in three distinct and apparently unrelated families is suggestive of a founder effect. The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy.
ABSTRACT
BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number. RESULTS: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies. CONCLUSION: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies.
Subject(s)
DNA Copy Number Variations , Muscular Atrophy, Spinal , Child, Preschool , Humans , Mutation , Oligonucleotides/therapeutic use , Survival of Motor Neuron 2 Protein/geneticsABSTRACT
Background and Objectives: DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants. Methods: The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency. Results: Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types. Discussion: The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.